NATMED25 • Natural Medicine Offer

Table of Contents

NATMED25 • Natural Medicine Offer

How to Receive Credit

NetCE 4 Hour Course #98100 • Complementary Therapies for Menopause

98100 • Complementary Therapies for Menopause

1. MENOPAUSE AND PERIMENOPAUSE

2. CONVENTIONAL TREATMENT

3. LIFESTYLE MODIFICATION

4. COMPLEMENTARY MODALITIES

5. HERBAL THERAPIES

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 3 Hour Course #98320 • Natural Psychedelics

98320 • Natural Psychedelics

1. INTRODUCTION

2. DEFINITIONS

3. PSYCHEDELICS AS THERAPY

4. UNIQUE CONSIDERATIONS

5. NATURAL PSYCHEDELICS

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 4 Hour Course #98120 • Diets and Dietary Approaches to Weight Loss

98120 • Diets and Dietary Approaches to Weight Loss

1. OVERVIEW

2. DIETING AND DIETARY PATTERNS

3. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #98190 • Supplements for Aging

98190 • Supplements for Aging

1. INTRODUCTION

2. SUPPLEMENT USE IN OLDER ADULTS

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

5. NUTRITIONAL SUPPLEMENTS

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 3 Hour Course #98210 • Medicinal Mushroom Supplements

98210 • Medicinal Mushroom Supplements

1. INTRODUCTION AND BACKGROUND

2. WHAT ARE MUSHROOMS?

3. MEDICINAL MUSHROOMS WITH INSUFFICIENT EVIDENCE TO SUPPORT USE FOR CERTAIN INDICATIONS

4. MEDICINAL MUSHROOMS WITH POSSIBLE EFFICACY FOR CERTAIN INDICATIONS

5. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

NATMED25 • Natural Medicine Offer

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

NATMED25 • Natural Medicine Offer

Expiration Date: 12/31/2025

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

98100 • Complementary Therapies for Menopause

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2023 NetCE, All rights reserved.

Complementary and alternative medicines are increasing in popularity, and most Americans now report the regular use of at least one supplement. Patients may be asking about these options for the management of menopause-related symptoms and long-term health concerns. Healthcare professionals should be well informed about supplements, lifestyle changes, and complementary modalities so that they can provide evidence-based recommendations.

Table of Contents

98100 • Complementary Therapies for Menopause

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Individual State Behavioral Health Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. MENOPAUSE AND PERIMENOPAUSE

COMMON SYMPTOMS

2. CONVENTIONAL TREATMENT

BIOIDENTICAL HRT

3. LIFESTYLE MODIFICATION

NUTRITION

EXERCISE

CAUTIONS

4. COMPLEMENTARY MODALITIES

ACUPOINT THERAPIES

MINDFULNESS

YOGA

5. HERBAL THERAPIES

PHYTOESTROGENS

OTHER HERBAL MEDICATIONS

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98100 • Complementary Therapies for Menopause

Education Category. Alternative Medicine

Release Date. 02/01/2023

Expiration Date. 01/31/2026

Course Overview

Complementary and alternative medicines are increasing in popularity, and most Americans now report the regular use of at least one supplement. Patients may be asking about these options for the management of menopause-related symptoms and long-term health concerns. Healthcare professionals should be well informed about supplements, lifestyle changes, and complementary modalities so that they can provide evidence-based recommendations.

Audience

This course is designed for healthcare professionals whose patients are taking or are interested in using complementary therapies to manage symptoms of menopause.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6361. Programs that do not qualify for NBCC credit are clearly identified. NetCE is solely responsible for all aspects of the programs. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. Continuing Education (CE) credits for psychologists are provided through the co-sponsorship of the American Psychological Association (APA) Office of Continuing Education in Psychology (CEP). The APA CEP Office maintains responsibility for the content of the programs. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 4 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 4 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 4 ANCC contact hour(s). NetCE designates this continuing education activity for 2 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 4.8 hours for Alabama nurses. NetCE designates this continuing education activity for 1.5 NBCC clock hour(s). Social workers participating in this intermediate to advanced course will receive 4 Clinical continuing education clock hours. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 4 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.4 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190;

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to help healthcare professionals in all practice settings increase their understanding of nutrients, lifestyle changes, complementary modalities, and herbal products that are often used during menopause.

Learning Objectives

Upon completion of this course, you should be able to:

1. List the most common health concerns associated with menopause.

2. Discuss the risks and benefits of certain vitamins and minerals in menopause.

3. Review the evidence for lifestyle changes and complementary modalities during menopause.

4. Describe the proposed and actual effects of phytoestrogens for menopause-related symptoms.

5. Explain the safety concerns associated with the use of herbs during menopause.

Faculty

Chelsey McIntyre, PharmD, is a clinical pharmacist who specializes in drug information, literature analysis, and medical writing. She earned her Bachelor of Science degree in Genetics from the University of California, Davis. She then went on to complete her PharmD at Creighton University, followed by a clinical residency at the Children’s Hospital of Philadelphia (CHOP). Dr. McIntyre held the position of Drug Information and Policy Development Pharmacist at CHOP until her move to Washington state in 2017, after which she spent the next six years as a clinical editor for Natural Medicines, a clinical reference database focused on natural products and alternative therapies. She continues to create rigorous professional analysis and patient education materials for various publications while also practicing as a hospital pharmacist. Her professional interests include provider and patient education, as well as the application of evidence-based research to patient care.

Faculty Disclosure

Contributing faculty, Chelsey McIntyre, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Sharon Cannon, RN, EdD, ANEF

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. MENOPAUSE AND PERIMENOPAUSE

Evidence Based Practice Recommendation

The National Institute for Health and Care Excellence recommends giving information to menopausal women and their family members or carers (as appropriate) that includes an explanation of the stages of menopause; common symptoms and diagnosis; lifestyle changes and interventions that could help general health and well-being; benefits and risks of treatments for menopausal symptoms; and long-term health implications of menopause.

https://www.nice.org.uk/guidance/ng23

Last Accessed: January 23, 2023

Level of Evidence: Expert Opinion/Consensus Statement

Natural menopause typically occurs between 40 and 58 years of age, with an average age of 51 years. Considering that the average life expectancy for a woman in the United States is 81.4 years, the average woman can expect to spend many years post-menopause. There are currently about 50 million postmenopausal adults in the United States [1].

Prior to entering menopause, a person must go through perimenopause (also called climacteric or the menopausal transition). This marks the transition between fertility and menopause when menses becomes less frequent. This process, which is often defined by the presence of various symptoms, may last for years. Menopause occurs when the menstrual cycle ceases for 12 consecutive months.

COMMON SYMPTOMS

Symptoms of perimenopause can persist for weeks, months, or years, and symptom severity varies greatly. An early sign of perimenopause is irregular or prolonged menstrual bleeding that can become severe. As estrogen levels decline, vasomotor symptoms, including hot flashes and night sweats (hot flashes with drenching sweats), can also occur. These symptoms can interfere with sleep, which in turn can cause exhaustion, irritability, and altered mood. Up to 85% of people experience hot flashes with widely varying intensity and frequency [1].

Many people will also experience non-vasomotor symptoms, including:

- Anxiety

- Depression

- Difficulty with concentration and/or memory

- Headaches

- Incontinence

- Insomnia

- Irritability and mood swings

- Joint pain

- Loss of libido

- Tiredness

- Vaginal dryness

Long-Term Effects of Menopause

Menopause is associated with a number of other long-term changes in the body, including bone loss, weight redistribution, and muscle loss.

Bone Loss

The reduction in estrogen levels that occurs with menopause accelerates age-related bone loss. It is estimated that, on average, a person loses up to 10% of bone mass in the first five years after menopause [1].

Weight Redistribution

The hormonal changes that occur during menopause can change the way that weight distributes in the body. Those who are postmenopausal may be more likely to gain weight around the abdomen than around the hips and thighs.

Muscle Loss

The loss of muscle tissue that occurs with age can reduce overall metabolism, which can contribute to the accumulation of fat and weight gain. Age-related muscle loss occurs in all adults and is not necessarily tied to menopause. However, menopause may worsen the apparent effects of age-related muscle loss.

2. CONVENTIONAL TREATMENT

For many years, hormone replacement therapy (HRT) was a commonly accepted treatment during perimenopause and postmenopause. However, in 2000, the results from the Women's Health Initiative (WHI) study and the Heart and Estrogen/Progestin Replacement Study (HERS II) changed this approach. These studies found an association between the use of oral conjugated estrogen plus medroxyprogesterone and increased risk of myocardial infarction, stroke, venous thromboembolism, breast cancer, and gallbladder disease [2].

Since these initial findings were released, further studies, meta-analyses, and subgroup analyses have suggested that these risks may be limited to patients older than 60 years of age and may also be minimized with the use of alternate routes of administration, lower doses, and limited duration of use [2].

Although HRT still has a place in the management of menopausal symptoms, awareness of the risks associated with this option have limited the widespread and long-term use of systemic hormones. This has led many patients and healthcare professionals to consider alternative or complementary options.

BIOIDENTICAL HRT

Some patients may ask about compounded bioidentical HRT as a "natural alternative" to traditional HRT. However, this is a misconception. The term bioidentical simply indicates that the hormone has the same chemical and molecular structure as the endogenous hormone. Many of the prescription hormones that are approved by the U.S. Food and Drug Administration (FDA) for the management of vasomotor symptoms in menopause are also bioidentical. And although some of the hormones used in compounded products may be derived from natural sources, these natural hormones must still be converted to the active form in a laboratory [22].

In most cases, the dosing of compounded bioidentical HRT is based on unvalidated hormone testing, often using serum, salivary, or urine samples. The use of these tests to guide HRT dosing has not been validated in clinical research and is generally considered unreliable due to natural inter- and intra-individual variations in hormone levels [22]. Additionally, due to a lack of oversight, these compounded products carry a risk of under- or overdosing, lack of sterility, and the presence of impurities.

3. LIFESTYLE MODIFICATION

Menopause marks a significant change in the way that the body functions. Although each person responds differently to these changes, some general guidance on lifestyle modifications can significantly improve both short-term and long-term health.

NUTRITION

Nutrition can have an important impact on some of the long-term changes that occur after menopause. Ensuring adequate intake of certain nutrients can help reduce the risk of osteoporosis that comes with the rapid bone loss associated with menopause.

Calcium and Vitamin D

Although calcium and vitamin D have distinctive effects, they are often discussed in combination in relation to bone health, and for good reason. While calcium is the nutrient that directly builds and maintains bone, vitamin D is crucial to the appropriate absorption of calcium from the intestine. Thus, adequate vitamin D intake is an important component of adequate calcium intake [3,4].

Due to age-related bone loss, the recommended dietary allowance (RDA) for both calcium and vitamin D increases with age (Table 1). And due to hormonal changes associated with menopause, the recommended intake for calcium increases faster for women than for men.

Table 1: RECOMMENDED DIETARY ALLOWANCES OF CALCIUM AND VITAMIN D BY AGE AND SEX

Population

Recommended Daily Dietary Allowance

Vitamin D

Persons 1 to 70 years of age

600 IU (15 mcg)

Persons 71 years of age or older

800 IU (20 mcg)

Calcium

Women 19 to 50 years of age

1,000 mg

Women 51 years of age and older

1,200 mg

Men 19 to 69 years of age

1,000 mg

Men 70 years of age and older

1,200 mg

Source: [3,4]

Whenever possible, these RDAs should be met by obtaining nutrients from the diet. In fact, due to a lack of strongly supportive evidence, guidelines do not recommend the routine use of calcium and vitamin D supplements during menopause [4].

For the prevention of fractures in community-dwelling adults, the U.S. Preventive Services Task Force (USPSTF) concludes that there is insufficient evidence to assess the balance of benefits and harms when calcium and vitamin D are supplemented in doses of at least 1,000 mg daily and 400 IU daily, respectively. The USPSTF also recommends against daily supplementation with lower doses of calcium and/or vitamin D [5].

The Bone Health and Osteoporosis Foundation (BHOF) 2022 guidelines recommend a diet with adequate total calcium intake based on the RDA, incorporating calcium supplements if intake is insufficient. These guidelines also recommend maintenance of serum vitamin D sufficiency (a 25-hydroxyvitamin D level of 30–50 ng/mL), with the use of supplemental vitamin D as needed to achieve sufficient vitamin D levels [6].

The USPSTF guideline recommendation is based mostly on the results of the WHI study. This large study in postmenopausal women 50 to 79 years of age showed that although taking calcium 1,000 mg plus vitamin D 400 IU daily for seven years modestly improves bone mineral density (BMD), it does not significantly reduce fracture risk. It is possible that this lack of effect may have been due to low adherence to the treatment regimen. In those who were at least 80% adherent, supplementation reduced the risk of hip fracture by about 29% [3,5].

Clinical research on the use of calcium and vitamin D supplements specifically for the prevention of fractures is mixed and inconclusive. Although some research suggests that supplementation may modestly reduce the risk of fractures, the benefits appear to be greatest in those with existing osteoporosis, as well as the elderly and those who are no longer community dwelling [3,4].

Additionally, some experts have expressed concerns regarding the risks of calcium supplementation.

Safety Concerns with Calcium Supplementation

There has been some concern that calcium supplementation may increase the risk of cardiovascular disease (CVD) in postmenopausal adults. Although meta-analyses of high-quality clinical research have not confirmed an association between calcium supplementation and CVD in the general population, a meta-analysis of research in postmenopausal adults did find that taking calcium for two to seven years, often in amounts over the RDA, increases the risk of CVD and coronary heart disease by 1.1–1.2 times when compared with control. However, many of these studies have been criticized for excluding patients who were also taking vitamin D, and other clinical research has not confirmed this finding [3].

There is also some concern that calcium supplementation increases the risk of urinary tract stones. The WHI study suggests that for every 273 patients receiving calcium supplementation over seven years, one additional patient will be diagnosed with a urinary tract stone. However, this finding has not been corroborated in other large clinical trials evaluating the long-term health effects of calcium supplementation [3].

Until more is known, remind patients not to take calcium supplements in doses exceeding their age-based RDA, and ensure that all patients have adequate intake of vitamin D.

Based on the available evidence and guideline recommendations, most postmenopausal adults should focus on obtaining calcium and vitamin D from the diet. However, for patients who are unable to obtain adequate intake from the diet, healthcare professionals should be well-versed on the use of supplements [3,4].

Calcium Supplements

There are many different calcium supplements available on the market. Some of these supplements provide calcium alone, whereas others combine calcium with vitamin D. Although the body needs vitamin D to adequately absorb calcium, it is not necessary for vitamin D to be taken at the same time [3].

Calcium supplements are available in various salt forms, some of which provide greater amounts of elemental calcium. For example, calcium carbonate contains 400 mg of elemental calcium per gram, whereas calcium citrate contains 211 mg of elemental calcium per gram. The RDA for calcium is based on elemental calcium [3].

There may also be questions regarding the absorption of different calcium salts. For example, some early research suggested that calcium citrate may be better absorbed than calcium carbonate. However, a follow-up study using a highly sensitive tracer method found no significant difference in the absorption of calcium from either calcium citrate or calcium carbonate. Additionally, calcium from milk seems to be absorbed similarly to the calcium from supplements [3].

Calcium Absorption

The active transport system for calcium in the small intestine is easily saturated. Thus, calcium supplements are typically divided into two doses daily to increase absorption. It is also usually recommended to take it with food in doses providing no more than 500 mg elemental calcium [3].

In order to ensure appropriate calcium intake, educate patients on the difference between elemental calcium and calcium salt content. Also, encourage them to take calcium supplements with food in divided doses.

Vitamin D

Vitamin D supplements are available in two forms—D3 (cholecalciferol) and D2 (ergocalciferol). Although the RDA assumes that these forms are equivalent, some evidence suggests that vitamin D2 is less than one-third as potent as vitamin D3. Therefore, many experts now specifically recommend vitamin D3 [4].

For most patients, daily supplementation of 400–1,000 IU (10–25 mcg) is adequate to meet daily requirements. In fact, the BHOF recommends daily intake of 800–1,000 IU (20–25 mcg) for adults older than 50 years of age [4,6].

Except in patients with confirmed vitamin D deficiency, caution against the regular use of very high doses. Over the long-term, regular use of high doses, such as those above the tolerable upper intake level of 4,000 IU (100 mcg) daily, can increase the risk of serious adverse effects such as hypercalcemia, kidney stones, and azotemia. Toxicity typically occurs when blood levels exceed 150 ng/mL [4].

Magnesium

Magnesium, which is crucial to the structural integrity of bone tissue, is another important nutrient for bone health. Magnesium deficiency can increase the formation and activity of osteoclasts, which resorb bone. Increased bone resorption causes release of magnesium and calcium from the bone, which can increase magnesium levels in times of deficiency [7].

No large prospective studies have been conducted to evaluate the benefits of magnesium supplementation for the prevention of osteoporosis. However, it is important for patients to ensure adequate intake of magnesium from the diet.

The daily RDA for magnesium is 320 mg for those 31 years of age and older. Many foods are rich in magnesium (e.g., whole grains, dark-green, leafy vegetables) and will allow most patients to attain this RDA [7].

Some patients may be at increased risk for magnesium deficiency due to the use of certain medications, including certain antibiotics, diuretics, some antineoplastic drugs, calcineurin inhibitors, and proton pump inhibitors (PPIs). Healthcare professionals should be aware of the medications most likely to increase this risk and counsel patients accordingly.

There is also interest in the use of magnesium supplements for the management of menopausal symptoms such as hot flashes. However, a large, high-quality study shows that taking magnesium oxide 800–1,200 mg daily for eight weeks does not reduce hot flashes when compared with placebo [7].

Proton Pump Inhibitors (PPIs)

Taking a PPI long-term, especially for longer than one year, has been linked to an increased risk of hypomagnesemia in observational research. Higher doses are associated with a two-fold increase in the odds of hypomagnesemia when compared with lower doses.

The American College of Gastroenterology (ACG) does not provide a recommendation related to monitoring magnesium levels in patients taking PPIs. However, other experts, including the FDA, recommend that serum magnesium levels should be checked at baseline and annually thereafter in patients who are likely to take a PPI long-term. In up to 25% of patients who develop hypomagnesemia, the PPI will need to be discontinued permanently to return magnesium levels to normal. In some patients, it is possible to continue the PPI and take a magnesium supplement concurrently to maintain magnesium levels [7].

Diuretics

Loop diuretics and, to a lesser extent, thiazide diuretics interfere with magnesium reabsorption in the kidneys, increasing urinary losses and reducing serum magnesium levels. Potassium-sparing diuretics, however, are also magnesium-sparing, and can therefore counteract the magnesium losses seen with loop diuretics and thiazides. Although the overall risk for magnesium deficiency with diuretics is low, patients taking multiple medications that can lower magnesium levels may be at increased risk [7].

Protein

Due to concerns regarding age-related muscle loss, adequate protein intake is also important after menopause. The RDA for protein in all adults 18 years of age and older is 0.8 grams/kg. However, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) actually recommends a higher protein intake for women older than 50 years of age. This recommendation calls for 1–1.2 grams/kg. This comes out to about 20–25 grams of protein per meal [8].

As with other nutrients, patients should be counseled to obtain adequate protein intake from a well-rounded diet whenever possible. Although protein supplements may be appropriate for some patients, most patients are able to obtain adequate protein by making healthy changes to their diet.

EXERCISE

Increased physical activity and exercise can be key to combatting the increased weight gain that is seen after menopause. In addition, it can help to reverse age-related muscle loss (sarcopenia) and even slow bone loss.

The Centers for Disease Control and Prevention (CDC) recommends that all adults older than 65 years of age [9]:

- Obtain at least 150 minutes of moderate-intensity activity per week, such as brisk walking. Alternatively, this can be replaced with 75 minutes of vigorous-intensity activity, such as hiking, jogging, or running.

- Participate in muscle-strengthening exercises at least two days per week.

- Participate in activities that improve balance at least three days per week.

Muscle-strengthening exercises can include a wide range of options and are not solely limited to weightlifting. Patients can also consider the use of resistance bands; exercises that use their own body weight for resistance, such as push-ups, sit-ups, and certain forms of yoga and Pilates; and even heavy gardening.

Balance exercises are more specific and involve activities such as walking backwards, standing on one leg, or using a wobble board.

If a patient has had only limited physical activity and is interested in initiating a new exercise program, encourage them to seek guidance from a physical therapist. To avoid injury, patients should also be evaluated before initiating a new exercise program involving compressive or contractile stressors (such as running or weightlifting) [9].

CAUTIONS

Some of the lifestyle changes that can be most beneficial during menopause may require patients to break some long-standing habits. These recommendations should be customized to each individual patient, as needed.

Smoking

Smoking is known to be detrimental to overall health and is also detrimental to bone health. Smoking cessation should be encouraged, when relevant, for all postmenopausal adults.

Alcohol

Moderate alcohol intake, which is defined as 0.5 to 2 alcoholic beverages per day, does not seem to have detrimental effects on BMD. However, alcohol intake in amounts greater than two drinks per day can be detrimental to bone health.

There is conflicting evidence on other possible long-term effects from regular alcohol use. While some research indicates that moderate alcohol intake may have health benefits, other research suggests that it may increase the risk for certain conditions. In general, encourage patients to limit alcohol intake. Some experts recommend reducing intake to no more than 0.5 to 1 drink per day.

There have been reports of increased severity of hot flashes with alcohol use. This association has not been evaluated in prospective research, but patients may consider reducing alcohol consumption and monitoring symptoms to determine whether this improves quality of life.

Caffeine

Caffeine increases the excretion of calcium in the urine. At excessive doses, this might affect bone health. According to evidence reviews conducted in the United States and Canada, healthy adults with adequate calcium intake are not at increased risk for decreased BMD, osteoporosis, or fractures as long as daily caffeine intake is limited to 400 mg (about four cups of coffee) [10].

It should be noted that about 8% of people may have a specific genetic variant of the vitamin D receptor (VDR)—the CC genotype. This genotype increases the risk for bone loss with caffeine use. Testing for this variant is not standard practice, although it is included in some vitamin D deficiency and nephrology gene panels and is also offered as a single gene test through some laboratories. If a patient is known to be carrying the CC genotype, caffeine intake should be reduced to 200–300 mg daily and calcium intake may need to be increased [10].

Some people have reported increased severity of hot flashes with caffeine use. This association has not been evaluated in prospective research, but patients may consider reducing caffeine consumption and monitoring symptoms to determine whether this improves quality of life.

Spicy Foods

Some patients may find that spicy foods trigger or worsen hot flashes. If patients are struggling with persistent and/or severe hot flashes, suggest trialing the elimination of spicy foods from the diet.

4. COMPLEMENTARY MODALITIES

In addition to lifestyle changes, some patients may also benefit from various complementary therapy modalities. These include options such as acupuncture, mindfulness, meditation, and yoga.

ACUPOINT THERAPIES

Acupoint therapies, which utilize concepts based in traditional Chinese medicine, have grown in popularity over recent years. These include acupuncture, acupressure, moxibustion, and acustimulation.

Although there is general interest in the use of these therapies for the management of menopause-associated hot flashes, only acupuncture has been studied for this purpose, and the research thus far is inconclusive. While some research suggests that acupuncture may reduce hot flash severity, other studies have not supported this finding. Also, a large clinical study evaluating the use of electroacupuncture, administered in 24 separate treatment sessions over eight weeks, found no benefit for symptoms of menopause, although patients did experience a modest improvement in quality of life [11].

For now, let patients know that the evidence supporting the use of acupoint modalities is unclear. However, there is no reason to expect safety concerns as long as the therapy is administered by a licensed practitioner using appropriate technique.

MINDFULNESS

Mindfulness, a practice derived from Buddhist theory, has also become popular for general well-being and the management of various symptoms. Mindfulness involves a purposeful attention and awareness of present thoughts, emotions, and sensations without evaluation or judgment of what is occurring.

Mindfulness-based stress reduction (MBSR) is a well-studied and standardized mindfulness practice. It usually includes eight weekly 2.5-hour sessions, as well as daily home recordings of mindfulness exercises and a half-day retreat after the sixth class. It includes three main components [12]:

- Didactic material that explains the concept of mindfulness

- Practicing mindfulness exercises during group sessions and at home

- Discussing and sharing MBSR experiences with a group

Clinical research in various populations has shown that mindfulness or MBSR is beneficial for anxiety, insomnia, and stress. Although it has not been evaluated specifically for these uses in perimenopausal or postmenopausal adults, it would be reasonable to consider this as a safe treatment option [12].

Anxiety

In general, mindfulness seems to modestly reduce anxiety, although benefits appear to be short-term. It is unclear how mindfulness or MBSR compares with other nonpharmacologic options.

Meta-analyses, small clinical studies, and observational research in patients with various forms of anxiety, or without diagnosed anxiety, show that practicing MBSR or modified MBSR improves anxiety severity when compared with baseline or no intervention. However, most research shows that MBSR does not continue to reduce the severity of anxiety immediately after or 3 to 12 months after treatment when compared with cognitive-behavioral therapy (CBT) or psychotherapy education [12].

Insomnia

Most research suggests that mindfulness improves sleep quality, although it might not be beneficial for other measures of insomnia and may not be more beneficial than other nonpharmacologic modalities.

A meta-analysis in patients with insomnia shows that mindfulness meditation improves total wake time and sleep quality, but not sleep onset latency, total sleep time, or sleep efficiency, when compared with control. Another meta-analysis of randomized controlled trials in adults with insomnia shows that practicing MBSR or modified MBSR for six to eight weeks improves sleep quality when compared with receiving education or CBT. A secondary analysis of a clinical trial in generally healthy adults also shows that practicing MBSR for eight weeks improves sleep scores when compared with no intervention, but not when compared with exercise [12].

Stress

Research suggests that mindfulness may reduce stress in patients with various medical conditions, although it is unclear if it is beneficial for general stress.

Some clinical studies in patients being treated for cancer show that MBSR and other mindfulness-based therapies reduce stress and stress-related symptoms such as depression and quality of life. A small clinical study in patients with solid organ transplants shows that completing an MBSR program improves anxiety, depression, and sleep quality for up to one year when compared with a peer-led health education program. Similarly, a small clinical trial in women with infertility shows that an eight-week mindfulness-based program reduces stress when compared to baseline [12].

Research on the use of mindfulness specifically for the management of menopausal symptoms is limited. One small clinical study shows that practicing MBSR reduces menopause-related stress, sleep disturbance, and symptom severity when compared with a control group that was placed on a wait list. In the MBSR group, those that practiced at home more frequently had greater reductions in symptom severity. However, there was no improvement in pain or physical function [12].

Another small study shows that eight weekly sessions of MBSR modestly improves quality of life after menopause for up to three months after treatment when compared with control. Improvements were noted in psychosocial, physical, and sexual domains [12].

YOGA

The practice of mindfulness should not be confused with yoga, which may sometimes incorporate components of MBSR. Yoga is a key aspect of Ayurvedic medicine, a traditional system of medicine that originated in India. Yoga uses several exercises involving controlled breathing, meditation, and body posturing. Many different styles of yoga exist that use a variety of techniques at a range of intensities. However, Western yoga practice most often focuses on physical yoga poses specifically [13].

Effects in Menopause

Clinical research has found that yoga is beneficial for reducing feelings of perimenopause-related anxiety and depression. Yoga also seems to be beneficial for alleviating menopause-related hot flashes, sleep disturbances, and psychological, somatic, and urogenital symptoms when compared with no intervention. These beneficial effects appear comparable to those seen with other forms of exercise [13].

It is important to note that yoga is also recognized as a form of both muscle-strengthening and balancing exercises, which are recommended for all older adults. Considering that yoga has also shown benefit for the improvement of many menopause-related symptoms, it should be considered as a complementary treatment modality for those in perimenopause and post-menopause.

Safety

Yoga is generally considered safe, with temporary musculoskeletal pain as the most common adverse effect. However, for adults with limited prior exercise, mobility concerns, or other serious health issues, encourage a consultation with a trained practitioner prior to participation in yoga [13].

5. HERBAL THERAPIES

Some patients may also inquire about the use of herbal therapies for menopause. While a number of herbal therapies are touted online, only a small number of these options have been adequately evaluated in clinical research.

PHYTOESTROGENS

Most of the herbal therapies promoted for symptoms of menopause are classified as phytoestrogens, or "plant estrogens." The three main kinds of phytoestrogens are isoflavones, lignans, and coumestans. Of these, isoflavones are the most potent and also the most common.

Phytoestrogens are not structurally related to estrogen. Instead, they contain a phenolic ring that allows for binding to estrogen receptors. These chemicals are 100 to 10,000 times weaker than endogenous estrogen, and, depending on the tissue type and location in the body, phytoestrogens can act as estrogens or antiestrogens. This is similar to selective estrogen receptor modulators (SERMs) [14].

The estrogenic activity of phytoestrogens also appears to vary with the level of endogenous estrogen. In premenopausal adults with normal endogenous estrogen levels, isoflavones found in soy exhibit an antiestrogen effect, since they can displace endogenous estrogen from receptors. In postmenopausal adults with low endogenous estrogen levels, soy isoflavones are more likely to act as weak estrogens.

However, not all plants that contain phytoestrogens have clinically relevant estrogenic activity. The following section will review the evidence for the most well-studied and commonly used options.

Soy (Glycine max)

Vasomotor Symptoms

A large body of evidence suggests that consuming soy can decrease the frequency and severity of hot flashes. Improvement seems to be greater in those with a higher frequency of hot flashes at baseline.

The daily doses used in these studies include soy protein 15–60 grams, providing 34–100 mg isoflavones, as well as extracts providing 35–200 mg isoflavones. Higher isoflavone doses of 100–200 mg and higher frequency of dosing intervals seem to have greater benefit. Similarly, the amount of genistein found in these products may influence outcomes, with higher doses associated with more consistent benefits [14].

Soy has also been compared to conventional HRT, with most research indicating that soy isoflavones may have a similar or modestly reduced effect, and a slower onset of action, when compared with HRT. There is some speculation that the benefits of soy isoflavones for this purpose may partly depend on the conversion of daidzein to equol, which will be discussed in further detail later in this course.

Urogenital Symptoms

Three small clinical trials show that taking supplemental soy providing 50–118 mg of isoflavones daily for 12 weeks reduces urogenital symptoms when compared with a control group. However, this benefit may not occur in patients consuming soy as part of the diet. A small clinical study in perimenopausal patients shows that a soy-rich diet does not relieve urogenital symptoms, including vaginal dryness, vulvar itching, and urinary incontinence, when compared with a soy-free diet [14].

A vaginal gel containing soy extract has also been evaluated. One small clinical study suggests that applying one gram of soy extract 4% vaginal gel daily for 12 weeks reduces vaginal dryness and pain during sexual intercourse and improves vaginal epithelial thickness when compared with placebo [14].

Bone Health

Most clinical research suggests that soy protein or soy extract containing 75–90 mg of isoflavones can increase BMD, or attenuate BMD loss, in peri- and postmenopausal adults when compared with control. Also, an observational study in postmenopausal Asian adults has found that consuming higher dietary soy protein is associated with a lower risk of developing fractures when compared with lower amounts [14].

However, not all research has shown a benefit of soy protein on BMD in postmenopausal adults. These conflicting findings may be due to differences in formulations, concomitant treatments, or patient populations. Additionally, these effects may be modulated by the conversion of daidzein to equol.

Safety

Soy is well tolerated when consumed as part of the diet or as a supplement. The most commonly reported adverse effects are bloating, constipation, diarrhea, and nausea. In postmenopausal adults, specifically, soy isoflavone supplements have also been shown to increase the rate of insomnia.

As with other phytoestrogens, there have been many concerns raised over the years regarding the association between soy intake and the risk for long-term health issues. However, most research in postmenopausal adults indicates that these concerns are not likely to be clinically relevant [14].

Population research has found that soy, as part of the diet or as a supplement, is protective against breast cancer. This research has consistently found that a high-soy diet in Asian and Asian-American women is associated with a reduced risk of breast cancer. However, the amount of soy consumed in a Western diet, even among those who consume the highest amounts of soy, was not found to have a preventative effect [14].

Despite some early research suggesting that soy supplements might stimulate the growth of breast tissue, there does not seem to be a concern for increased risk of breast cancer with the use of soy, even in those with a history of breast cancer. One clinical study shows that taking a tablet containing 50 mg soy isoflavones daily for 12 months does not alter mammographic or breast MRI tissue density in those at high risk of breast cancer, those with non-endocrine-treated breast cancer, or those previously treated for breast cancer and without recurrence [14].

Population and clinical research suggest that soy foods do not have a proliferative effect on endometrial cells. In fact, increased dietary intake of soy and other phytoestrogens is associated with reduced endometrial cancer risk.

Soy supplements also do not seem to increase risk for endometrial cancer. Taking high doses of soy isoflavones, such as 150 mg daily for five years, might increase the risk of simple endometrial hyperplasia. However, there is no evidence that soy isoflavones increase the risk of atypical hyperplasia, which is a greater risk factor for the development of endometrial cancer [14].

There is some evidence that soy intake can inhibit thyroid hormone synthesis and increase the secretion of thyroid-stimulating hormone (TSH) in postmenopausal adults. However, this risk seems to be limited to those with low iodine levels. In postmenopausal patients with normal levels of iodine, taking a soy extract for six months did not affect thyroid hormone levels [14].

Interactions

Soy may potentiate the effects of antidiabetes or antihypertensive medications, potentially increasing the risk of hypoglycemia or hypotension. There is also some concern that soy isoflavones, including genistein and daidzein, might antagonize the antitumor effects of tamoxifen. Although research on this topic is conflicting, advise patients requiring treatment with tamoxifen to avoid the use of soy supplements [14].

Summary

It is important to remember that soy is also a good source of dietary protein and has been shown to improve muscle strength in older adults who are also participating in exercise. It does not seem to provide any additional benefit over other sources of protein, such as whey, beef, or dairy, for this purpose. However, soy protein as a source of soy isoflavones may offer various benefits for many postmenopausal patients [14].

Equol

Equol is an isoflavone that is produced when daidzein, a soy isoflavone, undergoes biotransformation. This is catalyzed by specific intestinal bacteria, including Asaccharobacter celatus and Slackia isoflanoniconvertans. The conversion of soy to equol is thought to be approximately 8–15 mg of equol for every 6–11 grams of soy consumed daily [15].

Equol is chemically classified as a nonsteroidal estrogen. The S-enantiomer of this chemical (S-equol) is the only form produced by humans. It has demonstrated an affinity for the beta estrogen receptor that is approximately 20% that of estrogen. Beta estrogen receptors are found in the heart, vasculature, bone, and bladder, but not the uterus [15].

Not all humans host the bacteria necessary to convert daidzein to equol, and thus, not all humans are considered "equol producers." Approximately 40% to 60% of Japanese, Korean, and Chinese adults, as well as vegetarians from Western countries, are capable of producing equol. Conversely, only about 20% to 30% of Western, non-vegetarian adults produce equol. It is not entirely clear what drives these differences, although some researchers have hypothesized that the types of soy foods consumed by each of these groups may play a role [15].

There is speculation that some of the variable benefits of soy seen in clinical trials are related to the equol-producing status of study participants. However, this has not been definitively confirmed in clinical research.

Effects in Menopause

Multiple clinical studies show that taking S-equol 10–30 mg daily modestly reduces symptoms of menopause, including hot flashes, and improves mood when compared with placebo. Most of this research has been conducted in Japan; however, one clinical trial has evaluated equol in North Americans. In this study, taking S-equol 10 mg, 20 mg, or 40 mg daily for two months resulted in similar reductions in hot flash frequency as a soy isoflavone tablet containing 24 mg daidzein, 22 mg genistein, and 2 mg glycitein. The lack of a placebo group limits the validity of these findings [15].

There is also interest in using equol for various other purposes during menopause, including for improving BMD and reducing facial wrinkles. However, the available research is exploratory, and findings are inconclusive.

Safety

Equol is generally well tolerated. As with soy, research does not suggest that taking equol increases the risk for breast or endometrial cancer. However, laboratory research suggests that equol may inhibit the binding of estradiol to serum proteins, which could theoretically increase the concentration of free, bioactive estrogen and increase the adverse effects of estrogen replacement therapy [15].

Black Cohosh (Actaea racemosa)

Black cohosh, an herb that is native to eastern North America, appears to have estrogen-like effects, although these effects are exerted via an unknown mechanism. Laboratory research suggests that black cohosh extracts do not bind to estrogen receptors or upregulate estrogen-dependent genes. However, it might have SERM-like activity, exerting estrogenic effects in some tissues and antiestrogenic effects in others. Clinically, black cohosh does not appear to affect levels of hormones such as estradiol, luteinizing hormone (LH), or follicle-stimulating hormone (FSH) [16].

Effects in Menopause

Research on the use of black cohosh for vasomotor symptoms of menopause has primarily evaluated a specific branded product (Remifemin). When taken in doses of 40–127 mg daily for up to 12 weeks, this product reduces symptoms of menopause and hot flash frequency when compared with placebo. It also seems to be comparable to certain forms of HRT, including low-dose transdermal estradiol 25 mcg every week, conjugated equine estrogens 0.625 mg daily, or tibolone 2.5 mg daily [16]. (Tibolone is a synthetic steroid with estrogenic properties that is approved for use in Europe.)

However, research evaluating other proprietary black cohosh extracts has been less consistent. One extract (Klimadynon/Menofem) taken as 40 mg daily for 60 to 90 days does not reduce menopausal symptoms when compared with control groups. However, another extract (Remixin) taken as 40 mg daily for six months modestly reduces hot flashes and night sweats when compared with fluoxetine 20 mg daily. Studies of non-branded black cohosh extracts have been mostly negative, suggesting a lack of benefit on vasomotor symptoms [16].

Although there is speculation that the benefits seen with Remifemin may be due to bias introduced by industry funding, it is also possible that conflicting findings may be related to cultivation and processing methods. Remifemin is standardized across batches to triterpene glycosides, whereas the contents of other products are not clearly defined. Additionally, some non-standardized black cohosh products have been found to contain other species of Actaea, which may have different effects [16].

There is also interest in the use of black cohosh for a variety of other purposes during menopause, such as anxiety, bone health, cognitive function, and cardiovascular risk. However, clinical research to date has shown no benefit for these uses.

Safety

Black cohosh seems to be generally well tolerated, with limited adverse effects reported in clinical studies. However, there are some specific safety concerns that may be relevant for certain patients.

In studies with Remifemin, some patients reported vaginal bleeding or breast tenderness; however, the frequency of these events seems to be less than that of tibolone [16].

There has been some concern about the risk of endometrial hyperplasia with black cohosh. Most clinical research in postmenopausal adults has found that taking black cohosh for up to 12 weeks does not increase endometrial thickening or the presence of superficial cells. However, the long-term effects of black cohosh remain unclear.

There is some concern that black cohosh might cause hepatotoxicity or hepatitis. These effects have not been seen in clinical studies, but multiple case reports have suggested a correlation. Many of these cases are poorly documented, and it is unclear whether black cohosh was contaminated or whether it was the probable cause for liver issues. Regardless, the U.S. Pharmacopeia (USP) recommends labeling on black cohosh products regarding potential liver toxicity. Until more is known, consider monitoring liver function during black cohosh use [16].

Interactions

There is conflicting information regarding the effect of black cohosh on cytochrome P450 (CYP) 2D6 metabolism. Some clinical research suggests that black cohosh might modestly inhibit CYP2D6. However, a clinical study evaluating Remifemin shows that taking 40 mg twice daily does not inhibit CYP2D6 metabolism in healthy volunteers. Until more is known, use black cohosh with caution in patients taking drugs metabolized by CYP2D6 [16].

Summary

Black cohosh may have modest benefits for some postmenopausal adults. However, only certain extracts seem to exert these benefits, and individual risk factors should be evaluated prior to use.

Chasteberry (Vitex agnus-castus)

Chasteberry is a deciduous shrub that is native to the Mediterranean and Central Asia. The plant has a long history of use for menstrual and menopausal conditions, as well as for reducing sexual desire. This contributed to its nickname as the "chaste tree."

Laboratory research suggests that chasteberry has activity at beta estrogen receptors. It is also thought to exert indirect effects on various neurotransmitters, including dopamine [17].

Effects in Menopause

One large clinical study shows that taking a chasteberry extract 15 mg twice daily for eight weeks improves some menopausal symptoms, including anxiety and vasomotor dysfunction, by 76% and 88%, respectively, when compared with baseline. However, there was no effect on depression or sexual dysfunction. Due to the lack of a comparator group, the clinical relevance of these findings is unclear [17].

Safety

Chasteberry is generally well tolerated, although it has been reported to cause diarrhea, fatigue, headache, insomnia, nausea, skin irritation, stomach pain, and vomiting [17].

Summary

The available evidence does not support the use of chasteberry for the management of menopausal symptoms.

Flaxseed (Linum usitatissimum)

Flaxseed, a common dietary source of fiber and omega-3 fatty acids, is also a rich source of lignan phytoestrogens.

Effects in Menopause

Most small studies evaluating flaxseed powder have identified modest benefit for reducing symptoms, but only when compared with baseline. The improvement identified in these studies is similar to that seen with placebo. Additionally, high-quality research on the use of flaxseed-containing food products has yielded negative findings, suggesting no benefit of these products for improving vasomotor symptoms. Similarly, research on the use of flaxseed, either as powder or extract, has shown no benefit on BMD [18].

Summary

Flaxseed can be utilized as a valuable source of fiber and omega-3 fatty acids in the diet. However, the evidence does not support its use for the management of menopausal symptoms [18].

Kudzu (Pueraria montanavar.lobata)

Kudzu is a climbing vine that is native to Asia but is now considered an invasive weed in the United States. It contains isoflavones, which have demonstrated estrogenic and antiestrogenic activity in laboratory research, similar to SERMs [19].

Effects in Menopause

Clinical research on the use of kudzu during or after menopause is limited. Small clinical studies in perimenopausal patients shows that taking kudzu 25 mg, 50 mg, or 100 mg daily for six months improves vasomotor symptoms when compared with baseline, and that taking 50 mg daily reduces vasomotor symptoms similarly to conjugated equine estrogen 0.625 mg, with or without medroxyprogesterone acetate 2.5 mg daily. However, taking kudzu does not seem to significantly improve sex hormone levels and may worsen lipid levels [19].

In postmenopausal adults, small clinical studies suggest that taking kudzu orally might improve flexible thinking and attention, although it does not appear to improve vaginal dryness or pH.

Research on a vaginal gel containing kudzu has yielded conflicting results. Although one study suggests that applying 0.5 grams of a gel containing kudzu 6% to the vagina for 11 weeks improves vaginal symptoms similarly to conjugated estrogen cream, another clinical study shows that applying a 5% gel does not improve symptoms when compared with a placebo gel [19].

Safety

Kudzu is generally well tolerated; most reported adverse effects occur at the same rate as placebo. However, there have been several case reports of elevated liver transaminases after the use of kudzu.

The isoflavones in kudzu are reported to have antiplatelet activity, which may be a concern for patients on anticoagulant or antiplatelet therapy. There is also some concern that kudzu might inhibit organic anion transporters (OATs), which are responsible for the excretion of various drugs [19].

Summary

Due to the limited research and inconsistent benefits identified to date, clinicians should not recommend kudzu for the relief of menopausal symptoms.

Ginseng

Many plants have been referred to as ginseng; Panax ginseng is the species most commonly associated with this name. The root of this plant has a long history of use in traditional Chinese medicine.

Although the hormonal effects of Panax ginseng remain controversial, some laboratory and clinical research has indicated the presence of some estrogen-like activity. Additionally, Panax ginseng may affect levels of dehydroepiandrosterone (DHEA) and testosterone [20].

Panax ginseng has been evaluated for various purposes in postmenopausal adults; however, the available research is limited and conflicting.

Vasomotor Symptoms

One study shows that taking Panax ginseng 1 gram three times daily for 12 weeks reduces hot flashes and other symptoms when compared with placebo. Another study shows that taking an extract of Korean red ginseng, a specific form of Panax ginseng, 500 mg four times daily for two months modestly improves fatigue severity scores when compared with placebo. However, one study shows that taking a lower dose of 200 mg daily orally for four months does not improve symptoms when compared with placebo [20].

Genitourinary Symptoms

A small clinical trial in postmenopausal adults with genitourinary syndrome shows that taking Panax ginseng 500 mg twice daily for four weeks does not affect vaginal maturation index or pH but may improve vaginal itching and burning when compared with placebo. One study also shows that taking Korean red ginseng 3 grams daily for two months modestly improves sexual arousal and satisfaction when compared with placebo [20].

Safety

The most common adverse effect reported with Panax ginseng is insomnia. In postmenopausal adults, specifically, it has also been reported to cause vaginal bleeding. Panax ginseng has also been associated with prolongation of the QT interval when used short-term; its effects when used long-term are unclear [20].

There is some evidence that Panax ginseng can modestly inhibit the CYP2D6 enzyme, although the clinical significance of this effect is unclear. Panax ginseng may also modify the function of the CYP3A4 enzyme [20].

Some reports suggest that it can inhibit CYP3A4 activity, while other research suggests it may induce activity. Until more is known, use Panax ginseng with caution in patients taking CYP2D6 or CYP3A4 substrates.

There is also some concern that Panax ginseng may decrease platelet aggregation or alter the metabolism of warfarin. However, the available research is conflicting and clinical relevance is unclear [20].

Summary

Panax ginseng may offer modest benefits for some patients with vasomotor or genitourinary symptoms. However, it should be used with caution in patients with certain medical conditions or those taking certain medications.

Wild Yam (Dioscorea species)

Wild yams contain diosgenin, which has been used historically to synthesize corticosteroids and sex hormones. Some wild yam products are actually promoted as natural DHEA, which is a precursor for human sex hormones. However, DHEA can only be synthesized from diosgenin in a laboratory. This transformation does not occur in the human body. Thus, wild yam should not be recommended as a treatment for menopause [21].

Other Phytoestrogens

There is interest in using a number of other plants as potential phytoestrogens. However, many have shown weak or absent estrogenic effects in clinical and laboratory research. These plants include dong quai (Angelica sinensis), red clover (Trifolium pratense), hops (Humulus lupulus), and common sage (Salvia officinalis).

OTHER HERBAL MEDICATIONS

St. John's Wort (Hypericum perforatum)

St. John's wort is a plant native to Europe with yellow, star-shaped flowers. It is relatively well-known for its modest antidepressant effects, as well as its ability to cause significant drug-drug interactions by inducing CYP enzymes [23].

St. John's wort has been shown to modulate the effects of serotonin, dopamine, and norepinephrine, and inhibit the reuptake of these chemicals. These effects are thought to be beneficial in menopause.

Effects in Menopause

Most clinical research shows that taking St. John's wort can reduce symptoms of perimenopause. A meta-analysis of small clinical trials shows that taking St. John's wort up to 900 mg daily for up to 16 weeks, alone or in combination with other herbs, reduces the frequency and severity of hot flashes when compared with placebo. Some research also suggests that St. John's wort might improve quality of life and psychological symptoms when compared with placebo [23].

Safety

St. John's wort is generally well tolerated but may cause diarrhea, dizziness, dry mouth, mild gastrointestinal discomfort, fatigue, headache, insomnia, and sedation.

This plant is a potent inducer of CYP3A4 and a moderate inducer of CYPs 1A2, 2B6, 2C19, and 2C9, as well as P-glycoprotein. Thus, St. John's wort interacts with many drugs available on the market and should be used with caution in most patients [23].

Other Miscellaneous Herbs

Evidence Based Practice Recommendation

For postmenopausal women seeking relief of vasomotor symptoms of menopause with over-the-counter or complementary medicine therapies, the Endocrine Society suggests counseling regarding the lack of consistent evidence for benefit for botanicals, black cohosh, omega-3-fatty acids, red clover, vitamin E, and mind/body alternatives including anxiety control, acupuncture, paced breathing, and hypnosis.

https://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-guidelines/treatment-of-menopause

Last Accessed: January 23, 2023

Level of Evidence: 2|⊕⊕ (Suggestion based on low-quality evidence)

There has been interest in using many other plants and extracts for the management of menopause-related symptoms. The proposed mechanism of action for each of these supplements varies. However, most have either not been adequately evaluated in clinical research or have not shown promise in clinical studies. Examples include evening primrose oil (Oenothera biennis), saffron (Crocus sativus), valerian (Valeriana officinalis), ashwagandha (Withania somnifera), and black seed (Nigella sativa).

6. CONCLUSION

Menopause introduces a number of short- and long-term health effects, which patients may be interested in managing via nonpharmacologic methods. Many menopause-related health effects may be mitigated by a variety of lifestyle modifications, including exercise and dietary changes, with a focus on increasing the intake of beneficial substances and decreasing the intake of detrimental substances. These lifestyle modifications should be recommended for most adults in perimenopause and postmenopause.

Some complementary modalities, such as mindfulness and yoga, can also offer short- and long-term benefits. Additionally, certain herbal therapies, such as soy, can be considered as complementary treatment options for many patients. However, some herbal therapies that are commonly discussed for menopause should be used with caution and individualized to patient needs and risk factors.

Works Cited

1. OlaOlorun FM, Shen W. Menopause. Available at https://oxfordre.com/publichealth/display/10.1093/acrefore/9780190632366.001.0001/acrefore-9780190632366-e-176. Last accessed January 10, 2023.

2. The North American Menopause Society 2022 Hormone Therapy Position Statement Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794.

3. TRC Healthcare Natural Medicines Database. Calcium. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=781. Last accessed January 10, 2023.

4. TRC Healthcare Natural Medicines Database. Vitamin D. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=929. Last accessed January 10, 2023.

5. U.S. Preventive Services Task Force. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: U.S. Preventive Services Task Force recommendation statement. JAMA. 2018;319(15):1592-1599.

6. LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis. Osteoporosis International. 2022;33:2049-2102.

7. TRC Healthcare Natural Medicines Database. Magnesium. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=998. Last accessed January 10, 2023.

8. Rizzoli R, Stevenson JC, Bauer JM, et al. The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: a consensus statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Maturitas. 2014;79(1):122-132.

9. Centers for Disease Control and Prevention. How Much Physical Activity Do Older Adults Need? Available at https://www.cdc.gov/physicalactivity/basics/older_adults/index.htm. Accessed on January 10, 2023.

10. TRC Healthcare Natural Medicines Database. Caffeine. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=979. Last accessed January 10, 2023.

11. TRC Healthcare Natural Medicines Database. Acupuncture. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=1219. Last accessed January 10, 2023.

12. TRC Healthcare Natural Medicines Database. Mindfulness. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=1599. Last accessed January 10, 2023.

13. TRC Healthcare Natural Medicines Database. Yoga. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=1241. Last accessed January 10, 2023.

14. TRC Healthcare Natural Medicines Database. Soy. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=975. Last accessed January 10, 2023.

15. TRC Healthcare Natural Medicines Database. Equol. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=1269. Last accessed January 10, 2023.

16. TRC Healthcare Natural Medicines Database. Black Cohosh. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=857. Last accessed January 10, 2023.

17. TRC Healthcare Natural Medicines Database. Vitex agnus-castus. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=968. Last accessed January 10, 2023.

18. TRC Healthcare Natural Medicines Database. Flaxseed. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=991. Last accessed January 10, 2023.

19. TRC Healthcare Natural Medicines Database. Kudzu. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=750. Last accessed January 10, 2023.

20. TRC Healthcare Natural Medicines Database. Panax Ginseng. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=1000. Last accessed January 10, 2023.

21. TRC Healthcare Natural Medicines Database. Wild Yam. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=970. Last accessed January 10, 2023.

22. TRC Healthcare Natural Medicines Database. Progesterone. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=760. Last accessed January 10, 2023.

23. TRC Healthcare Natural Medicines Database. St. John's Wort. Available at https://naturalmedicines.therapeuticresearch.com/databases/health-wellness/professional.aspx?productid=329. Last accessed January 10, 2023.

Evidence-Based Practice Recommendations Citations

1. National Institute for Health and Care Excellence. Menopause: Diagnosis and Management. Available at https://www.nice.org.uk/guidance/ng23. Last accessed January 23, 2023.

2. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(11):3975-4011. Available at https://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-guidelines/treatment-of-menopause. Last accessed January 23, 2023.

98320 • Natural Psychedelics

Chelsey McIntyre, PharmD

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Interest in the use of psychedelics in general, as well as natural psychedelics, has been increasing over the past few years. Patients may be using these substances recreationally or may be asking about these options for the treatment of various medical conditions. Healthcare professionals should be well informed about the unique considerations associated with the safe, effective, and legal use of these substances.

Table of Contents

98320 • Natural Psychedelics

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Individual State Behavioral Health Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. DEFINITIONS

3. PSYCHEDELICS AS THERAPY

4. UNIQUE CONSIDERATIONS

LEGAL CONCERNS

RESEARCH LIMITATIONS

OTHER SPECIAL CONSIDERATIONS

5. NATURAL PSYCHEDELICS

AYAHUASCA (DMT)

HAWAIIAN BABY WOODROSE (LYSERGIC ACID AMIDE)

IBOGA (IBOGAINE)

PSILOCYBIN MUSHROOMS

PEYOTE (MESCALINE)

SALVIA DIVINORUM (SALVINORIN A)

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98320 • Natural Psychedelics

Education Category. Alternative Medicine

Release Date. 07/01/2023

Expiration Date. 06/30/2026

Course Overview

Interest in the use of psychedelics in general, as well as natural psychedelics, has been increasing over the past few years. Patients may be using these substances recreationally or may be asking about these options for the treatment of various medical conditions. Healthcare professionals should be well informed about the unique considerations associated with the safe, effective, and legal use of these substances.

Audience

This course is designed for healthcare professionals whose patients are taking or have questions about natural psychedelic products.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE has been approved by NBCC as an Approved Continuing Education Provider, ACEP No. 6361. Programs that do not qualify for NBCC credit are clearly identified. NetCE is solely responsible for all aspects of the programs. As a Jointly Accredited Organization, NetCE is approved to offer social work continuing education by the Association of Social Work Boards (ASWB) Approved Continuing Education (ACE) program. Organizations, not individual courses, are approved under this program. Regulatory boards are the final authority on courses accepted for continuing education credit. Continuing Education (CE) credits for psychologists are provided through the co-sponsorship of the American Psychological Association (APA) Office of Continuing Education in Psychology (CEP). The APA CEP Office maintains responsibility for the content of the programs. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 3 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 3 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 3 ANCC contact hour(s). NetCE designates this continuing education activity for 3 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 3.6 hours for Alabama nurses. NetCE designates this continuing education activity for 1 NBCC clock hour(s). Social workers participating in this intermediate to advanced course will receive 3 Clinical continuing education clock hours. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 3 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. NetCE is authorized by IACET to offer 0.3 CEU(s) for this program. AACN Synergy CERP Category A. NetCE designates this continuing education activity for 3 credit(s).

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Individual State Behavioral Health Approvals

In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190;

Special Approvals

This course has been approved by NetCE, as a NAADAC Approved Education Provider, for educational credits, NAADAC Provider #97847. NetCE is responsible for all aspects of their programming. NetCE is approved as a provider of continuing education by the California Association of DUI Treatment Programs (CADTP). Provider Number 185. NetCE is approved as a provider of continuing education by the California Association for Alcohol/Drug Educators. Provider Number CP40 889 H 0626. This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency. NetCE designates this continuing education activity for 3 continuing education hours for addiction professionals.

Course Objective

The purpose of this course is to provide healthcare professionals with an increased understanding of natural psychedelics and the considerations associated with the safety, effectiveness, and legal use of these substances.

Learning Objectives

Upon completion of this course, you should be able to:

1. Define the terminology associated with psychedelic substances.

2. Review the regulatory and practical limitations to conducting research on natural psychedelics.

3. Identify the most commonly used natural psychedelics and their active constituents.

4. Discuss the evidence for the use of natural psychedelics for therapeutic purposes.

Faculty

Chelsey McIntyre, PharmD, is a clinical pharmacist who specializes in drug information, literature analysis, and medical writing. She earned her Bachelor of Science degree in Genetics from the University of California, Davis. She then went on to complete her PharmD at Creighton University, followed by a clinical residency at the Children’s Hospital of Philadelphia (CHOP). Dr. McIntyre held the position of Drug Information and Policy Development Pharmacist at CHOP until her move to Washington state in 2017, after which she spent the next six years as a clinical editor for Natural Medicines, a clinical reference database focused on natural products and alternative therapies. She continues to create rigorous professional analysis and patient education materials for various publications while also practicing as a hospital pharmacist. Her professional interests include provider and patient education, as well as the application of evidence-based research to patient care.

Faculty Disclosure

Contributing faculty, Chelsey McIntyre, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Margo A. Halm, RN, PhD, NEA-BC, FAAN

Alice Yick Flanagan, PhD, MSW

Margaret Donohue, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Natural psychedelics have a long history of use in various cultures. This history covers a wide range of uses, including within sacred rituals and as therapeutic remedies. Over the past several decades, many of these substances have also become known for their use as recreational drugs. However, there has also been growing interest in the mainstream use of psychedelics as medical treatments, particularly for mental health disorders.

Some of this interest focuses on synthetic chemicals that have other accepted medical uses, such as ketamine. However, there is also a growing interest and body of research on the use of natural psychedelics, which are derived from plants. This course will focus on the natural psychedelics.

2. DEFINITIONS

Hallucinogens are a class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception, among other changes. Hallucinogens can be split into three sub-categories: psychedelics, dissociatives, and deliriants [1,2].

Psychedelics are substances causing unusually strong experiences of color, sound, smell, taste, and touch, and other mental effects, such as feelings of deep understanding or hallucination. Examples of chemicals in this class include dimethyltryptamine (DMT), ibogaine, lysergic acid diethylamide (LSD), and psilocybin. Although a psychedelic is considered a hallucinogen, not all hallucinogens are considered psychedelics.

Dissociatives are substances that cause feelings of separation and detachment from the body or physical environment. At high doses, these substances can cause analgesia, amnesia, and cataplexy. They can also cause hallucinations and other changes in thoughts, emotions, and consciousness. Examples of drugs in this class include ketamine, phencyclidine (PCP), and nitrous oxide.

Deliriants are substances that cause a state of delirium, often characterized by confusion and a lack of control of one's actions. Angel's trumpet (Brugmansia suaveolens), western jimsonweed (Datura wrightii), jimsonweed (Datura stramonium), and henbane (Hyoscyamus niger) are all considered deliriants.

Many plants that are classified as deliriants exert their effects via anticholinergic activity. These effects are often caused by tropane alkaloids, many of which (e.g., scopolamine, atropine) have known therapeutic uses when purified and administered in small doses. Because the quantity of these constituents can vary based on growing conditions, time of year, and method of preparation, many of these plants are considered toxic. In fact, deaths have been reported with even small doses of many popular deliriants, including jimsonweed and angel's trumpet [3,4].

This course will focus on plants and plant-derived chemicals that have been traditionally classified as psychedelics.

3. PSYCHEDELICS AS THERAPY

Although psychedelics are considered to be a promising option for the treatment of mental health disorders, understanding of their effects is limited. Much of the original interest in this use grew out of anecdotal reports of promising improvements after recreational use. Since that time, some exploratory research has further encouraged interest in this area.

Most psychedelics exert their effects via the serotonin (5-HT) system. This system is involved in the pathology and treatment of psychiatric disorders, including depression, anxiety, and cognitive deficits. Although many psychedelic chemicals are thought to exert effects via a number of other pathways as well, the known activity within the serotonin system has been considered supportive of the potential use of psychedelics for mental health care [5].

Exploratory research in humans has also confirmed that psychedelic substances can alter the function of the brain. For example, LSD and psilocybin have been shown to increase connectivity between some regions of the brain and decrease connectivity between others. These chemicals have also been shown to alter the level of blood flow to different regions of the brain. Other research has indicated that various psychedelic chemicals might alter the processing of sensory information, including emotions and facial expressions, which may have a measurable improvement in certain mental health conditions [5].

4. UNIQUE CONSIDERATIONS

Natural psychedelics present a unique set of considerations that should be kept in mind with any type of use, from recreational to therapeutic.

LEGAL CONCERNS

Since the 1970s, most psychedelic substances have been classified as Schedule I controlled substances by the U.S. Drug Enforcement Agency (DEA). This classification indicates that these substances have "no currently accepted medical use and a high potential for abuse." Although many countries have imposed similar restrictions on these substances, a small number of countries, such as Portugal and the Netherlands, have not criminalized their use [1].

The use, possession, sale, and manufacture of Schedule I substances is considered federally illegal. As such, the heavy restrictions placed on these chemicals can make it very difficult to conduct both preclinical and clinical research. In the late 1990s, the DEA began to permit limited research on certain psychedelics; however, there are still many barriers to conducting research on these substances [1].

Although the federal regulatory status of psychedelics in the United States has remained the same since the 1970s, other changes are occurring. For example, the U.S. Food and Drug Administration (FDA) has designated some psilocybin-based therapies as breakthrough therapies for treatment-resistant depression [6]. This status is intended to expedite the development and review of drugs that may treat a serious condition. Also, some municipalities and states have moved toward decriminalizing certain psychedelic substances, typically psilocybin, and developing laws that allow for the supervised use of these substances [7].

Over the past two decades, research has begun to suggest that certain psychedelic substances may carry a low potential for dependence and provide possible therapeutic benefits. If these findings are replicated in high-quality research, this may prompt a review of the Schedule I classification for certain chemicals [1].

RESEARCH LIMITATIONS

Although higher-quality research on some psychedelic chemicals has recently become available, much of the older research in this area is limited to anecdotal reporting. This introduces a risk for reporting bias, a situation in which there may have been a tendency to report on positive, but not negative, outcomes. Additionally, even though many of the studies being conducted today are utilizing a randomized, controlled design, even these studies are subject to inherent weaknesses that occur with the use of psychedelic chemicals [8].

Appropriate Placebo Selection

There is still significant controversy on the selection of an appropriate placebo for psychedelic research. Examples of placebos used in recent clinical trials include very low, nontherapeutic doses of the same psychedelic substance being evaluated, as well as treatment doses of drugs with known neurologic effects, such as diphenhydramine. However, the majority of patients in these studies have been able to accurately guess the treatment group to which they were assigned. Inadequate blinding and masking prevent studies from appropriately controlling for a placebo effect, which may skew study results.

Subject Expectations

Many patients enrolled in studies of psychedelic products have preconceived expectations related to the upcoming experience, referred to as response expectancy. This confounder is a known issue in the field of psychiatry and has been discussed in relation to the study of antidepressants. For psychedelics, response expectancy can further undermine attempts to control for the placebo effect. This can result in subjective reports that indicate a greater positive effect with the psychedelic chemical and general absence of effect with the placebo.

Controlled Environment

Research on the use of psychedelics to date has typically provided the study subjects with a highly controlled, positive environment in which to experience the effects of the substance. For example, many studies allow or require the subject to remain in a clinic environment, with access to a therapist, for eight hours after dosing. If the intent is for patients to take the substance outside of a clinic, this experience is dissimilar from the intended use of psychedelic chemicals. However, to date, therapeutic use of psychedelics has been limited to controlled clinical settings.

When these individual limitations are considered together, their potential to result in an overestimation of the treatment effect becomes even greater. Experts in the field have recommended standard assessments of blinding/masking and response expectancy to provide a clearer picture of the risk of bias in any given study. These limitations should be kept in mind when interpreting the literature in this area.

OTHER SPECIAL CONSIDERATIONS

Whole Plant versus Isolated Chemical

Some people may choose to consume a fresh or dried plant for psychedelic effects. Others may choose to consume psychedelic chemicals that have been purified from these plants. These differing sources are often discussed interchangeably by the media and consumers. However, it is important to recognize that these two different sources may provide very different effects.

For example, consuming psilocybin mushrooms can produce a psychedelic effect. However, the concentration of psilocybin (the chemical responsible for this effect) present varies from 0.37% to 1.3% depending on the exact species of mushroom consumed. Further, samples of psilocybin mushrooms obtained from various sources have yielded psilocybin concentrations that vary by a factor of four to ten [9,10,11]. For most plants, the time of year that harvesting occurs, as well as the methods used to harvest and process the plant, can also significantly alter chemical composition.

Purified psilocybin, however, can be given in very exact doses, similar to a prescription drug. When psilocybin is evaluated in clinical research, it is provided and dosed in the purified form, ensuring consistent potency and reproducible effects. The use of psilocybin mushrooms, on the other hand, would be expected to provide less consistent effects and potency.

This consideration is important for all natural psychedelics, as the psychedelic effects of any given plant are mostly obtained from one or two constituents found in that plant. Some examples include:

- Ayahuasca: This concoction is made from whole plants and contains DMT.

- Iboga: This plant contains the psychedelic alkaloids ibogaine, ibogaline, and ibogamine

- Peyote: This cactus contains the psychedelic chemical mescaline.

- Salvia divinorum: The leaf of this herb contains salvinorin A, a psychedelic chemical.

When potency concerns are raised, many people immediately consider the impact on therapeutic and psychedelic effects. However, variable potency can also lead to the development of significant and unexpected adverse effects that do not occur consistently with each use. There are many case reports of whole psychedelic plants causing serious adverse effects and even death in people with a history of use [119].

Therapeutic Dosing versus Microdosing

As might be expected, psychedelic substances have traditionally been used in doses that are intended to exert a hallucinogenic effect. Most often, psychedelics are taken in single doses or isolated doses taken weeks or months apart from each other. Similar doses are also used in clinical research and tend to be considered "therapeutic" doses for these chemicals.

However, there has been interest in the use of very small doses that are not expected to exert a hallucinogenic effect. These small doses, referred to as microdoses, are not strictly defined, but are often about 10% of the amount that would be expected for a "medium to high" single therapeutic dose, taken either every three days or two to four times per week [9,12].

The theory behind this dosing strategy is that regular use of nonpsychedelic doses will boost mood and energy and reduce anxiety without causing a hallucinogenic high. Unfortunately, any research on this theory is very limited and most publications provide only anecdotal reports. Currently, people who utilize this dosing strategy have self-selected for this use and have determined their own dosing regimen. Thus, this form of treatment is thought to be particularly prone to response expectancy and a placebo effect [9,13].

Microdosing with psilocybin mushrooms may be particularly difficult, as concentrations of the psychedelic substance can vary widely between mushrooms. These concentrations can also change depending on whether the mushroom has been processed in any way.

Many people aiming to microdose have ended up taking much larger doses than intended, leading to hallucinations, paranoia, and increased blood pressure and heart rate. Even when doses are correctly measured, there is limited information on the short- and long-term safety of this practice [9,12].

5. NATURAL PSYCHEDELICS

AYAHUASCA (DMT)

Ayahuasca is a psychotropic drink that is used for therapeutic and religious rituals in several Amazonian countries, including Brazil, Peru, Colombia, and Ecuador. The word ayahuasca is based on the Quechua language and comes from aya, meaning spirit or soul, and huasca, meaning rope or vine [14,15,16,17,18,19,20].

Ayahuasca is most commonly brewed by boiling the vine of Banisteriopsis caapi with the leaves of Psychotria viridis. In some cases, other plants, such as Diplopterys cabrerana and other Psychotria species, may be used as the source of leaves, or the leaves may be excluded entirely.

Regardless of the specific ingredients used, ayahuasca brews contain DMT, a known psychedelic chemical. Some other constituents, including harmine and tetrahydroharmine, may act to enhance the psychedelic effects of DMT [19,21,22,23,24]. DMT is classified as a Schedule I controlled substance by the DEA [121].

In addition to ayahuasca's historical use in rituals, there has also been growing interest in its use as a therapeutic agent for various mental health disorders. In fact, some resorts and clinics in Mexico, where ayahuasca is legal, now offer ayahuasca-based retreats.

The exact contents of ayahuasca change with each brew, and the concentration of its therapeutic constituents can vary significantly. Most tested preparations of ayahuasca have been found to contain DMT in quantities ranging from 0.088 mg/mL to 2.687 mg/mL and harmine in quantities ranging from 0.14 mg/mL to 4.44 mg/mL [24]. This wide variability from batch to batch would be expected to significantly alter any therapeutic or adverse effects that occur with use.

Mechanism of Action

DMT is a serotonin (5-HT) 2A, 2C, and 1A receptor agonist in the central nervous system (CNS). Harmine is a reversible inhibitor of monoamine oxidase (MAO)-A. This is thought to enhance the effect of DMT by inhibiting its metabolism in the gastrointestinal tract and allowing larger quantities to reach the CNS. Another constituent, tetrahydroharmine, has demonstrated activity as a selective inhibitor of serotonin reuptake, which may also produce neurologic effects [25].

However, there is limited reliable research on the actual effects of ayahuasca in humans. The available literature suggests that any effects may be dose- and patient-dependent. Some animal research suggests that low doses may produce stimulant effects, whereas high doses may reduce CNS activity. A small study in humans suggests that baseline mental health diagnoses may alter the outcomes of ayahuasca use [120].

Clinical Effects

Depression

Evidence Based Practice Recommendation

The U.S. Department of Veterans Affairs asserts that ayahuasca use may be associated with a short-term reduction in depression symptoms and suicidality.

https://www.hsrd.research.va.gov/publications/esp/psychedelics-mh-brief.pdf

Last Accessed: June 16, 2023

Level of Evidence: Low

To date, evidence on the use of ayahuasca for depression is limited to very small, low-quality trials, most of which were conducted in Mexico. In one trial of 29 patients with moderate-to-severe treatment-resistant depression, taking a single dose of ayahuasca 1 mL/kg moderately improved symptoms of depression after seven days when compared with placebo. The response rate with ayahuasca was two- to three-fold greater than that seen with placebo [23]. Two small, open-label trials in patients with recurrent major depressive disorder show that taking a single dose of ayahuasca 2.2 mL/kg improved symptoms of depression when compared with baseline [26,27].

Prolonged Grief Disorder

One observational study in patients with prolonged grief disorder found that taking part in a retreat including four to nine ceremonial ayahuasca experiences was associated with moderately reduced grief severity when compared with baseline. About 50% of the patients at the retreat attributed a sense of healing to the ayahuasca [19]. There is no prospective clinical research evaluating ayahuasca for this purpose.

Substance Use Disorder

There is interest in the use of ayahuasca for multiple forms of substance use disorder, including alcohol, opioids, cannabis, and mixed substances. However, no prospective clinical research has evaluated its use for this indication.

Observational research in patients with multiple self-reported addictions has found that taking ayahuasca twice during a four-day group-counseling retreat is associated with improved feelings of hopefulness, empowerment, mindfulness, and quality of life for up to six months after the retreat. Use of alcohol, tobacco, and cocaine, but not cannabis or opioids, may also decrease [28].

Safety

Ayahuasca has been associated with a number of adverse effects, ranging from mild to severe. The most common adverse effects reported with use include gastrointestinal upset, mydriasis, slurred speech, tingling, trembling, and sweating [21,23,26,27,30,31]. It can also cause transient elevations in blood pressure and heart rate that typically return to normal after 30 minutes [16,21,32]. The hallucinations that occur with ayahuasca can last for several hours and may cause disorientation, delusion, agitation, and dissociation [16,21,110].

Some of the more serious adverse effects reported with use have included convulsions, coma, and psychosis. However, due to the anecdotal nature of many of these reports, it is unclear if ayahuasca was the cause or if there were other precipitating factors [25,33,34,35].

Interactions

Some of the alkaloids in ayahuasca, such as harmine and harmaline, have been shown to inhibit cytochrome P450 (CYP) 2D6 and 3A4 in laboratory research. Although this effect has not been confirmed in humans, ayahuasca should be used with caution in patients taking drugs that are substrates of these enzymes [36].

Because DMT, harmaline, and harmine all have serotonergic effects, or the ability to enhance the serotonergic effects of other substances, ayahuasca should be used with caution in patients taking serotonergic drugs. In fact, there has been at least one case report of serotonin syndrome in a patient who was stabilized on fluoxetine 20 mg daily and consumed ayahuasca 100 mL [25,37].

Serotonin syndrome occurs when high levels of serotonin build up in the body, typically due to the use of multiple drugs that increase serotonin levels. Although this is a rare occurrence, serotonin syndrome can be life-threatening. Symptoms include shivering, diarrhea, muscle rigidity, tremors, fever, severe headache, altered mental status, and seizures.

Although many drugs may have minor serotonergic activity, the drug classes most commonly associated with serotonin syndrome include:

- Monoamine oxidase inhibitors (MAOIs)

- Selective serotonin reuptake inhibitors (SSRIs)

- Selective serotonin-norepinephrine reuptake inhibitors (SNRIs)

- Tricyclic antidepressants (TCAs)

- Atypical antipsychotics

The risk for serotonin syndrome increases with the addition of each serotonergic drug to any drug regimen. However, the risk is highest when MAOIs are used in combination with other serotonergic drugs. This is because MAOIs inhibit the breakdown of serotonin, perpetuating the effects of other serotonergic agents.

Many herbs and supplements can also increase the risk for serotonin syndrome and should be included in patient risk evaluations.

Summary

Although there have been many promising anecdotal reports suggesting that ayahuasca may be beneficial in patients with treatment-resistant mental health disorders, there is not enough clinical research to support its use for any purpose. Additionally, ayahuasca should be used with caution in patients with certain underlying conditions and medication regimens.

HAWAIIAN BABY WOODROSE (LYSERGIC ACID AMIDE)

Hawaiian baby woodrose (Argyreia nervosa), also referred to as elephant creeper, is a flowering vine that grows in Florida, California, and Hawaii. The seeds of this plant are sometimes touted online as "natural LSD" due to the presence of a chemical called lysergic acid amide (LSA), which is structurally similar to LSD. This plant and others containing LSA have been used in shamanistic rituals in South America [111].

The seeds of the plant have been shown to contain LSA in concentrations up to 83%. However, the alkaloid content of the seeds varies significantly from batch to batch. When used recreationally, the seeds may be eaten whole, crushed, or soaked in water [38,112]. Despite the presence of a known psychoactive chemical, this plant and its seed remain legal for sale in the United States.

Mechanism of Action

LSA has effects at the dopamine D2 receptor. It also seems to be a partial agonist or antagonist at adrenergic and serotonergic receptors, including serotonin 2A. The hallucinogenic effects that occur with LSA are thought to be similar to those seen with LSD [39,40]. However, LSD is a synthetic chemical that does not occur in nature.

LSA in doses of 2–5 mg is considered enough to cause hallucinations. In pharmacokinetic studies, LSA has become detectable in the blood within 30 to 40 minutes of ingestion and levels continue to increase for approximately 90 minutes. Psychedelic effects are reported to last approximately four to eight hours [41,42,43].

Clinical Effects

Hawaiian baby woodrose continues to be used primarily as a recreational drug and has not garnered attention as a potential therapeutic agent. There is currently no clinical research evaluating its use for any medical purpose.

Safety

Hawaiian baby woodrose has been associated with many side effects, including nausea and vomiting, fatigue, dizziness, mydriasis, and sweating, as well as elevations in blood pressure and heart rate. In addition to hallucinations, it has also been reported to cause blurred vision and altered visual perception. Multiple reports also suggest that consuming the seeds of this plant can cause suicidal ideations, paranoia, weakness, and vertigo [38,41,42,43].

Interactions

Hawaiian baby woodrose has serotonergic effects and should be used with caution in patients taking other serotonergic agents. It may increase the risk of serotonin syndrome.

Summary

There is no known medical use for Hawaiian baby woodrose; its primary use has been for recreational purposes, as a "natural" source of an LSD-like chemical. Because its use is associated with many adverse effects, some serious in nature, it should not be recommended for any purpose.

IBOGA (IBOGAINE)

Iboga (Tabernanthe iboga) is a shrub that grows wild in certain parts of Africa. Its root bark is used in some ceremonial practices for its hallucinogenic and stimulant properties. The root bark contains the psychoactive chemical ibogaine. It also contains a number of other constituents that are thought to contribute to hallucinogenic effects, including ibogaline, ibogamine, and tabernanthine [44,45,46,47].

Although iboga has a long history of traditional use, any modern research for therapeutic purposes has used purified ibogaine only. It is not clear how much ibogaine is naturally found in iboga, or how the processing of iboga may alter the total ibogaine content. Ibogaine is classified as a Schedule I controlled substance by the DEA [121].

Mechanism of Action

Pure ibogaine has been shown to exert serotonergic effects, act as an agonist at kappa-opioid receptors, and act as an antagonist at N-methyl-D-aspartate (NMDA) receptors. Noribogaine, a metabolite of ibogaine, seems to have overlapping, and possibly stronger, affinities for these same receptors. Noribogaine has also demonstrated activity at the mu-opioid receptor [48,49].

Clinical Effects

There is interest in the use of iboga for various purposes, including depression, fatigue, and sexual arousal. However, all available clinical reports are specific to ibogaine, are anecdotal or observational in nature, and evaluate patients with substance use disorders.

Multiple case series in patients with opioid use disorder suggest that ibogaine may offer some benefit for the acute relief of opioid withdrawal symptoms. These reports also suggest that some patients may experience long-term relief of withdrawal symptoms for up to 14 weeks. The doses used in these studies ranged from a single dose of 12–25 mg/kg to 25–55 mg/kg provided over multiple doses within 24 to 96 hours [49,50,51,52].

One observational study in patients in withdrawal due to opioid dependence has found that taking ibogaine 25–55 mg/kg, given in multiple doses over 24 to 96 hours, is associated with a reduction in addiction severity, drug use, and feelings of depression for 12 months after treatment [52]. An additional observational study has found that providing ibogaine as part of a one-week detoxification protocol for opioid use is associated with the elimination or significant reduction of withdrawal symptoms in 80% of patients. Additionally, cravings and opioid use were modestly reduced [53].

One observational report evaluated the effects of ibogaine in patients with mixed substance use disorder—these patients primarily had cocaine use disorder, but some also used alcohol, tobacco, and cannabis. A single dose of ibogaine was associated with 5.5 months of self-reported abstinence; multiple doses of ibogaine were associated with 8.4 months of self-reported abstinence. It is important to note, however, that these patients had already been required to maintain abstinence for 30 days prior to treatment, which may have increased the success rate [113].

There are no prospective clinical studies that have evaluated the use of ibogaine for any purpose. The reports discussed here represent anecdotal evidence and should be interpreted with caution.

Safety

All known safety information is specific to ibogaine, as opposed to the whole plant. In general, ibogaine is known to cause multiple adverse effects, which may range from mild to very severe. The most common adverse effects reported with pure ibogaine are ataxia, confusion, diarrhea, headache, nausea, and vomiting. Multiple case reports have also associated the use of ibogaine with ventricular arrhythmias, cardiac arrest, and QT interval prolongation. QT interval prolongation progressed to torsades de pointes in some cases. In many of these reports, the patients had no prior history of heart disease [46,47,48,54,55,56,57,58,59,60,114].

There have also been multiple reports of death after ibogaine use. Although the exact cause of death is unclear in these cases, most reports provide objective data, such as serum ibogaine levels, that suggest ibogaine may have been a contributing factor [50,52,61,62,115].

There are also at least two reports of death occurring after the use of the iboga plant. In one case, the patient reported taking one teaspoon of iboga root in addition to methadone and diazepam and died 12 hours after ingestion [44]. In the other case, the patient consumed an unknown quantity of a powder that was labelled as iboga [63]. In both cases, ibogaine was detected in postmortem serum.

Interactions

Ibogaine can cause serotonergic effects and should be used with caution in patients taking other serotonergic agents [48]. Additionally, ibogaine is a substrate of CYP2D6, suggesting that its metabolism may be altered by drugs that inhibit or induce this enzyme [45,59].

In fact, one clinical study found that paroxetine, a CYP2D6 inhibitor, can delay the metabolism of ibogaine [65]. Taking paroxetine 20 mg daily increased exposure to ibogaine and its metabolite, noribogaine, by twofold [65]. Considering that paroxetine is also a serotonergic drug, it is important that patients avoid the use of these chemicals in combination.

Because ibogaine has been reported to cause QT interval prolongation, it should be used with caution in patients taking drugs that are known to prolong the QT interval.

Summary

Although there is growing interest in the use of ibogaine for substance use disorder, there is no prospective clinical research supporting its use for any medical purpose. As its use has also been associated with serious adverse effects, it should not be recommended as a treatment option.

The whole iboga plant should be avoided, as there is no research on its safety or effectiveness and its use has been associated with reports of death.

PSILOCYBIN MUSHROOMS

The term "magic mushrooms" refers to various mushrooms that contain a psychedelic chemical called psilocybin. Most of these mushrooms are in the genus Psilocybe. However, there are also other mushrooms that contain psilocybin, including certain species in the genera Conocybe, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, and Pluteus. These mushrooms have a history of traditional use for religious and spiritual rituals. However, they are also well known for their popular use as recreational drugs [10,11,66].

As mentioned, psilocybin can comprise 0.37% to 1.3% of the dry mushroom and there is high variability in the total psilocybin content for psilocybin mushrooms sold in various venues [9,10,11]. Psilocybin is classified as a Schedule I controlled substance by the DEA, though its use has been decriminalized in some states/cities [121].

Mechanism of Action

Purified psilocybin has recently been the focus of an extensive amount of laboratory and clinical research. Although there is limited information available on the use of psilocybin mushrooms, information on the safety and effectiveness of psilocybin is increasing rapidly.

Psilocybin is a prodrug that metabolizes to psilocin, a hallucinogenic tryptamine that acts at serotonin 2A receptors [67,68,69,70]. Although this seems to be the primary site of action, it is thought that psilocybin may also act on other pathways in humans. Some brain imaging suggests that it may have activity at serotonin 1A receptors as well. It seems to have little affinity for dopamine receptors [10,69,116].

The hallucinogenic effects of psilocybin involve visual, auditory, tactile, and other illusions, as well as changes in time and space perception. Some patients have reported recurrent drug-like experiences, mostly visual in nature, that occurred more than 24 hours after the last dose of psilocybin. These flashbacks lasted for seconds to minutes and were considered mild in nature [66,71,72,73,74,75,76,77,78].

Clinical Effects

Psilocybin has been evaluated in a number of small prospective studies. The evidence to date suggests that it may be beneficial for some people, although the benefits vary and it is unclear how these benefits compare to standard therapies.

Anxiety

Small studies on the use of psilocybin for anxiety suggest that, when used in combination with psychotherapy, it may reduce symptoms of anxiety in some patients for up to six months when compared with either a niacin placebo or low-dose psilocybin. However, most of this research was not conducted in patients with a specific diagnosis of anxiety at baseline. Rather, patients had anxiety, depression, and/or existential distress related to cancer. These studies used psilocybin 0.2–0.43 mg/kg, provided either as one or two doses [71,73,79,80,117].

Depression

Evidence Based Practice Recommendation

According to the U.S. Department of Veterans Affairs, psilocybin-assisted psychotherapy may reduce depression severity and lead to sustained remission for some participants at 12 months compared to wait list controls, but these benefits were not observed when psilocybin-assisted psychotherapy was compared to intensive psychotherapy and daily escitalopram.

https://www.hsrd.research.va.gov/publications/esp/psychedelics-mh-brief.pdf

Last Accessed: June 16, 2023

Level of Evidence: Low

The largest study conducted to date enrolled 59 patients and compared psilocybin 25 mg, taken as two separate doses three weeks apart, to escitalopram 20 mg daily for six weeks. The patients in this study were also receiving psychological support. The study found that psilocybin and escitalopram were equally effective for reducing symptoms of depression. Additionally, 57% of patients taking psilocybin achieved remission, compared with 28% of those taking escitalopram. However, it is unclear if these effects persisted beyond the six-week time period [81].

Small clinical studies also indicate that taking psilocybin as an adjunct to psychotherapy reduces symptoms of depression in some patients for up to 12 months when compared to baseline, delayed treatment, niacin placebo, or low-dose psilocybin. However, most of this research was not conducted in patients with a specific diagnosis of depression. Rather, patients had anxiety, depression, and/or existential distress related to cancer. Psilocybin was given as a single dose of 0.2–0.43 mg/kg or 10 mg and 25 mg given seven days apart [71,73,79,80,82,83,84,85,117,118].

Substance Use Disorder

There is significant interest in the use of psilocybin as a treatment for various forms of addiction and substance use disorder, including alcohol, tobacco, and opioids. Clinical research in this area is very limited and has mostly involved small, uncontrolled exploratory studies.

The highest quality study to date was conducted in patients with alcohol dependence. This study, which enrolled 93 patients, suggests that psilocybin may be modestly beneficial for further reducing alcohol intake when compared with diphenhydramine. However, it did not increase rates of total abstinence, and it is unclear if it would be beneficial in patients with more severe alcohol use disorder. In this study, psilocybin was provided as a single dose of 25 mg per 70 kg in the fourth week and a single dose of 25–40 mg per 70 kg in the eighth week [86].

Other Uses

There has also been some early research on the use of psilocybin for a variety of other mental health conditions, including demoralization and obsessive-compulsive disorder, as well as for the general improvement of psychological well-being. However, the available research is limited and inconclusive.

Safety

The use of nonstandardized psilocybin mushrooms has been associated with multiple cases of toxicity. For example, seizures, myocardial infarction, and acute kidney failure have been reported in some patients [11,87,88].

There is also a growing body of literature on the adverse effects of purified psilocybin. Most clinical research agrees that the most common side effects noted at therapeutic doses are headache, nausea, anxiety, and transient elevations in blood pressure and heart rate. The increases in heart rate and blood pressure seem to peak at about two hours and last for approximately six hours after use [73,86]. Unlike iboga, psilocybin has not been associated with QT interval prolongation [73,89].

Headaches associated with psilocybin are typically mild to moderate in nature. They have most often been reported to start about seven hours after psilocybin use and last for one to two days [71,72,79,83,84,118].

The experience with psilocybin may be patient-dependent and may also be strongly influenced by environment. Some patients in clinical trials have reported experiencing fear, paranoia, anxiety, emotional disorder, and affect lability [76,78,88,90]. These symptoms are generally mild to moderate. However, some patients have also reported experiencing severe anxiety that lasted days to weeks [78,91].

Similarly, some patients responding to surveys have noted a reduction in feelings of well-being, and while some people have had a remission of suicidal ideation, some have experienced a worsening of suicidality [92]. It should be noted that many patients in these trials had underlying depression or anxiety, potentially confounding these findings.

There is very limited information available on the safety of microdosing, an increasingly popular method of administration for psilocybin. A survey of 278 individuals who reported microdosing found that physiological discomfort, including visions, numbness, temperature dysregulation, insomnia, headaches, and gastrointestinal issues, were reported by 18% of people. Impaired focus and cognition, excessive or inadequate energy, increased anxiety, and worsening mood were reported in 2.3% to 8.8% of respondents. However, these were all subjective, anecdotal reports, and some patients were also microdosing with LSD [12].

Interactions

Psilocybin should be used with caution in patients taking serotonergic drugs. Psilocybin has known serotonergic activity and may increase the risk for serotonin syndrome. Additionally, psilocybin has demonstrated stimulant activity in the CNS and should be used with caution in patients taking CNS stimulants.

Summary

Growing research on the use of psilocybin for various mental disorders is encouraging, although findings suggest a more modest benefit than what is often touted in mainstream news. It is important to remember that studies on psilocybin are at risk for response expectancy and that, to date, no studies have identified a method for adequate blinding.

Additionally, psilocybin has consistently been studied in conjunction with psychotherapy and provided to patients in a controlled, pleasant environment. Administering psilocybin in this environment allows the patient to be monitored for serious adverse effects and elevations in blood pressure and heart rate. It also provides a positive environment that can influence the psychedelic experience. This context should be kept in mind when interpreting the research.

PEYOTE (MESCALINE)

Peyote (Lophophora williamsii) is a type of cactus that grows in dry, desert regions of Mexico and Texas. Certain parts of the cactus have been used traditionally in rituals and recreationally as a hallucinogen [64,93,94,95].

Most often, the disc-shaped buttons found on the cactus crown are sliced and dried. The dried buttons can either be chewed or soaked in water to make a tea. The psychoactive effects of peyote are attributed to the chemical mescaline [93]. The entire plant is considered a Schedule I controlled substance by the DEA, although this designation does not apply to the use of this plant in religious ceremonies conducted by the Native American Church [64,121].

Mechanism of Action

Mescaline has known sympathomimetic and hallucinogenic activity that is similar in nature to LSD. However, mescaline is known to be much less potent than LSD. Its effects typically occur within 1 hour of ingestion, peak within about 4 to 6 hours, and seem to last for approximately 12 hours [93].

Clinical Effects

Unlike many other psychedelic plants with a long history of ritualistic use, peyote has not gained much traction as a potential therapeutic agent. To date, there is no clinical research evaluating its use for any medical purpose.

Safety

The most commonly reported adverse effects with peyote are nausea, vomiting, and diarrhea. These effects typically occur within 30 to 60 minutes of ingestion. It has also been reported to cause mydriasis, sweating, tremor, and elevations in blood pressure and heart rate within one hour after ingestion [95,96].

The hallucinations that occur with peyote have also been associated with anxiety, paranoia, fear, and emotional instability that has the potential to lead to self-inflicted or accidental injury [95,97,98].

Mescaline, the major active constituent of peyote, has been reported to cause respiratory depression when used in large doses (20 mg/kg or more) and, rarely, death. Most symptoms seen with mescaline subside within 24 hours of use [95,96].

Summary

There is no known medical use for peyote. Its recreational use can be associated with unpleasant experiences and serious adverse effects. It should not be recommended for any medical purpose.

SALVIA DIVINORUM (SALVINORIN A)

Salvia divinorum, which is sometimes referred to as diviner's mint or diviner's sage, is a plant native to central Mexico. It has traditionally been used in rituals by the Mazatec people in Oaxaca, Mexico. However, it is also popular as a recreational psychedelic [29,99,100,101].

The leaves are the part of the plant used for hallucinogenic purposes. They are chewed and swallowed, chewed and sucked on, brewed into a tea, or smoked. The chemical thought to be responsible for its psychedelic effects is salvinorin A, which is also called divinorin A. Ingestion of this plant is reported to cause auditory, visual, tactile, and kinesthetic hallucinations [29,99,100,101]. Although the growth and use of this plant is prohibited in some countries, it can be grown legally in some parts of the United States. As of 2023, it is considered a drug of concern by the DEA and in Canada.

Mechanism of Action

Salvinorin A is thought to cause hallucinations through activity at the kappa-opioid receptor. In contrast to many other natural psychedelic chemicals, salvinorin A does not seem to have activity at mu- or delta-opioid receptors, nor have any effect on serotonin, dopamine, or monoamine oxidase [101,102,103,104,105].

The onset of hallucinogenic effects occurs within 5 to 10 minutes of chewing on the leaves or within 10 seconds of inhaling the leaves. The effects seem to last for about one hour after chewing or about 20 to 45 minutes after inhalation. However, the duration of effect may be dose-dependent [29,100,106].

Clinical Effects

Despite some interest in the use of salvinorin A for the treatment of depression and substance use disorders, there is no clinical research evaluating either the whole plant or the chemical for this purpose.

One small, exploratory study in adults with a history of hallucinogen use shows that inhaling salvinorin A can affect the brain default mode network. This refers to the parts of the brain that are more active during passive tasks, as opposed to tasks that require direct attention. However, research in animals undergoing alcohol withdrawal found no benefit with salvinorin A [106,107]. To date, it is unclear whether Salvia divinorum or salvinorin A may be beneficial for any therapeutic purposes.

Safety

Ingestion of Salvia divinorum has been reported to cause headache, restlessness, hyperactivity, disorientation, loss of coordination, dizziness, slurred speech, and fatigue [99,100,101,103,108]. Some people also report feelings of severe anxiety, fear, and panic with the use of this plant, and it has been associated with reports of both acute and chronic psychotic episodes [101,108,109].

Summary

Although there is interest in the use of Salvia divinorum for medical purposes, there is no clinical research to support its use for any indication. It should not be recommended for any medical use.

6. CONCLUSION

Although a number of psychedelic plants have a long history of use for various purposes, only some of these substances have been pursued as potential therapeutic agents. Regardless of whether a specific substance has been evaluated for therapeutic use, recreational use persists, and healthcare professionals should have a general understanding for potential risks and benefits.

Due to natural variation in chemical concentrations within a given plant, which often depend on time of year, growing conditions, and processing methods, the form of the natural psychedelic will impact its safety and efficacy. When natural psychedelics are studied as therapeutic agents, researchers utilize the purified chemical responsible for the psychedelic effect. The use of whole plants will not necessarily mirror the outcomes reported with purified chemicals in clinical research.

In general, natural psychedelics are associated with self-limiting adverse effects, including transient increases in blood pressure and heart rate, headache, mydriasis, sweating, and tremors. Although specific effects vary by chemical and plant, most adverse and hallucinogenic effects resolve within 6 to 12 hours of use. Although most patients report a positive experience, some patients (particularly those with pre-existing psychosis or a risk for psychotic episodes) do report a worsening of mental state and mental health issues after use; patients should be made aware of this risk.

Some natural psychedelics can also cause very severe adverse effects. In some cases, they have been associated with reports of death. However, just as anecdotal reports of benefit should be interpreted with caution, case reports connecting serious adverse effects and death to a specific substance must also be interpreted with caution.

The true benefits of some of these chemicals remain unclear, even those that have been the subject of higher-quality research, such as psilocybin. Methodological limitations, including inadequate blinding and controlling for response expectancy, continue to hamper the production of high-quality, reproducible research. Additionally, the legal status of many of these substances limits the widespread evaluation of their clinical use.

As additional research is published, the place in therapy, if any, for these substances will become clearer. As this research receives attention from media and patients, healthcare professionals should critically evaluate any claims and consider the unique research limitations with these substances.

Works Cited

1. Marks M, Cohen IG. Psychedelic therapy: a roadmap for wider acceptance and utilization. Nat Med. 2021;27(10):1669-1671.

2. Alcohol and Drug Foundation (ADF). Dissociatives. Available at https://adf.org.au/drug-facts/dissociatives/. Last accessed June 13, 2023.

3. Adams JD Jr, Garcia C. Spirit, mind and body in Chumash healing. Evid Based Complement Alternat Med. 2005;2(4):459-463.

4. Evans WC, Woolley JG. The alkaloids of Datura meteloides D.C. J Chem Soc Perkin1. 1965;4936-4939.

5. De Gregorio D, Aguilar-Valles A, Preller KH, et al. Hallucinogens in mental health: preclinical and clinical studies on LSD, psilocybin, MDMA, and ketamine. J Neurosci. 2021;41(5):891-900.

6. US Food and Drug Administration (FDA). Breakthrough Therapy. Available at https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy. Last accessed June 13, 2023.

7. Oregon Health Authority (OHA). Oregon Psilocybin Services. Available at https://www.oregon.gov/oha/ph/preventionwellness/pages/oregon-psilocybin-services.aspx. Last accessed June 13, 2023.

8. Muthukumaraswamy SD, Forsyth A, Lumley T. Blinding and expectancy confounds in psychedelic randomized controlled trials. Expert Rev Clin Pharmacol. 2021;14(9):1133-1152.

9. Rosenbaum D, Weissman C, Anderson T, et al. Microdosing psychedelics: demographics, practices, and psychiatric comorbidities.J Psychopharmacol. 2020;34(6):612-622.

10. Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology. 2018;142:143-166.

11. Borowiak KS, Ciechanowski K, Waloszczyk P. Psilocybin mushroom (Psilocybe semilanceata) intoxication with myocardial infarction.J Toxicol Clin Toxicol. 1998;36(1-2):47-49.

12. Anderson T, Petranker R, Christopher A, et al. Psychedelic microdosing benefits and challenges: an empirical codebook. Harm Reduct J. 2019;16(1):43.

13. Cavanna F, Muller S, de la Fuente LA, et al. Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study.Transl Psychiatry. 2022;12(1):307.

14. Dos Santos RG, Osório FL, Crippa JAS, Riba J, Zuardi AW, Hallak JEC. Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years.Ther Adv Psychopharmacol. 2016;6(3):193-213.

15. Schenberg EE. Ayahuasca and cancer treatment. SAGE Open Med. 2013;1:2050312113508389.

16. Pomilio AB, Vitale AA, Ciprian-Ollivier J, Cetkovich-Bakmas M, Gómez R, Vázquez G. Ayahoasca: an experimental psychosis that mirrors the transmethylation hypothesis of schizophrenia. J Ethnopharmacol. 1999;65(1):29-51.

17. Barbosa PCR, Mizumoto S, Bogenschutz MP, Strassman RJ. Health status of ayahuasca users. Drug Test Anal. 2012;4(7-8):601-609.

18. Lesiak AD, Musah RA. Application of ambient ionization high resolution mass spectrometry to determination of the botanical provenance of the constituents of psychoactive drug mixtures. Forensic Sci Int. 2016;266:271-280.

19. González D, Cantillo J, Pérez I, et al. Therapeutic potential of ayahuasca in grief: a prospective, observational study. Psychopharmacology (Berl). 2020;237(4):1171-1182.

20. Ona G, Kohek M, Massaguer T, et al. Ayahuasca and public health: health status, psychosocial well-being, lifestyle, and coping strategies in a large sample of ritual ayahuasca users. J Psychoactive Drugs. 2019;51(2):135-145.

21. Riba J, Rodríguez-Fornells A, Urbano G, et al. Subjective effects and tolerability of the South American psychoactive beverage ayahuasca in healthy volunteers. Psychopharmacology (Berl). 2001;154(1):85-95.

22. Uthaug MV, van Oorsouw K, Kuypers KPC, et al. Sub-acute and long-term effects of ayahuasca on affect and cognitive thinking style and their association with ego dissolution. Psychopharmacology (Berl). 2018;235(10):2979-2989.

23. Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655-663.

24. Kaasik H, Souza RCZ, Zandonadi FS, Tófoli LF, Sussulini A. Chemical composition of traditional and analog ayahuasca. J Psychoactive Drugs. 2021;53(1):65-75.

25. dos Santos RG. A critical evaluation of reports associating ayahuasca with life-threatening adverse reactions. J Psychoactive Drugs. 2013;45(2):179-188.

26. Sanches RF, de Lima Osório F, Dos Santos RG, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J Clin Psychopharmacol. 2016;36(1):77-81.

27. Osório F de L, Sanches RF, Macedo LR, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015;37(1):13-20.

28. Thomas G, Lucas P, Capler NR, Tupper KW, Martin G. Ayahuasca-assisted therapy for addiction: results from a preliminary observational study in Canada. Curr Drug Abuse Rev. 2013;6(1):30-42.

29. Siebert DJ. Salvia divinorum and salvinorin A: new pharmacologic findings. J Ethnopharmacol. 1994;43(1):53-56.

30. Mello SM, Soubhia PC, Silveira G, et al. Effect of ritualistic consumption of ayahuasca on hepatic function in chronic users.J Psychoactive Drugs. 2019;51(1):3-11.

31. Dos Santos RG, Osório F de L, Rocha JM, et al. Ayahuasca improves self-perception of speech performance in subjects with social anxiety disorder: a pilot, proof-of-concept, randomized, placebo-controlled trial. J Clin Psychopharmacol. 2021;41(5):540-550.

32. Dos Santos RG, Grasa E, Valle M, et al. Pharmacology of ayahuasca administered in two repeated doses. Psychopharmacology (Berl). 2012;219(4):1039-1053.

33. dos Santos RG. Safety and side effects of ayahuasca in humans--an overview focusing on developmental toxicology. J Psychoactive Drugs. 2013;45(1):68-78.

34. Sklerov J, Levine B, Moore KA, King T, Fowler D. A fatal intoxication following the ingestion of 5-methoxy-N,N-dimethyltryptamine in an ayahuasca preparation. J Anal Toxicol. 2005;29(8):838-841.

35. Palma-Álvarez RF, Grau-López L, Ros-Cucurull E, et al. Psychosis induced by abuse of ayahuasca: a case report. Rev Colomb Psiquiatr (Engl Ed). 2021;50(1):43-46.

36. Zhao T, He YQ, Wang J, Ding KM, Wang CH, Wang ZT. Inhibition of human cytochrome P450 enzymes 3A4 and 2D6 by β-carboline alkaloids, harmine derivatives. Phytother Res. 2011;25(11):1671-1677.

37. Callaway JC, Grob CS. Ayahuasca preparations and serotonin reuptake inhibitors: a potential combination for severe adverse interactions. J Psychoactive Drugs. 1998;30(4):367-369.

38. Kremer C, Paulke A, Wunder C, Toennes SW. Variable adverse effects in subjects after ingestion of equal doses of Argyreia nervosa seeds. Forensic Sci Int. 2012;214(1-3):e6-e8.

39. López-Giménez JF, González-Maeso J. Hallucinogens and serotonin 5-HT2A receptor-mediated signaling pathways. Curr Top Behav Neurosci. 2018;36:45-73.

40. Paulke A, Kremer C, Wunder C, Wurglics M, Schubert-Zsilavecz M, Toennes SW. Identification of legal highs--ergot alkaloid patterns in two Argyreia nervosa products. Forensic Sci Int. 2014;242:62-71.

41. Al-Assmar SE. The seeds of the Hawaiian baby woodrose are a powerful hallucinogen. Arch Intern Med. 1999;159(17):2090.

42. Shawcross WE. Recreational use of ergoline alkaloid from Argyreia nervosa. J Psychoactive Drugs. 1983;15(4):251-259.

43. Vigor C, Fabre N, Fourasté I, Moulis C. Neoclerodane diterpenoids from Croton eluteria. J Nat Prod. 2002;65(8):1180-1182.

44. Mazoyer C, Carlier J, Boucher A, Péoc'h M, Lemeur C, Gaillard Y. Fatal case of a 27-year-old male after taking iboga in withdrawal treatment: GC-MS/MS determination of ibogaine and ibogamine in iboga roots and postmortem biological material. J Forensic Sci. 2013;58(6):1666-1672.

45. Rodriguez P, Urbanavicius J, Prieto JP, et al. A single administration of the atypical psychedelic ibogaine or its metabolite noribogaine induces an antidepressant-like effect in rats. ACS Chem Neurosci. 2020;11(11):1661-1672.

46. Grogan J, Gerona R, Snow JW, Kao L. Ibogaine consumption with seizure-like episodes, QTc-prolongation, and captured cardiac dysrhythmias. J Emerg Med. 2019;57(4):e99-e104.

47. Steinberg C, Deyell MW. Cardiac arrest after ibogaine intoxication. J Arrhythm. 2018;34(4):455-457.

48. Litjens RPW, Brunt TM. How toxic is ibogaine? Clin Toxicol (Phila). 2016;54(4):297-302.

49. Malcolm BJ, Polanco M, Barsuglia JP. Changes in withdrawal and craving scores in participants undergoing opioid detoxification utilizing ibogaine. J Psychoactive Drugs. 2018;50(3):256-265.

50. Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J. Treatment of acute opioid withdrawal with ibogaine. Am J Addict. 1999;8(3):234-242.

51. Sheppard SG. A preliminary investigation of ibogaine: case reports and recommendations for further study. J Subst Abuse Treat. 1994;11(4):379-385.

52. Noller GE, Frampton CM, Yazar-Klosinski B. Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. Am J Drug Alcohol Abuse. 2018;44(1):37-46.

53. Davis AK, Barsuglia JP, Windham-Herman AM, Lynch M, Polanco M. Subjective effectiveness of ibogaine treatment for problematic opioid consumption: short- and long-term outcomes and current psychological functioning. J Psychedelic Stud. 2017;1(2):65-73.

54. O'Connell CW, Gerona RR, Friesen MW, Ly BT. Internet-purchased ibogaine toxicity confirmed with serum, urine, and product content levels. Am J Emerg Med. 2015;33(7):985.e5-e6.

55. Vlaanderen L, Martial LC, Franssen EJF, van der Voort PHJ, Oosterwerff E, Somsen GA. Cardiac arrest after ibogaine ingestion.Clin Toxicol (Phila). 2014;52(6):642-643.

56. Hoelen DWM, Spiering W, Valk GD. Long-QT syndrome induced by the antiaddiction drug ibogaine. N Engl J Med. 2009;360(3):308-309.

57. Paling FP, Andrews LM, Valk GD, Blom HJ. Life-threatening complications of ibogaine: three case reports. Neth J Med. 2012;70(9):422-424.

58. Pleskovic A, Gorjup V, Brvar M, Kozelj G. Ibogaine-associated ventricular tachyarrhythmias. Clin Toxicol (Phila). 2012;50(2):157.

59. Henstra M, Wong L, Chahbouni A, Swart N, Allaart C, Sombogaard F. Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine. Clin Toxicol (Phila). 2017;55(6):600-602.

60. Knuijver T, Schellekens A, Belgers M, et al. Safety of ibogaine administration in detoxification of opioid dependent individuals: a descriptive open-label observational study. Addiction. 2022;117(1):118-128.

61. Papadodima SA, Dona A, Evaggelakos CI, Goutas N, Athanaselis SA. Ibogaine related sudden death: a case report. J Forensic Leg Med. 2013;20(7):809-811.

62. Meisner JA, Wilcox SR, Richards JB. Ibogaine-associated cardiac arrest and death: case report and review of the literature. Ther Adv Psychopharmacol. 2016;6(2):95-98.

63. Aćimović T, Atanasijević T, Denić K, Lukić V, Popović V, Bogdanović M. Death due to consumption of ibogaine: case report. Forensic Sci Med Pathol. 2021;17(1):126-129.

64. U.S. Drug Enforcement Administration Diversion Control Division. Code of Federal Regulations: §1307.31 Native American Church. Available at https://www.ecfr.gov/current/title-21/chapter-II/part-1307/subject-group-ECFR68c82f2ca866120/section-1307.31. Last accessed June 12, 2023.

65. Glue P, Winter H, Garbe K, et al. Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers. J Clin Pharmacol. 2015;55(6):680-687.

66. Brown RT, Nicholas CR, Cozzi NV, et al. Pharmacokinetics of escalating doses of oral psilocybin in healthy adults. Clin Pharmacokinet. 2017;56(12):1543-1554.

67. Higgins GA, Carroll NK, Brown M, et al. Low doses of psilocybin and ketamine enhance motivation and attention in poor performing rats: evidence for an antidepressant property. Front Pharmacol. 2021;12:640241.

68. Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci U S A. 2021;118(17):e2022489118.

69. Winter JC, Rice KC, Amorosi DJ, Rabin RA. Psilocybin-induced stimulus control in the rat. Pharmacol Biochem Behav. 2007;87(4):472-480.

70. Kometer M, Schmidt A, Bachmann R, Studerus E, Seifritz E, Vollenweider FX. Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors. Biol Psychiatry. 2012;72(11):898-906.

71. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197.

72. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PCR, Strassman RJ. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 2015;29(3):289-299.

73. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer.Arch Gen Psychiatry. 2011;68(1):71-78.

74. Griffiths RR, Johnson MW, Richards WA, et al. Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. J Psychopharmacol. 2018;32(1):49-69.

75. Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl). 2004;172(2):145-156.

76. Bienemann B, Ruschel NS, Campos ML, Negreiros MA, Mograbi DC. Self-reported negative outcomes of psilocybin users: a quantitative textual analysis. PLoS One. 2020;15(2):e0229067.

77. Carbonaro TM, Johnson MW, Griffiths RR. Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan. Psychopharmacology (Berl). 2020;237(8):2293-2304.

78. Anderson BT, Danforth A, Daroff R, et al. Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: an open-label safety and feasibility pilot study. EClinicalMedicine. 2020;27:100538.

79. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12):1165-1180.

80. Vargas AS, Luís Â, Barroso M, Gallardo E, Pereira L. Psilocybin as a new approach to treat depression and anxiety in the context of life-threatening diseases-a systematic review and meta-analysis of clinical trials. Biomedicines. 2020;8(9):331.

81. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402-1411.

82. Carhart-Harris RL, Roseman L, Bolstridge M, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep. 2017;7(1):13187.

83. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619-627.

84. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489.

85. Gukasyan N, Davis AK, Barrett FS, et al. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: prospective 12-month follow-up. J Psychopharmacol. 2022;36(2):151-158.

86. Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. JAMA Psychiatry. 2022;79(10):953-962.

87. Bickel M, Ditting T, Watz H, et al. Severe rhabdomyolysis, acute renal failure and posterior encephalopathy after "magic mushroom" abuse. Eur J Emerg Med. 2005;12(6):306-308.

88. van Poorten JF, Stienstra R, Dworacek B, Moleman P, Rupreht J. Physostigmine reversal of psilocybin intoxication. Anesthesiology. 1982;56(4):313.

89. Dahmane E, Hutson PR, Gobburu JVS. Exposure-response analysis to assess the concentration-QTc relationship of psilocybin/psilocin. Clin Pharmacol Drug Dev. 2021;10(1):78-85.

90. Becker AM, Holze F, Grandinetti T, et al. Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther. 2022;111(4):886-895.

91. Studerus E, Kometer M, Hasler F, Vollenweider FX. Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 2011;25(11):1434-1452.

92. Carbonaro TM, Bradstreet MP, Barrett FS, et al. Survey study of challenging experiences after ingesting psilocybin mushrooms: acute and enduring positive and negative consequences. J Psychopharmacol. 2016;30(12):1268-1278.

93. US Drug Enforcement Administration (DEA). Peyote and Mescaline Drug Fact Sheet. Available at https://www.dea.gov/sites/default/files/2020-06/Peyote%20and%20Mescaline-2020_0.pdf. Last accessed June 14, 2023.

94. Franco-Molina M, Gomez-Flores R, Tamez-Guerra P, Tamez-Guerra R, Castillo-Leon L, Rodríguez-Padilla C. In vitro immunopotentiating properties and tumour cell toxicity induced by Lophophora williamsii (peyote) cactus methanolic extract. Phytother Res. 2003;17(9):1076-1081.

95. Carstairs SD, Cantrell FL. Peyote and mescaline exposures: a 12-year review of a statewide poison center database. Clin Toxicol (Phila). 2010;48(4):350-353.

96. Nolte KB, Zumwalt RE. Fatal peyote ingestion associated with Mallory-Weiss lacerations. West J Med. 1999;170(6):328.

97. Lu BY, Woofter C, Escalona R. A case of prolonged peyote-induced psychosis resolved by sleep. J Clin Psychiatry. 2004;65(10):1433-1434.

98. Pelner L. Peyote cult, mescaline hallucinations, and model psychosis. N Y State J Med. 1967;67(21):2838-2843.

99. Valdés LJ III, Díaz JL, Paul AG. Ethnopharmacology of ska María Pastora (Salvia divinorum, Epling and Játiva-M.). J Ethnopharmacol. 1983;7(3):287-312.

100. Valdés LJ III. Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. J Psychoactive Drugs. 1994;26(3):277-283.

101. El-Khoury J, Sahakian N. The association of Salvia divinorum and psychotic disorders: a review of the literature and case series.J Psychoactive Drugs. 2015;47(4):286-292.

102. Halpern JH. Hallucinogens and dissociative agents naturally growing in the United States. Pharmacol Ther. 2004;102(2):131-138.

103. González D, Riba J, Bouso JC, Gómez-Jarabo G, Barbanoj MJ. Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug Alcohol Depend. 2006;85(2):157-162.

104. Roth BL, Baner K, Westkaemper R, et al. Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proc Natl Acad Sci U S A. 2002;99(18):11934-11939.

105. Butelman ER, Harris TJ, Kreek MJ. The plant-derived hallucinogen, salvinorin A, produces kappa-opioid agonist-like discriminative effects in rhesus monkeys. Psychopharmacology (Berl). 2004;172(2):220-224.

106. Doss MK, May DG, Johnson MW, et al. The acute effects of the atypical dissociative hallucinogen Salvinorin A on functional connectivity in the human brain. Sci Rep. 2020;10(1):16392.

107. Vázquez-León P, Arenas-Martínez U, Córdova-Maqueda D, Fregoso-Aguilar T, Ramírez-San Juan E, Miranda-Páez A. Salvia divinorum increases alcohol intake and tonic immobility whilst decreasing food intake in Wistar rats. Acta Neurobiol Exp (Wars). 2021;81(1):34-42.

108. Addy PH, Garcia-Romeu A, Metzger M, Wade J. The subjective experience of acute, experimentally-induced Salvia divinorum inebriation. J Psychopharmacol. 2015;29(4):426-435.

109. Bücheler R, Gleiter CH, Schwoerer P, Gaertner I. Use of nonprohibited hallucinogenic plants: increasing relevance for public health? A case report and literature review on the consumption of Salvia divinorum (Diviner's Sage). Pharmacopsychiatry. 2005;38(1):1-5.

110. Gómez-Sousa M, Jiménez-Garrido DF, Ona G, et al. Acute psychological adverse reactions in first-time ritual ayahuasca users: a prospective case series. J Clin Psychopharmacol. 2021;41(2):163-171.

111. Gertsch JH, Wood C. Case report: an ingestion of Hawaiian baby woodrose seeds associated with acute psychosis. Hawaii Med J. 2003;62(6):127, 129.

112. Paulke A, Kremer C, Wunder C, Toennes SW. Analysis of lysergic acid amide in human serum and urine after ingestion of Argyreia nervosa seeds. Anal Bioanal Chem. 2012;404(2):531-538.

113. Schenberg EE, de Castro Comis MA, Chaves BR, da Silveira DX. Treating drug dependence with the aid of ibogaine: a retrospective study. J Psychopharmacol. 2014;28(11):993-1000.

114. Asua I. Growing menace of ibogaine toxicity. Br J Anaesth. 2013;111(6):1029-1030.

115. Alper KR, Stajić M, Gill JR. Fatalities temporally associated with the ingestion of ibogaine. J Forensic Sci. 2012;57(2):398-412.

116. Preller KH, Duerler P, Burt JB, et al. Psilocybin induces time-dependent changes in global functional connectivity. Biol Psychiatry. 2020;88(2):197-207.

117. Goldberg SB, Pace BT, Nicholas CR, Raison CL, Hutson PR. The experimental effects of psilocybin on symptoms of anxiety and depression: a meta-analysis. Psychiatry Res. 2020;284:112749.

118. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018;235(2):399-408.

119. Schlag AK, Aday J, Salam I, Neill JC, Nutt DJ. Adverse effects of psychedelics: from anecdotes and misinformation to systematic science. J Psychopharmacol. 2022;36(3):258-272.

120. Uthaug MV, Mason NL, Toennes SW, et al. A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats. Psychopharmacology (Berl). 2021;238(7):1899-1910.

121. U.S. Drug Enforcement Administration. Drug Scheduling. Available at https://www.dea.gov/drug-information/drug-scheduling. Last accessed June 15, 2023.

Evidence-Based Practice Recommendations Citations

1. U.S. Department of Veterans Affairs. Evidence Brief: Psychedelic Medications for Mental Health and Substance Use Disorders. Washington, DC: U.S. Government Printing Office; 2022. Available at https://www.hsrd.research.va.gov/publications/esp/psychedelics-mh-brief.pdf. Last accessed June 16, 2023.

98120 • Diets and Dietary Approaches to Weight Loss

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

The most important consideration for a patient that is attempting to lose weight is the long-term sustainability of the diet for that specific individual. Although some of the diets discussed here might produce impressive results initially, extreme diets in any form do not usually work long-term. The most effective diets are those that people can live with day in and day out for the rest of their lives. This course will outline various approaches to diets and dietary modifications, with a focus on the impact of these approaches on weight.

Table of Contents

98120 • Diets and Dietary Approaches to Weight Loss

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. OVERVIEW

BACKGROUND

DEFINING OVERWEIGHT AND OBESITY

COMPLICATIONS

2. DIETING AND DIETARY PATTERNS

OVERVIEW

DIETARY GUIDELINES

DIETARY STRATEGIES

3. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98120 • Diets and Dietary Approaches to Weight Loss

Education Category. Alternative Medicine

Release Date. 08/01/2024

Expiration Date. 07/31/2027

Course Overview

The most important consideration for a patient that is attempting to lose weight is the long-term sustainability of the diet for that specific individual. Although some of the diets discussed here might produce impressive results initially, extreme diets in any form do not usually work long-term. The most effective diets are those that people can live with day in and day out for the rest of their lives. This course will outline various approaches to diets and dietary modifications, with a focus on the impact of these approaches on weight.

Audience

This course is designed for for all physicians, nurses, and allied professionals involved in the care of patients who are interested in exploring dietary options to weight control.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 4 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 4 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 4 ANCC contact hour(s). NetCE designates this continuing education activity for 4.8 hours for Alabama nurses. NetCE designates this activity for 4 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-032-H04-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 4 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 0.4 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide healthcare professionals in all practice settings the knowledge necessary to counsel patients regarding diets and dietary approaches to weight management.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the risk factors for and complications of overweight and obesity.

2. Compare and contrast the evidence associated with popular dietary strategies for weight loss.

3. Discuss the possible benefits and risks of plant-based diets.

4. Review the benefits and limitations of low-fat and low-carbohydrate diets.

5. Provide counseling points regarding misconceptions with different dietary strategies.

Faculty

Chelsey McIntyre, PharmD, is a clinical pharmacist who specializes in drug information, literature analysis, and medical writing. She earned her Bachelor of Science degree in Genetics from the University of California, Davis. She then went on to complete her PharmD at Creighton University, followed by a clinical residency at the Children’s Hospital of Philadelphia (CHOP). Dr. McIntyre held the position of Drug Information and Policy Development Pharmacist at CHOP until her move to Washington state in 2017, after which she spent the next six years as a clinical editor for Natural Medicines, a clinical reference database focused on natural products and alternative therapies. She continues to create rigorous professional analysis and patient education materials for various publications while also practicing as a hospital pharmacist. Her professional interests include provider and patient education, as well as the application of evidence-based research to patient care.

Faculty Disclosure

Contributing faculty, Chelsey McIntyre, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. OVERVIEW

BACKGROUND

Obesity is an epidemic in North America, particularly in the United States. An estimated 74% of adults in the United States are considered to be overweight, and approximately 42% are obese. The prevalence of obesity is highest among Black adults (50%) and Hispanic adults (46%), followed by White adults (41%), and Asian adults (16%). Additionally, approximately 32% of children and adolescents in the United States are considered to be overweight, and about 20% are obese [1].

Obesity is not limited to only the United States. Recent worldwide obesity rates have more than doubled from what they were in 1980. In 2016, approximately 39% of the world's adult population was overweight, and 13% was obese. Furthermore, a majority of the world's current population lives in countries in which obesity causes more deaths than being underweight [2].

Why are so many people becoming overweight? There are several explanations, but the most common reason for obesity is related to consuming more calories than the number of calories burned. This is primarily due to unhealthy eating behaviors and a lack of physical activity, both of which may be the result of environmental and socioeconomic factors that can limit access to healthy, whole foods and safe places to exercise [3].

Due to occupational and societal changes, physical activity has decreased dramatically. Many Americans engage in less than 30 minutes of exercise per week. Other factors of modern life, including sprawling cities and suburbs requiring motorized transportation, video games, computers, escalators, and elevators, also decrease physical activity. For many people, a lack of time is considered a barrier to physical activity, as is a lack of energy or motivation [5]. Americans also have unprecedented access to affordable food options, which may come in the form of prepared foods or eating out, both of which are known to increase overall calorie intake [4].

Although increased intake of calories and decreased physical activity are the two most common reasons for obesity, other factors may contribute. Genetics and family history can affect a person's weight. Also, health conditions, such as hypothyroidism, Cushing syndrome, and polycystic ovarian syndrome (PCOS), may cause a person to become overweight. In addition, some medications, certain emotional factors, smoking cessation, aging, pregnancy, and lack of sleep can contribute to weight gain [3].

DEFINING OVERWEIGHT AND OBESITY

The World Health Organization (WHO) codified the body mass index (BMI) as a screening index for obesity in 1995. Although it is an imperfect measure, BMI, which is calculated using height and weight, is the most widely used screening tool for overweight and obesity (Table 1). Although BMI does not measure body fat directly, it has been moderately correlated with more direct measures of body fat. It is also strongly correlated with specific adverse health outcomes, including development of diabetes, hypertension, heart disease, stroke, and other conditions [1].

Table 1: BMI DEFINITIONS OF WEIGHT

Weight Category

BMI Definition (kg/m^2)

Adult

Adult, East Asian

Pediatrica

Underweight

<18.5

<18.5

<5th percentile

Normal

18.5–24.9

18.5–22.9

5th–85th percentile

Overweight

25–29.9

23–24.9

≥85th percentile

Class I obesity

30–34.9

25–29.9

Obesity: ≥95th percentile

Class II obesity

35–39.9

30–34.9

Class III obesity (severe obesity)

≥40

≥35

Severe obesity: ≥120% of the 95th percentile

aBased on sex-specific BMI for age

Source: [89,90,91]

BMI is a fast and easy measure with a significant limitation—it estimates body fat based on excess weight. This means that it does not distinguish between excess weight due to fat, muscle, or bone mass. Consequently, BMI calculations may overestimate body fat in muscular individuals or underestimate body fat in people who have lost muscle. As a result, a fit, muscular person may have a BMI that suggests obesity, when that is clearly not the case. Also, an elderly person who has lost significant lean muscle may have a "normal" BMI despite having a very high body fat content.

Because of this limitation, many experts recommend using BMI only as a screening tool to identify patients who may need further evaluation. Additional evaluation may include health screenings, family history, and other body composition tests including abdominal circumference, skin fold tests, and body fat measured by biometrical impedance.

In 2023, the AMA adopted a policy that recognizes the issues with BMI measurement (e.g., historical harm, no consideration of gender/ethnicity) and suggests that it be used in conjunction with other valid measures of risk, including but not limited to visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic or metabolic factors [92].

The AMA policy recognizes that [92]:

- BMI is significantly correlated with the amount of fat mass in the general population but loses predictability when applied on an individual level.

- Relative body shape and composition heterogeneity across race and ethnic groups, sexes, genders, and age-span are essential to consider when applying BMI as a measure of adiposity.

- BMI should not be the sole criterion used to deny appropriate insurance reimbursement.

The AMA also modified existing policy on the clinical utility of measuring BMI, body composition, adiposity, and waist circumference to support greater emphasis on education about the risk differences within and between demographic groups.

COMPLICATIONS

Repercussions of the obesity epidemic are already being felt. Obesity increases a person's risk for metabolic syndrome, which in turn increases the risk of type 2 diabetes and cardiovascular disease. Obesity also directly raises the risk of developing diabetes by 10 to 20 times. Patients with poorly managed or uncontrolled type 2 diabetes are at an increased risk for a number of significant health complications, including heart disease, nerve damage, eye problems, and kidney disease [6].

Similarly, obesity is associated with hypertension. Evidence suggests that every 10 kg increase in body weight is associated with a 3 mm Hg increase in systolic and 2.3 mm Hg increase in diastolic blood pressure. Obesity is also associated with dyslipidemia and elevated levels of fibrinogen and C-reactive protein. All of these factors increase the risk of cardiovascular disease, including coronary heart disease, myocardial infarction, and heart failure, as well as stroke and chronic kidney failure [7].

Obesity also increases a person's risk for some less obvious, but equally significant, health complications. Increased weight burden on the body can worsen osteoarthritis and exacerbate respiratory problems, such as obstructive sleep apnea, asthma, and obesity hypoventilation syndrome. It can also damage the gallbladder, due to an increased tendency to develop gallstones, and the liver, through the development of non-alcoholic steatohepatitis (NASH), also known as metabolic-associated steatohepatitis (MASH). Finally, obesity also increases the risk for various forms of cancer [6].

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends offering or referring adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet.

https://jamanetwork.com/journals/jama/fullarticle/2773280

Last Accessed: July 25, 2024

Level of Evidence: B (High certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial)

The good news is that even modest weight loss, such as a 5% to 10% reduction in total body weight, can lead to measurable health benefits. These include improvements in blood glucose levels, cholesterol, and blood pressure levels. Research shows that overweight patients who reduce their weight by 6.8 kg or more lower their long-term risk of hypertension by 21% to 29% [8]. Even if a patient remains overweight or obese after weight loss, their overall risk factors for the chronic diseases associated with obesity will be reduced [9].

Similarly, weight loss can help to relieve symptoms from other obesity-associated conditions, including osteoarthritis and sleep apnea. Weight loss of 5% has been shown to provide some relief in patients with osteoarthritis, and weight loss of 10% can provide a significant reduction in pain. Most research also shows that this level of weight loss improves overall quality of life [9].

2. DIETING AND DIETARY PATTERNS

OVERVIEW

Dieting has become so common in the United States that it has been referred to as a national pastime. Each year, approximately 50% of adults younger than 50 years of age report following a diet, with the majority of people pursuing that diet in an effort to either lose weight or improve overall health.

Since 2020, the nation's perceptions of obesity and diet have begun to change. Surveys suggest that many adults are interested in focusing on healthier behaviors in place of specific weight-loss goals and are following a diet or dietary pattern for this purpose. Many adults report dieting for other health-related reasons as well—37% for increased energy, 29% for digestive health, 28% for cardiovascular health, and 26% for better sleep [10].

Interestingly, younger generations may be driving some of these changes. Adults 18 to 24 years of age report pursuing healthier eating strategies for the purpose of improving mental health, the only age group to include this in the top three reasons for dieting. Additionally, more than 70% of adults 40 years and younger report considering the environment when choosing foods, making them more likely to choose products labeled as "carbon neutral" or "plant-based" [10].

In fact, the shift to "plant-based" foods is dramatic, with almost one in three adults reporting that they ate more protein from whole-plant sources in 2022 than the previous year. Additionally, 23% of adults report consuming plant-based dairy alternatives, and 18% report consuming more soy-based milk or yogurt [10].

Although obesity and weight loss continue to be the primary drivers for adults following a diet, it is important for healthcare professionals to understand how widespread the use of dietary patterns has become and to understand the risks and benefits of each of these patterns. Young or otherwise healthy patients may be following dietary patterns that can affect other aspects of their health or quality of life, increasing the importance of having open conversations with patients about their lifestyle choices.

DIETARY GUIDELINES

Before discussing some of the more popular dietary patterns, it is important to understand foundational strategies for healthy eating.

The U.S. government produces dietary guidelines for Americans every five years. In the past, these guidelines have been relatively prescriptive, providing specific recommendations on caloric intake and food groups. In the Dietary Guidelines for Americans, 2020–2025 from the U.S. Department of Health and Human Services (HHS), the government took a more flexible approach to the guideline to produce four key recommendations [11]. These include:

- Follow a healthy dietary pattern at every life stage.

- Customize and enjoy nutrient-dense food and beverage choices to reflect personal preferences, cultural traditions, and budgetary considerations.

- Focus on meeting food group needs with nutrient-dense foods and beverages, and stay within calorie limits.

- Limit foods and beverages higher in added sugars, saturated fats, and sodium, and limit alcoholic beverages.

These guidelines advise watching portion sizes to help reduce calorie intake. This can be done with some simple tools such as using smaller plates or eliminating access to regular snacks. Shifting to healthier, low-, or no-calorie beverage choices is another simple way for patients to initiate long-term calorie reduction. Patients should also focus on creating meals out of multiple food groups to ensure a well-rounded diet and a lower density of caloric intake [11].

The document also provides general guidance on the typical calorie requirements for people of different biological sexes and ages [11]:

19 to 30 years of age:

- Women: 1,800–2,400 calories daily

- Men: 2,400–3,000 calories daily

31 to 59 years of age:

- Women: 1,600–2,200 calories daily

- Men: 2,200–3,000 calories daily

60 years of age and older:

- Women: 1,600–2,000 calories daily

- Men: 2,000–2,400 calories daily

It is important to remember that these calorie needs will vary with each individual based on size, genetics, patient history, typical physical activity, and more. The best approach for sustained, healthy weight loss is to target a caloric intake that is modestly below daily requirements. For most people, this means lowering total daily calorie intake by 500–1,000 kcal. This approach can decrease weight by 8% over 3 to 12 months.

Macronutrients

Although the primary focus of any person trying to consume a healthy diet should be the basic principles outlined by national guidelines, it is also important for patients to understand the different macronutrients that comprise a well-rounded diet: carbohydrates, fat, and protein.

Each of these classes of macronutrients provides calories, and each contributes important molecules for bodily function. Although many popular diets over the past decades have vilified an entire class of macronutrients—most commonly carbohydrates and fats—it is important for patients to understand that each of these groups is crucial to overall healthy eating.

According to the U.S. Dietary Guidelines, a relatively healthy distribution of calories from these macronutrient groups is [11]:

- Carbohydrates: 45% to 65%

- Fats: 25% to 35%

- Protein: 10% to 35%

It is important to note that these ranges are relatively wide, allowing for flexibility between each person, and even between days for the same person, in how they obtain their calories. It is also important to remember that different patients may require different alterations to their diets. For example, very active adults or athletes will require higher protein intake. Adults with impaired glucose intolerance or diabetes may want to target the lower end of carbohydrate intake, with a focus on foods with a lower glycemic index, which will be discussed later in this course.

Unfortunately, the general public does not always understand the importance of each macronutrient to a healthy diet. In fact, in 2022, a survey found that only 25% of Americans believed that all calorie sources contribute to weight gain equally. Approximately 19% of Americans believe that fats are more likely to cause weight gain, a number that has risen over time. Additionally, 22% of adults believe that sugar is more likely to cause weight gain than other calorie sources [10].

In alignment with these misunderstandings, respondents also gravitated toward foods that were labeled as "fresh" or "low in sugar" as a way to identify healthier food options. It is important to dispel misunderstandings from patients that certain macronutrients contribute to weight gain more than others [10].

Fats

Patients should also understand that each of these macronutrients is made up of many subgroups. For instance, fats are an important part of the diet, but not all fats are created equal. Saturated fats are known to be especially bad for cardiovascular health, and the Dietary Guidelines recommend limiting intake to no more than 10% of daily calories [11]. Saturated fats are most commonly found in high-fat meat, full-fat dairy products, and in certain oils, such as butter, coconut oil, and palm oil. Thus, fried foods, which use these oils, tend to be high in saturated fat as well. Replacement oils that are low in saturated fat include canola oil, olive oil, soybean oil, and sunflower oil [11].

Certain fats, called polyunsaturated fats, are important components of cell membranes and contribute to reduced levels of inflammation in the body. These are essential fatty acids and are considered part of a healthy diet. Patients may recognize the types of fats that fall into this class: omega-3 and omega-6 fatty acids. These are found in fish, seeds, nuts, soy, eggs, and many other foods [12].

Carbohydrates

Carbohydrates are also comprised of many subgroups. Sugar itself is not an inherently bad thing for people to eat. In fact, many foods, such as fruit, contain healthy and important sugars. However, added sugars are not the same chemicals as the sugars found in fruit. These added sugars, which may include preservatives or high fructose corn syrup, are added to foods and increase their calorie content dramatically [11].

The Dietary Guidelines recommend keeping added sugars to less than 10% of daily calorie intake, similar to the recommendation for saturated fat. One of the fastest ways for some people to cut added sugars from their diets is to eliminate sugar-sweetened beverages and processed desserts [11].

An important and healthy type of carbohydrate is fiber. The U.S. Food and Drug Administration (FDA) has an established definition for what can be called a dietary fiber on a product label. This definition essentially states that the fiber must be a naturally occurring, nondigestible carbohydrate obtained from plants that has beneficial effects in the body. It is recommended that most adult women consume 25–28 grams of fiber daily, and that most adult men consume 31–34 grams daily [11].

Fiber can be either water-soluble or water-insoluble. Water-soluble fibers, such as oats, beta-glucans, and barley, help to lower both blood glucose and cholesterol levels. Water-insoluble fibers, such as wheat bran and rice bran, help the body digest food and improve bowel health. Each of these fibers can help to slow the absorption of other carbohydrates by the body, resulting in lower blood glucose levels after eating [13].

Proteins

Unlike carbohydrates and fats, there are no subgroups of protein that are considered to be more detrimental to overall health. However, a healthy diet includes the consumption of a variety of different types of protein. Proteins are made up of amino acids, which have many important functions in the body. The body requires 20 different amino acids to function properly, 9 of which must come from food because the body cannot make them on its own [14].

Proteins can be obtained from a wide range of sources, including plants, animals, and animal-derived products. This includes meats, eggs, dairy products, and seafood, as well as nuts, seeds, and soy products. Beans, peas, lentils, and other legumes are also important sources of protein. Consuming fresh or frozen forms of these protein sources as opposed to processed forms (e.g., hot dogs, ham) helps to ensure that these protein sources remain healthy and lower in calories [11].

DIETARY STRATEGIES

For patients looking to lose weight, there is no shortage of strategies that claim to help with this endeavor. Some of these strategies are fad diets, such as those that claim to be the fastest approach, or even a "hack," for weight loss. Other strategies have been around for some time and fall into relatively straightforward categories, such as "low-carbohydrate" and "low-fat." Other strategies, such as the Dietary Approaches to Stop Hypertension (DASH) diet and Mediterranean diet, are supported by evidence.

While the popularity of specific diets tends to wax and wane over the years, clinical research has consistently revealed that most diets that ensure adequate nutritional intake, regardless of the food group that is limited, result in similar weight loss. In other words, overall calorie reduction, as opposed to the specific diet chosen, is the most important factor for weight loss. One large meta-analysis evaluated the effectiveness of different diet programs. After compiling the results from 48 randomized controlled trials, the study found that significant weight loss was observed with all diets, and that the differences between diets were minimal [15].

Similarly, various studies have evaluated the benefits of diets that focus on macronutrient intake. One clinical trial of more than 300 adults with moderate obesity showed that following a Mediterranean diet, low-fat diet, or low-carbohydrate diet for two years results in comparable weight loss [16]. Another prospective clinical study in more than 600 adults with obesity found that following a low-fat or low-carbohydrate diet for one year resulted in comparable weight loss [17]. Finally, a clinical study in more than 800 overweight adults found that diets emphasizing various amounts of fat, protein, or carbohydrate intake in conjunction with calorie reduction all produced similar weight loss [18].

Regardless, it is important for healthcare professionals to understand the different diets that their patients may be considering, whether for weight loss or overall health benefits. There are important considerations with every diet, including understanding nuances related to risks and benefits. It is also helpful to be familiar with the evidence base (or lack thereof) in order to coach patients in identifying the dietary strategy that may best align with their preferences, needs, and risk factors.

Low-Carbohydrate Diets

Some of the most popular diets over the past few decades have focused on reducing carbohydrate intake, such as the Atkins diet, ketogenic diet, and South Beach diet. The premise of these diets is that carbohydrates increase insulin levels and induce metabolic changes that cause weight gain.

It is now understood that different forms of carbohydrates have different effects on blood glucose levels immediately after eating. For instance, research has found that some starchy foods can increase blood glucose as much or more than similar amounts of sucrose. In 1981, the glycemic index was developed to address the effect of foods on blood glucose. The glycemic index rates foods based on how much they raise blood glucose levels in the two hours after they are eaten. Higher glycemic index foods raise glucose levels more than lower glycemic index foods [19].

Low-glycemic index foods, which are digested and absorbed more slowly in the small intestine, are thought to promote weight control by causing a feeling of fullness. They also cause less postprandial insulin secretion, which may delay hunger. This reduction of postprandial glucose levels may also be beneficial in patients with impaired glucose tolerance or diabetes [20].

Not surprisingly, added sugars increase the glycemic index of any food. Whole foods that contain natural sugar, on the other hand, may have a lower glycemic index than some people would expect. For example, many fruits, including apples, bananas, strawberries, and peaches, have relatively low glycemic indices. This is due to the fiber content of these foods. Whole grains, which are primarily comprised of carbohydrates, also have a lower glycemic index due to fiber content. Processed grains, on the other hand, such as white bread, corn flakes, and instant porridge, have a high glycemic index [20].

Based on what we know about glucose levels, consuming more low-glycemic index foods is likely to be considered a healthy dietary choice. However, there is no solid evidence that a low-glycemic diet will reduce weight more than any other diet [21]. It is also important to keep in mind that most people eat meals, not single foods at one time. While a single food may have a low- or high-glycemic index, a meal may combine foods of a variety of types, which alters the way that the body breaks down and absorbs the nutrients from each food item.

The Atkins Diet

The Atkins diet is a high-fat, low-carbohydrate diet that does not utilize the glycemic index [22]. This diet follows four distinct phases, starting with very restrictive limitations on carbohydrate consumption and slowly allowing for increased intake as weight loss progresses. The initial, highly restrictive phase limits carbohydrate consumption to 20 grams per day and is intended to cause rapid weight loss. After this phase, weight loss occurs more slowly and the quantity of carbohydrates consumed increases in increments. The final phase, or lifetime maintenance, is intended to achieve a diet with a carbohydrate equilibrium that results in maintaining the target weight [23].

The Atkins diet seems to cause more short-term weight loss than a traditional low-fat diet. But at the end of one year, weight loss is similar to conventional low-fat diets [21,24,25]. Some experts suggest that Atkins and similar diets could have a beneficial role for jumpstarting weight loss, before switching to a long-term, more sustainable maintenance diet. However, there does not seem to be a long-term benefit with the Atkins diet when compared with other calorie-restrictive diets.

The South Beach Diet

The South Beach diet is a spin-off of the Atkins diet. Like the Atkins diet, the South Beach diet is a low-carbohydrate diet that consists of multiple phases that restrict carbohydrates significantly at the beginning and then slowly allow for an increase in carbohydrate consumption as weight loss progresses. Unlike the Atkins diet, the South Beach diet uses the glycemic index to segregate carbohydrates into "good" and "bad" carbohydrates. Higher glycemic index foods are considered "bad," while lower glycemic index foods are considered "good." Because the South Beach diet allows the consumption of "good" carbs, it is considered more balanced than the Atkins diet [22].

The Ketogenic Diet

The ketogenic diet is a low-carbohydrate diet that requires a relatively high intake of fat and a very low intake of carbohydrates. There are many variations of this diet, including the modified Atkins diet, the medium-chain triglyceride diet, and the low glycemic index diet. All of these variations rely on the same basic concept of forcing the body into a state of ketosis. When glucose is unavailable to the brain as an energy source, the liver produces ketone bodies from fat. This is thought to result in the reduction of fat stores [26,27,28].

Some proponents of the Atkins diet claim that it also induces ketosis. However, the ketogenic diet typically requires carbohydrate intake of less than 20 grams per day, which is stricter than the strictest phase of the Atkins diet [23]. Additionally, unlike the Atkins or South Beach diets, most forms of the ketogenic diet require consistent, long-term maintenance of severe carbohydrate restriction. Due to the lack of a gradual, multi-step approach to carbohydrate reduction, long-term adherence to this diet may be difficult.

Most research on the ketogenic diet, though low quality, shows that it can help to reduce weight in overweight or obese adults. In fact, severely restricting carbohydrate intake to less than 20 grams daily for 24 to 56 weeks can reduce body weight by 10% to 30% when compared with baseline [29,30]. However, this research also shows that the greatest weight loss is achieved at 24 to 36 weeks, followed by slight weight gain [29]. Furthermore, a meta-analysis of clinical research comparing the ketogenic diet with low-fat diets found that the ketogenic diet resulted in less than 1 kg of additional weight loss [31].

Safety

Although these diets seem to be safe when used for up to one year, their safety in the long-term is less clear, particularly in relation to the ketogenic diet. Most clinical studies of these diets have not lasted longer than one year, and adherence rates at that point in time are also relatively low. Limited observational research has found that consuming carbohydrates as 39% or less of total daily calorie intake is associated with a higher risk of mortality when compared with higher intakes of carbohydrates. The lowest risk of mortality is associated with a carbohydrate intake of 50% or 55% [32,33,34].

It is important to note that a low-carbohydrate diet that consists of high amounts of saturated fat and nutrient-poor foods can negatively impact health outcomes in the long-term. As with any diet, the consumption of varied, nutrient-rich foods should be encouraged.

To capitalize on the low-carbohydrate craze, food manufacturers and many restaurants often offer low-carbohydrate versions of everything from ketchup to beer. Unlike "low-fat," the FDA has not published a definition of "low-carbohydrate." Statements on food labels such as "reduced carbohydrate" or "low-carb" are not based on any formalized standard [35].

Some labels list only "net carbs" or "effective carbs." These are terms used to define the portion of total carbohydrates that affect post-consumption blood sugar levels. Listing "net carbs" makes carbohydrate contents appear lower by excluding ingredients like fiber and sweeteners such as maltitol, lactitol, or sucralose. Patients should be advised to read labels closely and look at calories, not just carbohydrates. Foods labeled "low-carb" or low in "net carbs" may actually have a higher calorie content [35].

Low-Fat Diets

Low-fat diets such as the Pritikin diet and the Ornish diet were once very popular but have become less so in recent years. This may, in part, be due to the fact that low-fat diets are notoriously difficult to maintain in the long-term. The Ornish diet allows only 10% of calories per day from fat [36]. However, these diets do allow and encourage fruits and vegetables, which are excluded or minimized in low-carbohydrate diets. Like other diets, low-fat diets can aid in weight loss, likely due to overall caloric restriction [37].

Low-fat diets are often recommended for improving outcomes in heart disease. An older clinical study found that following the Ornish diet in addition to exercise for up to five years decreases cardiac events, including myocardial infarction, coronary angioplasty, coronary artery bypass surgery, heart-related hospitalizations, and heart-related deaths in patients with coronary atherosclerosis [38]. However, a low-fat diet alone may not be effective for reducing the risk for heart disease. In fact, a large, long-term clinical trial enrolling more than 48,000 postmenopausal adults found that a diet containing less than 20% of calories from fat did not reduce the risk of heart disease or stroke [39].

Ornish and Pritikin Diets

It is important to keep in mind that the Pritikin and Ornish programs have evolved into much more than just diets. These programs now include overarching lifestyle modifications, including exercise, stress management, and smoking cessation. Together, this combination of lifestyle interventions has been shown to improve outcomes in cardiovascular disease. Because of this, the U.S. Medicare program covers the Ornish Program for Reversing Heart Disease and the Pritikin Program for patients requiring intensive cardiac rehabilitation (ICR) following events such as acute myocardial infarction [40,41].

The only other similar intervention program to be covered by Medicare for this purpose is the Benson-Henry Institute Cardiac Wellness Program, which consists of lifestyle intervention in addition to following the American Heart Association (AHA) diet. Unlike the Ornish and Pritikin programs, however, the AHA diet recommends consuming 25% to 35% of total daily calories from fats [42].

Dietary Approaches to Stop Hypertension (DASH) Diet

The DASH diet is a low-fat, low-sodium diet commonly recommended by healthcare professionals. As the name implies, the primary goal of the DASH diet is to lower blood pressure in people with prehypertension or hypertension. A large body of clinical research shows that following the DASH diet lowers systolic blood pressure by about 5–11 mm Hg and diastolic blood pressure by 3–6 mm Hg when compared with a control diet. Improvements can be seen as early as one week after implementing the diet [43,44,45,46].

Some research also shows that the DASH diet may be beneficial for weight loss. A meta-analysis of clinical research shows that adhering to the DASH diet can reduce body weight by about 3 pounds more than a control diet [43]. However, this analysis did not assess weight loss in patients with overweight and obesity separately from patients with normal weight at baseline.

There is currently no research comparing the DASH diet to other diets for the purposes of weight loss. However, in patients with hypertension, the main principles of the DASH diet, including reduced intake of sodium and cholesterol and increased consumption of vegetables, fruits, and low-fat dairy products, should be considered an important part of blood pressure control.

Patients should be advised to be wary of low-fat foods in the grocery store. In order to keep these foods tasty, many low-fat foods contain added sugar. That means many low-fat foods can still be high in calories.

Plant-Based Diets

Plant-based diets are becoming an increasingly popular topic of discussion. As might be expected, there is interest in plant-based diets for the purpose of improving overall health and increasing weight loss. Thanks to significant food science research in this area, some innovative plant-based food products have made this dietary strategy more available and appealing to a broader audience.

Plant-based diets encompass a wide range of dietary strategies:

- Vegan diet: This is the strictest form of a plant-based diet, in which no products originating from animals are consumed.

- Classic vegetarian diet: Also called the lacto-ovo-vegetarian diet, this diet does not allow for meat, fish, or poultry, but does permit eggs and dairy.

- Pesco-vegetarian diet: This diet does not allow for meat or poultry but permits fish and shellfish in the diet.

- Semi-vegetarian or "flexitarian" diet: This dietary pattern allows for limited amounts of meat and poultry in a diet that is otherwise plant- and fish-based.

- Eco-Atkins diet: This is a vegetarian iteration of the Atkins diet. This low-carbohydrate vegan diet contains 26% of calories from carbohydrates, 31% of calories from vegetable proteins, and 43% of calories from vegetable oils.

Evidence for Weight Loss

Some clinical research shows that plant-based diets can result in modest weight loss. Meta-analyses of clinical studies show that following a vegetarian diet for anywhere from one month to one year is associated with a 2–3.4 kg reduction in weight [47,48,49]. Patients following a vegan diet had a greater weight loss when compared with those following a lacto-ovo-vegetarian diet, with a weight loss of 2.5 kg and 1.5 kg, respectively. However, subgroup analyses found that overweight or obese adults had a weight loss of only 2 kg, compared with 2.6 kg in those that were not overweight or obese [47].

Despite the modest weight loss seen in these studies, multiple expert panels agree that a lacto-ovo-vegetarian diet with calorie restriction is one option that can be considered to help overweight or obese individuals lose weight [50]. The benefits of other plant-based diets for weight loss have not been adequately evaluated.

Evidence for General Health Benefits

Research on the health benefits of plant-based diets that are not related to weight loss is growing but limited. A meta-analysis of the available clinical research shows that shifting a diet to contain a higher amount of plant-based proteins in place of red meat-based proteins can modestly reduce total cholesterol and low-density lipoprotein (LDL) cholesterol levels [51]. Some prospective cohort studies have also shown that increased consumption of red meat is associated with higher overall mortality rates when compared with lower consumption [52]. However, meta-analyses of the available observational research suggest that any reduction in overall risks obtained by reducing red meat consumption are likely to be very small [53]. It is not clear how non-red-meat protein sources compare with plant-based proteins.

Additional observational research has found that higher adherence to a plant-based diet reduces cardiovascular mortality by a small amount when compared with low adherence. However, as with all observational dietary research, it is unclear whether this is a causative relationship. People who voluntarily follow a plant-based diet are more likely to be generally healthy, female, and engaged in other healthy practices, such as increased physical activity [54]. Similarly, people who consume large quantities of red and/or processed meats are also more likely to consume diets higher in sugar and saturated fats and to participate in less physical activity [53,55]. This makes it difficult to draw any firm conclusions regarding the health benefits of reducing meat intake or following a plant-based diet.

Notably, population research suggests that people who regularly consume meat are unlikely to eliminate meat from the diet even when confronted with serious health warnings [55]. Considering the likelihood for poor adherence to a plant-based diet in people who regularly consume meat, the current evidence does not support recommending this dietary strategy in this population.

Whole versus Processed Plant Foods

It is important to distinguish between the quality of foods considered "plant-based" in some of the available research. Some studies have shown that the consumption of highly processed foods is associated with excess calorie intake and weight gain [56]. The reduction in cardiovascular risk factors that was seen with increased consumption of plant-based proteins only occurred when those protein sources were considered to be high-quality. These benefits did not occur with increased intake of low-quality carbohydrates [51]. Furthermore, the increase in mortality rates that was seen with increased consumption of red meats was particularly elevated in adults who consumed high quantities of processed red meats, such as hot dogs, sausages, salami, and cured meat. Unprocessed red meat was associated with a 9% increased risk for mortality, while processed red meat was associated with a 13% increased risk [52].

Advances in meat-like plant products, such as Impossible and Beyond meat-replacement products, have contributed to the appeal of plant-based diets. Some of the more popular products include soy protein and pea protein isolates. Some, but not all, of these products are genetically modified to contain heme from soy leghemoglobin, which results in an appearance and texture that mimics real meat [57]. Due to the processing necessary to produce the desired texture and flavor, these products are higher in saturated fats and are also likely to be lower in nutrients and phytochemicals than their fresh, unprocessed counterparts. They are also higher in sodium than red meat products [58].

Although the exact health benefits of a plant-based diet are unclear, patients may be interested in following one of these diets. These patients should be counseled on ensuring that the diet is implemented safely. As with any other diet, patients should be aware of the quality of the foods that they choose to consume. The health benefits of one product might not be the same as the next product, and the benefits of any diet can be lost if most of the selected foods are highly processed. Additionally, it is important to remember that any health benefits that might be gained from a plant-based diet will occur only when nutrient-dense foods are consumed, as opposed to simply avoiding meat. Diets that only avoid meat and contain large quantities of foods that are high in sugar and saturated fats can be detrimental.

Plant-based diets are often motivated by non-health factors, most significantly a wish to avoid harming animals. As noted, plant-based diets are also gaining attention for an entirely different reason: the potential to reduce a person's environmental impact, or "carbon footprint." If a patient is interested in changing their diet for environmental or animal-rights purposes, ensure that they understand the importance of food quality and product selection to avoid negative health impacts with this dietary change.

Safety

Plant-based diets, including vegetarian and vegan diets, are safe when used appropriately. The Academy of Nutrition and Dietetics states that a nutritionally adequate vegetarian diet is appropriate for adults and children. However, it is particularly important to ensure that all nutritional needs are met when following a vegetarian diet. Nutrients of concern may include omega-3 fatty acids, iron, zinc, calcium, vitamin D, and vitamin B12 [59]. In fact, one observational study has found that following a vegetarian diet or vegan diet is associated with lower bone mineral density at the femoral neck and lumbar spine when compared with diets that incorporate animal products [60].

Mediterranean Diet

The Mediterranean diet is a balanced and nutrient-dense diet that originally gained popularity as a preventive measure for cardiovascular disease. It has also gained popularity for reducing the risk of dementia, management of diabetes, and improving overall health. It is a moderate-fat diet that emphasizes consuming large amounts of fruits, vegetables, fish, and whole grains, using olive oil as a fat source, and eating low amounts of dairy, red meat, and refined grains. It also allows for the consumption of wine in low-to-moderate amounts, although some forms of the diet exclude this component [62]. This diet is generally considered to be safe as long as nutritional needs are met.

Weight Loss

There is a growing body of research evaluating the Mediterranean diet for weight loss, although the evidence remains limited and conflicting. One clinical study in adults with obesity showed that following a calorie-reduced Mediterranean diet for 12 months reduced body weight by 3.8 kg and waist circumference by 2.6 cm when compared with following a standard calorie-reduced low-fat diet [63]. However, a separate clinical study in adults with overweight shows that the Mediterranean diet was no more effective than a lacto-ovo-vegetarian diet for weight loss or fat loss when calorie restriction is equivalent [64]. As with the other diets discussed, the Mediterranean diet may simply serve as a healthy option for patients who enjoy fish and whole grains.

Other Indications

Based on a number of observational studies, some experts, including the WHO, recommend the Mediterranean diet for the prevention of dementia in healthy adults [65]. Although observational research suggests that higher adherence to the Mediterranean diet is associated with a reduced risk of cardiovascular events and cardiovascular mortality when compared with lower adherence, it does not seem to be associated with a lower total incidence of cardiovascular disease [66]. Also, results from clinical research indicate that the Mediterranean diet has only modest benefit, if any, for the primary prevention of cardiovascular disease.

A landmark clinical study (the PREDIMED study) found that following the Mediterranean diet for about 4.8 years reduces the rate of major cardiovascular events such as myocardial infarction, stroke, or death from cardiac causes by about 30% when compared with a control diet in patients at high cardiovascular risk. However, this study was later retracted and re-published after the exclusion of multiple study sites that violated the study protocol [67]. When clinical endpoints were analyzed separately, the Mediterranean diet was found to reduce the risk of stroke by 40%, with no significant reduction in the risk of myocardial infarction, total mortality, or cardiovascular mortality [68,69].

"Fasting" Dietary Patterns

There are many variations on "fasting" diets, some of which have become popular in the 2010s and 2020s. As a general rule, fasting involves a voluntary restriction of energy intake for a period of time. However, unlike more traditional forms of fasting, which were sometimes undertaken for religious purposes, the form of fasting that has gained popularity for weight loss and overall health is called "intermittent fasting."

Intermittent fasting, which is also called time-restricted feeding, involves consuming calories by eating freely during a certain time frame and then fasting during the remaining hours of the day. While time frames may vary, maximum fasting time frames of up to 16 hours have been proposed, which often overlaps with time spent sleeping [71].

Some other forms of fasting have also gained popularity, albeit less so than intermittent fasting. One form, alternate-day fasting, involves fasting followed by "feasting" on alternate days. On fasting days, ≤25% of baseline energy is consumed during that 24-hour period. On feasting days, food is consumed as desired. This cycle is then repeated indefinitely. Another form, periodic fasting, involves very low-calorie intake for one to six days weekly, followed by consuming food as desired for the remainder of the week. The most common type of periodic fasting is the 5:2 diet, which includes two days each week with a very low caloric intake [71].

Each type of fasting tends to result in an overall reduction in caloric intake, and most research indicates that this calorie restriction is the reason that fasting diets can lead to weight loss. Clinical studies, which have mostly been conducted in adults with overweight or obesity, shows that intermittent fasting, often combined with calorie restriction either all day or just on non-fasting days, can reduce weight by about 3–14 kg or up to 14.7% after 8 to 52 weeks. Body size and fat mass also appear to be reduced [71]. However, most research shows that this weight loss is similar to that seen with continuous energy restriction, or a standard calorie-restricted diet [72,73].

Overall, intermittent fasting is safe as long as all nutritional needs are met. Some patients might find that an intermittent fasting diet works best for their schedule and lifestyle and is a more sustainable approach to weight loss. However, ensure that patients understand it does not seem to offer any additional benefits for weight loss.

Cautions

The forms of fasting discussed here should not be confused with "juice fasting" or "detoxification diets." Juice fasting is based on the theory that juices can enhance the body's natural detoxification process. In general, these diets lasts 3 to 10 days and involve consuming a limited amount of carbohydrate-derived calories (about 150–300 daily) from vegetable and fruit drinks [74]. However, there is no evidence to support these theories and juice fasts can cause serious health issues. They are not intended to provide adequate nutrition and involve the consumption of large amounts of fluids, which can result in electrolyte imbalances when used short-term and malnutrition when used long-term [75].

Detoxification (detox) diets typically claim to eliminate toxins, while some also claim to increase weight loss. There are many "branded" diets that last from a couple of days to weeks in length and involve eliminating certain foods, using laxatives, and increasing intake of specific liquids and supplements [76]. There is no evidence to support the majority of these diets or their claims, and there is the risk for short- and long-term health issues with these diets that can be similar to those seen with juice fasting.

Miscellaneous Diets

There are also a number of popular diets that are not built on the idea of vilifying or avoiding specific food groups. Instead, these diets tend to promote a more balanced approach to food.

Anti-Inflammatory Dietary Patterns

Anti-inflammatory diets have become increasingly popular due to celebrity attention. However, there is a common misconception that there is one single anti-inflammatory diet. Rather, there are simply many variations of an overarching anti-inflammatory dietary style. As a whole, these diets focus on eliminating foods that induce inflammation while also consuming foods and supplements with anti-inflammatory properties.

Despite their popularity, the research supporting the use of anti-inflammatory diets is limited to observational evidence only. Most of this research utilizes an evidence-based, validated scale called the dietary inflammatory index (DII) that was developed to evaluate the inflammatory potential of specific dietary patterns. The DII includes 45 food parameters that have been shown to impact inflammatory markers such as C-reactive protein and tumor necrosis factor. The scale ranges from maximally anti-inflammatory to maximally pro-inflammatory [77]. The available observational research suggests that there is a link between consuming an anti-inflammatory dietary style and a reduced rate of cardiovascular events and cardiovascular mortality [77,78].

Research on following an anti-inflammatory diet for weight loss is limited. A small study in adults with obesity shows that consuming an energy-restricted anti-inflammatory diet for 24 weeks is similarly effective to a standard energy-restricted diet for weight and visceral fat loss. The anti-inflammatory energy-restricted diet used in this study was based on whole-grain products, legumes, fruit and vegetables, nuts and seeds, fish, herbs and spices [79]. Conversely, a clinical trial in adults with overweight and osteoarthritis shows that following an anti-inflammatory low-calorie diet for two months results in an additional 4.1-kg weight loss when compared with a standard low-calorie diet. The anti-inflammatory diet in this study was comprised of about 66% of energy intake from fruits and vegetables, along with whole grains and protein derived from plants, fish, and low-fat dairy sources [80].

Clinicians should be aware that some diets that are advertised as anti-inflammatory do not actually produce anti-inflammatory scores on the DII. Rather, some diets are simply trying to capitalize on the popularity of the anti-inflammatory dietary pattern. If a patient is interested in following an anti-inflammatory diet, let them know that they may be better off following established diets that score well on the DII, such as the Mediterranean diet and the paleo diet.

Organic Foods

Organic foods have become widely available over the past decade and are often touted as superior to or healthier than non-organic foods. These foods, which are typically fruits and vegetables, but can also include grains and other plants, are grown without synthetic chemicals and are often considered safer to consume because they contain fewer pesticides. However, research on the health effects of consuming pesticides found on foods is limited and conflicting [81,82].

Some organic food proponents claim that these foods are more nutritive than nonorganic options. Unfortunately, research confirming this claim is limited, and clinical research on the benefits of organic foods remains inconclusive. Although some studies suggest that organic foods might contain higher quantities of certain nutritive components, such as antioxidants and polyunsaturated fatty acids, other research has yielded the opposite finding [83,84,85].

If a patient is interested in eating organic foods, let them know that it is not yet clear if organic foods are better for overall health. Considering the higher price point for these items, some patients may benefit more from other lifestyle changes.

The Paleo Diet

The paleo (or paleolithic) diet is another popular diet program. The idea behind the paleo diet is to "eat like a caveman." Before the Agricultural Revolution, people sustained themselves on the foods that were readily available. These included fruits, vegetables, meats, eggs, nuts, and seafood. Advocates argue that the paleo diet is the diet that humans are genetically adapted to eat. Therefore, following this approach will result in optimized performance, weight, and health.

A small study showed that following the paleo diet for three to five weeks reduces weight by about 2.3 kg in healthy volunteers [86]. A more recent study in postmenopausal adults with overweight showed that, when compared with a low-fat diet, the paleo diet increased weight loss by about 4–5 kg at 6, 12, and 18 months, but not at 24 months [87].

Keep in mind that due to the strict restriction on the foods that can be consumed, the paleo diet can be difficult for many people to follow long-term. Also, there is some concern that the paleo diet does not provide adequate amounts of calcium or vitamin D [88]. People following the paleo diet long-term may require supplementation to prevent nutrient deficiencies.

The Zone Diet

The Zone diet consists of 40% carbohydrates, 30% protein, and 30% fat, uses a 40-30-30 rule. It advocates for limited intake of grains and starches. The yet-unproven theory behind the Zone diet is that a balance of carbohydrates, proteins, and fats maintains insulin levels "in the zone" and therefore minimizes fat storage and inflammation. The Zone diet is promoted to reduce the insulin-to-glucagon ratio. According to Zone diet proponents, this reduction affects metabolism of eicosanoids, which are produced from polyunsaturated fatty acids. This is intended to produce a metabolic state with decreased hunger, increased weight loss, increased energy, enhanced immunity, and a reduction in chronic disease risk [23].

Currently, there is no scientific support for the connections between diet, endocrinology, and eicosanoid metabolism. Additionally, following the Zone diet can be difficult. Meals must be planned with the required proportions of protein, fat, and carbohydrates, and vegetable portions are very large. The complexity of the Zone diet makes long-term maintenance of weight loss difficult [23].

3. CONCLUSION

The most important consideration for a patient that is attempting to lose weight is the long-term sustainability of the diet for that specific individual. Although some of the diets discussed here might produce impressive results initially, extreme diets in any form do not usually work long-term. The most effective diets are those that people can live with day in and day out for the rest of their lives.

An individual's preferences and cultural traditions should always be taken into account when choosing a dietary strategy, and any selected strategy should be integrated into the person's lifestyle gradually and consistently. Similarly, food quality should be emphasized for all patients. Each patient should be counseled on avoiding highly processed foods and focusing on consuming whole foods whenever possible, while ensuring adequate nutrient intake.

Works Cited

1. Centers for Disease Control and Prevention. Overweight & Obesity: Data & Statistics. Available at https://www.cdc.gov/obesity/data/index.html. Last accessed July 14, 2024.

2. World Health Organization. Obesity and Overweight. Available at https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Last accessed July 14, 2024.

3. National Heart, Lung, and Blood Institute. Overweight and Obesity: Causes and Risk Factors. Available at https://www.nhlbi.nih.gov/health/overweight-and-obesity/causes. Last accessed July 14, 2024.

4. Nguyen BT, Powell LM. The impact of restaurant consumption among US adults: effects on energy and nutrient intakes. Public Health Nutr. 2014;17(11):2445-2452.

5. Centers for Disease Control and Prevention. Overcoming Barriers to Physical Activity. Available at https://www.cdc.gov/physicalactivity/basics/adding-pa/barriers.html. Last accessed July 14, 2024.

6. National Heart, Lung, and Blood Institute. Overweight and Obesity: Management. Available at https://www.nhlbi.nih.gov/health/overweight-and-obesity/management. Last accessed July 14, 2024.

7. Akil L, Ahmad HA. Relationships between obesity and cardiovascular diseases in four southern states and Colorado. J Health Care Poor Underserved. 2011;22(4 Suppl):61-72.

8. Moore LL, Visioni AJ, Qureshi MM, Bradlee ML, Ellison RC, D'Agostino R. Weight loss in overweight adults and the long-term risk of hypertension: the Framingham study. Arch Intern Med. 2005;165(11):1298-1303.

9. Ryan DH, Yockey SR. Weight loss and improvement in comorbidity: differences at 5%, 10%, 15%, and over. Curr Obes Rep. 2017;6(2):187-194.

10. International Food Information Council. 2022 Food and Health Survey. Available at https://foodinsight.org/wp-content/uploads/2022/06/IFIC-2022-Food-and-Health-Survey-Report-May-2022.pdf. Last accessed July 14, 2024.

11. U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025. Available at https://www.dietaryguidelines.gov/sites/default/files/2021-03/Dietary_Guidelines_for_Americans-2020-2025.pdf. Last accessed July 14, 2024.

12. The European Food Information Council. The Importance of Omega-3 and Omega-6 Fatty Acids. Available at https://www.eufic.org/en/whats-in-food/article/the-importance-of-omega-3-and-omega-6-fatty-acids. Last accessed July 14, 2024.

13. U.S. Food and Drug Administration. Questions and Answers on Dietary Fiber. Available at https://www.fda.gov/food/food-labeling-nutrition/questions-and-answers-dietary-fiber. Last accessed July 14, 2024.

14. Lopez MJ, Mohiuddin SS. Biochemistry, Essential Amino Acids. Treasure Island, FL: StatPearls Publishing; 2024.

15. Johnston BC, Kanters S, Bandayrel K, et al. Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis. JAMA. 2014;312(9):923-933.

16. Shai I, Schwarzfuchs D, Henkin Y, et al. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008;359(3):229-241.

17. Gardner CD, Trepanowski JF, Del Gobbo LC, et al. Effect of low-fat vs low-carbohydrate diet on 12-month weight loss in overweight adults and the association with genotype pattern or insulin secretion: the DIETFITS randomized clinical trial. JAMA. 2018;319(7):667-679.

18. Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates.N Engl J Med. 2009;360(9):859-873. doi:10.1056/NEJMoa0804748

19. Ludwig DS. The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. JAMA. 2002;287(18):2414-2423.

20. Atkinson FS, Brand-Miller JC, Foster-Powell K, Buyken AE, Goletzke J. International tables of glycemic index and glycemic load values 2021: a systematic review. Am J Clin Nutr. 2021;114(5):1625-1632.

21. Last AR, Wilson SA. Low-carbohydrate diets. Am Fam Physician. 2006;73(11):1942-1948.

22. Blanck HM, Gillespie C, Serdula MK, Khan LK, Galusk DA, Ainsworth BE. Use of low-carbohydrate, high-protein diets among americans: correlates, duration, and weight loss. MedGenMed. 2006;8(2):5.

23. Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA. 2007;297(9):969-977.

24. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med. 2003;348(21):2082-2090.

25. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348(21):2074-2081.

26. Barry D, Ellul S, Watters L, Lee D, Haluska R Jr, White R. The ketogenic diet in disease and development. Int J Dev Neurosci. 2018;68:53-58.

27. Zajac A, Poprzecki S, Maszczyk A, Czuba M, Michalczyk M, Zydek G. The effects of a ketogenic diet on exercise metabolism and physical performance in off-road cyclists. Nutrients. 2014;6(7):2493-2508.

28. Paoli A. Ketogenic diet for obesity: friend or foe? Int J Environ Res Public Health. 2014;11(2):2092-2107.

29. Yancy WS Jr, Westman EC, McDuffie JR, et al. A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Arch Intern Med. 2010;170(2):136-145.

30. Dashti HM, Al-Zaid NS, Mathew TC, et al. Long term effects of ketogenic diet in obese subjects with high cholesterol level. Mol Cell Biochem. 2006;286(1-2):1-9.

31. Al Aamri KS, Alrawahi AH, Al Busaidi N, et al. The effect of low-carbohydrate ketogenic diet in the management of obesity compared with low caloric, low-fat diet. Clin Nutr ESPEN. 2022;49:522-528.

32. Seidelmann SB, Claggett B, Cheng S, et al. Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis. Lancet Public Health. 2018;3(9):e419-e428.

33. Noto H, Goto A, Tsujimoto T, Noda M. Low-carbohydrate diets and all-cause mortality: a systematic review and meta-analysis of observational studies. PLoS One. 2013;8(1):e55030.

34. Mazidi M, Katsiki N, Mikhailidis DP, Sattar N, Banach M. Lower carbohydrate diets and all-cause and cause-specific mortality: a population-based cohort study and pooling of prospective studies. Eur Heart J. 2019;40(34):2870-2879.

35. O'Flaherty MJ. "Low-Carb" Food Labeling; 2019. Available at https://ofwlaw.com/low-carb-food-labeling/. Last accessed July 14, 2024.

36. Atkins RC, Ornish D, Wadden T. Low-carb, low-fat diet gurus face off. Interview by Joan Stephenson. JAMA. 2003;289(14):1767-1768, 1773.

37. Tobias DK, Chen M, Manson JE, Ludwig DS, Willett W, Hu FB. Effect of low-fat diet interventions versus other diet interventions on long-term weight change in adults: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3(12):968-979.

38. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998;280(23):2001-2007.

39. Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295(6):655-666.

40. Centers for Medicare and Medicaid Services. The Pritikin Program. Available at https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=340&ncdver=1. Last accessed July 14, 2024.

41. Centers for Medicare and Medicaid Services. Ornish Program for Reversing Heart Disease. Available at https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=341&ncdver=1. Last accessed July 14, 2024.

42. Centers for Medicare and Medicaid Services. Benson-Henry Institute Cardiac Wellness Program. Available at https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=362&ncdver=1&bc=AgAAgAAAAAAAAA%3D%3D. Last accessed July 14, 2024.

43. Lari A, Sohouli MH, Fatahi S, et al. The effects of the Dietary Approaches to Stop Hypertension (DASH) diet on metabolic risk factors in patients with chronic disease: a systematic review and meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis. 2021;31(10):2766-2778.

44. Guo R, Li N, Yang R, et al. Effects of the modified DASH diet on adults with elevated blood pressure or hypertension: a systematic review and meta-analysis. Front Nutr. 2021:8:725020.

45. Gibbs J, Gaskin E, Ji C, Miller MA, Cappuccio FP. The effect of plant-based dietary patterns on blood pressure: a systematic review and meta-analysis of controlled intervention trials. J Hypertens. 2021;39(1):23-37.

46. Hall ME, Cohen JB, Ard JD, et al. Weight-loss strategies for prevention and treatment of hypertension: a scientific statement from the American Heart Association. Hypertension. 2021;78(5):e38-e50.

47. Huang RY, Huang CC, Hu FB, Chavarro JE. Vegetarian diets and weight reduction: a meta-analysis of randomized controlled trials.J Gen Intern Med. 2016;31(1):109-116.

48. Kahleova H, Fleeman R, Hlozkova A, Holubkov R, Barnard ND. A plant-based diet in overweight individuals in a 16-week randomized clinical trial: metabolic benefits of plant protein. Nutr Diabetes. 2018;8(1):58.

49. Barnard ND, Alwarith J, Rembert E, et al. A Mediterranean diet and low-fat vegan diet to improve body weight and cardiometabolic risk factors: a randomized, cross-over trial. J Am Nutr Assoc. 2022;41(2):127-139.

50. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt B):2985-3023.

51. Guasch-Ferré M, Satija A, Blondin SA, et al. Meta-analysis of randomized controlled trials of red meat consumption in comparison with various comparison diets on cardiovascular risk factors. Circulation. 2019;139(15):1828-1845.

52. Zheng Y, Li Y, Satija A, et al. Association of changes in red meat consumption with total and cause specific mortality among US women and men: two prospective cohort studies. BMJ. 2019:365:l2110.

53. Johnston BC, Zeraatkar D, Han MA, et al. Unprocessed red meat and processed meat consumption: dietary guideline recommendations from the Nutritional Recommendations (NutriRECS) Consortium. Ann Intern Med. 2019;171(10):756-764.

54. Kim H, Caulfield LE, Garcia-Larsen V, Steffen LM, Coresh J, Rebholz CM. Plant-based diets are associated with a lower risk of incident cardiovascular disease, cardiovascular disease mortality, and all-cause mortality in a general population of middle-aged adults. J Am Heart Assoc. 2019;8(16):e012865.

55. Valli C, Santero M, Prokop-Dorner A, et al. Health related values and preferences regarding meat intake: a cross-sectional mixed-methods study. Int J Environ Res Public Health. 2021;18(21):11585.

56. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):67-77.e3.

57. U.S. Food and Drug Administration. Press Release: FDA Announces Effective Date for Final Rule Adding Soy Leghemoglobin to List of Color Additives Exempt from Certification. Available at https://www.fda.gov/food/cfsan-constituent-updates/fda-authorizes-soy-leghemoglobin-color-additive. Last accessed July 14, 2024.

58. Hu FB, Otis BO, McCarthy G. Can plant-based meat alternatives be part of a healthy and sustainable diet? JAMA. 2019;322(16):1547-1548.

59. Melina V, Craig W, Levin S. Position of the Academy of Nutrition and Dietetics: vegetarian diets. J Acad Nutr Diet. 2016;116(12):1970-1980.

60. Iguacel I, Miguel-Berges ML, Gómez-Bruton A, Moreno LA, Julián C. Veganism, vegetarianism, bone mineral density, and fracture risk: a systematic review and meta-analysis. Nutr Rev. 2019;77(1):1-18.

61. Godfray HCJ, Aveyard P, Garnett T, et al. Meat consumption, health, and the environment. Science. 2018;361(6399):eaam5324.

62. Bloomfield HE, Koeller E, Greer N, MacDonald R, Kane R, Wilt TJ. Effects on health outcomes of a Mediterranean diet with no restriction on fat intake: a systematic review and meta-analysis. Ann Intern Med. 2016;165(7):491-500.

63. Pavić E, Hadžiabdić MO, Mucalo I, et al. Effect of the Mediterranean diet in combination with exercise on metabolic syndrome parameters: 1-year randomized controlled trial. Int J Vitam Nutr Res. 2019;89(3-4):132-143.

64. Sofi F, Dinu M, Pagliai G, et al. Low-calorie vegetarian versus Mediterranean diets for reducing body weight and improving cardiovascular risk profile: CARDIVEG Study (cardiovascular prevention with vegetarian diet). Circulation. 2018;137(11):1103-1113.

65. World Health Organization. Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. Available at https://www.who.int/publications/i/item/9789241550543. Last accessed July 14, 2024.

66. Becerra-Tomás N, Blanco Mejía S, Viguiliouk E, et al. Mediterranean diet, cardiovascular disease and mortality in diabetes: a systematic review and meta-analysis of prospective cohort studies and randomized clinical trials. Crit Rev Food Sci Nutr. 2020;60(7):1207-1227.

67. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14):1279-1290.

68. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med. 2018;378(25):e34.

69. Rees K, Takeda A, Martin N, et al. Mediterranean-style diet for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2019;3(3):CD009825.

70. Temple NJ, Guercio V, Tavani A. The Mediterranean diet and cardiovascular disease: gaps in the evidence and research challenges. Cardiol Rev. 2019;27(3):127-130.

71. Allaf M, Elghazaly H, Mohamed OG, et al. Intermittent fasting for the prevention of cardiovascular disease. Cochrane Database Syst Rev. 2021;1(1):CD013496.

72. He S, Wang J, Zhang J, Xu J. Intermittent versus continuous energy restriction for weight loss and metabolic improvement: a meta-analysis and systematic review. Obesity (Silver Spring). 2021;29(1):108-115.

73. Zhang Q, Zhang C, Wang H, et al. Intermittent fasting versus continuous calorie restriction: which is better for weight loss? Nutrients. 2022;14(9):1781.

74. Lien YHH. Juicing is not all juicy. Am J Med. 2013;126(9):755-756.

75. National Center for Complementary and Integrative Health. "Detoxes" and "Cleanses": What You Need to Know. Available at https://www.nccih.nih.gov/health/detoxes-and-cleanses-what-you-need-to-know. Last accessed July 14, 2024.

76. Klein AV, Kiat H. Detox diets for toxin elimination and weight management: a critical review of the evidence. J Hum Nutr Diet. 2015;28(6):675-686.

77. Ji M, Hong X, Chen M, Chen T, Wang J, Zhang N. Dietary inflammatory index and cardiovascular risk and mortality: a meta-analysis of cohort studies. Medicine (Baltimore). 2020;99(20):e20303.

78. Liang Z, Feng Y, Shivappa N, Hebert JR, Xu X. Dietary inflammatory index and mortality from all causes, cardiovascular disease, and cancer: a prospective study. Cancers (Basel). 2022;14(19):4609.

79. Kenđel Jovanović G, Mrakovcic-Sutic I, Pavičić Žeželj S, Šuša B, Rahelić D, Klobučar Majanović S. The efficacy of an energy-restricted anti-inflammatory diet for the management of obesity in younger adults. Nutrients. 2020;12(11):3583.

80. Dolatkhah N, Toopchizadeh V, Barmaki S, et al. The effect of an anti-inflammatory in comparison with a low caloric diet on physical and mental health in overweight and obese women with knee osteoarthritis: a randomized clinical trial. Eur J Nutr. 2023;62(2):659-672.

81. Juhler RK, Larsen SB, Meyer O, et al. Human semen quality in relation to dietary pesticide exposure and organic diet. Arch Environ Contam Toxicol. 1999;37(3):415-423.

82. Barański M, Srednicka-Tober D, Volakakis N, et al. Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: a systematic literature review and meta-analyses. Br J Nutr. 2014;112(5):794-811.

83. Średnicka-Tober D, Kazimierczak R, Ponder A, Hallmann E. Biologically active compounds in selected organic and conventionally produced dried fruits. Foods. 2020;9(8):1005.

84. Średnicka-Tober D, Kopczyńska K, Góralska-Walczak R, et al. Are organic certified carrots richer in health-promoting phenolics and carotenoids than the conventionally grown ones? Molecules. 2022;27(13):4184.

85. Ponder A, Hallmann E. The effects of organic and conventional farm management and harvest time on the polyphenol content in different raspberry cultivars. Food Chem. 2019;301:125295.

86. Osterdahl M, Kocturk T, Koochek A, Wändell PE. Effects of a short-term intervention with a paleolithic diet in healthy volunteers.Eur J Clin Nutr. 2008;62(5):682-685.

87. Mellberg C, Sandberg S, Ryberg M, et al. Long-term effects of a palaeolithic-type diet in obese postmenopausal women: a 2-year randomized trial. Eur J Clin Nutr. 2014;68(3):350-357.

88. Hoffman R. Can the paleolithic diet meet the nutritional needs of older people? Maturitas. 2017;95:63-64.

89. Haam JH, Kim BT, Kim EM, et al. Diagnosis of obesity: 2022 update of clinical practice guidelines for obesity by the Korean Society for the Study of Obesity. J Obes Metab Syndr. 2023;32(2):121-129.

90. Blüher M, Aras M, Aronne LJ, et al. New insights into the treatment of obesity. Diabetes Obes Metab. 2023;1-15.

91. Weir CB, Jan A. BMI classification percentile and cut off points. StatPearls. Treasure Island, FL: StatPearls Publishing; 2023.

92. Berg S. AMA: Use of BMI Alone is an Imperfect Clinical Measure. Available at https://www.ama-assn.org/delivering-care/public-health/ama-use-bmi-alone-imperfect-clinical-measure. Last accessed July 19, 2024.

Evidence-Based Practice Recommendations Citations

1. U.S. Preventive Services Task Force. Behavioral counseling interventions to promote a healthy diet and physical activity for cardiovascular disease prevention in adults with cardiovascular risk factors: U.S. Preventive Services Task Force recommendation statement.JAMA. 2020;324(20):2069-2075. Available at https://jamanetwork.com/journals/jama/fullarticle/2773280. Last accessed July 25, 2024.

98190 • Supplements for Aging

Chelsey McIntyre, PharmD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

Table of Contents

98190 • Supplements for Aging

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. SUPPLEMENT USE IN OLDER ADULTS

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

BEERS CRITERIA

DRUG INTERACTIONS

CONDITION INTERACTIONS

PRODUCT QUALITY

5. NUTRITIONAL SUPPLEMENTS

MULTIVITAMINS

INDIVIDUAL MICRONUTRIENTS

OTHER NUTRITIONAL SUPPLEMENTS

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

MUSCULOSKELETAL HEALTH

EYE HEALTH

CARDIOVASCULAR HEALTH

JOINT HEALTH

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

LIFESTYLE INTERVENTIONS

NUTRIENT SUPPLEMENTS

HERBAL SUPPLEMENTS

ENDOGENOUS SUBSTANCES

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

98190 • Supplements for Aging

Education Category. Alternative Medicine

Release Date. 06/01/2024

Expiration Date. 05/31/2027

Course Overview

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

Audience

This course is designed for healthcare professionals whose older patients are taking or are interested in supplements.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 5 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 5 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 6 hours for Alabama nurses. NetCE designates this activity for 5 ACPE credit(s). ACPE Universal Activity Number: JA4008164-0000-24-017-H04-P. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 5 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. NetCE is authorized by IACET to offer 0.5 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide healthcare professionals in all practice settings the knowledge necessary to increase their understanding of the supplements that may be used by their older adult patients.

Learning Objectives

Upon completion of this course, you should be able to:

1. List the dietary supplements most commonly used for age-related changes.

2. Explain the safety concerns associated with the use of natural products in older adults.

3. Discuss the risks and benefits of common vitamins and minerals in older adults.

4. Review the evidence for the use of dietary supplements for age-related changes in physical health.

5. Describe the proposed and actual effects of dietary supplements for dementia.

Faculty

Chelsey McIntyre, PharmD, is a clinical pharmacist who specializes in drug information, literature analysis, and medical writing. She earned her Bachelor of Science degree in Genetics from the University of California, Davis. She then went on to complete her PharmD at Creighton University, followed by a clinical residency at the Children’s Hospital of Philadelphia (CHOP). Dr. McIntyre held the position of Drug Information and Policy Development Pharmacist at CHOP until her move to Washington state in 2017, after which she spent the next six years as a clinical editor for Natural Medicines, a clinical reference database focused on natural products and alternative therapies. She continues to create rigorous professional analysis and patient education materials for various publications while also practicing as a hospital pharmacist. Her professional interests include provider and patient education, as well as the application of evidence-based research to patient care.

Faculty Disclosure

Contributing faculty, Chelsey McIntyre, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

As the population ages, maintaining both physical and cognitive health becomes increasingly important. In recent years, the use of dietary supplements, including vitamins, minerals, fibers, and proteins, has gained significant attention for their potential to improve various aspects of health. Older adults may turn to these supplements to address age-related deficiencies, enhancing physical vitality, and supporting cognitive function. This course is designed to provide a comprehensive review of the role of supplements in promoting well-being among older adults.

2. SUPPLEMENT USE IN OLDER ADULTS

Older adults, defined as those at least 65 years of age, are a rapidly growing portion of the United States population that is expected to make up 20% of the country's total population by 2030 [1]. As life expectancy and overall quality of life continues to improve for this age group, many older adults have shown an increased interest in taking an active role in their health, often seeking out alternative and complementary options for both prevention and treatment.

The term "complementary therapy" covers a wide range of modalities, from breathing exercises and yoga, to healing touch and massage, to herbs and vitamins. For many Americans, the most commonly utilized complementary therapy is dietary supplements, a category that includes herbal products, vitamins, minerals, fibers, probiotics, fish oil, and many more.

In fact, as of 2017, 70% of older adults reported using at least one dietary supplement. A full 54% reported taking two supplements and 29% reported taking four or more supplements. The most frequently used supplements were multivitamins, Vitamin D, calcium, and omega-3s. At least 9% also reported using an herbal/botanical product, a number that is likely to have increased since the time of this survey [2].

Most older adults reported using these products to improve overall health. Other commonly cited reasons included bone health, nutritional supplementation, heart health and cholesterol, and eye health. Women, who reported using supplements more often than men, were more likely to use supplements for musculoskeletal health. Not surprisingly, most of this use was not related to recommendations from healthcare professionals, although the use of calcium, vitamin D, iron, and fiber products, specifically, was more likely to be associated with a recommendation from a healthcare professional [2].

3. PHYSIOLOGICAL CHANGES IN OLDER AGE

There are many physiological changes that occur as the body ages. These changes affect almost every organ system and can alter the way that the body responds to activity, food, and medications.

Some of the most striking changes occur in the musculoskeletal system. These changes often manifest as a reduced tolerance for physical activity, changes in overall mobility, and an increase in various forms of pain. As the body ages, it naturally loses muscle and water content and increases fat stores. It also loses bone mass and experiences a reduction in joint lubrication [3].

Most older adults are also aware of changes to their cardiovascular system. As the body ages, cardiac output decreases, along with resting and maximal heart rate. Conversely, systemic vascular resistance increases, which leads to increased blood pressure. The cardiovascular system in general has a reduced response to stress and a reduction in baroreceptor activity. Many older adults also have high levels of cholesterol. These changes increase the risk for various adverse cardiovascular outcomes, as well as an increased likelihood for cardiovascular adverse effects from medications and natural products [3].

Another commonly recognized change occurs in the nervous system. As the central nervous system ages, portions of the brain, such as the hippocampus and the frontal and temporal lobes, shrink in size, which reduces the capacity for short-term memory and executive function. Sleep patterns also change, commonly resulting in insomnia. Older adults also undergo a reduction in neuroreceptors and an increase in receptor sensitivity. This can increase sensitivity to medications and natural products that affect the nervous system, such as those with anticholinergic or sedating activity [3].

Reduced production of hormones, specifically estrogen in women and testosterone in men, can cause a myriad of changes to the body. Older adults also often experience a reduction in taste perception [3].

Many of the other changes that occur with aging are more likely to alter the body's response to foods and medications, without necessarily causing noticeable changes in physical function [3,4,5]:

- The liver undergoes a reduction in volume and blood flow, reducing the functional capacity to metabolize chemicals.

- The large intestine becomes less motile, which may impact the absorption of various nutrients and chemicals.

- The kidneys undergo a gradual reduction in overall mass and blood flow, which reduces the glomerular filtration rate (GFR). These changes can reduce the clearance of medications and other chemicals that are normally eliminated by the kidneys.

- Thinning skin can increase the absorption of chemicals that are applied topically, whether absorption is intended or not.

4. SAFETY CONCERNS WITH NATURAL PRODUCTS

As mentioned, various physiologic changes place older adults at an increased risk for adverse reactions to medications and natural products. The most predictable effects occur in relation to reduced kidney and/or liver function. However, reduced body water and increased body fat can also significantly alter the distribution and storage of chemicals in the body, which can increase sensitivity to the chemical and alter the likelihood for adverse effects.

In fact, medication-related adverse effects occur up to seven times more frequently in older adults when compared with younger adults. As many natural products are physiologically active and are cleared by the kidney and/or liver, this increased risk applies to natural products as well [6].

BEERS CRITERIA

Many healthcare professionals are familiar with the Beers Criteria, a list of drugs and drug classes that an expert panel, led by the American Geriatrics Society (AGS), considers to be potentially inappropriate for use in older adults. These include medications that are potentially harmful in all older adults, as well as those considered to be of concern in older adults with specific conditions or who are taking specific medications. In essence, this list identifies medications and medication classes for which potential harm is thought to outweigh expected benefit [7].

Although this list does not specifically include natural products, healthcare professionals should keep in mind that many supplements have pharmacological effects, some of which fall into classes listed on the Beers Criteria.

For example, sedative medications are a concern in older adults and should be used with caution. Many natural products are known to have clinically significant sedative effects and should thus be used with caution. Some common examples include kava, hops, passionflower, and valerian [8]. Anticholinergic medications are also considered to be of high concern in older adults. Some natural products, including bitter yam, European barberry, muira puama, and scopolia, have potent anticholinergic effects [9].

Various supplements also have anti-inflammatory activity, which may introduce many of the risks associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Similarly, many supplements can increase the risk of bleeding and should be used with caution in this population.

DRUG INTERACTIONS

Older adults are often prescribed multiple medications, which increases their risk of drug-drug and drug-supplement interactions. In fact, in the 2017 survey discussed earlier, older adults that reported taking at least three prescription drugs were more likely to also take dietary supplements, further increasing the risk for interactions [2].

Many of the same principles apply to drug-drug interactions and drug-supplement interactions:

- Many supplements are metabolized by the same enzymes that metabolize drugs, including the cytochrome P450 (CYP) enzyme family. Drugs that inhibit or induce these enzymes can alter the effects of natural products.

- Some supplements can cause significant inhibition of drug metabolizing enzymes, which can increase or decrease the effects and adverse effects of prescribed medications.

- Drug transporters, such as P-glycoprotein and the organic anion transporter (OAT) family, also transport the chemicals contained in supplements.

- Because supplements can have significant physiological effects, taking a supplement and drug with similar activity can cause additive effects. Examples of this type of interaction include additive reductions in blood glucose or blood pressure, additive antiplatelet activity, and additive photo-sensitization.

However, it is important to understand that there is much greater uncertainty and risk associated with drug-supplement interactions. This is due to two major factors. The first is the low quantity and quality of evidence available for drug-supplement interactions. Because there are no regulations requiring the evaluation of possible interactions with supplements, very few human studies are available. Thus, most of the proposed interactions are based on extrapolation from case reports, proposed physiological effects, and laboratory research. And more importantly, many possible interactions remain completely unknown.

The second factor is the variability of contents in natural products. Natural products do not necessarily contain reliable quantities of each ingredient, as is expected with medications. Some of this variability is due to inaccurate labelling and poor quality assurance by manufacturers. But in the case of herbs and botanicals, this variability is completely natural. Growing conditions, seasonal weather variations, harvesting practices, and extraction methods can all alter the chemical composition of herbal products. This makes it difficult to predict the likelihood for effects and interactions.

CONDITION INTERACTIONS

As with medications, natural products also carry a risk for condition interactions, particularly conditions that are more prevalent in older adults. Many of the physiological changes discussed previously can alter the effects of medications and natural products in the body.

Liver Disease

As mentioned, natural products are metabolized by many of the same enzymes involved in drug metabolism. Patients with liver disease may require lower doses, and natural products that have been associated with hepatoxicity should be avoided completely. These include some relatively well-known supplements, such as green tea extract, kava, garcinia, ephedra, turmeric, red yeast rice, and black cohosh [10].

Kidney Disease

Similarly, many natural products are excreted by the kidneys and should thus be used with caution in patients with kidney disease. Natural products that have been associated with nephrotoxicity should be avoided completely, including cannabis, colloidal silver, horse chestnut, saffron, and yohimbine [11].

Anticoagulation

Certain natural products have demonstrated clinically relevant antiplatelet or anticoagulant effects. In patients requiring the use of antiplatelet or anticoagulant medications, these products should be avoided. Some examples include garlic, ginseng, ginkgo, high doses of vitamin E or fish oil, and many others [12].

PRODUCT QUALITY

Variable Quality

As mentioned, the actual contents of supplements can vary, either due to inaccurate labelling or poor quality assurance by the manufacturer. To ensure the selection of a high-quality product, look for third-party quality certification stamps, such as those from United States Pharmacopeia (USP) or NSF.

USP

The USP is typically considered the standard for verifying the quality of dietary supplements. In addition to inspecting manufacturing facilities for compliance with Good Manufacturing Practices (GMP) at least two times in a three-year period, USP will also conduct random off-the-shelf analyses of verified products to ensure that the contents of the product match those listed on the label. This random testing holds manufacturers to a high standard. The USP verification stamp can be found on a product's label.

NSF

NSF is also a strong source of dietary supplement quality verification. However, general NSF certification does not always imply the same quality standards as USP verification. For a manufacturer to list NSF certification on their website, they must pass an NSF inspection of GMP compliance every six months. However, NSF does not conduct off-the-shelf analyses of products unless the manufacturer is enrolled in the "Contents Tested and Certified" or "Certified for Sport" programs. Under these programs, products are subject to random off-the-shelf testing. These products can carry the NSF seal of approval on the label. The seal will typically state "NSF: Contents Certified" or "NSF: Certified SPORT."

5. NUTRITIONAL SUPPLEMENTS

The class of dietary supplements most commonly used by older adults is micronutrients, which includes vitamins and minerals. There are a number of reasons that these products may be used, including for the improvement of overall health and bone health and for supplementation of the diet.

MULTIVITAMINS

Formulations

About 40% of all older adults that take dietary supplements report using a multivitamin [2]. Many people consider multivitamins to be a quick and easy well-rounded supplement to the diet. These products contain 20 to 30 different micronutrients. However, each multivitamin product contains different ingredients and different ingredient quantities.

All dietary supplement labels are required to provide the % daily value (DV) for each nutrient included in the product. This DV derives from the Dietary Reference Intakes established by the Institute of Medicine [13,14,15]. This can act as a helpful way to determine whether the product contains too much or too little of a specific micronutrient. In some cases, products will contain only a small portion of the dietary requirement (1% to 20%). In other cases, they may contain much more than is recommended in the daily diet (more than 1,000%). There is no legal limit on the amount of any micronutrient that can be included in a dietary supplement.

Although older adults may be using a wide range of specific multivitamin products, some of the best-selling multivitamins on the market are specifically targeted to older men and women, with formulas that claim to specifically address nutrient concerns related to age and biological sex. These best sellers (e.g., Centrum Silver) can be used as an example of the multivitamin composition that many older adults are likely to be taking. As with other multivitamins, these products contain more than 25 individual ingredients, with percent of DVs ranging from 17% to 1,042%.

Safety

The safety of taking doses that are much higher than the DV depends on the specific nutrient in question. Fat-soluble vitamins, which are stored in the body, can cause toxicity over time. These include vitamins A, D, E, and K. Water-soluble vitamins are typically eliminated by the kidneys when quantities exceed physiological needs. Thus, toxicity is much less likely when these vitamins are taken in large quantities.

In addition to developing DVs for each nutrient, the Institute of Medicine also developed tolerable upper intake levels (ULs) to help guide patients and healthcare professionals in preventing toxicity and adverse effects. Some ULs are based on the risk for long-term toxicity, as is the case for vitamin D [13]. Other ULs, such as that of vitamin C, are based on the risk for temporary adverse effects, including gastrointestinal upset [15].

It is important to keep in mind that many patients who take multivitamins also take individual vitamin or mineral supplements. For example, it is not uncommon for patients to take a multivitamin along with a vitamin D/calcium supplement. Healthcare professionals should be aware of these duplicate therapies so that they can prevent a total intake of doses above the UL.

One simple way to avoid consuming too much of any one micronutrient is to first attempt to obtain all of these nutrients from foods in the diet. If a patient is concerned about adequate intake, encourage them to consider how much of each nutrient is obtained from both food and drinks and to identify ways to boost dietary intake. If the patient is already taking a multivitamin or other supplements, remind them to also consider the quantity of each nutrient found in these products.

Another consideration that is not often addressed with multivitamins is the potential for reduced or enhanced absorption of various micronutrients in the presence of other micronutrients. For example, vitamin C (ascorbic acid) can increase the absorption of chromium and iron [16,17]. The presence of vitamin D increases the absorption of calcium in the intestine [18]. Iron and zinc can interfere with each other's absorption when taken on an empty stomach [19,20]. Thus, it can be difficult to predict the actual benefits and risks with these products, particularly in patients with specific nutritional needs or medical conditions.

Many multivitamin tablets and capsules are large, which may increase the risk of choking in some patients, particularly older adults. From 2006 to 2015, about 20% of the reports submitted to the U.S. Food and Drug Administration (FDA) Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) concerning dietary supplements involved choking or other swallowing problems. About 73% of these reports involved multivitamin supplements, and most of the adverse reports occurred in older adult patients [22]. Clinicians should ensure that older patients with swallowing difficulties are not placing themselves at risk for choking with the use of multivitamins.

Benefits

Despite the widespread use of multivitamin products, the evidence to-date, which includes many large randomized controlled trials, does not support their use. The U.S. Preventive Services Task Force (USPSTF) currently states that there is insufficient evidence to recommend the use of multivitamins for the prevention of cardiovascular disease (CVD) or cancer [21]. Research evaluating these products for reducing overall mortality has shown no benefit.

Considering this lack of benefit in the context of high product costs and variable quality, consider steering patients away from taking multivitamins or relying on them for adequate nutrition.

INDIVIDUAL MICRONUTRIENTS

Unlike multivitamins, there is supportive evidence for the use of various individual micronutrients in older adults. Although the recommended daily intake for the majority of nutrients is the same for older adults as for younger adults, there are some important exceptions.

Vitamin B12 (Cyanocobalamin)

The recommended daily intake for vitamin B12 is the same for all adults, regardless of age. However, as humans age, their ability to absorb vitamin B12 from the intestinal tract decreases. Additionally, many older adults take medications that have the potential to further reduce the absorption of vitamin B12. Some examples of these medications include metformin and proton pump inhibitors (PPIs), such as pantoprazole and omeprazole [22,23]. Due to this reduced absorption, it is recommended that older adults consume fortified foods, such as breakfast cereal. However, some may also require vitamin B12 supplements to meet their needs [24].

Vitamin B6 (Pyridoxine)

It is recommended that older adults obtain more vitamin B6 from the diet than younger adults. Prior to 51 years of age, all adults are recommended to consume 1.3 mcg per day. Beginning at 51 years of age, the recommendation for women increases to 1.5 mcg; for men, it increases to 1.7 mcg [24]. This recommendation is related to an increased rate of vitamin B6 deficiency in older adults, which is thought to be due to reduced absorption and increased catabolism [25]. As with vitamin B12, vitamin B6 can be obtained from fortified foods. Supplements can be considered if dietary intake is inadequate.

Calcium and Vitamin D

One of the most popular combination supplements available on the market is calcium-vitamin D. Although calcium and vitamin D have distinctive effects, they are often discussed, and provided, in combination for bone health. While calcium is the nutrient that directly builds and maintains bone, vitamin D is crucial to the appropriate absorption of calcium from the intestine. Thus, adequate vitamin D intake is an important component of adequate calcium intake and bone health.

Due to age-related bone loss, the recommended daily intake for both calcium and vitamin D increases with age. And due to hormonal changes associated with menopause, the recommended intake for calcium increases faster for women than for men [13]. The recommended vitamin D intake is [13]:

- 1 to 70 years of age: 600 IU (15 mcg)

- 71 years of age and older: 800 IU (20 mcg)

The recommended intake of calcium is [13]:

- Women:

- 19 to 50 years of age: 1,000 mg

- 51 years of age and older: 1,200 mg

- Men:

- 19 to 69 years of age: 1,000 mg

- 70 years of age and older: 1,200 mg

Many older adults take calcium-vitamin D supplements to improve bone health and ensure adequate intake of both nutrients. However, this may not always be necessary or even appropriate. Whenever possible, experts recommend obtaining these nutrients from the diet. In fact, due to a lack of strongly supportive evidence, guidelines have not recommended the routine use of calcium and vitamin D supplements in many older adults [26,27]. For the prevention of fractures in community-dwelling, postmenopausal adults, the USPSTF found insufficient evidence to assess the balance of benefits and harms when calcium and vitamin D are supplemented in doses of at least 1,000 mg daily and 400 IU daily, respectively. The USPSTF also recommends against daily supplementation with lower doses of calcium and/or vitamin D. For the primary prevention of fractures in men and premenopausal women, the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D and calcium supplementation, alone or combined.

The Bone Health and Osteoporosis Foundation (BHOF) recommends a diet with adequate total calcium intake based on the recommended daily intake, incorporating calcium supplements if intake is insufficient. They also recommend maintenance of serum vitamin D sufficiency (a 25-hydroxyvitamin D level of 30–50 ng/mL), with the use of supplemental vitamin D as needed to achieve sufficient vitamin D levels.

In 2024, the Endocrine Society published a new evidence-based guideline for using vitamin D supplementation in select patient populations [118]. The Endocrine Society Panel advises against routine use of vitamin D supplements in most healthy adults younger than 75 years of age and recommends against testing for vitamin D blood levels in the general population. The Panel does suggest empiric vitamin D supplementation for the following groups [118]:

- Children 1 to 18 years of age, to prevent rickets and potentially lower the risk of respiratory infections

- Adults older than 75 years of age, because of its potential to lower the risk of mortality

- Pregnant individuals, because of its potential to lower the risk of pre-eclampsia, intra-uterine mortality, preterm birth, and other neonatal complications

- Adults with prediabetes who are at high risk for progression to type 2 diabetes

The Panel advises that empiric vitamin D supplementation may include daily intake of fortified foods, vitamin formulations that contain vitamin D, and/or daily intake of a vitamin D supplement [118]. For nonpregnant older adults for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, approximating the age-adjusted dosage specified by the Institute of Medicine (600 IU for persons 1 to 70 years of age; 800 IU for those older than 70 years of age) rather than intermittent use of higher doses [13,118].

There has also been interest in the use of vitamin D supplements for reducing fall risk. However, high-quality research on this topic has yielded negative results. The USPSTF actually recommends against vitamin D supplementation to prevent falls in community-dwelling older adults [28].

Potassium

There is no recommendation for increased intake of potassium in older adults. However, the 2017 American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines recommend increased intake of potassium in patients with elevated blood pressure or hypertension [112]. This recommendation should be considered with caution in older adults, who may have reduced kidney function or be taking medications that reduce potassium excretion. In fact, the guideline specifies that potassium supplementation should be obtained through the intake of potassium-rich foods as opposed to potassium supplements. This reduces the risk of excessive potassium intake or hyperkalemia.

Magnesium

Magnesium is an important nutrient for bone health. Magnesium deficiency can increase the formation and activity of osteoclasts, which resorb bone. Increased bone resorption causes release of magnesium and calcium from the bone, which can increase magnesium levels in times of deficiency. However, no large prospective studies have been conducted to evaluate the benefits of magnesium supplementation for the prevention of osteoporosis.

Regardless, it is important for patients to ensure adequate intake of magnesium from the diet. The daily recommended intake for magnesium is 320 mg for all adults 31 years and older [24]. Many foods are rich in magnesium and will allow most patients to attain this intake level.

However, some older adults may be at increased risk for magnesium deficiency due to the use of certain medications. The most important culprits are diuretics and PPIs. For diuretics, loop diuretics are the greatest cause for concern. This risk increases when taken with other magnesium-depleting drugs like PPIs. For patients taking PPIs long-term, the FDA recommends checking serum magnesium levels at baseline and annually thereafter. Although some patients may need to discontinue the PPI permanently, others with hypomagnesemia can take a PPI and magnesium supplement concurrently [29].

OTHER NUTRITIONAL SUPPLEMENTS

Protein

Due to the loss of muscle mass that occurs with age, protein consumption becomes particularly important for older adults. However, research shows that many older adults do not consume enough protein to keep up with the daily requirements, and that protein consumption actually decreases with age. The recommended daily intake of protein for all adults 18 years of age and older is 0.8 grams/kg [24].

However, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommends a higher protein intake for women older than 50 years of age. This recommendation calls for 1–1.2 grams/kg, as postmenopausal women experience an even greater loss in muscle mass [30].

As with other nutrients, patients should be counseled to obtain adequate protein intake from a well-rounded diet whenever possible. Although protein supplements may be appropriate for some patients, most patients are able to obtain adequate protein by making healthy changes to their diet. Common protein supplements, including whey, pea, and soy protein, will be discussed later in this course.

Fibers

Fiber is an important component of the diet. It is recommended that older women consume 25 grams daily and that older men consume 28 grams daily [24]. These intakes are actually less than those recommended for adults younger than 51 years of age. However, research shows that, as with protein, many older adults are not obtaining enough fiber from the diet.

The FDA has an established definition for what can be called a dietary fiber on a product label. This definition essentially states that the fiber must be a naturally occurring, nondigestible carbohydrate obtained from plants that has beneficial effects in the body. Fiber can be either water-soluble or water-insoluble. Water-soluble fibers, such as oats, beta-glucans, and barley, help to lower both blood glucose and cholesterol levels. Water-insoluble fibers, such as wheat bran and rice bran, help the body digest food and improve bowel health [31].

Most people will be able to meet their dietary fiber needs by increasing their intake of certain foods, such as oatmeal, whole wheat cereals, and grains. However, some patients may wish to take a fiber supplement as well. Most of the popular fiber supplements on the market contain blond psyllium (Plantago ovata), which is a water-soluble fiber that has shown benefits for constipation, coronary heart disease, hyperlipidemia, and diabetes. In these studies, patients typically consumed 10–20 grams of supplemental psyllium daily [32].

6. NATURAL PRODUCTS FOR PHYSICAL CHANGES

Almost all systems of the body are affected by age. Some changes can be directly tied to specific events, such as menopause, whereas other changes simply happen slowly over time. This section will explore some of the natural products most commonly used to counteract the physical changes that occur with age.

MUSCULOSKELETAL HEALTH

As mentioned, one of the best ways to improve musculoskeletal health in older age is to ensure adequate dietary intake of calcium, vitamin D, and protein. However, for those who would like to improve their overall physical performance and ability to recover from exercise, other natural products may be considered.

Physical Activity

First and foremost, it is important to ensure that patients are getting adequate physical activity for their age. This can be key to combatting the increased weight gain that is seen after menopause. In addition, it can help to reverse age-related muscle loss (sarcopenia) and even slow bone loss in all older adults.

The Centers for Disease Control and Prevention (CDC) recommends that all adults older than 65 years of age [33]:

- Obtain at least 150 minutes of moderate-intensity activity per week, such as brisk walking. Alternatively, this can be replaced with 75 minutes of vigorous-intensity activity, such as hiking, jogging, or running.

- Participate in muscle-strengthening exercises at least two days per week

- Participate in activities that improve balance at least three days per week

Muscle-strengthening exercises can include a wide range of options and are not solely limited to weightlifting. Patients can also consider the use of resistance bands; exercises that use their own body weight for resistance, such as push-ups, sit-ups, and certain forms of yoga and Pilates; and even heavy gardening [33]. Balance exercises are more specific and involve activities such as walking backwards, standing on one leg, or using a wobble board [33].

If a patient has had only limited physical activity and is interested in initiating a new exercise program, encourage them to seek guidance from a physical therapist. To avoid injury, patients should also be evaluated before initiating a new exercise program involving compressive or contractile stressors (such as running or weightlifting).

Supplements for Physical Performance

Some older adults may struggle to complete these recommendations due to fatigue or reduced muscle mass. Others may wish to exceed these recommendations but feel that they do not have adequate strength or energy to do so.

Protein Supplements

Protein was briefly discussed in the last section, within the context of ensuring adequate protein intake throughout the day. For a small number of older adults who cannot obtain adequate protein from the diet, protein supplements may be considered. There is also increasing interest in the use of protein supplements to improve physical performance and exercise endurance.

There are many protein supplement products on the market. The majority of these products use whey protein, which is derived from milk [34]. Other products use pea protein or soy protein. All three of these are considered complete proteins, meaning they contain all essential amino acids, which are amino acids that cannot be made by the body and must be obtained from the diet. Collagen is also becoming popular as a protein supplement. It is important to note that all collagen protein products are derived from animals and that collagen is not a complete protein [35]. Older adults should not rely on collagen protein supplements as a primary source of protein in the diet.

It is not clear if the form of protein used affects outcomes. Some small studies in young athletes suggests that whey, soy, beef, chicken, and dairy protein are similarly beneficial for improving muscle strength [36]. However, there is no researching comparing protein sources in older adults, so it is unclear if different protein formulations can be interchanged.

Some research suggests that taking 35 grams of whey protein three times weekly, either before or after resistance training, can modestly increase muscle mass, muscle strength, and functional capacity [37,38]. However, it is unclear if these benefits are clinically significant. Additionally, it is unclear if there are any benefits to muscle mass in people who are not regularly exercising [39].

There is very little, inconclusive research available for using soy protein to improve physical performance in older adults. To date, pea protein and collagen have not been studied for this purpose.

Branched-Chain Amino Acids (BCAAs)

Although branched-chain amino acids (BCAAs) are not protein supplements, they are comprised of amino acids, the building blocks of protein. BCAA products typically contain leucine, isoleucine, and valine, which are all essential amino acids.

Research on the use of BCAAs in older adults has mostly been limited to those who are relatively malnourished or are known to have inadequate dietary protein intake. The small studies that are available have overall shown no benefit for muscle strength or physical function [40,41].

Creatine

Most research shows that taking creatine while taking part in a resistance training program can increase upper and/or lower body muscle strength in older adults. Research also suggests that creatine improves total muscle mass in older adults [42,43]. In the available research, most participants took a loading dose of up to 20 grams daily for up to 7 days, followed by a maintenance dose of 2.25–10 grams daily for up to 12 weeks. The benefits of creatine at larger doses or for longer than 12 weeks is unknown.

Some case reports have suggested that taking creatine can worsen kidney dysfunction in some people. Additionally, creatine has been reported to cause water retention and edema in some adults [44]. In most clinical studies, participants did not experience these adverse effects. However, because older adults are more likely to have reduced kidney function, as well as cardiovascular dysfunction, recommend that patients monitor their fluid intake and output when initiating creatine supplementation.

Hydroxymethylbutyrate (HMB)

Hydroxymethylbutyrate (HMB), a metabolite of the amino acid leucine, is a naturally occurring molecule that is thought to be involved in protein synthesis. This has led to some interest in its use for performance enhancement.

Studies in older adults suggest that it might increase muscle mass or minimize the loss of muscle mass, particularly in those adults who have already experienced a loss of muscle mass [45,46,47]. However, it does not seem to improve muscle mass or overall exercise tolerance when used in conjunction with exercise [48,49].

Beta-Alanine

Beta-alanine, a beta-amino acid, is naturally found in the diet. Over the years, it has become a popular supplement for improving exercise performance.

The available research in older adults does show that taking beta-alanine 2.4–3.2 grams daily for 4 to 12 weeks improves exercise capacity and reduces fatigue by a small amount. However, it does not improve strength or exercise performance [50,51,52]. Beta-alanine is generally well-tolerated, but some people experience a dose-dependent feeling of pins and needles, as well as skin flushing [53,54].

EYE HEALTH

One of the leading causes of vision impairment in adults older than 55 years of age is age-related macular degeneration (AMD). Although it does not cause complete blindness, this condition blurs a person's central vision. This can significantly limit the ability to complete activities of daily living by making it harder to see faces, read, drive, or do close-up tasks like cooking or repairs [55].

The most common form of AMD, dry AMD, occurs in three stages—early, intermediate, and late. People with early and intermediate AMD typically do not experience symptoms. However, those with late AMD tend to notice a blurry area in their field of vision, which may get bigger over time.

Evidence Based Practice Recommendation

According to the American Academy of Ophthalmology, antioxidant vitamin and mineral supplementation as per the Age-Related Eye Disease Study (AREDS2) should be considered in patients with intermediate or advanced AMD. There is no evidence to support the use of these supplements for patients who have less than intermediate AMD and no evidence of any prophylactic value for family members without signs of AMD.

https://www.aaojournal.org/article/S0161-6420(19)32091-3/pdf

Last Accessed: May 29, 2024

Level of Evidence: Expert Opinion/Consensus Statement

One of the recommended preventive measures for AMD is a multinutrient supplement. Extensive research, referred to as the Age-Related Eye Disease Studies (AREDS), has been conducted on the use of very specific nutrient formulations to limit the progression of AMD. The American Academy of Ophthalmology Guideline recommends one of these formulations, AREDS2, for all patients who have progressed to intermediate or advanced AMD in at least one eye [55].

Because there is still some confusion regarding the appropriate product to recommend for patients with AMD, it can be helpful to review the formulations that have been studied (Table 1) [55]. Both formulations contain the same quantities of vitamin C, vitamin E, and copper. However, they differ in relation to the type of carotenoid provided. Carotenoids are dietary precursors to vitamin A that are converted to vitamin A in the body. The Original AREDS formulation provided beta-carotene, whereas the AREDS2 formulation provides a mixture of two carotenoids, lutein and zeaxanthin.

Table 1: MULTI-NUTRIENT SUPPLEMENTATION FOR AMD

Nutrient

Dose

Original AREDS

Vitamin C

500 mg

Vitamin E

400 IU

Beta-Carotene

15 mg

Zinc (zinc oxide)

80 mg

Copper (cupric oxide)

2 mg

AREDS2

Vitamin C

500 mg

Vitamin E

400 IU

Lutein/zeaxanthin

10 mg/2 mg

Zinc (zinc oxide)

80 mg OR 25 mg

Copper (cupric oxide)

2 mg

Source: [55]

One of the primary reasons that beta-carotene was removed from the AREDS2 formulation was safety concerns. Multiple studies have shown that heavy smokers who take beta-carotene supplements have an increased risk of lung cancer and an increased rate of mortality. In fact, these known risks led the USPSTF to recommend against the use of beta-carotene supplements [21].

The quantity of zinc in these products also differs. In AREDS2 studies, two different doses of zinc were evaluated. Importantly, only the higher dose of zinc was found to be beneficial, suggesting that only products containing 80 mg of zinc should be used. Research also suggests that taking zinc alone, or taking the other ingredients found in AREDS2 without zinc, results in reduced benefits for patients with advanced AMD. Thus, patients should be counseled to take the specific combination product studied in AREDS2 providing 80 mg zinc [55].

CARDIOVASCULAR HEALTH

Another common area of concern for older adults is cardiovascular health. As discussed, many older adults experience elevated blood pressure and cholesterol. Additionally, there is interest in using supplements to assist in maintaining optimal cardiac function and health for as long as possible.

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends against the use of beta carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer.

https://jamanetwork.com/journals/jama/fullarticle/2793446

Last Accessed: May 29, 2024

Level of Evidence: D (Evidence is insufficient to assess the balance of benefits and harms)

As noted, multivitamins are incredibly popular with older adults, and one of the stated reasons for use is cardiovascular health. However, the USPSTF has concluded that there is insufficient evidence to assess the balance of benefits and harms with the use of multivitamin supplements for the prevention of CVD or cancer in community-dwelling adults [21]. Similarly, the USPSTF has found that there is insufficient evidence to assess the balance of benefits and harms for the use of single or paired nutrient supplements for these purposes [21]. In general, multivitamins and vitamin/mineral supplements should not be recommended for cardiovascular health.

Omega-3 Fatty Acids

Some of the supplements most frequently used by older adults are omega-3 fatty acid supplements. These supplements typically contain fish oil, which is high in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Many fish contain large amounts of omega-3 fatty acids, and fish oil supplements can be derived from various fish, ranging from anchovy to mackerel to sturgeon. Fish oil supplements can vary significantly in contents and quality, with EPA content ranging from 18% to 51% and DHA content ranging from 12% to 32% [113].

Omega-3 fatty acids are generally considered "healthy fats" and are found in high concentrations in the human brain, retina, and spermatozoa. The reason that these are popular for cardiovascular health ties in to multiple purported and confirmed benefits. However, research has identified significant differences between the benefits of fish oil supplements and fish oil obtained from dietary intake of fish.

Prescription vs. Supplemental Fish Oil

Two prescription fish oil products have been approved by the FDA. The first product, with the original brand name Lovaza, provides omega-3 acid ethyl esters. It was approved for triglyceride levels greater than 500 mg/dL in patients who do not have adequate reduction in triglycerides after lifestyle and dietary modifications. For this purpose, the medication is taken as 4 grams daily. The other product, with the original brand name Vascepa, provides icosapent ethyl, which is a derivative of EPA. Similar to the omega-3-acid ethyl esters, this product is approved for the treatment of hypertriglyceridemia at a dose of 4 grams daily. For both products, the daily dose is obtained by taking four capsules [114].

It is important to note that the contents of these prescription products have been purified and standardized and that each capsule contains the exact amount of each omega-3 fatty acid stated on the label. In general, fish oil supplements have not been purified and also may not be standardized.

Another important note to consider is that the quantity of omega-3 fatty acids found in prescription products is significantly higher than that found in supplements. Although some fish oil supplements may have some benefit for reducing triglycerides, these forms of fish oil are generally considered inadequate in comparison to prescription products because doses of up to 12 capsules, as opposed to four capsules of the prescription preparation, may be needed to produce the same effect [56].

Cardiovascular Disease (CVD)

Clinical and observational research has found that routinely eating fatty fish, such as salmon or mackerel, as part of the diet may reduce the risk of developing heart disease and all-cause mortality in adults without a history of CVD [57,58]. In fact, the AHA recommends one to two weekly servings of non-fried fish in place of less healthy sources of protein and fat to reduce the risk of CVD [59]. However, the use of fish oil supplements for the primary prevention of heart disease does not seem to be beneficial. In addition, neither increased dietary intake of fish oil nor fish oil supplements are associated with a benefit in patients who already have CVD [57,58].

The best evidence to date shows that fish oil supplements, which are typically taken in doses of 1 gram daily, are not beneficial for primary or secondary prevention of CVD. Additionally, prescription fish oil products in higher doses of 4 grams daily do not seem to be beneficial for the prevention of CVD. Although the benefits of consuming fish oil as part of the diet might offer only modest benefits for the primary or secondary prevention of CVD, people should continue to eat fish and other foods that provide omega-3 fatty acids, as these foods make up part of a healthy diet. In fact, in 2019, the FDA determined that it would allow a qualified health claim stating that foods containing EPA and DHA may reduce the risk of CVD. However, the FDA states that this claim is based on supportive, rather than conclusive, evidence [60].

Hypertension

There is some promising research on using fish oil supplements for blood pressure reduction, although most research suggests that this benefit may only occur in patients with very elevated blood pressure as opposed to those with mild hypertension. A meta-analysis of clinical research shows that, overall, fish oil reduces systolic blood pressure by about 3–5.5 mm Hg and diastolic blood pressure by 2–3.5 mm Hg in patients with hypertension. It is not clear whether the hypotensive effect of fish oil is dose-dependent [61,62].

Interestingly, some studies have suggested that different antihypertensive medications can alter the effect of fish oil on blood pressure. Some clinical evidence shows that adding fish oil 5 grams daily for six weeks does not provide additive blood pressure reduction in patients being treated with ACE inhibitors. However, other clinical research shows that fish oil provides additive reduction of systolic and diastolic blood pressure in hypertensive patients taking beta-blockers or diuretics [63].

If patients are interested in taking fish oil to reduce blood pressure, remind them that fish oil supplements have not been shown to provide any benefit for preventing CVD. Also, counsel patients that supplements containing only DHA or EPA, the omega-3 fatty acids in fish oil, have not been shown to provide the same benefits as fish oil for either blood pressure or CVD. Finally, the doses used in studies of fish oil supplements for hypertension are very high and can be difficult to obtain. This is similar to the need to take 12 capsules of supplemental fish oil versus 4 capsules of prescription fish oil for the treatment of hypertriglyceridemia.

Safety Concerns

Older adults may be at risk for some specific potential side effects from fish oil products. One commonly discussed adverse effect of omega-3 fatty acids is a potential increased risk for bleeding. This concern is due to some older research which suggested that doses greater than 3 grams per day can inhibit blood coagulation and potentially increase bleeding risk [64]. The most rigorous research to date shows that short-term doses of fish oil 10 grams daily and long-term doses of 1.5 grams daily for up to one year do not increase the risk of bleeding or affect coagulation parameters in chronically ill patients [64]. However, the doses studied for hypertension and hypertriglyceridemia exceed 1.5 grams daily; use caution when recommending fish oil supplements for older adults.

More recently, large randomized controlled trials have identified a possible increased risk for atrial fibrillation in people taking prescription fish oil. One large clinical study, called the STRENGTH trial, found that taking prescription fish oil 4 grams daily for up to six years was associated with an increased risk for atrial fibrillation, with a number needed to harm of 114 when compared with a corn oil control [65]. Also, meta-analyses show that taking omega-3 fatty acid supplements increases the incidence rate ratio for atrial fibrillation by up to 37% when compared with placebo. This incidence rate seems to increase with doses of more than 1 gram daily [66,67]. Thus, fish oil supplements should be used with caution in older adults at risk for atrial fibrillation.

Other adverse effects of fish oil are milder in nature and are typically limited to the gastrointestinal tract. Some patients experience fishy hiccups and a fishy breath odor and/or aftertaste. If patients experience diarrhea, heartburn, bloating, discomfort, or indigestion, they should be encouraged to start at a lower dose and increase slowly, and to take their supplements with meals.

Some fish may contain unsafe levels of certain toxins, including dioxins, mercury, and polychlorinated biphenyls (PCBs). PCBs are found in fish living in polluted waters and in some farmed fish, such as salmon. Freshwater fish frequently contain high levels of these chemicals, which may be carcinogenic [68]. Dioxins may be found in high concentrations in the feed given to farmed fish. Farmed salmon, the most common store-bought salmon in North America, is more likely to contain high concentrations of dioxin than wild-caught salmon [69]. Thus, fish should be consumed in moderation.

For patients who would like to take a fish oil supplement, make sure to only recommend products with appropriate quality certifications, including USP-Verified and NSF: Contents Certified. These supplements have been verified to reliably contain what is stated on the label and to be free of unsafe levels of contaminants, such as pesticides and heavy metals.

JOINT HEALTH

Joint health is another common concern that comes with aging. While some people may already have osteoarthritis, others are interested in taking supplements to prevent the development or slow the progression of the condition.

Glucosamine and Chondroitin

The most popular supplements for joint health are glucosamine and chondroitin, often taken together in a combination product. Glucosamine is an amino sugar that occurs naturally in humans. It is necessary for the synthesis of glycoproteins, glycolipids, and glycosaminoglycans. These compounds are found in tendons, ligaments, cartilage, synovial fluid, mucous membranes, blood vessels, heart valves, and structures of the eye. There are multiple forms of glucosamine available on the market [70]. Glucosamine sulfate is the most common form. This form must be created semi-synthetically in a lab. Glucosamine hydrochloride is the second most common form. This salt occurs naturally and can be obtained from shellfish, fungi, or corn via a simple extraction process. N-acetyl glucosamine, the acetylated derivative of glucosamine, is the least common form found in supplements [71].

Chondroitin sulfate is a glycosaminoglycan found naturally in the body, particularly in connective tissues. It is a very large molecule; the species or tissue of origin, as well as the extraction method used, can affect its final size [72].

Extensive research has been conducted on the use of glucosamine for the management of osteoarthritis. Thus far, the best evidence is for glucosamine sulfate. Glucosamine hydrochloride has not shown any real benefit in clinical research.

Glucosamine

Most research has focused on the use of oral glucosamine sulfate for the management of knee osteoarthritis. Meta-analyses of the available research show that taking glucosamine sulfate 1,500 mg daily for up to three years modestly improves pain and function when compared with placebo [73]. Individual studies have shown a 28% to 41% pain reduction and 21% to 46% improvement in function [74]. Small studies comparing glucosamine sulfate with NSAIDs, such as ibuprofen 400 mg three times daily or piroxicam 20 mg daily, suggest that these treatments provide similar benefit. However, NSAIDs appear to relieve symptoms within two weeks, whereas glucosamine sulfate can take four to eight weeks [75].

The benefits of glucosamine sulfate seem to vary depending on the product used. To date, the most consistently positive evidence for glucosamine sulfate has been seen with Dona, a specific, pharmaceutical-grade, crystalline glucosamine sulfate product. This formulation of glucosamine sulfate has demonstrated high bioavailability resulting in high plasma concentrations, although the clinical relevance of this is unclear [76]. Experts currently disagree as to whether the benefit seen with this product is due to bias introduced by industry funding or due to a higher quality product.

Chondroitin Sulfate

Chondroitin sulfate, when taken alone, has demonstrated modest benefit for reducing pain and improving function in some patients with knee osteoarthritis. Meta-analyses of the available research show that taking chondroitin sulfate 800–2,000 mg in single or divided doses daily for at least three months can modestly reduce pain and disability when compared with placebo [77]. Other clinical research in adults with knee or hip osteoarthritis shows that taking chondroitin sulfate daily at a dose of at least 800 mg for two years might modestly reduce joint degeneration and narrowing when compared with placebo or celecoxib [78,79].

Glucosamine Sulfate and Chondroitin Sulfate Combinations

Although most evidence evaluating glucosamine sulfate or chondroitin sulfate alone suggests modest benefit for knee osteoarthritis, research on the use of combination products is less conclusive. Some long-term studies in patients with osteoarthritis show that taking this combination modestly reduces joint space narrowing when compared with a control group [71,80]. But not all research is positive. Some individual clinical studies, as well as meta-analyses of the available research, have not shown a reduction in pain in patients taking chondroitin sulfate in combination with either glucosamine hydrochloride or glucosamine sulfate [81].

The place of glucosamine and chondroitin in clinical practice is unclear. In fact, clinical guidelines provide conflicting recommendations [71,82]. The American College of Rheumatology (ACR) strongly recommends against the use of any glucosamine or chondroitin products for any form of osteoarthritis. Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends for the use of pharmaceutical-grade glucosamine sulfate or chondroitin sulfate products in patients with osteoarthritis. The ESCEO also provides a weak recommendation against the use of glucosamine and chondroitin in combination.

These conflicting recommendations are related to differing interpretations of the previously discussed evidence. The ACR has determined that the positive benefits identified in industry-funded studies indicates the introduction of industry bias [82]. The ESCEO, on the other hand, has determined that the positive benefits identified in industry-funded studies is due to the higher quality and bioavailability of the products used [71].

If a patient would like to use these products, be sure to recommend one that carries a third-party quality certification to minimize concerns related to product quality and potency.

Safety

Both glucosamine and chondroitin are relatively safe for most adults. The most commonly reported adverse effects are minor gastrointestinal disturbances, such as abdominal pain, bloating, constipation, diarrhea, and heartburn.

Some case reports have suggested that glucosamine and/or chondroitin may interact with warfarin, causing an elevation in international normalized ratio (INR). Although the likelihood of this risk is unclear, use caution in patients taking warfarin and monitor INR closely.

Collagen

Another supplement that has gained popularity for osteoarthritis and joint health is collagen. Collagen is a hard, insoluble protein that occurs naturally in the human body and is found in the bones, cartilage, muscles, skin, and tendons. It is a structural protein, meaning that it is crucial to the shape and structure of cells and tissues in the body [83].

Some supplements contain intact collagen, often either collagen type I, II, or III. However, much more often, collagen supplements contain hydrolyzed collagen, or collagen peptides, that are derived from these intact forms of collagen. This is also sometimes referred to on labels as collagen hydrolysate.

Benefits

Collagen types I and II have been evaluated for use in knee osteoarthritis, with small studies suggesting the potential for modest benefit with certain formulations. However, the most extensive research has been conducted with collagen peptides [84,85].

Some clinical studies in adults with knee osteoarthritis suggest that collagen peptides 5–10 grams, taken for three to six months, may modestly reduce pain. However, any improvements appear to be small, and not all research has yielded positive findings. One clinical study shows that taking oral collagen peptides reduces pain by at least 30% in 42% more patients when compared with placebo. However, there was no improvement when the Western Ontario and McMaster Universities (WOMAC) scale was used [84]. In another study, taking collagen peptides reduced pain by about two points on a 100-point scale, compared with a 0.9-point reduction in those taking glucosamine sulfate 1,500 mg. There was no reduction in the use of ibuprofen in these patients [85].

Although some research suggests the potential for modest benefit, it is not clear that collagen peptides can improve pain to a clinically meaningful degree. Patients should not rely on collagen peptides for the management of knee osteoarthritis, although it may be considered as an adjunct therapy in patients with more severe disease.

Safety

Overall, collagen appears to be safe for adults when taken by mouth at doses evaluated in clinical research. There are very limited reports of adverse effects with collagen products. Some minor gastrointestinal upset has been reported rarely with the use of collagen peptides.

7. NATURAL PRODUCTS FOR COGNITIVE CHANGES

One of the major concerns that comes with age is a decline in cognitive function, which can present as either cognitive impairment or dementia. Because there are no approved or confirmed preventive strategies for reducing the risk of age-related cognitive impairment or dementia, many people consider the use of supplements. Similarly, some people use supplements to slow the advancement of cognitive impairment and/or dementia.

It should be noted that many studies of supplements for the improvement of cognitive function in older adults are small and may be of low quality. For example, some studies do not use a placebo control, and the majority of these products have not been compared to prescription drugs for dementia. Although this does not invalidate all of the available research, the results should be interpreted with caution.

LIFESTYLE INTERVENTIONS

First, it is worth noting that lifestyle changes are the most commonly recommended preventive measures for mild cognitive decline or dementia. The World Health Organization (WHO) recommends that all adults, with or without cognitive impairment, get adequate physical activity (as discussed) to reduce the risk of cognitive impairment. The organization also recommends that all adults consume a Mediterranean-like diet in order to slow cognitive decline (Table 2) [86]. However, it should be noted that the research identifying a benefit for age-related cognitive impairment involved strict adherence to the Mediterranean diet; people who had only moderate adherence did not experience a benefit [87,88].

Table 2: WHAT IS A MEDITERRANEAN-LIKE DIET?

A Mediterranean-like diet emphasizes foods such as olive oil, fruits, vegetables, legumes, and whole grains. This is intended to provide a high ratio of monounsaturated-to-saturated fat. The diet also emphasizes fish and reduces overall meat intake, while allowing for moderate-to-modest amounts of red wine and dairy. In general, the diet avoids highly processed foods, refined grains, and sugars.

Source: Author

In general, regular consumption of fruits, vegetables, and fish is most consistently associated with a reduced risk of dementia. This has led to interest in the use of fish oil to prevent cognitive decline. However, the observational research that has been conducted to date has not found an association between risk of mild cognitive impairment or dementia and the use of fish oil supplements [89,90,91].

The WHO also recommends weight loss for people who are overweight or obese, as well as reducing alcohol consumption. Both of these changes can have multiple downstream health benefits, but there is also some early evidence suggesting that they can reduce cognitive decline [86].

Finally, the WHO recommends social participation and social support, which "are strongly connected to good health and well-being throughout life and social inclusion should be supported over the life-course" [86]. However, it is important to note that there is no evidence showing a direct association between social participation and cognitive function. For now, encourage social support and participation due to the many other benefits it can offer, including to mental health [86].

NUTRIENT SUPPLEMENTS

Vitamin E

Vitamin E is one of the most popular vitamin supplements for dementia and cognitive impairment. In fact, there is some evidence to show that taking vitamin E can modestly slow cognitive function decline in patients with Alzheimer disease. However, it does not seem to prevent the onset of Alzheimer disease or prevent cognitive decline in general. Thus, the WHO recommends against the use of vitamin E for prevention [86].

Additionally, there are concerns about the safety of vitamin E in older adults. Most of the studies showing benefit for Alzheimer disease used a dose of 2,000 IU daily. Some research in middle-aged and older patients with chronic diseases suggests that vitamin E in doses above 400 IU daily may increase the risk of adverse outcomes and mortality [115]. On the other hand, these doses appear to be safe in otherwise healthy adults. It is not entirely clear which population is safe to use large supplemental doses of vitamin E, but it should be used with caution in older adults, particularly those with multiple comorbidities.

Idebenone

Another nutrient-like supplement that is sometimes touted for cognitive function is idebenone. This is a synthetic analogue of coenzyme Q10. Some older studies have shown that taking 90–120 mg three times daily for six months slows the decline of cognitive function in adults with Alzheimer disease [92]. However, there is no available research in adults with mild cognitive impairment or other forms of dementia.

Idebenone seems to be well tolerated by most adults although it can cause some gastrointestinal side effects such as nausea and vomiting, abdominal pain, and loose stools.

HERBAL SUPPLEMENTS

Ginkgo

Ginkgo (Ginkgo biloba) is one of the most popular herbal supplements for dementia and cognitive impairment. The leaves of this plant have a long history of use in traditional Chinese medicine, and there is some evidence to support their use in people who already have dementia. Research in people with Alzheimer disease, vascular dementia, or mixed dementia shows that taking ginkgo 240 mg daily for about six months modestly improves cognition and activities of daily living when compared with placebo. A lower dose of 120 mg daily does not seem to offer the same benefit [93,94,95,96].

It is important to note that the product used in these studies was a specific ginkgo supplement—Egb 761. This supplement differs from other ginkgo products because it has been standardized to contain 22% to 27% flavone glycosides and 5% to 7% terpene lactones, which includes ginkgolides A, B, and C. Other ginkgo supplements may not be standardized to these same chemicals, and thus they may have different (or lower) activity [97].

As with vitamin E, ginkgo has not shown benefit for the prevention of dementia in those with normal cognitive function or in those with mild cognitive impairment. It also does not seem to prevent disease progression in people with Alzheimer disease. Thus, the WHO guidelines do not recommend ginkgo for the prevention of MCI or dementia [86].

Ginkgo is considered generally safe for most adults. There have been some rare reports of arrhythmia in patients who take ginkgo supplements. It is unclear if this relationship is coincidental or causative, but there have been enough reports to lead Health Canada and the WHO to release warnings about the use of these products [86,98].

There is also significant interest in the use of ginkgo supplements for tinnitus, another issue that becomes more common with age. In fact, tinnitus can even contribute to cognitive impairment and lack of social participation. Unfortunately, clinical studies show that taking ginkgo leaf extract does not improve symptoms of tinnitus [99,100]. It should not be recommended for this purpose.

Huperzine A

Huperzine A is a chemical that is isolated from a type of moss, called the Chinese club moss (Huperzia serrata). Because it is derived from moss, this chemical is sometimes sold as a supplement, either as a single ingredient or in combination with other ingredients. There are multiple reasons that this chemical is of interest for dementia and mild cognitive impairment, including its antioxidant and anti-apoptotic effects, as well as its possible activity against beta-amyloid.

Clinical research in adults with Alzheimer disease shows that taking huperzine A 200–800 mg in divided doses daily for two to nine months improves cognitive function on the Mini-Mental State Exam (MMSE) when compared with placebo [101,102]. It should be noted that most research has been conducted in China, where this chemical is an approved drug. One clinical study conducted in the United States shows that taking 400 mg twice daily improves performance on the MMSE and the Alzheimer Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) when compared with placebo. A lower dose of 200 mg twice daily was not consistently beneficial [103].

Huperzine can cause cholinergic side effects such as dizziness, sweating, insomnia, nausea, vomiting, and diarrhea. However, it is generally well tolerated by most adults.

Bacopa

Another herbal supplement that is sometimes touted for cognitive health in older adults is bacopa (Bacopa monnieri). This plant is found in India and has been used for centuries in Ayurvedic medicine. There is interest in its use for dementia and cognitive impairment because it has demonstrated cholinergic activity in laboratory studies. However, only one small study has evaluated bacopa in adults with Alzheimer disease or mild cognitive impairment. This study showed that taking bacopa 300 mg daily for 12 months did not offer any benefits when compared with donepezil or baseline [104].

Bacopa has been reported to cause increased stool frequency, nausea, and abdominal cramps in 16% to 30% of patients in clinical studies [116]. Considering that it has not shown benefit for cognitive function in older adults, steer patient away from bacopa supplements.

ENDOGENOUS SUBSTANCES

Alpha-L-Carnitine

Alpha-L-carnitine is an ester of L-carnitine, which is an amino acid derivative that is found naturally in the body. It is made in the brain, liver, and kidneys, and the body can convert it to and from L-carnitine as needed. Alpha-L-carnitine is structurally similar to acetylcholine, which has led to interest in its use for dementia and mild cognitive impairment. Small clinical studies show that taking 1.5–2 grams daily for three months can improve some measures of cognitive function in older adults with mild cognitive impairment [105,106]. Similarly, small clinical studies show that taking 1.5–3 grams daily for three to 12 months can slow the rate of Alzheimer disease progression and improve some measures of cognitive function [107].

Alpha-L-carnitine is generally well tolerated by most adults, although it can cause headache, insomnia, and agitation in some people. Let patients know that it can also cause the breath, urine, and sweat to have a fishy odor, which is not harmful [108].

Phosphatidylserine

Phosphatidylserine is a phospholipid that is naturally made by the human body. It is a component of the cell membrane and is found in high quantities in the brain. Thus, there is interest in its use for improving cognitive function in all age groups.

To date, the best evidence for the use of phosphatidylserine is for the improvement of cognitive function in adults with age-related mild cognitive impairment or Alzheimer disease. This research shows that taking phosphatidylserine, usually as 300 mg daily in divided doses, for six weeks to six months improves attention, verbal fluency, and memory. However, it should be noted that these studies were very small, and some did not use blinding or a placebo control group. Additionally, the studies are old and may not be representative of current standards of care [109,110].

As for preventing the development of Alzheimer disease or mild cognitive impairment, clinical research has not shown a benefit. Also, there is currently no research on the use of phosphatidylserine in other types of dementia. However, phosphatidylserine is generally safe to use, with the most common adverse effects being flatulence and nausea. This may be a reasonable option for patients interested in taking a supplement.

Citicoline

Citicoline is a chemical that occurs during the synthesis of choline from phosphatidylcholine in the body. Some small clinical studies in older adults with MCI have shown that taking citicoline 500–2,000 mg daily for up to three months moderately improves memory scores when compared with placebo [111]. The research in patients with Alzheimer disease is relatively limited, and there is no available research in patients with other forms of dementia. Citicoline is well tolerated by most adults.

Alpha-GPC

Alpha-GPC is another chemical that is related to choline, except that this chemical is naturally produced by the body from choline. It is a precursor to acetylcholine, a neurotransmitter. There has been some research on the use of this supplement in patients with vascular dementia and Alzheimer disease that shows modest benefit, but these studies are small and should not be relied upon [117]. The most common adverse effects with alpha-GPC are diarrhea, heartburn, nausea, and vomiting.

8. CONCLUSION

Aging causes a number of changes to the body that affect physical function, cognitive function, and overall quality of life. Older adults frequently report using supplements, often for the purpose of improving overall health, but also for the purposes of improving musculoskeletal health, nutrition, cardiovascular health, and more. It is important for healthcare professionals to be aware that supplements can interact with drugs and medical conditions, and that some supplements carry serious health risks for certain patients. However, some supplements may be a reasonable option for older patients who are looking to improve their health and quality of life and can be safely recommended.

Works Cited

1. Institute of Medicine Committee on the Future Health Care Workforce for Older Americans. Retooling for an Aging America: Building the Health Care Workforce. Washington, DC: National Academies Press; 2008.

2. Gahche JJ, Bailey RL, Potischman N, Dwyer JT. Dietary supplement use was very high among older adults in the United States in 2011–2014. J Nutr. 2017;147(10):1968-1976.

3. Alvis BD, Hughes CG. Physiology considerations in geriatric patients. Anesthesiol Clin. 2015;33(3):447-456.

4. Tan JL, Eastment JG, Poudel A, Hubbard RE. Age-related changes in hepatic function: an update on implications for drug therapy. Drugs Aging. 2015;32(12):999-1008.

5. Aymanns C, Keller F, Maus S, Hartmann B, Czock D. Review on pharmacokinetics and pharmacodynamics and the aging kidney. Clin J Am Soc Nephrol. 2010;5(2):314-327.

6. Guaraldo L, Cano FG, Damasceno GS, Rozenfeld S. Inappropriate medication use among the elderly: a systematic review of administrative databases. BMC Geriatr. 2011;11:79.

7. 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081.

8. TRC Healthcare NatMed PRO Database. Sedative-Hypnotic Agents. Available at https://naturalmedicines.therapeuticresearch.com/tools/charts/chartdisplay.aspx?classificationID=45. Last accessed May 17, 2024.

9. TRC Healthcare NatMed PRO Database. Anticholinergic Agents. Last accessed August 2, 2023. https://naturalmedicines.therapeuticresearch.com/tools/charts/chartdisplay.aspx?classificationID=3. Last accessed May 17, 2024.

10. TRC Healthcare NatMed PRO Database. Hepatotoxic Agents. Last accessed August 2, 2023. https://naturalmedicines.therapeuticresearch.com/tools/charts/chartdisplay.aspx?classificationID=25. Last accessed May 17, 2024.

11. TRC Healthcare NatMed PRO Database. Nephrotoxic Agents. Last accessed August 2, 2023. https://naturalmedicines.therapeuticresearch.com/tools/charts/chartdisplay.aspx?classificationID=31. Last accessed May 17, 2024.

12. TRC Healthcare NatMed PRO Database. Anticoagulant Agents. Last accessed August 2, 2023. https://naturalmedicines.therapeuticresearch.com/tools/charts/chartdisplay.aspx?classificationID=4. Last accessed May 17, 2024.

13. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2010.

14. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academies Press; 2002.

15. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academies Press; 2002.

16. Fidler MC, Davidsson L, Zeder C, Walczyk T, Hurrell RF. Iron absorption from ferrous fumarate in adult women is influenced by ascorbic acid but not by Na2EDTA. Br J Nutr. 2003;90(6):1081-1085.

17. Davidsson L, Walczyk T, Zavaleta N, Hurrell R. Improving iron absorption from a Peruvian school breakfast meal by adding ascorbic acid or Na2EDTA. Am J Clin Nutr. 2001;73(2):283-287.

18. Shapses SA, Sukumar D, Schneider SH, et al. Vitamin D supplementation and calcium absorption during caloric restriction: a randomized double-blind trial. Am J Clin Nutr. 2013;97(3):637-645.

19. Donangelo CM, Woodhouse LR, King SM, Viteri FE, King JC. Supplemental zinc lowers measures of iron status in young women with low iron reserves. J Nutr. 2002;132(7):1860-1864.

20. O'Brien KO, Zavaleta N, Caulfield LE, Yang DX, Abrams SA. Influence of prenatal iron and zinc supplements on supplemental iron absorption, red blood cell iron incorporation, and iron status in pregnant Peruvian women. Am J Clin Nutr. 1999;69(3):509-515.

21. U.S. Preventive Services Task Force, Mangione CM, Barry MJ, et al. Vitamin, mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer: U.S. Preventive Services Task Force recommendation statement. JAMA. 2022;327(23):2326.

22. Kim J, Ahn CW, Fang S, Lee HS, Park JS. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore). 2019;98(46):e17918.

23. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442.

24. U.S. Department of Agriculture. Dietary Guidelines for Americans, 2020–2025. Available at http://www.dietaryguidelines.gov. Last accessed May 17, 2024.

25. Kjeldby IK, Fosnes GS, Ligaarden SC, Farup PG. Vitamin B6 deficiency and diseases in elderly people: a study in nursing homes. BMC Geriatr. 2013;13:13.

26. U.S. Preventive Services Task Force, Grossman DC, Curry SJ, et al. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: U.S. Preventive Services Task Force recommendation statement. JAMA. 2018;319(15):1592.

27. LeBoff MS, Greenspan SL, Insogna KL, et al. The clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2022;33(10):2049-2102.

28. U.S. Preventive Services Task Force, Grossman DC, Curry SJ, et al. Interventions to prevent falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement. JAMA. 2018;319(16):1696.

29. U.S. Food and Drug Administration. Proton Pump Inhibitor Drugs (PPIs): Drug Safety Communication: Low Magnesium Levels Can Be Associated With Long-Term Use. Available at https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-low-magnesium-levels-can-be-associated-long-term-use-proton-pump. Last accessed May 17, 2024.

30. Rizzoli R, Stevenson JC, Bauer JM, et al. The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: a consensus statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Maturitas. 2014;79(1):122-132.

31. U.S. Food and Drug Administration. Questions and Answers on Dietary Fiber. Available at https://www.fda.gov/food/food-labeling-nutrition/questions-and-answers-dietary-fiber. Last accessed May 17, 2024.

32. Noureddin S, Mohsen J, Payman A. Effects of psyllium vs. placebo on constipation, weight, glycemia, and lipids: a randomized trial in patients with type 2 diabetes and chronic constipation. Complement Ther Med. 2018;40:1-7.

33. Centers for Disease Control and Prevention. How Much Physical Activity Do Older Adults Need? Available at https://www.cdc.gov/physicalactivity/basics/older_adults/index.htm. Last accessed May 17, 2024.

34. Gernigon G, Piot M, Beaucher E, Jeantet R, Schuck P. Physicochemical characterization of mozzarella cheese wheys and stretchwaters in comparison with several other sweet wheys. J Dairy Sci. 2009;92(11):5371-5377.

35. Kuivaniemi H, Tromp G. Type III collagen (COL3A1): gene and protein structure, tissue distribution, and associated diseases. Gene. 2019;707:151-171.

36. Lynch HM, Buman MP, Dickinson JM, Ransdell LB, Johnston CS, Wharton CM. No significant differences in muscle growth and strength development when consuming soy and whey protein supplements matched for leucine following a 12 week resistance training program in men and women: a randomized trial. Int J Environ Res Public Health. 2020;17(11):3871.

37. Nabuco HCG, Tomeleri CM, Sugihara Junior P, et al. Effects of whey protein supplementation pre- or post-resistance training on muscle mass, muscular strength, and functional capacity in pre-conditioned older women: a randomized clinical trial. Nutrients. 2018;10(5):563.

38. Sugihara Junior P, Ribeiro AS, Nabuco HCG, et al. Effects of whey protein supplementation associated with resistance training on muscular strength, hypertrophy, and muscle quality in preconditioned older women. Int J Sport Nutr Exerc Metab. 2018;28(5):528-535.

39. Mertz KH, Reitelseder S, Bechshoeft R, et al. The effect of daily protein supplementation, with or without resistance training for 1 year, on muscle size, strength, and function in healthy older adults: a randomized controlled trial. Am J Clin Nutr. 2021;113(4):790-800.

40. Peng LN, Yu PC, Hsu CC, et al. Sarcojoint, the branched-chain amino acid-based supplement, plus resistance exercise improved muscle mass in adults aged 50 years and older: a double-blinded randomized controlled trial. Exp Gerontol. 2022;157:111644.

41. Ikeda T, Matsunaga Y, Kanbara M, et al. Effect of exercise therapy combined with branched-chain amino acid supplementation on muscle strength in elderly women after total hip arthroplasty: a randomized controlled trial. Asia Pac J Clin Nutr. 2019;28(4):720-726.

42. Forbes SC, Candow DG, Ostojic SM, Roberts MD, Chilibeck PD. Meta-analysis examining the importance of creatine ingestion strategies on lean tissue mass and strength in older adults. Nutrients. 2021;13(6):1912.

43. Dos Santos EEP, de Araújo RC, Candow DG, et al. Efficacy of creatine supplementation combined with resistance training on muscle strength and muscle mass in older females: a systematic review and meta-analysis. Nutrients. 2021;13(11):3757.

44. Groeneveld GJ, Beijer C, Veldink JH, Kalmijn S, Wokke JHJ, van den Berg LH. Few adverse effects of long-term creatine supplementation in a placebo-controlled trial. Int J Sports Med. 2005;26(4):307-313.

45. Lin Z, Zhao Y, Chen Q. Effects of oral administration ofβ-hydroxyβ-methylbutyrate on lean body mass in older adults: a systematic review and meta-analysis. Eur Geriatr Med. 2021;12(2):239-251.

46. Osuka Y, Kojima N, Sasai H, et al. Effects of exercise and/orβ-hydroxy-βmethylbutyrate supplementation on muscle mass, muscle strength, and physical performance in older women with low muscle mass: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2021;114(4):1371-1385.

47. Peng LN, Cheng YC, Yu PC, Lee WJ, Lin MH, Chen LK. Oral nutritional supplement withβ-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. J Nutr Health Aging. 2021;25(6):767-773.

48. Rathmacher JA, Pitchford LM, Khoo P, et al. Long-term effects of calciumβ-hydroxy-β-methylbutyrate and vitamin D3 supplementation on muscular function in older adults with and without resistance training: a randomized, double-blind, controlled study. J Gerontol A Biol Sci Med Sci. 2020;75(11):2089-2097.

49. Courel-Ibáñez J, Vetrovsky T, Dadova K, Pallarés JG, Steffl M. Health benefits ofβ-hydroxy-β-methylbutyrate (HMB) supplementation in addition to physical exercise in older adults: a systematic review with meta-analysis. Nutrients. 2019;11(9):2082.

50. Furst T, Massaro A, Miller C, Williams BT, LaMacchia ZM, Horvath PJ. β-Alanine supplementation increased physical performance and improved executive function following endurance exercise in middle aged individuals. J Int Soc Sports Nutr. 2018;15(1):32.

51. McCormack WP, Stout JR, Emerson NS, et al. Oral nutritional supplement fortified with beta-alanine improves physical working capacity in older adults: a randomized, placebo-controlled study. Exp Gerontol. 2013;48(9):933-939.

52. del Favero S, Roschel H, Solis MY, et al. Beta-alanine (Carnosyn) supplementation in elderly subjects (60–80 years): effects on muscle carnosine content and physical capacity. Amino Acids. 2012;43(1):49-56.

53. Varanoske AN, Hoffman JR, Church DD, et al. Comparison of sustained-release and rapid-releaseβ-alanine formulations on changes in skeletal muscle carnosine and histidine content and isometric performance following a muscle-damaging protocol. Amino Acids. 2019;51(1):49-60.

54. Perim P, Gobbi N, Duarte B, et al. Beta-alanine did not improve high-intensity performance throughout simulated road cycling. Eur J Sport Sci. 2022;22(8):1240-1249.

55. Flaxel CJ, Adelman RA, Bailey ST, et al. Age-related macular degeneration preferred practice pattern. Ophthalmology. 2020;127(1):P1-P65.

56. Backes J, Anzalone D, Hilleman D, Catini J. The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia. Lipids Health Dis. 2016;15(1):118.

57. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7(7):CD003177.

58. ASCEND Study Collaborative Group, Bowman L, Mafham M, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379(16):1540-1550.

59. Rimm EB, Appel LJ, Chiuve SE, et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2018;138(1):e35-e47.

60. U.S. Food and Drug Administration. Letter Responding to Health Claim Petition dated November 3, 2003 (Martek Petition): Omega-3 Fatty Acids and Reduced Risk of Coronary Heart Disease (Docket No. 2003Q-0401). Available at http://wayback.archive-it.org/7993/20171114183727/https://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm072932.htm. Last accessed May 17, 2024.

61. Miller PE, Van Elswyk M, Alexander DD. Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a meta-analysis of randomized controlled trials. Am J Hypertens. 2014;27(7):885-896.

62. Campbell F, Dickinson HO, Critchley JA, Ford GA, Bradburn M. A systematic review of fish-oil supplements for the prevention and treatment of hypertension. Eur J Prev Cardiol. 2013;20(1):107-120.

63. Howe PR, Lungershausen YK, Cobiac L, Dandy G, Nestel PJ. Effect of sodium restriction and fish oil supplementation on BP and thrombotic risk factors in patients treated with ACE inhibitors. J Hum Hypertens. 1994;8(1):43-49.

64. Jeansen S, Witkamp RF, Garthoff JA, van Helvoort A, Calder PC. Fish oil LC-PUFAs do not affect blood coagulation parameters and bleeding manifestations: analysis of 8 clinical studies with selected patient groups on omega-3-enriched medical nutrition. Clin Nutr Edinb Scotl. 2018;37(3):948-957.

65. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH Randomized Clinical Trial. JAMA. 2020;324(22):2268-2280.

66. Gencer B, Djousse L, Al-Ramady OT, Cook NR, Manson JE, Albert CM. Effect of long-term marineɷ-3 fatty acids supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes: a systematic review and meta-analysis. Circulation. 2021;144(25):1981-1990.

67. Khan SU, Lone AN, Khan MS, et al. Effect of omega-3 fatty acids on cardiovascular outcomes: a systematic review and meta-analysis. EClinicalMedicine. 2021;38:100997.

68. Wilson JF. Balancing the risks and benefits of fish consumption. Ann Intern Med. 2004;141(12):977-980.

69. Foran JA, Carpenter DO, Hamilton MC, Knuth BA, Schwager SJ. Risk-based consumption advice for farmed Atlantic and wild Pacific salmon contaminated with dioxins and dioxin-like compounds. Environ Health Perspect. 2005;113(5):552-556.

70. McAlindon T. Why are clinical trials of glucosamine no longer uniformly positive? Rheum Dis Clin North Am. 2003;29(4):789-801.

71. Bruyère O, Honvo G, Veronese N, et al. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum. 2019;49(3):337-350.

72. O'Rourke M. Determining the efficacy of glucosamine and chondroitin for osteoarthritis. Nurse Pract. 2001;26(6):44-46, 49-52.

73. Gregori D, Giacovelli G, Minto C, et al. Association of pharmacological treatments with long-term pain control in patients with knee osteoarthritis: a systematic review and meta-analysis. JAMA. 2018;320(24):2564-2579.

74. Eriksen P, Bartels EM, Altman RD, Bliddal H, Juhl C, Christensen R. Risk of bias and brand explain the observed inconsistency in trials on glucosamine for symptomatic relief of osteoarthritis: a meta-analysis of placebo-controlled trials. Arthritis Care Res. 2014;66(12):1844-1855.

75. Müller-Fassbender H, Bach GL, Haase W, Rovati LC, Setnikar I. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage. 1994;2(1):61-69.

76. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis. Rheumatol Int. 2010;30(3):357-363.

77. Honvo G, Bruyère O, Geerinck A, Veronese N, Reginster JY. Efficacy of chondroitin sulfate in patients with knee osteoarthritis: a comprehensive meta-analysis exploring inconsistencies in randomized, placebo-controlled trials. Adv Ther. 2019;36(5):1085-1099.

78. Pelletier JP, Raynauld JP, Beaulieu AD, et al. Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study. Arthritis Res Ther. 2016;18(1):256.

79. Singh JA, Noorbaloochi S, MacDonald R, Maxwell LJ. Chondroitin for osteoarthritis. Cochrane Database Syst Rev. 2015;1(1):CD005614.

80. Zeng C, Wei J, Li H, et al. Effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015;5:16827.

81. Simental-Mendía M, Sánchez-García A, Vilchez-Cavazos F, Acosta-Olivo CA, Peña-Martínez VM, Simental-Mendía LE. Effect of glucosamine and chondroitin sulfate in symptomatic knee osteoarthritis: a systematic review and meta-analysis of randomized placebo-controlled trials. Rheumatol Int. 2018;38(8):1413-1428.

82. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol Hoboken NJ. 2020;72(2):220-233.

83. Sibilla S, Godfrey M, Brewer S, Budh-Raja A, Genovese L. An overview of the beneficial effects of hydrolysed collagen as a nutraceutical on skin properties: scientific background and clinical studies. Open Nutraceuticals J. 2015;8(1):29-42.

84. Benito-Ruiz P, Camacho-Zambrano MM, Carrillo-Arcentales JN, et al. A randomized controlled trial on the efficacy and safety of a food ingredient, collagen hydrolysate, for improving joint comfort. Int J Food Sci Nutr. 2009;60(Suppl 2):99-113.

85. Trč T, Bohmová J. Efficacy and tolerance of enzymatic hydrolysed collagen (EHC) vs. glucosamine sulphate (GS) in the treatment of knee osteoarthritis (KOA). Int Orthop. 2011;35(3):341-348.

86. World Health Organization. WHO Guidelines: Risk Reduction of Cognitive Decline and Dementia. Available at https://www.who.int/publications/i/item/9789241550543. Last accessed May 17, 2024.

87. Charisis S, Ntanasi E, Yannakoulia M, et al. Mediterranean diet and risk for dementia and cognitive decline in a Mediterranean population. J Am Geriatr Soc. 2021;69(6):1548-1559.

88. Andreu-Reinón ME, Chirlaque MD, Gavrila D, et al. Mediterranean diet and risk of dementia and Alzheimer's disease in the EPIC-Spain Dementia Cohort Study. Nutrients. 2021;13(2):700.

89. Ma H, Zhou T, Li X, Heianza Y, Qi L. Use of fish oil supplements is differently related to incidence of all-cause and vascular dementia among people with the distinct APOEε4 dosage. Clin Nutr Edinb Scotl. 2022;41(3):731-736.

90. Huang Y, Deng Y, Zhang P, et al. Associations of fish oil supplementation with incident dementia: evidence from the UK Biobank cohort study. Front Neurosci. 2022;16:910977.

91. Brainard JS, Jimoh OF, Deane KHO, et al. Omega-3, omega-6, and polyunsaturated fat for cognition: systematic review and meta-analysis of randomized trials. J Am Med Dir Assoc. 2020;21(10):1439-1450.

92. Weyer G, Babej-Dölle RM, Hadler D, Hofmann S, Herrmann WM. A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease. Neuropsychobiology. 1997;36(2):73-82.

93. Hashiguchi M, Ohta Y, Shimizu M, Maruyama J, Mochizuki M. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia. J Pharm Health Care Sci. 2015;1:14.

94. Thancharoen O, Limwattananon C, Waleekhachonloet O, Rattanachotphanit T, Limwattananon P, Limpawattana P. Ginkgo biloba extract (egb761), cholinesterase inhibitors, and memantine for the treatment of mild-to-moderate Alzheimer's disease: a network meta-analysis. Drugs Aging. 2019;36(5):435-452.

95. Sawangjit R, Chuenchom C, Sanverm T, et al. Efficacy and safety of herbal medicine on dementia and cognitive function: an umbrella review of systematic reviews and meta-analysis. Phytother Res PTR. 2023;37(6):2364-2380.

96. Liao Z, Cheng L, Li X, Zhang M, Wang S, Huo R. Meta-analysis of Ginkgo biloba preparation for the treatment of Alzheimer's disease. Clin Neuropharmacol. 2020;43(4):93-99.

97. Decker L, Basta D, Burkart M, Ernst A. Balance training with vibrotactile neurofeedback and Ginkgo biloba extract in age-related vertigo. Front Neurol. 2021;12:691917.

98. Health Canada. Ginkgo Biloba-Containing Products and the Risk of Cardiac Arrhythmias. Available at https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/health-product-infowatch/february-2021.html#ginkgo_biloba. Last accessed May 17, 2024.

99. Chauhan B, Arya S, Chauhan K. Ginkgo biloba administered singly and combined with antioxidants in tinnitus patients. J Audiol Otol. 2023;27(1):37-44.

100. Sereda M, Xia J, Scutt P, Hilton MP, El Refaie A, Hoare DJ. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev. 2022;11(11):CD013514.

101. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis. J Neural Transm Vienna Austria. 2009;116(4):457-465.

102. Cui CC, Sun Y, Wang XY, Zhang Y, Xing Y. The effect of anti-dementia drugs on Alzheimer disease-induced cognitive impairment: a network meta-analysis. Medicine (Baltimore). 2019;98(27):e16091.

103. Rafii MS, Walsh S, Little JT, et al. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology. 2011;76(16): 1389-1394.

104. Prabhakar S, Vishnu VY, Modi M, et al. Efficacy of Bacopa monnieri (brahmi) and donepezil in Alzheimer's disease and mild cognitive impairment: a randomized double-blind parallel phase 2b study. Ann Indian Acad Neurol. 2020;23(6):767-773.

105. Salvioli G, Neri M. L-acetylcarnitine treatment of mental decline in the elderly. Drugs Exp Clin Res. 1994;20(4):169-176.

106. Passeri M, Cucinotta D, Bonati PA, Iannuccelli M, Parnetti L, Senin U. Acetyl-L-carnitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res. 1990;10(1-2):75-79.

107. Hudson S, Tabet N. Acetyl-L-carnitine for dementia. Cochrane Database Syst Rev. 2003;2003(2):CD003158.

108. Evans AM, Fornasini G. Pharmacokinetics of L-carnitine. Clin Pharmacokinet. 2003;42(11):941-967.

109. Fünfgeld EW, Baggen M, Nedwidek P, Richstein B, Mistlberger G. Double-blind study with phosphatidylserine (PS) in parkinsonian patients with senile dementia of Alzheimer's type (SDAT). Prog Clin Biol Res. 1989;317:1235-1246.

110. Schreiber S, Kampf-Sherf O, Gorfine M, Kelly D, Oppenheim Y, Lerer B. An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline. Isr J Psychiatry Relat Sci. 2000;37(4):302-307.

111. Nakazaki E, Mah E, Sanoshy K, Citrolo D, Watanabe F. Citicoline and memory function in healthy older adults: a randomized, double-blind, placebo-controlled clinical trial. J Nutr. 2021;151(8):2153-2160.

112. Paul K Whelton, Robert M Carey, Wilbert S Aronow, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269-1324.

113. National Institutes of Health. Omega-3 Fatty Acids: Fact Sheet for Health Professionals. Available at https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional. Last accessed May 17, 2024.

114. U.S. Food and Drug Administration. FDA Approves Use of Drug to Reduce Risk of Cardiovascular Events in Certain Adult Patient Groups. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups. Last accessed May 17, 2024.

115. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37-46.

116. Morgan A, Stevens J. Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo-controlled, double-blind trial. J Altern Complement Med. 2010;16(7):753-759.

117. Sagaro GG, Traini E, Amenta F. Activity of choline alphoscerate on adult-onset cognitive dysfunctions: a systematic review and meta-analysis. J Alzheimers Dis. 2023;92(1):59-70.

118. Demay MB, Pittas AG, Bikle DD, et al. Vitamin D for the prevention of disease: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism. 2024; [Epub ahead of print].

Evidence-Based Practice Recommendations Citations

1. American Academy of Ophthalmology. Age-Related Macular Degeneration: Preferred Practice Pattern. Washington, DC: American Academy of Ophthalmology; 2019. Available at https://www.aaojournal.org/article/S0161-6420(19)32091-3/pdf. Last accessed May 29, 2024.

2. U.S. Preventive Services Task Force. Vitamin, Mineral, and Multivitamin Supplementation to Prevent Cardiovascular Disease and Cancer: U.S. Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(23):2326-2333. Available at https://jamanetwork.com/journals/jama/fullarticle/2793446. Last accessed May 29, 2024.

98210 • Medicinal Mushroom Supplements

Natalie Yates, PharmD

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Interest and use of medicinal mushrooms has been increasing over the past few years. Patients may be using medicinal mushrooms to help treat various health conditions. Healthcare professionals need to be well-informed about the safety, effectiveness, and use of medicinal mushrooms to provide the best care for their patients.

Table of Contents

98210 • Medicinal Mushroom Supplements

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION AND BACKGROUND

2. WHAT ARE MUSHROOMS?

MEDICINAL MUSHROOMS

3. MEDICINAL MUSHROOMS WITH INSUFFICIENT EVIDENCE TO SUPPORT USE FOR CERTAIN INDICATIONS

AGARICUS BLAZEI MUSHROOM

BLACK HOOF MUSHROOM

CHAGA MUSHROOM

FLY AGARIC MUSHROOM

LION'S MANE MUSHROOM

MAITAKE MUSHROOM

PORIA MUSHROOM

REISHI MUSHROOM

SHIITAKE MUSHROOM

4. MEDICINAL MUSHROOMS WITH POSSIBLE EFFICACY FOR CERTAIN INDICATIONS

CORDYCEPS

5. SUMMARY

Works Cited

Evidence-Based Practice Recommendations Citations

98210 • Medicinal Mushroom Supplements

Education Category. Alternative Medicine

Release Date. 10/01/2024

Expiration Date. 09/30/2027

Course Overview

Interest and use of medicinal mushrooms has been increasing over the past few years. Patients may be using medicinal mushrooms to help treat various health conditions. Healthcare professionals need to be well-informed about the safety, effectiveness, and use of medicinal mushrooms to provide the best care for their patients.

Audience

This course is designed for healthcare professionals in any practice setting whose patients may be taking mushrooms for potentially medicinal uses.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 3 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 3 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 3 ANCC contact hour(s). NetCE designates this continuing education activity for 1 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 3.6 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 3 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the activity with individual assessments of the participant and feedback to the participant, enables the participant to earn 3 MOC points in the American Board of Pediatrics' (ABP) Maintenance of Certification (MOC) program. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABP MOC credit. This activity has been designated for 3 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. NetCE is authorized by IACET to offer 0.3 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through July 29, 2025); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2025; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to help healthcare professionals in all practice settings increase their knowledge base on medicinal mushrooms.

Learning Objectives

Upon completion of this course, you should be able to:

1. Name the main bioactive compounds found in medicinal mushrooms.

2. Discuss which medicinal mushrooms should be used cautiously with certain disease states.

3. Recognize which medicinal mushrooms have the potential to cause severe adverse effects.

4. Identify interactions between specific medicinal mushrooms and drugs, herbs, and supplements.

5. Describe which conditions specific medicinal mushrooms have evidence to support their use.

Faculty

Natalie Yates, PharmD, is an Assistant Clinical Editor at TRC Healthcare, specializing in content development for Natural Medicines, a clinical reference focused on natural products and alternative therapies. She holds a Doctor of Pharmacy from the University of California, San Francisco, and a Bachelor of Science in Psychology from the University of California, San Diego. With expertise in clinical pharmacy, medical writing, and natural medicine research, Dr. Yates is dedicated to integrating evidence-based natural therapies into healthcare education, contributing to both professional and patient-focused resources.

Faculty Disclosure

Contributing faculty, Natalie Yates, PharmD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Mary Franks, MSN, APRN, FNP-C

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION AND BACKGROUND

In 1991, a Neolithic corpse called the "Ice Man" was discovered in an Alpine glacial field near the Austrian-Italian border who, according to radiocarbon dating, lived between 3350 and 3100 B.C.E. Among the Ice Man's belongings were three fungal objects. There is still speculation about whether the intended use of the mushrooms was medicinal, spiritual, or utilitarian, but this discovery suggests that humans and mushrooms share a long history [1].

Humans have used medicinal mushrooms for thousands of years for their culinary, nutritional, and medicinal value. Recently, there is increased public interest in medicinal mushrooms due to possible anticancer, antidiabetic, antimicrobial, antioxidant, anti-obesity, and immunomodulatory effects [2]. However, the therapeutic properties and mechanisms of action are still not well understood. In vitro and animal research is used to elucidate the pharmacological activity of medicinal mushrooms, but studies in humans on the safety and efficacy of medicinal mushrooms are lacking [3]. This course reviews the properties of certain medicinal mushrooms and the current evidence for their safety and use as medicine.

2. WHAT ARE MUSHROOMS?

Mushrooms are part of the Eukarya domain, which includes all organisms that have a nucleus. Mushrooms are members of the Fungi kingdom, which also includes yeast. Mushrooms are mostly multicellular, but there are some types that are unicellular. The general structure of the most commonly known mushrooms, sporophores, is the fruiting bodies made up of the cap and the stalk, which stem from an underground network of strands called mycelium [4]. Mushroom mycelia can live for hundreds of years, so long as there is a food supply available and temperature and moisture levels are adequate [4]. Less recognizable mushrooms, called polyphores, are heterogeneous in form but usually include fruiting bodies with pores on the underside and grow on dead or living trees, sometimes as pathogenic organisms [4].

By fresh weight, most commercially available mushrooms are approximately 90% water, 3% protein, 5% carbohydrates, 1% fat, and 1% minerals and vitamins [4]. The most important bioactive compound with potential use for prevention and treatment of human disease are polysaccharides, which are structural components of the fungal cell wall [3]. It is theorized that polysaccharides are responsible for immunomodulatory effects of medicinal mushrooms by binding to certain cell wall receptors and stimulating specific immune responses [3]. Polysaccharides are also thought to contribute to antitumor, antioxidant, anti-inflammatory, antimicrobial, and antidiabetic effects of medicinal mushrooms [3]. Another important bioactive compound in medicinal mushrooms are terpenes, which modulate the immune system by stimulating the expression of genes implicated in immune responses [3]. They are also thought to have anti-inflammatory, antioxidant, and antitumor properties [3]. Other bioactive constituents of medicinal mushrooms thought to contribute to their medicinal value are proteins, phenolic compounds, antioxidants, copper-containing oxidases, and fatty acids [3].

MEDICINAL MUSHROOMS

Medicinal mushrooms are used to enhance health or treat certain medical conditions and do not cause people to hallucinate. Table 1 provides a summary of the medicinal mushrooms discussed in this course, including details on their effectiveness, adverse effects, and potential interactions. Psychedelic mushrooms contain psychoactive compounds, such as psilocybin and ibotenic acid, that can cause hallucinations during which people see, hear, and feel things that are not there. However, the lines between medicinal and psychedelic mushrooms are becoming increasingly blurred as research has ramped up on the possible health benefits of psychedelic mushrooms, particularly for mood disorders, substance misuse, and pain.

Table 1: SUMMARY OF MEDICINAL MUSHROOMS EFFICACY AND SAFETY

Mushroom

Description

Adverse Effects

Effectiveness

Interactions

Agaricus blazei

Small brownish cap mushroom from Brazil

Gastrointestinal

Hepatotoxicity

None known

Hypoglycemic agents

Liver disease

5-S-Cysteinyldopa lab test

Black hoof

Orange mushroom grows on mulberry trees

None known

None known

CYP1A1, 1A2, 2E1

Immunosuppressants

Benign prostatic hyperplasia (BPH)

Chaga

Parasitic fungus that forms "conks" on birch tree trunks

Acute oxalate nephropathy

None known

Anticoagulants and antiplatelets

Hypoglycemic agents

Immunosuppressants

Cordyceps

Fungus that grows on moth caterpillar larvae

Gastrointestinal

CKD, diabetic nephropathy

Anticoagulants and antiplatelets

Immunosuppressants

Testosterone

Fly agaric

Red cap mushroom with white spots

Poisonous

Gastrointestinal, hallucinations, coma, cardiac arrest

None known

None known

Lion's mane

Long, dangling fleshy spines grows on hardwood trunks

Gastrointestinal, skin rash

None known

Anticoagulants and antiplatelets

Hypoglycemic agents

Immunosuppressants

Maitake

Mushroom clumps on stumps or trunks of trees

Gastrointestinal

None known

Hypoglycemic agents

Hypotensive agents

Warfarin

Poria

Sclerotium that grows on pine tree roots

None, other than rare mild allergic reactions

None known

Anticholinergics

Cholinergics

CNS depressants

Reishi

Shiny, woody flesh with bitter taste

Gastrointestinal

Allergic reactions

Hepatitis

None known

Anticoagulants and antiplatelets

Hypoglycemic agents

Hypotensive agents

Shiitake

Umbrella-shaped caps

Gastrointestinal

Shiitake dermatitis

None known

CYP2D6

Immunosuppressants

Hypereosinophilic Syndrome

Turkey tail

Grows in clusters of leathery brackets

None known

Cancer

Hypoglycemic agents

Cyclophosphamide

Source: Compiled by Author

3. MEDICINAL MUSHROOMS WITH INSUFFICIENT EVIDENCE TO SUPPORT USE FOR CERTAIN INDICATIONS

The majority of medicinal mushrooms have insufficient evidence to support their use for certain indications. However, many of them are still consumed and have important safety concerns and potential interactions.

AGARICUS BLAZEI MUSHROOM

TheAgaricus blazei mushroom, also called the Brazil mushroom, is native to the mountains of Piedade in Brazil [5]. It was first discovered by a Japanese researcher in 1965 who sent it to be studied in Japan and later identified by a Belgian botanist [5,6].Agaricus blazei is now cultivated in Brazil, China, Japan, and the United States for use in food, tea, and medicine.

Safety and Dosing

Agaricus blazei mushrooms are generally well-tolerated and have been used safely in doses up to 1,500 mg daily, usually administered as Agaricus mushroom extract 500 mg three times daily for up to 12 months [5]. There is no information about the use of Agaricus mushrooms in people who are pregnant or lactating, so avoid use in those populations [5].

Adverse Effects

One clinical study reported mild gastrointestinal side effects, such as nausea, diarrhea, and abdominal discomfort [5]. In individual case reports, Agaricus mushroom has been associated with allergic reactions including hives and allergic contact dermatitis on the lips (cheilitis), both of which resolved upon discontinuation of the Agaricus mushroom product [5]. In another case report, a patient developed interstitial lung disease [5].

There are also three case reports of severe hepatotoxicity in females receiving chemotherapy for ovarian or breast cancer who also took Agaricus mushroom supplements [5]. Two of the patients developed elevated liver function tests which progressed to fatal, fulminant hepatitis within days of starting Agaricus mushroom supplements [5]. The third patient turned out to be a carrier of hepatitis B virus, but her liver function tests improved upon discontinuation of Agaricus mushroom [5].

Uses and Benefit

There is interest in using Agaricus mushrooms for a variety of purposes including diabetes, hepatitis B, hyperlipidemia, inflammatory bowel disease, osteoporosis, and peptic ulcers, but there is no good evidence to support the use of Agaricus mushrooms for these conditions [5].

Drug, Herb, Supplement, and Disease Interactions

Hypoglycemic Agents

Theoretically, Agaricus mushroom might increase the risk of hypoglycemia when taken with antidiabetes drugs [5]. One clinical study in patients with type 2 diabetes on oral antidiabetes agents reported hypoglycemia in three subjects who were also taking Agaricus mushroom extract 500 mg three times daily [5]. Due to the risk of hypoglycemia, use caution when combining Agaricus mushroom with antidiabetes drugs and herbs and supplements with hypoglycemic potential, such as cinnamon, fenugreek, and bitter melon [5,7]. Additionally, perioperative control of blood glucose levels is associated with improved surgical outcomes [8]. Since Agaricus mushroom could theoretically lead to hypoglycemia, advise patients to discontinue Agaricus mushroom at least two weeks prior to surgical procedures [5].

Liver Disease

There is some concern that Agaricus mushroom might cause or exacerbate liver disease; therefore, it should be avoided in people with liver disease. As discussed, three cases of severe hepatotoxicity have been reported in adults with ovarian or breast cancer receiving chemotherapy who also took Agaricus mushroom supplements [5].

Interactions with Lab Tests

5-S-Cysteinyldopa

Agaricusmushroom use may lead to false-positive results on tests that use serum 5-S-cysteinyldopa (5-S-CD) as a marker of tumor growth or recurrence [5]. Elevated serum 5-S-CD levels have been reported in patients takingAgaricusmushroom extracts [5].

BLACK HOOF MUSHROOM

Black hoof mushroom (Phellinus linteus) is an orange polyphore mushroom that grows on mulberry trees [9]. It has been used as medicine for centuries in China, Japan, Korea, and Taiwan where it is known as the sanghuang mushroom [10]. The earliest recorded medicinal use of black hoof mushroom appears in the oldest known Chinese medical book Shennong's Compendium of Materia Medica, which was written about 2,000 years ago [10]. Black hoof mushroom is also referenced in written form dating back to the Tang Dynasty in 630 C.E. and in the world's earliest known pharmacopoeia issued in China in 659 C.E. [10].

Despite a long history of human use, particularly in Asia, there is very little research into the safety and efficacy of this type of mushroom. In traditional Asian medicine, black hoof mushroom is used for allergies, arthritis, cancer, diabetes, and gastrointestinal disorders [9]. Animal and in vitro research suggests that black hoof mushroom could have anti-allergy, antimicrobial, anti-inflammatory, antihyperlipidemic, anticancer, immunostimulatory, and gastroprotective effects [9]. There has also been interest in using black hoof mushroom to treat COVID-19, but there is no good evidence to support the use of black hoof mushroom for this purpose.

Dosing and Safety

Currently available research suggests that black hoof mushroom extract has been used safely when taken orally in doses of 1 or 2 grams daily for up to 12 weeks [9]. There is no safety information currently available on the use of black hoof mushroom in adults who are pregnant or lactating, so advise patients in these special groups to avoid using black hoof mushroom until more information is available. Black hoof mushroom seems to be well-tolerated, and no adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted to date.

Drug, Herb, Supplement, and Disease Interactions

Cytochrome P450 (CYP) Substrates

Despite apparent safety in human research, in vitro evidence suggests that polysaccharides in black hoof mushroom inhibit CYP1A1, 1A2, and 2E1 activity, potentially leading to increased levels and clinical effects of other drugs metabolized by these CYP enzymes [9]. Although these effects have not been reported in humans, patients should be advised to use caution when taking black hoof mushroom in combination with substrates of CYP1A1, 1A2, and 2E1. Examples of CYP1A1, CYP1A2, and CYP2E1 substrates include [11,12,13,14]:

- CYP1A1: Theophylline, tobacco

- CYP1A2: Clozapine, theophylline

- CYP2E1: Acetaminophen, nicotine

Immunosuppressants

In vitro and animal research suggest that polysaccharides in black hoof mushroom could stimulate immune responses, theoretically reducing the effects of immunosuppressant drugs and exacerbating autoimmune diseases, such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), or rheumatoid arthritis (RA) [9]. Due to potential immunostimulant effects, people on immunosuppressant medications or those with autoimmune diseases should either avoid or use black hoof mushroom with caution.

Benign Prostatic Hyperplasia (BPH)

In an animal model of BPH, black hoof mushroom extract enlarged the prostate, particularly in the stroma region [9]. Even though this has not been shown in humans, patients with BPH should avoid using black hoof mushroom.

CHAGA MUSHROOM

Chaga (Inonotus obliquus), sometimes also referred to as birch mushroom, is a pathogenic parasitic fungus that grows on and destroys birch tree trunks throughout cool, humid climates in Europe, Russia, Korea, China, United States, and Canada [15,16]. Chaga produces a woody growth on the tree surface referred to as a conk or canker, which is the part of chaga that is harvested and used for medicinal purposes [15]. The woody growth is supported by root-like mycelium structures that grow inside the tree, extracting nutrients and degrading the tree while producing decay known as white rot [16]. The canker that grows on the exterior of the tree releases spores, which are spread to other birch trees to continue chaga's parasitic life cycle [16].

Safety and Adverse Effects

There is no current reliable information on the dosing, safety, or adverse effects of chaga mushroom in children or adults. Additionally, there is no information available on the use of chaga in pregnant adults or those who are lactating, so advise patients in these groups to avoid using chaga.

Overdose and Toxicity

Due to its high oxalate content, excessive ingestion of chaga mushroom can result in acute oxalate nephropathy caused by the deposition of calcium oxalate crystals in the renal tubules [17]. There are two case reports of kidney failure and one case report of acute oxalate nephropathy in patients taking chaga mushroom powder doses of 3–22 grams daily for six months to five years [15]. Renal biopsies showed tubular atrophy, interstitial fibrosis, and the presence of oxalate crystals [15]. In all of these cases, the kidney damage was attributed to the high oxalate content in chaga mushroom [15].

Uses and Benefits

Traditionally, chaga mushroom is used to stimulate the immune system, prevent cancer, and treat certain conditions including gastritis, liver disease, and tuberculosis [15]. Recently, there has been interest in using chaga for cardiovascular disease, COVID-19, and diabetes [15]. However, there is currently no sufficient evidence to support the use of chaga for any of these conditions. There are in vitro and animal research that shows chaga mushroom could have anticancer, antidiabetes, anti-inflammatory, antioxidant, antihyperlipidemic, radioprotective, and immunostimulatory effects [15].

Drug, Supplement, and Disease Interactions

Anticoagulant and Antiplatelet Agents

In vitro and animal research suggests that chaga mushroom extract might inhibit platelet aggregation [15]. Therefore, chaga should be used with caution in combination with drugs or supplements with antiplatelet or anticoagulant effects due to an increased risk of bleeding. Additionally, people with bleeding disorders should use caution when taking chaga mushroom due to an increased risk of bleeding. However, this risk is theoretical and has not been shown in human research.

Hypoglycemic Agents

Animal research suggests that chaga mushroom might decrease blood glucose levels and increase insulin levels. Exercise caution when chaga mushroom is used in combination with antidiabetes drugs and herbs or supplements with hypoglycemic potential due to the additive risk of hypoglycemia [15]. However, this risk is theoretical and has not been shown in human research.

Surgery

Since chaga mushroom could increase the risk of bleeding and interfere with blood glucose control, advise patients to discontinue chaga mushroom at least two weeks prior to elective surgical procedures [15].

Immunosuppressants

In vitro research suggests that certain constituents of chaga mushroom could stimulate immune function [15]. Even though this interaction has not been reported in humans, it could theoretically reduce the effectiveness of immunosuppressive therapy, so use caution in patients on immunosuppressants. Also exercise caution in people with autoimmune diseases, such as MS, SLE, or RA, since immune system stimulation by chaga mushroom could worsen these conditions [15].

FLY AGARIC MUSHROOM

Fly agaric mushroom (Amanita muscaria), also known by the common name red toadstool, is a beautiful, distinctive, and very recognizable mushroom with a red or orange cap covered with small white plaques [18]. The applicable part of fly agaric mushroom is the fruiting body, and the levels of bioactive and chemical compounds vary considerably throughout the seasons and depend on the freshness of the mushroom [18]. The fly agaric mushroom got its name because it was once used as a fly poison. The cap was broken and sprinkled into saucers of milk. The ibotenic acid in fly agaric mushroom attracts and kills flies.

Due to its distinctive appearance, accidental ingestion is rare. However, it is a common cause of mushroom poisoning, especially when it is accidentally consumed by children or people seeking hallucinogenic experiences [19]. Historically, fly agaric mushroom was used by Buddhist monks in the 2nd and 9th centuries to achieve enlightenment [18]. Since boiling or other processing methods eliminates most of the water-soluble toxic compounds in fly agaric mushrooms, some traditional recipes have used it as a homeopathic remedy for neuropathy, fever, and joint pain [20,21].

Additionally, there are reports of people consuming fly agaric mushroom as a means of suicide, or more recently, for its psychedelic effects [20]. Despite historical use for various spiritual and physical human conditions, there is no current recommended use for fly agaric mushroom for any medical or psychological conditions [18]. No information is currently available about drug, herb, supplement, or disease-state interactions with fly agaric mushroom. When consumed orally, fly agaric mushroom is highly poisonous and is not safe for anyone to consume [18].

Accidental fly agaric mushroom poisoning is rare because of its distinctive appearance. However, heavy rains can wash away the white spots, causing it to be mistaken for a different, edible species of mushroom,Amanita caesarea.

Toxicity and Overdose

Most cases of fly agaric mushroom overdose are associated with suicide attempts or people seeking a hallucinogenic experience [18]. Death due to fly agaric mushroom is rare but can occur in up to 5% of users [18]. Toxic symptoms have been observed after consuming just one mushroom, mind-altering effects are seen after consuming 2 to 4 mushrooms, and survival has been reported with consumption of as many as 20 large fly agaric mushrooms [18]. The mind-altering effects of fly agaric mushroom are thought to be due to the presence of ibotenic acid, muscimol, muscazone, and muscarine [18].

There are three stages of fly agaric mushroom poisoning [18,19]:

- Stage 1: 15 to 90 minutes after ingestion

- Gastrointestinal symptoms: Nausea, vomiting, diarrhea, and abdominal pain

- Stage 2: Peak effects occur two to three hours after ingestion and usually last for about 12 hours

- Psychiatric symptoms: Hallucinations, mania, confusion, agitation, and suicide attempts

- Neurological symptoms: Sedation and drowsiness

- Stage 3: Resolution of symptoms, usually takes about 12 hours but can take up to 5 days

There are two case reports of prolonged coma after fly agaric mushroom ingestion [18]. These patients were treated with gastric lavage, activated charcoal, and supportive care [18]. In both cases, the patients recovered within a few days [18]. In another case report, a 44-year-old male went into cardiac arrest several hours after ingesting 6 to 10 dried fly agaric mushrooms [18].

LION'S MANE MUSHROOM

Lion's mane mushroom (Hericium erinaceus) is an edible white mushroom that grows as singular long dangling fleshy spines on the dead trunks of hardwood trees (e.g., oak, beech, Japanese walnut) in East Asian countries, such as Japan and China [22,23]. Other common names for lion's mane mushroom include bearded tooth, hedgehog fungus, monkey head, pom pom, tree hedgehog, and yamabushitake [22]. The fruiting body of lion's mane mushroom has been used in East Asian traditional medicine since ancient times. The fruiting bodies and mycelium are the parts of lion's mane mushroom that are consumed as medicine [22].

Safety and Adverse Effects

Lion's mane mushroom has been used with apparent safety in doses up to 1 gram daily for up to 16 weeks [22]. It is generally well-tolerated, but gastrointestinal discomfort, nausea, and skin rash have been reported [22]. Avoid using lion's mane mushroom in adults who are pregnant or lactating because there is no information available about safety in these special populations.

Uses and Benefits

Historically, lion's mane mushroom was thought to have antioxidant, antimicrobial, and anticancer effects [23]. More recently, there has been heightened interest in the neuroprotective, neuroregenerative, and mood-enhancing properties of lion's mane mushroom [23]. In vitro and animal research suggests that lion's mane mushroom might have anticancer, antidiabetic, anti-obesity, antioxidant, antihyperlipidemic, gastroprotective, hepatoprotective, and neuroprotective effects [22]. Despite interest and limited research, there is currently not enough information to recommend lion's mane mushroom for specific indications.

Neurological and Cognitive Function

There is interest in using lion's mane mushroom for neurological and cognitive benefit for Alzheimer disease, normal cognitive function, mild cognitive impairment, dementia, memory, and Parkinson disease, but there is insufficient reliable information about the clinical effects of lion's mane mushrooms for these conditions.

A small clinical study in older adults with mild Alzheimer disease shows that taking 1,050 mg of lion's mane mushroom mycelia daily for 49 weeks improves some activities of daily living when compared with placebo and some measures of cognitive impairment when compared to baseline [22]. Another study in older Japanese patients with mild cognitive impairment shows that taking lion's mane mushroom powder 3 grams daily for 16 weeks increases cognitive function when compared with placebo, but this benefit did not endure beyond 4 weeks after treatment termination [22].

There is no evidence that lion's mane mushroom is beneficial in people with normal cognitive function. A small clinical trial shows that middle aged to older adults taking lion's mane mushroom 3.2 grams daily for 12 weeks does not improve most measures of cognitive function when compared with placebo [22]. Another small clinical study in younger adults shows that taking a lion's mane mushroom product that was 50% dried mushroom and 50% mushroom extract 10 grams daily for 4 weeks does not improve measures of cognition during a period of exercise-induced fatigue when compared with taking placebo [22]. More human research and larger trials are needed to determine whether lion's mane mushroom is beneficial for neurological conditions and cognitive function.

Drug, Supplement, and Disease Interactions

Anticoagulants and Antiplatelets

In vitro research suggests that lion's mane mushroom might inhibit platelet aggregation [22]. Therefore, lion's mane mushroom should be used with caution in combination with drugs, herbs, or supplements with antiplatelet or anticoagulant effects and in people with bleeding disorders due to an increased risk of bleeding.

Hypoglycemic Agents

Animal research suggests that an aqueous extract of lion's mane mushroom might decrease serum blood glucose levels and increase serum insulin levels [22]. Lion's mane mushroom should be used cautiously when taken in combination with antidiabetes drugs or herbs and supplements with hypoglycemic potential due to the additive risk of hypoglycemia.

Surgery

Since lion's mane mushroom could increase the risk of bleeding and might interfere with blood glucose control perioperatively, lion's mane mushroom should be discontinued at least two weeks prior to elective surgical procedures.

Immunosuppressants

Animal and in vitro research suggest that polysaccharides in lion's mane mushroom might stimulate the immune system [22]. Therefore, caution should be used when taking lion's mane mushroom with immunosuppressant drugs due to the theoretical possibility of reduced immunosuppressant drug efficacy. Also exercise caution in people with autoimmune diseases, such as MS, SLE, or RA, because lion's mane mushroom could theoretically stimulate autoimmune disease activity.

MAITAKE MUSHROOM

Maitake mushroom (Grifola frondosa), also widely known as hen-of-the-woods, is an edible mushroom that grows in large clumps at the base of stumps or trunks or broadleaf trees in the temperate forests of Asia, Europe, and the eastern United States [24].The medicinally useful parts of maitake mushroom are the fruiting body and mycelium [24]. Active constituents are polysaccharides, specifically beta-glucan constituents referred to as "D-fraction" and "SX-fraction" [24].

Formulations and Dosing

Maitake mushroom extract has been used with apparent safety at a dose of 3 mg/kg twice daily for up to 12 weeks and 5 mg/kg twice daily for up to 3 weeks [24]. Some clinical trials have used products standardized for certain constituents, including polysaccharides. A concentrated formulation of maitake mushroom polysaccharides (MMP) 1–1.5 grams daily has also been used with apparent safety for up to two years [24].

Adverse Effects

Maitake mushroom is generally well-tolerated when taken orally. The most commonly reported adverse effects are gastrointestinal side effects, such as diarrhea, epigastric pain, and nausea [24]. There are also individual case reports of rash with pruritis and joint swelling after taking MPP extract and hypersensitivity pneumonitis after taking maitake mushroom spores [24]. There is no sufficient reliable information on safety or adverse effects of maitake mushroom in people who are pregnant or lactating, so avoid use in these populations.

Uses and Benefits

Cancer

There is interest in using maitake mushrooms for treating cancer and side effects related to chemotherapy treatment. However, the currently available evidence is insufficient to conclude that maitake mushrooms are beneficial for these conditions.

One clinical study in patients with advanced laryngeal and pharyngeal cancer undergoing chemoradiation shows that taking MPP 1 gram three times daily prevents a decline in quality of life, reduces the incidence of some adverse effects associated with cancer treatment, and modestly increases five-year survival when compared with placebo [24].

Drug, Herb, Supplement, and Disease Interactions

Hypoglycemic Agents

A study in humans with type 2 diabetes shows that taking MPP might lower blood glucose levels [24]. Use caution in patients taking maitake mushrooms in combination with antidiabetes drugs or herbs and supplements with hypoglycemic effects due to the potential additive risk of hypoglycemia.

Hypotensive Agents

Animal research suggests that maitake mushroom can lower blood pressure [24]. Therefore, use caution in patients taking antihypertensive drugs or herbs and supplements with hypotensive effects due to the increased risk of additive hypotension.

Warfarin

There is a case report of a patient previously stabilized on warfarin developing an elevated international normalized ratio (INR) of 5.1 after taking a specific liquid maitake mushroom product at a dose of 1 drop/kg daily for a week [24]. The elevated INR resolved after holding warfarin for two days, followed by an 11% dose reduction [24]. While the evidence is limited to a single case report, this suggests that maitake mushroom could increase the anticoagulant effects of warfarin. Exercise caution in patients taking this combination.

Surgery

Due to potential hypoglycemic effects, maitake mushroom might interfere with perioperative blood glucose control. Advise patients to stop taking maitake mushroom at least two weeks prior to elective surgical procedures.

PORIA MUSHROOM

Poria mushroom (Wolfiporia cocos) is an edible medicinal mushroom of which the sclerotium, or resting spore, is the portion used as medicine [25]. The sclerotium of poria mushroom grows around the roots of certain pine trees in China and other East Asian countries. The availability of the appropriate pine tree species limits the availability of poria mushroom sclerotium. Poria mushroom has been used for more than 2,000 years in traditional Chinese medicine for anxiety, cough, diabetes, insomnia, memory, and vertigo [26]. The main bioactive component of poria mushroom is poria cocos polysaccharide (PCP), which accounts for 84% by weight of all constituents in the dried sclerotium [26].

Safety and Side Effects

There is currently no information about the safety of poria mushroom in children, adults, and special populations, such as those who are pregnant or lactating. However, animal research suggests that poria mushroom has low toxicity [26]. There is also no research on the long-term risks associated with taking poria mushroom. Poria mushroom seems to be well-tolerated, but a thorough evaluation of safety outcomes has not been conducted. In rare cases, there have been reports of mild allergic reactions, such as allergic rhinitis and allergic asthma, after taking poria mushroom [25].

Uses and Benefits

There is currently no evidence that poria mushroom is effective for any human conditions. However, animal and in vitro research show that poria mushroom might inhibit tumor growth, enhance immune function, and exhibit antioxidant activity [26].

Drug, Supplement, and Disease Interactions

Anticholinergic and Cholinergic Agents

Animal research suggests that poria mushroom essential oil reduces acetylcholinesterase activity [25]. Theoretically, taking poria mushroom could decrease the effectiveness of anticholinergic drugs [25]. Conversely, poria mushroom taken in combination with cholinergic drugs could have additive effects and increase the risk of adverse effects or toxicity [25]. Although this interaction has not been shown in humans, use caution in patients taking anticholinergic or cholinergic drugs with poria mushroom.

CNS Depressants

Animal research suggests that poria mushroom extract might have sedative properties, which could enhance therapeutic and adverse effects of other medications, herbs, or supplements with sedative effects [25]. Although this interaction has not been shown in humans, use caution in patients who are taking poria mushroom with CNS depressants, such as alcohol, opioids, or benzodiazepines. Additionally, due to the risk of CNS depression perioperatively, tell patients to discontinue poria mushroom extract at least two weeks prior to elective surgical procedures.

REISHI MUSHROOM

Reishi mushroom (Ganoderma lucidum) is a type of fungus with shiny, tough, woody flesh and a bitter taste that is black, orange, red, or other colors depending on the growing conditions [27,28]. Reishi mushroom thrives in hot, humid, subtropical conditions but is rarely found in the wild. Reishi mushroom is now commercially cultivated and is available in a wide range of formulations containing the fruiting bodies, mycelia, and spore powder [28].

Long referred to as the "mushroom of immortality," the reishi mushroom has been used in traditional Asian medicine for more than 2,000 years for promoting health, longevity, and spiritual potency [3,28]. Before reishi mushroom cultivation, reishi mushroom was so rarely found in the wild that only the nobility could afford it as medicine [28]. As a result, it is unclear whether reishi mushroom is highly prized for its actual effects or due to is rarity and use only by the privileged members of ancient Chinese society [28].

Safety and Standardization

Reishi mushrooms are commercially available as extracts and powders. Extracts of reishi mushroom have been used safely in adults in doses of 6 mg daily for up to one year [27]. Powdered reishi mushroom has been used in doses of 1,400–5,400 mg daily for up to 16 weeks [27]. There is no sufficient reliable information on the use of reishi mushroom in children or adults who are pregnant or lactating, so avoid use in those populations.

There is some concern about the standardization and consistency of reishi mushroom products available in the United States. One study analyzed 19 reishi mushroom products and found that only 26% contained the labeled amount of reishi mushroom and 68% of tested reishi mushroom products contained polysaccharide fillers in place of active ingredients [27]. Therefore, advise patients to use caution when selecting products and to stick to high quality formulations that have been independently tested.

Adverse Effects

Orally, reishi mushroom is generally well-tolerated, but there have been some reports of mild immunologic, gastrointestinal, and other adverse effects [27]. There have been reports of allergic reactions resulting in dermatologic itching, rash, and other skin reactions and reishi mushroom spores have caused respiratory allergies characterized by sore throat and runny nose [27]. Reishi mushroom could also cause dryness of the mouth, throat, or nasal cavity and can lead to gastrointestinal adverse effects, such as nausea, diarrhea, and stomach upset [27].

There have also been serious hepatic adverse effects associated with reishi mushroom use, but the causation is not certain [27]. There are two case reports of hepatotoxicity in patients who took a specific reishi mushroom powder for one to two months, with one of the cases resulting in fatal fulminant hepatitis [27]. In another case report, a patient developed hypereosinophilic syndrome associated with hepatic nodules after using a reishi mushroom powder product for two months, which resolved after discontinuation [27].

Uses and Benefits

The pharmacological properties of reishi mushroom are mainly due to the presence of triterpenes and polysaccharides [3]. But there is currently no conclusive evidence that reishi mushroom benefits any human health conditions. However, there is in vitro and animal data to support anticancer, immunomodulatory, antihypertensive, cytotoxic, antidiabetic, antioxidant, antihyperlipidemic, antimutagenic, antiaging, antimicrobial, hepatoprotective, and gastroprotective properties, and many others [3].

There is interest in using reishi mushroom for hyperlipidemia and diabetes, but current research in humans shows that reishi mushroom is not beneficial for either of these conditions. However, there may be some benefits in cancer and lower urinary tract symptoms with various etiologies. Most human research is small, low-quality, and conflicting. No currently available evidence is strong enough to conclusively recommend reishi mushroom for a specific condition.

Drug, Supplement, and Disease Interactions

Anticoagulant and Antiplatelet Agents

Human research shows that reishi mushroom does not inhibit platelet aggregation at lower doses of 1.5 grams daily, but does inhibit platelet aggregation at a higher doses of 3 grams daily [27]. Therefore, reishi mushroom at high doses should be used with caution in combination with drugs, herbs, or supplements with antiplatelet or anticoagulant effects and in people with bleeding disorders due to an increased risk of bleeding.

Hypoglycemic Agents

Animal research suggests that reishi mushroom decreases serum blood glucose levels [27]. However, research in humans with type 2 diabetes shows that reishi mushroom does not reduce fasting blood glucose levels and the effects on HbA1c are unclear [27]. Until more evidence of the effects of reishi mushroom on blood glucose levels is available, reishi mushroom should be used cautiously when taken in combination with drugs, herbs, or supplements with hypoglycemic potential due to the additive risk of hypoglycemia.

Surgery

Since reishi mushroom could increase the risk of bleeding and might interfere with blood glucose control, it should be discontinued at least two weeks prior to elective surgical procedures.

Hypotensive Agents

Animal research suggests that reishi mushroom can lower blood pressure [27]. Research in humans suggests that reishi mushroom reduces blood pressure in some, but not all, patients with hypertension [27]. Therefore, use caution in patients taking antihypertensive drugs or herbs and supplements with hypotensive effects due to the increased risk of hypotension.

SHIITAKE MUSHROOM

Shiitake mushroom is a type of edible fungus and is the second most commonly eaten mushroom in the world [29]. This type of mushroom is native to Japan and China, where it has a long history of use in traditional medicine [29]. Most clinical research is on the standardized oligosaccharide-rich shiitake mushroom mycelial extract called AHCC.

Safety and Adverse Effects

Shiitake mushroom is likely safe and well-tolerated when cooked and consumed in typical food amounts [29]. The shiitake mushroom extract AHCC is also likely safe and has been used in clinical trials and in population-based research in doses ranging from 3–6 grams daily for up to nine years [29]. There is no information available on the safety of shiitake mushroom consumption greater than food amounts in adults who are pregnant or lactating, so avoid use in these populations.

While shiitake mushrooms as part of the diet are generally well-tolerated, there are some adverse effects associated with their use. Discussed further below, the most common adverse effects are gastrointestinal, while the most serious adverse effect, which occurs rarely, is shiitake dermatitis. There are also individual reports of eosinophilia, allergic contact dermatitis, general allergic symptoms, joint stiffness, and hypersensitivity pneumonitis in people who have consumed shiitake mushrooms [29].

Gastrointestinal

Orally, shiitake mushrooms can cause abdominal discomfort, including bloating, nausea, pain, vomiting, and diarrhea [29]. Consumption of large pieces of shiitake mushroom with inadequate chewing can cause abdominal obstruction that has resulted in death in one case and surgical intervention in two others [29]. In another case, parenteral nutrition was used exclusively until the shiitake mushroom pieces were passed [29]. When used as an oral rinse for gum disease or gingivitis, shiitake mushroom extract is associated with teeth sensitivity, teeth staining, and burning in the mouth [29].

Shiitake Dermatitis

The cell wall of shiitake mushrooms contains a thermolabile compound called lentinan, which is toxic when consumed raw but safe to eat when heated. As a result, consuming raw shiitake mushroom can cause shiitake dermatitis, a skin eruption resembling whiplash marks which can be accompanied by systemic symptoms [29]. Shiitake dermatitis usually occurs on the trunk and limbs and can look like whiplash marks, small purple spots, skin plaques, burns, blanching, and pustules [29]. In rare cases, the rash looks like measles [29]. Other symptoms associated with shiitake dermatitis include fever, aching, malaise, eosinophilia, diarrhea, prickling in the hands, trouble swallowing, conjunctivitis, and pustules with small ulcers in the mouth [29]. Symptom onset is usually within hours to days and can persist for 3 to 4 weeks before resolving on its own [29]. In some cases, treatment with steroids alone or in combination with antihistamines might reduce the duration of the rash [29].

Shiitake dermatitis is thought to be a delayed type hypersensitivity reaction to lentinan or other compounds found normally in uncooked or inadequately cooked shiitake mushroom [29]. Cooking shiitake mushroom generally prevents shiitake dermatitis, although there are reports of some cases in people who have consumed cooked sources [29]. It appears that to inactivate lentinan, cooking temperatures of at least 266°F (130°C) are needed [29].

Uses and Benefits

There is currently no evidence that shiitake mushroom is effective for any human conditions. However, animal and in vitro research show that poria mushroom might inhibit tumor growth, enhance immune function, and exhibit antioxidant, anti-inflammatory, and antimicrobial activity [29].

Drug, Supplement, and Disease Interactions

CYP2D6 Substrates

In vitro studies suggest that AHCC might induce CYP2D6, theoretically increasing the levels of other drugs metabolized by CYP2D6 [29]. Use caution in patients taking shiitake mushroom and CYP2D6 substrates.

Immunosuppressants

Data from human, animal, and in vitro studies suggests that shiitake mushroom extracts stimulate immune function [29]. Therefore, patients should use caution when taking shiitake mushroom extract with immunosuppressant drugs due to the theoretical possibility of reduced immunosuppressant drug efficacy. Also exercise caution in people with autoimmune diseases, such as MS, SLE, or RA, because shiitake mushroom could theoretically stimulate autoimmune disease activity.

Hypereosinophilic Syndrome

Shiitake mushroom can cause eosinophilia, which may exacerbate hypereosinophilic syndrome, a group of blood disorders characterized by persistently elevated eosinophils which can damage tissues and organs over time [29]. Avoid shiitake mushroom use in patients with this condition.

4. MEDICINAL MUSHROOMS WITH POSSIBLE EFFICACY FOR CERTAIN INDICATIONS

CORDYCEPS

The cordyceps species Ophiocordyceps unilateralis, also known as the zombie-ant fungus, achieved fame after playing a starring role in the post-apocalyptic video game and television series The Last of Us. In the story, rising temperatures cause zombie-ant fungus to evolve and mutate to infect humans instead of ants. The zombie-ant fungus parasitized human brains and turned them into zombies. Fortunately, there is no evidence that cordyceps can transition from usings insects to humans as hosts, and it is highly unlikely due to our sophisticated immune systems and high body temperatures.

Cordyceps is a genus containing more than 400 different species of fungus that grow on insect larvae [30]. Although many Cordyceps species have been identified around the world, Cordyceps sinensis is the primary species currently used as an herbal medicine and will be henceforth referred to as cordyceps for the purposes of this course [30].

Cordyceps is parasitic fungus that grows on the larvae of the moth Hepialus armoricanus Oberthur in China at high elevations [31]. Due to habitat destruction and overharvesting, the supply of natural cordyceps is extremely limited [30]. However, cultured cordyceps mycelial cells are available commercially through large-scale fermentation of natural cordyceps strains [30,32].The commercially available propagated form of cordyceps that is consumed as an herbal medicine usually contains only mycelial cells, not the fruiting body [32].

Dosing and Formulation

Cordyceps is available as capsules, powders, and liquid extracts [31]. Most studies use oral cordyceps doses of 3–6 grams daily for up to one year [32]. Most research is on two specific cordyceps products, Bailing (Cs-C-Q80) and Jinshuibao (Cs-4), which are fermented cordyceps mycelial products [32].

Safety and Adverse Effects

Cordyceps has been taken with apparent safety and seems to be well-tolerated in doses of 3–6 grams daily for up to one year [32]. However, there is no reliable information about the safety of cordyceps in people who are pregnant or lactating, so avoid use in these populations.

When cordyceps is taken orally, gastrointestinal side effects are the most common and include constipation, diarrhea, abdominal discomfort, dry mouth, and throat discomfort [32]. There have also been individual reports of lead poisoning and hepatitis, but it is suspected that these effects were due to contaminated cordyceps products [32].

Uses and Benefits

Cordyceps is used in traditional Chinese medicine for many conditions including fatigue, sexual dysfunction, cough, and immune stimulation [30]. Preclinical in vitro and animal research suggests that cordyceps has anticancer, anti-inflammatory, antitumor, radioprotective, antiplatelet, antidiabetic, and immune enhancing properties [30]. Research in humans shows that cordyceps does not improve athletic performance, but it might benefit certain types of kidney disease [32].

Athletic Performance

Although cordyceps is sometimes taken to increase strength and stamina, the currently available evidence shows that cordyceps does not improve athletic performance in adults [32]. One small clinical study in endurance-trained cyclists shows that taking a specific mycelial fermentation product of cordyceps 3.15 grams daily for five weeks does not improve endurance time trials or aerobic capacity when compared with placebo [32]. Another small study in healthy elderly adults shows that taking the same cordyceps preparation 3 grams daily for 12 weeks does not improve exercise performance when compared with placebo [32]. Despite these findings, cordyceps is still heavily marketed to trained and recreational athletes with claims that it enhances athletic performance, increases stamina, and fights muscle fatigue. Further research is needed to elucidate the effect of cordyceps on athletic performance.

Kidney Function

Chronic Kidney Disease (CKD)

Some clinical studies show that oral cordyceps modestly improves renal function in some patients. A meta-analysis of clinical studies conducted in China in patients with CKD shows that taking cordyceps 0.6–2 grams three times daily in addition to standard treatment decreases serum creatinine by 0.6 mg/dL and increases creatinine clearance by 9.2 mL/min when compared with standard treatment alone [32]. However, a meta-analysis of small clinical studies conducted in China in patients on hemodialysis suggests that taking cordyceps in addition to standard treatment does not seem to improve serum creatinine levels when compared with placebo.

Contrast-Induced Nephropathy

The currently available evidence is conflicting on whether cordyceps protects against contrast-induced nephropathy. A preliminary clinical study in patients with diabetic nephropathy shows that taking a specific oral cordyceps mycelial product 2–3 grams three times daily for three days before and after angiography reduces the risk of contrast-induced nephropathy by 48% to 66% when compared with standard treatment [32]. However, other preliminary clinical research in patients with stable angina pectoris shows that taking the same cordyceps product 3 grams orally three times daily for three days before and after angioplasty does not decrease the prevalence of contrast-induced nephropathy when compared with standard therapy [32]. Reasons for these discrepancies are unclear, but it is possible that cordyceps is protective against contrast-induced nephropathy in people with kidney damage at baseline, but not in people with normal kidney function at baseline.

Diabetic Nephropathy

Most research suggests that oral cordyceps modestly improves kidney function in patients with diabetic nephropathy, or diabetic kidney disease. A meta-analysis conducted in China in patients with diabetic kidney disease shows that taking cordyceps 0.5–2 grams three times daily with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) decreases blood urea nitrogen by 2 mg/dL and decreases serum creatinine levels by 0.1 mg/dL when compared with ACE inhibitor or ARB treatment alone [32]. Another meta-analysis of clinical studies in patients with diabetic kidney disease shows that taking cordyceps as adjunctive therapy to an ACE inhibitor or ARB for 2 to 24 weeks modestly improves markers of kidney function, such as serum creatinine, urea nitrogen, urinary albumin, and total protein, when compared to these medications alone [32].

Kidney Transplant

Small clinical studies suggest that oral cordyceps is not better than standard treatment at reducing transplant rejection, improving survival, or enhancing kidney function in patients with kidney transplant. A meta-analysis of four heterogeneous clinical trials evaluating patients in China immediately post-kidney transplant or patients with complications post-kidney transplant suggests that adding cordyceps to standard therapy with cyclosporine and steroids is not superior to adding azathioprine 50–150 mg for improving overall survival or graft survival or reducing rejection risk [32]. A higher quality systematic review suggests that adding oral cordyceps 3–6 grams to standard therapy daily is no better than azathioprine or cyclosporine for preventing organ rejection or improving kidney function or survival in patients after kidney transplant [32].

Drug, Supplement, and Disease Interactions

Anticoagulant and Antiplatelet Agents

In vitro and animal research suggests that cordyceps might inhibit platelet aggregation, so cordyceps should be used with caution in people with bleeding disorders and when taken in combination with drugs, herbs, or supplements with antiplatelet or anticoagulant effects due to an increased risk of bleeding [32]. Because of the theoretical risk of bleeding, patients should stop taking cordyceps at least two weeks prior to elective surgical procedures.

Immunosuppressants

Research is conflicting on how cordyceps impacts the immune system. A review of five clinical studies in kidney transplant recipients suggests that taking cordyceps with immunosuppressive therapy could reduce transplant rejection [32]. However, animal and in vitro research suggests that cordyceps could stimulate immune function [32]. Whether it stimulates or suppresses immune function, taking cordyceps could alter the effectiveness of immunosuppressive therapy, so use caution in patients taking immunosuppressants. Also exercise caution in people with autoimmune diseases, such as MS, SLE, or RA, since immune system stimulation by cordyceps could worsen these conditions [15].

Testosterone

In vitro and animal research suggests that cordyceps can increase testosterone levels, but the clinical significance of this finding is unclear. Theoretically, cordyceps could have additive effects when taken with testosterone. However, this interaction is minor considering that it has not been shown in humans and the extent and clinical significance of increased testosterone is not clear and requires further research.

TURKEY TAIL MUSHROOM

Turkey tail mushroom (Coriolus versicolor) is a common mushroom that grows on the stumps and other decomposing wood of broad-leaved trees [33]. In traditional Chinese medicine, it is used for enhancing immune function, removing toxins, promoting good health, and as treatment for cancer, hepatitis, and infections [3,33].

Two main bioactive polysaccharides of turkey tail mushroom, polysaccharide krestin (PSK) and polysaccharide peptide (PSP), are isolated and used medicinally [3]. They are among the most studied compounds in medicinal mushrooms, but their mechanisms of action are still not fully understood [3]. In adults, oral PSK is most commonly taken at a dose of 3 grams daily for up to 36 months [33]. When oral whole turkey tail mushroom is used, it has been studied at a dose of 2.4 grams daily for up to 12 weeks [33].

Safety and Adverse Effects

Turkey tail mushroom and its constituents PSK and PSP are likely safe when used orally and appropriately [33]. There is currently no safety information about other routes of administration. Additionally, there is no research available in people who are pregnant or lactating, so it is best to avoid the use of turkey tail mushroom and its constituents in these special populations.

Orally, turkey tail mushroom and its PSK component are generally well-tolerated. There have been reports of erythema, gastrointestinal side effects, hematological abnormalities, liver dysfunction, and palpitations, but these are in patients who received PSK in addition to standard chemotherapy [33]. It is not known if these are due to PSK, chemotherapy, or both.

Uses and Benefits

Cancer

Turkey tail mushroom constituents PSP and PSK have been officially approved for decades in routine clinical practice in Japan and China as an adjunct to chemotherapy and radiotherapy in doses ranging from 1–3.6 grams daily [3,33]. It has been studied for many different types of cancer, including breast, colorectal, esophageal, gastric, hepatic, leukemia, lung, and nasopharyngeal [33]. Most studies show that taking PSK as an adjunct to standard cancer therapy may improve response rates and survival in some patients with cancer [33]. However, it is unclear whether whole turkey tail mushroom or its constituent PSP is beneficial for patients with cancer [33].

Evidence Based Practice Recommendation

According to the National Cancer Institute, clinical studies of polysaccharide-K derived from turkey tail mushroom in colorectal cancer have shown reduction in recurrence and improvement in overall survival with adjuvant use.

https://www.cancer.gov/about-cancer/treatment/cam/hp/mushrooms-pdq

Last Accessed: October 1, 2024

Level of Evidence: Expert Opinion/Consensus Statement

A meta-analysis of 13 clinical trials including over 2,500 patients with esophageal, gastric, colon, rectal, breast, or nasopharyngeal cancer shows that taking PSK in addition to conventional cancer therapy reduces five-year mortality by 9% when compared with conventional therapy alone [33]. When individual cancer types are considered, the benefit of PSK is most evident in patients with breast, gastric, colon, or rectal cancer [33]. Another meta-analysis of 14 clinical trials shows that taking PSK, PSP, or whole turkey tail mushroom in combination with chemotherapy is associated with a 17% lower risk of mortality in some, but not all, types of cancer when compared with chemotherapy alone [33]. However, overall there was no difference in relapse-free survival or total clinical efficacy. The reliability and relevance of these meta-analyses is unclear since there was significant heterogeneity in cancer types, dose and duration of turkey tail mushroom therapy, and type of turkey tail mushroom used. Furthermore, all the included studies were conducted in China or other Asian countries, limiting the generalizability of the results to other populations.

Research on the use of whole turkey tail mushroom rather than its isolated constituents for treating cancer is limited. A small clinical study in 15 patients with inoperable hepatocellular carcinoma shows that taking turkey tail mushroom 2.4 grams daily for 6 to 12 weeks does not improve time to progression, progression-free survival, overall survival, or quality of life when compared with placebo [33].

Drug and Supplement Interactions

Hypoglycemic Agents

Animal research suggests that turkey tail mushroom constituents might have hypoglycemic effects [33]. Turkey tail mushroom should be used cautiously when taken in combination with antidiabetes drugs or herbs and supplements with hypoglycemic potential due to the additive risk of hypoglycemia. Since turkey tail mushroom could interfere with blood glucose control, it should be discontinued at least two weeks prior to elective surgery.

Cyclophosphamide

Animal research suggests that turkey tail constituent PSP can increase the area under the concentration-time curve (AUC) of cyclophosphamide by 44% to 50% and the half-life by 34% to 43% [33]. Theoretically, this interaction could increase the effects and adverse effects of cyclophosphamide. However, it is unclear whether PSP changes the levels of active metabolites of cyclophosphamide, which are responsible for its clinical activity. Due to this theoretical interaction, use caution in patients taking cyclophosphamide and turkey tail mushroom.

Tamoxifen

Animal research suggests that PSP increases the time to reach maximum concentration of a single dose of tamoxifen by about 9.5 hours, or 228% [33]. When repeated doses of tamoxifen were given, the time to reach maximum concentration of tamoxifen was increased by 5.6 hours or 93% [33]. However, PSP did not change the maximum concentration or the AUC of tamoxifen [33]. While this has not been shown in humans, PSP could theoretically interfere with the absorption of tamoxifen and caution should be used in patients taking this combination.

CYP2C9 Substrates

In vitro research suggests that PSP inhibits cytochrome P450 2C9 (CYP2C9) enzymes in a dose-dependent manner [33]. Theoretically, taking PSP with other drugs metabolized by CYP2C9 could increase drug levels and the risk of adverse effects. Even though this interaction has not been reported in humans, remain watchful when turkey tail mushroom is combined with CYP2C9 substrates.

5. SUMMARY

Interest in using medicinal mushrooms for various conditions is rapidly growing. Healthcare providers need to be aware if their patients are using these mushrooms, as they can cause adverse effects or interact with conventional medications, supplements, or existing medical conditions.

Works Cited

1. Poder, R. The Ice Man's Fungi: Facts and Mysteries. International Journal of Medicinal Mushrooms. 2005;7(3)357-359.

2. Łysakowska P, Sobota A, Wirkijowska A. Medicinal mushrooms: their bioactive components, nutritional value and application in functional food production: a review. Molecules. 2023;28(14):5393.

3. Venturella G, Ferraro V, Cirlincione F, Gargano ML. Medicinal mushrooms: bioactive compounds, use, and clinical trials. Int J Mol Sci. 2021;22(2):634.

4. Encyclopaedia Britannica. Mushroom. Available at https://www.britannica.com/science/mushroom. Last accessed May 31, 2024.

5. TRC Healthcare NatMed. Agaricus Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1165. Last accessed May 3, 2024.

6. Firenzuoli F, Gori L, Lombardo G. The medicinal mushroom Agaricus blazei Murrill: review of literature and pharmacotoxicological problems. Evid Based Complement Alternat Med. 2008;5(1):3-15.

7. Deng R. A review of the hypoglycemic effects of five commonly used herbal food supplements. Recent Pat Food Nutr Agric. 2012;4(1):50-60.

8. Kang ZQ, Huo JL, Zhai XJ. Effects of perioperative tight glycemic control on postoperative outcomes: a meta-analysis. Endocr Connect. 2018;7(12):R316-R327.

9. TRC Healthcare NatMed. Black Hoof Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1510. Last accessed May 6, 2024.

10. Shenghua W, Yu-cheng D, Hattori T, TuWen Y, et al. Species clarification for the medicinally valuable 'sanghuang' mushroom. Botanical Studies. 2012;53:135-149.

11. Munro AW. Cytochrome P450 1A1 opens up to new substrates. J Biol Chem. 2018;293(50):19211-19212.

12. Walsh AA, Szklarz GD, Scott EE. Human cytochrome P450 1A1 structure and utility in understanding drug and xenobiotic metabolism. J Biol Chem. 2013;288(18):12932-12943.

13. U.S. Food and Drug Administration. For Healthcare Professionals: FDA's Examples of Drugs that Interact with CYP Enzymes and Transporter Systems. Available at https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems. Last accessed May 28, 2024.

14. García-Suástegui WA, Ramos-Chávez LA, Rubio-Osornio M, Calvillo-Velasco M, Atzin-Méndez JA, Guevara J, Silva-Adaya D. The role of CYP2E1 in the drug metabolism or bioactivation in the brain. Oxid Med Cell Longev. 2017;2017:4680732.

15. TRC Healthcare NatMed. Chaga. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1474. Last accessed May 6, 2024.

16. Fordjour E, Manful CF, Javed R, Galagedara LW, Cuss CW, Cheema M, Thomas R. Chaga mushroom: a super-fungus with countless facets and untapped potential. Front Pharmacol. 2023;14:1273786.

17. Kwon O, Kim Y, Paek JH, Park WY, Han S, Sin H, Jin K. Chaga mushroom-induced oxalate nephropathy that clinically manifested as nephrotic syndrome: a case report. Medicine (Baltimore). 2022;101(10):e28997.

18. TRC Healthcare NatMed. Fly Agaric Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=190. Last accessed May 6, 2024.

19. Encyclopaedia Britannica. Fly agaric. Available at https://www.britannica.com/science/fly-agaric. Last accessed May 31, 2024.

20. Rampolli FI, Kamler P, Carnevale Carlino C, Bedussi F. The deceptive mushroom: accidental Amanita muscariapoisoning. Eur J Case Rep Intern Med. 2021;8(3):002212.

21. Carboué Q, Lopez M. Amanita muscaria: ecology, chemistry, myths. Encyclopedia. 2021;1(3):905-914.

22. TRC Healthcare NatMed. Lion's Mane Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1536. Last accessed May 7, 2024.

23. 23. Docherty S, Doughty FL, Smith EF. The acute and chronic effects of lion's mane mushroom supplementation on cognitive function, stress and mood in young adults: a double-blind, parallel groups, pilot study. Nutrients. 2023;15(22):4842.

24. TRC Healthcare NatMed. Maitake Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=560. Last accessed May 8, 2024.

25. TRC Healthcare NatMed. Poria Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=246. Last accessed May 8, 2024.

26. Li X, He Y, Zeng P, Liu Y, Zhang M, Hao C, Wang H, Lv Z, Zhang L. Molecular basis for Poria cocos mushroom polysaccharide used as an antitumour drug in China. J Cell Mol Med. 2019;23(1):4-20.

27. TRC Healthcare NatMed. Reishi Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=905. Last accessed May 9, 2024.

28. Wachtel-Galor S, Yuen J, Buswell JA, et al. Ganoderma lucidum (lingzhi or reishi): a medicinal mushroom. In: Benzie IFF, Wachtel-Galor S (eds). Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. Boca Raton, FL: CRC Press/Taylor & Francis; 2011.

29. TRC Healthcare NatMed. Shiitake Mushroom. Available at: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=680. Last accessed May 23, 2024.

30. Lin B, Li S. Cordyceps as an herbal drug. In: Benzie IFF, Wachtel-Galor S (eds). Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. Boca Raton, FL: CRC Press/Taylor & Francis; 2011.

31. Memorial Sloan Kettering Cancer Center. Cordyceps. Available at https://www.mskcc.org/cancer-care/integrative-medicine/herbs/cordyceps#msk_professional. Last accessed May 29, 2024.

32. TRC Healthcare NatMed. Cordyceps. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=602. Last accessed May 6, 2024.

33. TRC Healthcare NatMed. Turkey Tail Mushroom. Available at https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=648. Last accessed May 23, 2024.

Evidence-Based Practice Recommendations Citations

1. National Cancer Institute. Medicinal Mushrooms: Health Professional Version. Available at https://www.cancer.gov/about-cancer/treatment/cam/hp/mushrooms-pdq. Last accessed October 1, 2024.