#68010: Cannabinoid Overview

While cannabis is often used recreationally, either inhaled or ingested, it is frequently touted for a variety of conditions, such as amyotrophic lateral sclerosis, dementia, HIV/AIDS-related wasting, Crohn disease, epilepsy, glaucoma, chronic pain, and chemotherapy-induced nausea and vomiting. However, there is not good evidence indicating that cannabis is beneficial for use in these conditions. There is some evidence for the use of THC-containing products in patients with multiple sclerosis and in those with neuropathic pain.

Multiple Sclerosis

While it is unclear if smoking cannabis improves multiple sclerosis-related symptoms, a prescription product available in Canada and most of Europe, as well as other products containing the combination of THC and CBD, seem to reduce spasticity in patients with multiple sclerosis. Nabiximols, a prescription oromucosal spray containing whole-plant cannabis extract (Sativex), is available in most of Europe and Canada but is not yet approved in the United States. Each actuation of this cannabis extract spray is standardized to deliver THC 2.7 mg and CBD 2.5 mg [1].

A meta-analysis of the available research shows that using a prescription oromucosal spray containing cannabis extract for at least two weeks modestly reduces subjective spasticity, but not bladder dysfunction, when compared with placebo. Effects might last more than 11 months, but discontinuation of use may cause rebound symptoms. Much of the research on the prescription product was funded by the manufacturer.

The American Academy of Neurology asserts that clinicians might offer oral cannabis extract to patients with multiple sclerosis to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain).

(https://www.aan.com/Guidelines/home/GuidelineDetail/641 Last Accessed: October 25, 2022)

Level of Evidence: A (Established as effective for the given condition in the specified population.)

The American Academy of Neurology states that a prescription cannabis extract does not improve objective measures of spasticity, reduce the number of urinary incontinence episodes, or reduce multiple sclerosis-related tremors [1].

A meta-analysis of the available research in patients with multiple sclerosis shows that taking oral cannabis extracts containing THC 25–30 mg and CBD 8–18 mg (e.g., Cannador, Society of Clinical Research) daily for up to 15 weeks modestly reduces subjective spasticity, neuropathic pain, and bladder dysfunction, but not objective spasticity measures, when compared with placebo [1].

Despite generally positive research on multiple sclerosis-related symptoms with prescription or other standardized products, research on the use of any other cannabis products is limited. Keep in mind that nonprescription cannabis products can contain a wide range of THC or CBD, in very different ratios, which would be expected to significantly alter any effects, clinical or adverse.

Neuropathic Pain

The National Institute for Health and Care Excellence recommends against starting Cannabis sativa extract to treat neuropathic pain in non-specialist settings, unless advised by a specialist to do so.

(https://www.nice.org.uk/guidance/cg173 Last Accessed: October 25, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

Inhaled cannabis seems to temporarily improve neuropathic pain, but it is unclear what the optimal dose might be. A meta-analysis of small studies in patients with chronic neuropathic pain secondary to a variety of causes shows that inhaling cannabis containing THC 1.6–96 mg daily for up to two weeks reduces pain intensity. To achieve a pain reduction of at least 30%, six patients would need to be treated [1].

A small individual clinical study in patients with spinal cord injury shows that inhaling cannabis containing THC 2.9% or 6.7% reduces neuropathic pain, with a number needed to treat of three to achieve a pain reduction of at least 30% during an eight-hour period [1].

Safety

Most commonly, dizziness, dry mouth, fatigue, headache, increased appetite, nausea, paranoid and dissociative thinking, and sedation are associated with cannabis when consumed via any usual route. When inhaled, cannabis use has commonly been associated with upper respiratory tract symptoms, such as cough and wheeze. Intoxicating doses of cannabis can impair memory, motor coordination, reaction time, and visual perceptions for as long as eight hours [1].

Serious adverse effects have also been reported with ingestion or inhalation of cannabis, usually with large doses or with extended use. Respiratory effects specifically are associated with smoking or vaping cannabis and can include coughing, wheezing, inflammation of the upper respiratory tract, and e-cigarette, or vaping, product-use associated lung injury (EVALI). Potential neurologic effects include anxiety, psychosis, cognitive impairment, mood disturbances, cannabinoid hyperemesis syndrome (CHS), withdrawal syndrome, and seizures. Atrial fibrillation, ventricular arrhythmia, and myocardial infarction are possible cardiovascular effects [1].

Abuse Potential

Cannabis can be habit-forming. Meta-analyses show that as many as 47% of regular cannabis users develop some form of dependence and up to 9% of all users develop cannabis use disorder. For context, substance use disorders occur in approximately 20% to 30% of all tobacco users, 15% of those who try cocaine, and 25% of those who try heroin. However, it is not always clear if those presenting with cannabis use disorder are truly addicted or simply demonstrating high levels of dependence with heavy use. Additionally, it is unclear how the increasing concentration of THC in cannabis affects this dependence rate [1].

Drug Interactions

In vitro research and some case reports show that using cannabis can increase the risk of bleeding when administered with drugs, herbs, and supplements that increase the risk of bleeding. Patients receiving warfarin, other anticoagulants, or antiplatelet agents should be monitored more closely for bleeding, especially when cannabis use is not on a regular or consistent basis.

Cannabis can also affect certain cytochrome P450 (CYP450) enzymes. Based on pharmacology and some in vitro research, cannabis might inhibit or induce CYP450 enzymes, including CYP 2C9, 2E1, and 3A4, potentially increasing or decreasing the levels and corresponding effects of substrates of these enzymes. Based on pharmacology, certain CYP450 inhibitors and inducers might increase or decrease the levels and corresponding effects of cannabis, but these concerns are theoretical at this time [1]. Theoretically, using cannabis with drugs, herbs, and supplements that have sedative properties may cause additive therapeutic and adverse effects.

Even though many of these interactions have not been substantiated in humans, they could be useful to keep in mind, especially for patients taking narrow therapeutic index drugs or patients who are regular users of cannabis. Gather information from patients about cannabis use and add this to their medical history or patient profile. Consider the impact of cannabis use when patients start or stop a medication or complain of any new side effects.

Pregnancy and Lactation

Cannabis crosses the placenta, and use during pregnancy has been associated with numerous negative maternal and fetal outcomes in observational studies. THC is excreted into the breast milk for at least six weeks following cessation of use and can cause delayed motor development in the infant [1]. Patients should be informed of these risks and discouraged from using cannabis while pregnant or breastfeeding.

Patients with Diabetes

In patients with type 1 diabetes, cannabis use has been associated with worsened glycemic control, increased glycated hemoglobin (HbA1c), and an increased risk for diabetic ketoacidosis. In patients with type 2 diabetes, cannabis use has been associated with an increased risk for diabetic nephropathy, myocardial infarction, and peripheral arterial occlusion. Until more is known, tell patients with diabetes to be cautious using cannabis [1].

In May 2019, FDA approved of a specific, oil-based prescription formulation of CBD (Epidiolex). While the passage of the 2018 Farm Bill exempted hemp and its constituents, including CBD, from the Controlled Substances Act and made them legal for sale, FDA approval of a prescription CBD product further complicated things [3].

Because CBD is the active ingredient in a prescription product, it has been said that legally it cannot be included in foods and dietary supplements. However, this sentiment has been disputed and enforcement has been lacking. Dietary supplements and foods containing CBD are abundant in the marketplace [3].

CBD is frequently touted for mental health, pain management, sleep, substance use disorder, and gastrointestinal disorders, but the majority of the evidence for CBD use is for treatment-resistant epilepsy. Research for other purported indications is inconclusive [3].

Because of how readily available CBD products have become, you may be getting a lot of questions from patients about the touted uses of these products. We will first discuss the use of CBD with the most evidence, and then we will briefly review the evidence available for some other conditions of interest.

Treatment-Resistant Epilepsy

A prescription CBD solution approved by the FDA is labeled for the adjunctive treatment of Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Prescription CBD is an oil-based oral solution standardized to contain CBD extract 100 mg/mL in sesame oil. The extract is highly purified from a plant source. Originally classified by the DEA as a Schedule V controlled substance, it was descheduled in April 2020 [3].

In children with Dravet syndrome and children and adults with Lennox-Gastaut syndrome or tuberous sclerosis complex, adjunctive treatment with this prescription formulation reduces seizure frequency from baseline by 39% to 49%, compared with only 13% to 27% in those receiving placebo. Nearly half of patients experience at least a 50% reduction in seizure frequency from baseline. Results of open-label extension studies demonstrate similar efficacy for sustained periods of up to three years [3].

While this prescription formulation has also been evaluated for use in other forms of epilepsy (e.g., Sturge-Weber syndrome, febrile infection-related epilepsy syndrome [FIRES], epileptic encephalopathy of genetic origin), the available research is limited, and it is not labeled for these uses. It is unclear if other CBD products are beneficial for use in seizure disorders [3].

Mental Health

Research on the use of CBD for mental health benefits is inconclusive. In healthy patients, several small, low-quality studies show that oral CBD 15 mg or 150 mg modestly improves emotional exhaustion, depression or anxiety symptoms, and the ability to cope with stress, when compared with standard care or placebo, but it is not clear if CBD is beneficial in patients diagnosed with anxiety or depression [3].

In patients with social anxiety disorder, oral CBD 300–600 mg daily or as a single dose reduces overall anxiety and anxiety associated with public speaking. However, for some patients, anxiety was only reduced before or after and not necessarily during the speaking event. CBD does not seem to reduce speaking anxiety in patients at higher risk for psychiatric complications. Differences due to study size, baseline anxiety, and the use of nonstandardized products may explain some of the variability in outcomes observed [3].

In patients with post-traumatic stress disorder, a small study shows that taking high-purity oral CBD 300 mg attenuates cognitive impairment associated with the recall of traumatic events when compared with placebo. However, it does not improve anxiety, alertness, or discomfort. Patients in the CBD group had more psychiatric comorbidities at baseline [3].

Pain

Although CBD products, both oral and topical, are regularly touted for pain relief, they do not seem to reduce acute pain and effects on chronic pain are even less clear. Even though CBD salves and balms are really popular for muscle and joint pain relief, there does not seem to be evidence supporting topical absorption of CBD.

In healthy volunteers with experimentally induced pain, several small clinical studies show that single oral doses of CBD 200–800 mg do not seem to reduce acute pain when compared with placebo. In patients with acute low back pain presenting to the emergency department, oral CBD 400 mg, in addition to the standard treatment of acetaminophen 1,000 mg with ibuprofen 400 mg, does not reduce pain or the need for rescue analgesia with oxycodone over two hours when compared with placebo [3].

A small observational cohort study shows that taking oral CBD for eight weeks is associated with reductions in pain and opioid use and improvements in sleep quality. However, due to the observational nature of the study, it is unclear if this is a direct result of CBD use [3].

Sleep

Although CBD has demonstrated sedative effects in animal research, it has not been evaluated for insomnia or other sleep disorders in clinical studies [3].

Substance Use Disorders

In patients with various substance use disorders, CBD may play a role in reducing cravings and substance use, but it is unclear if these marginal benefits actually translate into relapse prevention. Unfortunately, most studies in this area are generally small and low quality. Interestingly, CBD has been evaluated for use in patients with cannabis use disorder.

In patients with cannabis use disorder of moderate severity, a small clinical study shows that taking synthetic CBD oil 400 mg or 800 mg in two divided doses daily for four weeks seems to reduce overall cannabis consumption, based on urine metabolite levels, when compared with placebo. The 400-mg dose, but not the 800-mg dose, seems to increase self-reported abstinence from cannabis by about 0.5 days per week when compared with placebo [3].

Oral CBD has been used with apparent safety at doses of 200–1,200 mg daily in the short term, for up to four to 13 weeks. CBD seems to be well tolerated when taken by mouth. Prescription CBD is reported to cause somnolence in up to 30% of patients and diarrhea in up to 24% of patients, but keep in mind that doses for treatment-resistant epilepsy exceed those used in most nonprescription CBD products. Doses of prescription CBD exceeding 15–20 mg/kg daily and/or taken in combination with other anticonvulsants (e.g., clobazam, valproic acid) are more likely to cause certain adverse effects like somnolence, diarrhea, elevation of liver transaminases, and weight loss/gain. Decreased appetite, drowsiness, dry mouth, fatigue, and vomiting have also been commonly reported. Pharmacogenetic variation has been shown to affect susceptibility to CBD-associated adverse effects including diarrhea, sedation, and elevation of liver transaminases [3].

There has been some concern that CBD can be used as a substance of abuse, but overall, these concerns seem unfounded. Single 750-mg doses of CBD were rated no differently than placebo for "drug-liking", likelihood of repeat use, or occurrence of positive effects (e.g., feeling "high" or "stoned") among healthy recreational polydrug abusers in a clinical study. Higher single doses of 1,500 mg or 4,500 mg were rated with a higher likelihood for repeat use and the presence of "positive effects", but these ratings were still lower than those for dronabinol, a synthetic version of THC, and alprazolam [3].

Unlike THC, limited research suggests that CBD does not cause driving impairment. A small study has found that inhaling vaporized cannabis containing CBD 13.75 mg does not increase lane weaving when compared with placebo. Lane weaving observed in those inhaling this product was equivalent to having a blood alcohol concentration (BAC) of 0.02%, which is below the lower limit of clinically relevant impairment that is considered to occur with a BAC of 0.05%. Keep in mind that the study only tested a single dose of CBD, which may not be indicative of real-world use [3].

Abrupt discontinuation following short-term CBD use does not seem to be associated with withdrawal symptoms in healthy volunteers [3].

CBD can affect certain CYP450 enzymes. Some clinical research has suggested that CBD might inhibit CYP2C9, 2C19, and 3A4, potentially increasing the levels and corresponding effects of substrates of these enzymes. This represents the potential for a large number of drug interactions. Based on in vitro and animal research, CBD also might inhibit CYP 1A1, 1A2, 1B1, 2A6, 2B6, and 2C8 enzymes, but these concerns are theoretical at this time. Patients receiving substrates of these enzymes, especially narrow therapeutic index drugs metabolized by CYP2C9, 2C19, or 3A4, should be monitored for potential interactions. Based on theoretical pharmacology, certain CYP450 enzyme inhibitors and inducers might increase or decrease the levels and corresponding effects of CBD [3].

Clinical studies have demonstrated modest to substantial increases in the concentrations of some drugs when CBD, including prescription CBD, is used concomitantly. These drugs include brivaracetam, caffeine, citalopram, clobazam, eslicarbazepine, everolimus, rufinamide, sirolimus, stiripentol, tacrolimus, topiramate, and zonisamide. Theoretically, using CBD with drugs, herbs, and supplements that have sedative properties may cause additive therapeutic and adverse effects [3].

Gather information from patients about CBD use and add this to their medical history or patient profile. Consider the impact of CBD use when patients start or stop a medication or complain of any new side effects.

Children

While a specific prescription CBD oral solution product has been used safely in children as young as 1 year of age, the safety of other forms of CBD have not been evaluated in children [3].

Pregnancy and Lactation

Due to concerns related to contamination with THC, heavy metals, pesticides, and more, CBD may not be safe for use while pregnant or breastfeeding. Frequent contamination of CBD can be dangerous to the fetus. Similarly, animal research has demonstrated that high levels of CBD can adversely affect the reproductive system of male offspring. The FDA strongly advises against its use during pregnancy [3].

Although there is interest in using cannabidivarin for various neurologic or neuromuscular and gastrointestinal disorders, research is mostly limited to in vitro and animal studies. While the FDA and the European Medicines Agency have granted cannabidivarin an orphan designation for use in the treatment of Fragile X syndrome and Rett syndrome, there is not enough reliable information about the clinical effects of cannabidivarin for these uses [4].

Epilepsy

A large, high-quality clinical study in patients with inadequately controlled focal seizures failed to show that adjunctive therapy with cannabidivarin reduces seizure frequency when compared with placebo, prompting the industry sponsor to abandon research for this indication [4].

Neuropathic Pain

There is limited evidence on the use of cannabidivarin in patients with HIV-associated neuropathic pain. A small clinical study in patients with HIV-associated neuropathic pain failed to show that cannabidivarin reduces pain or medication use when compared with placebo [4].

Cannabidivarin seems to be safe for short-term use in adults. Doses of up to 800 mg twice daily for up to eight weeks have been evaluated in clinical research, but there is no data for use of higher doses of longer durations. Diarrhea, dizziness, and nausea are commonly reported with use, and higher doses have been associated with abdominal pain, headache, rash, and somnolence [4].

This cannabinoid has not been extensively studied in humans, but there is increasing interest in its use as an anti-inflammatory, anticonvulsant, analgesic, antipsychotic, and appetite suppressant. Available research for these conditions is limited to in vitro and animal studies [5].

While tetrahydrocannabivarin has been used with apparent safety in clinical research for up to 13 weeks, a thorough evaluation of safety outcomes has not been conducted [5].

Although there is interest in using cannabinol as an analgesic, appetite stimulant, immunomodulator, and sleep aid, it has not been evaluated in clinical studies [6].

Cannabinol has not been thoroughly evaluated for safety [6].

In in vitro studies, certain CYP 450 enzyme inhibitors increased the levels and effects of cannabinol. In other in vitro research, cannabinol inhibited certain CYP450 enzymes, potentially increasing the levels and effects of substrates of these enzymes. Even though these interactions have not been substantiated in humans, they could be useful to keep in mind, especially for those taking narrow therapeutic index drugs or those who are regular users of cannabinol [6].

Although there is interest in using cannabigerol for conditions such as cachexia, dyslipidemia, Huntington disease, and inflammatory bowel disease, available research is limited to in vitro and animal studies. Some research shows that the anti-inflammatory effects of cannabigerol might be greater when used in combination with CBD, but cannabigerol also seems to reverse the antiemetic effects of CBD when used concomitantly [7].

Cannabigerol has not been thoroughly evaluated for safety [7].

Although there is interest in using cannabichromene for its anti-inflammatory, analgesic, and anticonvulsant effects, available research is limited to in vitro and animal studies. Some research shows that the analgesic effects of cannabichromene might be greater when used in combination with other cannabinoids (e.g., cannabinol) [8].

A thorough evaluation of safety outcomes with cannabichromene has not been conducted [8].

Preliminary clinical research suggests that cannabichromene might have sedative and hypnotic effects. Be aware that using cannabichromene with drugs, herbs, and supplements that have sedative properties may cause additive therapeutic and adverse effects [8].

Because delta-8 THC is not acknowledged in the 2018 Farm Bill, its U.S. federal regulatory status is unclear. It is banned or restricted in some states, while remaining legal in others. The combination of its unclear regulatory status and its psychoactive effects have led to rapid increases in delta-8 THC availability and interest [9].

A thorough evaluation of safety outcomes with delta-8 THC has not been conducted. In the first seven months of 2021 alone, hospitalization occurred in 18% of 661 reported exposures to delta-8 THC. In the eight-month period ending in July 2021, 14 of 22 cases reported to the FDA presented to the hospital for adverse effects related to delta-8 THC-containing products [9].

According to data compiled from sources including the FDA, the Centers for Disease Control and Prevention (CDC), and the American Association of Poison Control Centers, some of the most common adverse effects associated with delta-8 THC include difficulty thinking and speaking, a dreamlike state, euphoria, feeling "high," and vision and time distortion. Serious safety signals also have been observed, including Brugada ECG pattern and cannabinoid hyperemesis syndrome, frequently leading to emergency room visits and hospitalization [9].

Excessive and prolonged cannabis use (e.g., two to three times daily over two years) can lead to a condition called cannabinoid hyperemesis syndrome (CHS). It is characterized by cyclic attacks of nausea and vomiting that are not alleviated by conventional antiemetics. Anecdotally, patients commonly report temporary relief of their symptoms with bathing in extremely hot water, and this is often what clues providers in to this diagnosis. CHS has occurred with smoking and/or oral use and has even been linked to severe complications resulting in death in several cases [10].

There are also case reports of CHS with delta-8 THC and K2/Spice. Non-THC cannabinoids (e.g., CBD, cannabigerol) also may play a role [10].

The cornerstone of long-term treatment for CHS is complete discontinuation of cannabis use, but benzodiazepines and capsaicin also may play a role in short-term symptom management [10].

E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults and children using e-cigarette, or vaping, products. The majority of patients experiencing EVALI reported using THC-containing products in the three months prior to the development of symptoms. It is not clear if EVALI is the direct result of THC or another component of the formulation, like vitamin E acetate. The FDA has warned the public to stop using all THC-containing vaping products because of this risk [1].

Product quality is lacking and cross contamination of cannabis products with other cannabinoids is abundant. Commercially available CBD products, especially those intended for vaping, have been frequently shown to be contaminated with THC or synthetic cannabinoids.

An analysis of seven commercially available CBD e-liquid formulations found that two products were contaminated with an undeclared synthetic cannabimimetic (5F-ADB) and another two contained undeclared THC. Off-the-shelf evaluations of commercially available oral CBD products have consistently demonstrated issues with product standardization and labeling.

In an analysis of 84 commercially available CBD products in the United States, only 31% of products were accurately labeled and 21% of products contained unlabeled THC. Other assessments of 14 products commercially available in Europe and 25 products available in the United States found that up to 90% of the products were inaccurately labeled and that up to 86% of products contained detectable quantities of THC [11,12].

CBD is also available in an e-liquid formulation for use in e-cigarettes intended for vaping. Interestingly, when CBD is exposed to temperatures typically occurring in e-cigarettes, it can be converted to delta-8 THC, cannabinol, cannabichromene, and other cannabinoids. Commercially available CBD, especially those intended for vaping, may be contaminated with synthetic cannabinoids, increasing the risk of serious associated adverse effects [11,12].

The increasing prevalence of delta-8 THC is also causing contamination concerns, as both the contaminant and the frequently contaminated. Some products labeled as hemp containing CBD might contain undeclared delta-8 THC. Delta-8 THC products might also contain other cannabinoids given that they are synthesized from other cannabinoids [9].

There has been a recent uptick in accidental ingestion of cannabis-containing edibles in children ages 12 years and younger. Legalization of recreational cannabis and the availability of these more appealing food forms, like gummies, are likely to blame. Accidental ingestion of cannabis-containing edibles in children has been associated with ataxia, coma, hypotonia, hypothermia, lethargy, nystagmus, respiratory depression, seizures, and tremors [1].

With the rise in popularity of delta-8 THC, delta-8 THC-containing gummies and other products resembling candy or cookies have been mistakenly consumed by children, often resulting in hospital admission. In the first seven months of 2021 alone, the American Association of Poison Control Centers statistics indicate that 39% of the 661 reported exposures to delta-8 THC occurred in children younger than 18 years old, with some requiring ICU admission. In two cases, children presented with deep sedation, hypotension, and a slowed heart rate following accidental ingestion of gummies containing delta-8 THC. In another case, a 2-year-old child presented with sedation and acute encephalopathy following accidental ingestion of gummies containing an estimated delta-8 THC dose of 15 mg/kg [9].

While prescription CBD (Epidiolex) has been safely used in children, there is not enough reliable information about the safety of other forms of CBD in children. In a poison control center report of 1,581 CBD exposures in children and adults, 5.7% of cases involved tachycardia. Most exposures were oral, single-substance exposures, but it is not clear what doses of CBD precipitated these reports [3].