The evolution of Cannabis sativa has been traced to the Central Asian/Himalayan region roughly 36 million years ago [18]. Over time, cannabis spread to all regions with human habitation, reflecting the value placed on its medicinal, spiritual, and dietary utility [19].

Western medicine was introduced to cannabis by a 1839 publication of O'Shaughnessy, a physician who described its successful use in his patients as an analgesic, appetite stimulant, antiemetic, muscle relaxant, and anticonvulsant, and by the 1845 publication of Moreau, a psychiatrist who documented the results of cannabis use in his patients, his students, and himself [20,21]. Support for medical cannabis use was disseminated by these publications from England and France throughout Europe and North America. Cannabis was entered in the U.S. Dispensatory in 1854, and the first medical conference on cannabis was held in 1860 by the Ohio State Medical Society. By 1900, more than 100 scientific articles on cannabis efficacy had been published in the United States and Europe. Cannabis was usually available as a tincture comprised of plant extract. Aware of the therapeutic potential, researchers worked to resolve its limitations, including lack of water solubility, delayed onset of action (when given orally), variable potency, difficulty in standardized dosing, and individual differences in response. The importance of dose titration was stressed [20,22]. The late 19th to early 20th century was the pinnacle of cannabis use in Western medicine. Cannabis extracts were marketed by Merck, Burroughs-Wellcome, Bristol-Meyers Squibb, Parke-Davis, and Eli Lilly. The 1924 edition of the influential medical textbook Sajous's Analytic Cyclopedia of Practical Medicine listed numerous indications for cannabis, including [20,22]:

Sedative or hypnotic: Insomnia, melancholia, delirium tremens, chorea, tetanus, rabies, hay fever, bronchitis, pulmonary tuberculosis, coughs, spasm of the bladder

Analgesic: Headaches, migraine, eye strain, menopause, brain tumors, neuralgia, gastric ulcer, indigestion, multiple neuritis, pain not due to lesions, dysmenorrhea, chronic inflammation, acute rheumatism, eczema and pruritus, tingling, numbness of gout, dental pain

Other uses: To improve appetite and digestion associated with "pronounced anorexia following exhausting diseases," dyspepsia, diarrhea, dysentery, cholera, nephritis, diabetes mellitus, vertigo

Research and clinical interest in cannabis was re-ignited with identification of the chemical structure for THC in 1964, followed by discovery and cloning of cannabinoid receptors and isolation of the endogenous cannabinoid anandamide in the 1970s to early 1990s [24]. The first sporadic scientific reporting of medical marijuana benefit started in the 1970s, particularly with nausea and vomiting from chemotherapy. As the acquired immune deficiency syndrome (AIDS) epidemic spread through the 1980s, patients increasingly found that marijuana relieved many of their symptoms, particularly wasting symptoms associated with AIDS. A landmark 1999 IOM report described the scientific and clinical basis for supporting medical marijuana use. There were increasing media reports of medical marijuana users subjected to criminal prosecution during this period [8]. These events stimulated media attention and growing public demand for medical access. Despite its illegal status at the federal level, cannabis was reintroduced into medical use in 1996 by popular vote and legislative acts in California. By 2023, 38 states and the District of Columbia had followed suit [1]. (For information on laws pertaining to medical marijuana in your state, visit https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc.) In addition, cannabis is used by millions of patients for medicinal purposes in jurisdictions where it remains illegal for medical use [11]. In opposition to federal law, state medical marijuana programs have received support by official federal statements of cooperative noninterference by the Veterans Health Administration and the U.S. Department of Justice in 2009 [24].

The endogenous cannabinoid system (ECS) is a signaling system that includes cannabinoid receptors, endogenous receptor ligands (termed endocannabinoids), and their synthesizing and degrading enzymes [30]. Core functions of the ECS have been described as "relax, eat, sleep, forget, and protect," shorthand for the diversity of processes involving the ECS [31]. The ECS regulates neuronal excitability and inflammation in pain circuits and cascades and also helps regulate movement, appetite, aversive memory extinction, hypothalamic-pituitary-adrenal (HPA) axis modulation, immunomodulation, mood, wake/sleep cycles, blood pressure, bone density, tumor surveillance, neuroprotection, and reproduction. The so-called "runner's high" and the effects of osteopathic manipulative therapy and electroacupuncture are mediated by the ECS [32,33].

CB1 receptors are the most abundant G-protein-coupled receptors in the brain and are expressed at lower densities in many peripheral tissues. CB1 receptors solely mediate the psychotropic and behavioral effects of cannabinoids and regulate several peripheral processes, such as energy homeostasis, cardiovascular function, and reproduction[30,35].

As noted, CB2 receptor expression is highest in immune cells. CB2 activation mediates immunosuppressive effects, including inhibition of proinflammatory cytokine production and cytokine and chemokine release, and blockade of neutrophil and macrophage migration [36,59,60].

Cannabis possesses at least 489 distinct compounds from 18 different chemical classes that include terpenoids, flavonoids, phytosterols, and at least 100 cannabinoids. This does not mean there are 100 different cannabinoid effects or interactions; the cannabinoids fall into 10 groups of closely related cannabinoids, and most are not believed to contribute to cannabis's effects at their naturally occurring concentrations in the plant. THC is the primary psychoactive ingredient, and depending on the particular plant, THC or cannabidiol (CBD) is the most abundant cannabinoid. The relative concentration of THC, CBD, and other cannabinoids in a given plant is influenced by cannabis strain, soil and climate conditions, and cultivation techniques [8,67].

Dronabinol (branded as Marinol) is an isomer of THC, and across a wide range of oral doses, it is shown to be chemically identical to plant-derived THC [37]. Dronabinol was initially approved by the U.S. Food and Drug Administration (FDA) in 1985 for the treatment of chemotherapy-induced nausea and vomiting in patients lacking adequate response to existing antiemetics, and then in 1992 for anorexia and cachexia in patients with AIDS. Dronabinol is a Schedule III substance and is available in 2.5–10 mg oral capsules and 5 mg/mL oral solution [83].

The cannabis used by the CMCR is of comparable pharmaceutical quality to the medical cannabis in the Netherlands and Canada [26]. In contrast, legal medicinal cannabis purchased from dispensaries in the United States lacks government-controlled standardization of cultivation, potency, and purity [88]. In the United States, cannabis grown for recreational or medical use has been bred to increase THC effects by increasingly reducing the CBD concentration. This also increases the side effect potential, and medical cannabis users may want to avoid this by seeking strains bred for higher CBD concentration [89].

CBD produces pharmacologic actions different from, and often the opposite of, those of THC, and an increasing number of publications suggest broad therapeutic potential[103]. CBD is non-psychoactive but modulates ion channel, receptor, and enzyme targets. Preclinical studies suggest beneficial anti-inflammatory, analgesic, antiemetic, antipsychotic, anti-ischemic, anxiolytic, and antiepileptiform effects; human studies suggest anxiolytic efficacy[103,104,105]. CB2 receptor activity accounts for some anti-inflammatory and antinociceptive effects. CBD does not affect memory and probably curtails negative THC side effects by CB1 inverse agonist activity. The anxiolytic effects of CBD probably result from 5HT1-A receptor agonist activity[37].

Other mechanisms of therapeutic activity have been found. The neuroprotective properties of CBD are produced by inhibition of glutamate neurotoxicity and by antioxidant activity that surpasses ascorbic acid (vitamin C) and tocopherol (vitamin E)[93]. CBD modulates endocannabinoid activity as a TRPV1 agonist and an FAAH inhibitor, and through inhibition of THC first pass hepatic metabolism into the more highly psychoactive metabolite 11-hydroxy-THC, which prolongs THC half-life and reduces the unwanted THC side effects of intoxication, panic, anxiety, and tachycardia[106]. CBD inhibits tumor necrosis factor-alpha (TNF-α) in an animal model of rheumatoid arthritis and produces anti-inflammation and analgesia unrelated to COX-1 or COX-2 inhibition that involves promotion of adenosine receptor A2A signaling through adenosine transporter inhibition[31,107]. Many effects of CBD follow a bell-shaped dose-response curve, suggesting that dose is a key factor in CBD pharmacology[104].

With smoking, the onset of effect occurs within seconds to minutes. Maximal effect is experienced after 30 minutes, and the duration of effect is 2 to 3 hours [59]. Peak plasma THC occurs within 10 minutes and decreases to roughly 60% of peak by 15 minutes and to 20% of peak by 30 minutes. This rapid onset and predictable decay allows for effective dose titration not possible with oral cannabinoids [88]. The THC dose absorbed systemically is 25% to 27% of the total available THC content in a marijuana cigarette ("joint") [68,114].

Body fat is the major long-term storage site of THC and its biometabolites. Elimination occurs over several days due to the slow rediffusion of THC from body fat and other tissues. Roughly 20% to 35% of THC is eliminated in urine and 65% to 80% in feces, and by five days, 80% to 90% of THC is eliminated, although THC from a single dose can be detected in plasma up to 13 days later in chronic smokers as a result of extensive storage and release from body fat [59,121].

Cannabis may be contaminated by a variety of organisms, such as Aspergillus fungus and bacteria, that can result in fulminant pneumonia, especially in immunocompromised persons. Nonbiologic contaminants can include heavy metals such as aluminum and cadmium from the soil, with cadmium readily absorbed into the plant at high concentrations. Organophosphate pesticides are found less often in cannabis grown outdoors versus indoor cultivation [137]. Concerns over inorganic and biologic contaminant ingestion prompted Health Canada and the OMC to carefully control all aspects of cultivation, test the product for the presence of mold spores and 28 different metals including heavy metals, and pre-emptively irradiate all cannabis products before distribution to medical or research users [14,27]. This is not currently done to most cannabis available in the United States.

However, a subgroup of patients who are genetically vulnerable to cannabis-induced acute psychoses, and possibly cannabis-initiated schizophrenia, carry a functional polymorphism in the catechol-O-methyltransferase gene and a polymorphism in the brain-derived neurotrophic factor gene. Considering the potentially substantial risks, cannabis should be avoided in adolescents and adults with current, past, or family history of any psychotic disorder [59,156].

Until recently, considerable doubt surrounded the possibility of a cannabis withdrawal syndrome; however, cannabis withdrawal syndrome has now been unequivocally demonstrated in heavy chronic recreational users [163]. With abrupt cessation, withdrawal symptoms emerge within one to two days, reach peak intensity after two to six days, and generally resolve within one to two weeks. Common symptoms include irritability or anger, nervousness, tension, restlessness, reduced appetite, insomnia and sleep difficulties, dysphoria, and craving. Less frequent symptoms are chills, stomach pain, shakiness, and sweating [164]. Cannabis withdrawal can resemble a low-grade opioid withdrawal but usually lacks the severe aches and pains, piloerection, diarrhea, sweating, stuffy nose, and muscle spasms common to opioid withdrawal [28,126].

Studies of chronic non-malignant pain have found significant pain relief, reduced bother from pain, and prevention or reduction of opioid tolerance with cannabinoid addition to opioid therapy [186,187]. An RCT with patients with severe cancer pain found cannabinoid addition to opioid therapy led to pain level reduction of 30% to 50% in 43% of patients [60,188]. In patients with pain from chronic progressive multiple sclerosis, HIV-related neuropathy, or spinal trauma pain poorly controlled with high-dose opioids, one study found adding smoked cannabis led to opioid dose decreases of 60% to 100% and improvements in pain relief and function [189]. Abrams studied the effect on pain from giving four days of vaporized cannabis to 21 patients with mixed persistent chronic pain despite stable long-term use of morphine sustained-release (SR) or oxycodone SR (mean dose: 62 mg and 53 mg, respectively) [117]. Cannabis slightly reduced morphine levels, had no effect on oxycodone levels, and reduced pain by roughly 30%. A survey of 29 medicinal cannabis patients with chronic pain found that of the eight using cannabis as their sole analgesic, all had been prescribed but abandoned opioids for cannabis due to the greater perceived pain relief, fewer side effects, or absence of problematic opioid use risk [190].

An additional rationale for cannabis use in chemotherapy-induced nausea and vomiting involves the principle of optimizing treatment by combining agents that inhibit multiple neurotransmitter pathways that mediate nausea and vomiting reflexes. Cannabinoids have known activity in many of these systems and can effectively compensate for the deficiencies of 5-HT3 antagonists and NK1 receptor inhibitors in preventing nausea and delayed and breakthrough chemotherapy-induced vomiting. Because cannabidiol does not induce psychotropic effects, its potential role as an antiemetic for patients undergoing chemotherapy is being investigated[210]. An RCT with patients with gynecologic cancer found that a cannabinoid extract (THC:CBD 1:1) was an appropriate adjuvant to reduce chemotherapy-induced nausea and vomiting in patients receiving high-emetogenic chemotherapy [211].

As noted, cannabis is generally recommended for patients in whom standard therapies have been ineffective or intolerable. Appropriate indications for medical cannabis have most recently been formalized by the State of New York, the OMC in the Netherlands, and Health Canada and include [230,231,232]:

Disorders of pain and spasticity, including intractable spasticity, multiple sclerosis, and spinal cord damage or injury

Chronic neuropathic pain, including nerve damage, phantom limb pain, facial neuralgia, and postherpetic neuralgia

Pain from cancer and HIV/AIDS

Nausea and vomiting from chemotherapy, radiotherapy, and/or medication for HIV and hepatitis C

Neuropsychiatric disorders, including tics associated with Tourette syndrome, epilepsy, neuropathy, Parkinson disease, and PTSD

Autoimmune conditions, including arthritis, lupus, and Crohn disease

Palliative treatment of cancer and AIDS to stimulate appetite, avoid weight loss, and reduce debilitation and wasting syndrome

Treatment-resistant glaucoma

A debilitating symptom associated with a medical condition or the medical treatment of that condition, other than those described above

At this time, experts recommend limiting medical cannabis use to adults older than 18 years of age [14,231]. There are several other contraindications to the use of medical marijuana, including [14,231]:

Current, past, or family history of schizophrenia or other psychotic disorders

History of hypersensitivity to cannabinoids or smoke

Severe cardiopulmonary disease

Severe liver or renal disease

Pregnancy or planned pregnancy

Breastfeeding