#65173: Medical Marijuana and Other Cannabinoids

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].

CB1 distribution in the brain matches the known pharmacodynamic effects of cannabinoids; CB1 activation prominently modulates cognition and memory, perception, control of motor function, and analgesia[36]. The location and relative density of CB1 receptors in the brain and function mediated by CB1 activation are outlined in Table 1[37,38,39,40].

CB2 receptors are sparsely expressed in the central nervous system (CNS) but highly expressed in immune cells, where they play an important role in regulating immune function and inflammation. Their activation modulates immune cell migration and cytokine and chemokine release, and CB2 receptor expression on CNS microglia may explain cannabinoid efficacy in reducing cytokine-mediated neuroinflammation [30,41,42,43].

In addition to CB1 and CB2 receptors, endocannabinoids are thought to bind several other molecular targets. These include a third presumed cannabinoid receptor, GPR55 (sometimes termed CB3), the transient receptor potential cation channel subfamily V member 1 (TRPV1), and a class of nuclear receptors/transcription factors known as the peroxisome proliferator-activated receptors (PPARs) [30].

Anandamide and 2-arachidonoyl glycerol (2-AG) are the two primary endogenous cannabinoid receptor ligands.

Anandamide (Arachidonoyl Ethanolamide, AEA)

Anandamide was the first endogenous cannabinoid identified by researchers and was assigned its name after ananda, the Sanskrit word for "bliss" [37]. Anandamide is derived from arachidonic acid following synthesis from membrane phospholipid precursors. At CB receptors, anandamide acts as a partial agonist, with slightly higher binding affinity at CB1 versus CB2 [36]. Anandamide is hydrolysed by the enzyme fatty-acid amide hydrolase (FAAH) as the primary metabolic pathway [44].

2-Arachidonoyl Glycerol (2-AG)

2-AG binds essentially equally to both CB receptors (with slightly higher CB1 affinity) and possesses greater overall potency and efficacy than anandamide at both CB receptors [36]. 2-AG is an arachidonic acid derivative synthesized by the same process as anandamide. The metabolic pathway of 2-AG predominantly involves monoacylglycerol lipase (MGL or MAGL) [36,44].

Other endogenous molecules have been identified that mimic endocannabinoid effects. These include 2-AG ether (noladin ether),N-arachidonoyl dopamine (NADA), virodhamine,N-homo-γ-linolenoylethanolamine (HEA), andN-docosatetraenoylethanolamine. Although the molecules palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) bind to PPARs instead of cannabinoid receptors, their action potentiates anandamide effect by inhibiting FAAH (the enzyme that degrades anandamide) and by direct allosteric effects on other receptors. The sum of these effects is referred to as the "entourage effect"[45,46,47,48]. Advocates of the term suggest the effect mechanism is the underlying reason that many patients claim to experience an overall better effect from full-spectrumCannabisproducts. However, this suggestion relies mostly on anecdotal evidence from observational studies. Critics state that the "entourage effect" is unsupported by sound evidence and that the term is primarily used for marketing purposes in the cannabis industry [49,50,51,52]. PEA has become a research focus, with a growing number of clinical trials evaluating its pain-reducing efficacy in diverse chronic pain conditions[53,54].

The ECS facilitates rapid local response to pathologic states or disease. Increased intracellular calcium release from neuronal activation or cellular stress triggers membrane phospholipids to synthesize and immediately release anandamide or 2-AG, which binds and activates nearby CB receptors. This activation inhibits adenylyl cyclase activity, decreasing cyclic adenosine monophosphate (AMP) formation and protein kinase A activity, which in turn blocks Ca2+ influx through various calcium channels. CB receptor activation also stimulates inwardly rectifying potassium (K+) channels and the mitogen-activated protein kinase signaling cascades. Cellular uptake and enzymatic degradation rapidly clear the endocannabinoids [56].

The ECS alters CB1 or CB2 receptor expression during stress response, which is beneficial in some pathologic states (e.g., neuropathic pain, multiple sclerosis) because increased CB expression may curtail symptoms or disease progression and provide a protective role. Alteration in CB1 expression is maladaptive in other disease conditions, such as CB1 up-regulation in liver fibrosis and down-regulation in colorectal cancer [56,57,58].

In CNS tissue, CB1 activation inhibits neuronal calcium channels and activates potassium channels, as described. Anandamide and 2-AG are synthesized and released from post-synaptic neuron terminals, travel "backwards" across the synaptic cleft to presynaptic neurons, and bind CB1 receptors on pre-synaptic terminals. This, in turn, inhibits release from excitatory and inhibitory synapses of serotonin, glutamate, acetylcholine, gamma-aminobutyric acid (GABA), noradrenaline, dopamine, D-aspartate, and cholecystokinin. This process of post-synaptic release, backwards diffusion across the synaptic cleft, and pre-synaptic CB1 binding is termed "retrograde signaling" [36,59,60].

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].

Pain is the most frequent condition for which medical cannabis is used, and the antinociceptive (analgesic) actions of cannabinoids are distinct from mechanisms that mediate psychoactive effects [10,15]. For instance, THC enhances analgesia produced by kappa opioid receptor agonist drugs, and administration of a kappa opioid receptor antagonist blocks this analgesic effect but has no effect on the psychoactive effects of THC. Cannabinoids interact with opioid, serotonin, and N-methyl-d-aspartate (NMDA) receptors, all of which are highly relevant in pain modulation [37].

The efficacy of cannabinoids in the management of chronic neuropathic pain is partially explained by ECS modulation of the descending supraspinal inhibitory pathway, an important pain pathway functionally compromised in patients with chronic pain. Via periaqueductal grey and rostral ventromedial medulla inputs, cannabinoid activation of CB1 and CB2 receptors stimulates the endogenous noradrenergic pathway, which activates peripheral adrenoreceptors to induce antinociception. Other mechanisms of cannabinoid analgesia include functional CB2 receptor expression in dorsal root ganglion sensory neurons, the spinal cord, and brain regions highly relevant to nociceptive integration and modulation [37,61].

Serious gastrointestinal and cardiovascular adverse effects are associated with nonsteroidal anti-inflammatory drugs (NSAIDs), and their use is now recommended at the lowest effective dose over the shortest duration possible [62,63,64]. In theory, cannabis may have NSAID dose-sparing effects.

Cannabinoids and cyclo-oxygenase-2 (COX-2) have independent but interacting roles in pain. During inflammatory pain, prostanoids are produced, potentiating bradykinin to sensitize pain signal-transmitting C-fibers. COX-2 metabolizes anandamide and 2-AG to prostanoid compounds that potentiate this pain-inducing cascade, and COX-2 oxidizes 2-AG into the pro-nociceptive metabolic product prostaglandin E2 (PGE2)-G. Thus, inflammatory states with COX-2 up-regulation can nullify the antinociceptive effects of endogenous cannabinoids and produce pro-nociceptive byproducts from their metabolism. COX-2 inhibitors block this conversion, an effect shown in peripheral pain where anandamide release is the dominant analgesic mechanism, and in stress-induced CNS pain where 2-AG release is the dominant analgesic. Low-dose COX-2 inhibitors do not block COX-2 but block the conversion of 2-AG into pro-nociceptive PGE2-G. Acetaminophen prolongs the analgesic action of 2-AG by inhibiting its enzymatic degradation by FAAH [61]. These findings indicate that co-ingesting cannabinoids and COX-2 inhibitors synergistically inhibits prostaglandin and enhances endocannabinoid activity to produce greater analgesia than monotherapy with either agent [65]. Also, tolerance is a main unwanted development with all analgesic drugs, including cannabinoids, and COX-2 inhibition may prolong cannabinoid analgesia [66].

Terpenoids vary widely among Cannabis varieties, accounting for differences in fragrance among different strains and possibly contributing to the distinctive smoking qualities and character of the "high" from smoked cannabis. Preclinical studies suggest a broad spectrum of activity with terpenoids, including anti-oxidant, antianxiety, antibacterial, antineoplastic, and antimalarial action; however, these data await confirmation in clinical trials[70,71]. Analgesic and anti-inflammatory activity have been found in several cannabis terpenoids[72]. Myrcene is an analgesic that inhibits inflammation via PGE2 activity. Naloxone blocks this activity, suggesting an opioid-mediated mechanism[73].β-caryophyllene produces anti-inflammation via PGE1 inhibition comparable to phenylbutazone and also acts simultaneously as a gastric cytoprotective. It possesses selective CB2 agonist activity, and additional investigation has shown increasing promise with potentially broad clinical application[74]. Other possibly therapeutic terpenoids include the PGE1 inhibitorα-pinene and the local anesthetic linalool[71,75]. One study examined six common terpenoids, alone and in combination with cannabinoid receptor agonists, on CB1 and CB2 signaling in vitro[76]. The terpenoids were tested both individually and in combination for periods of up to 30 minutes. None of the six terpenoids tested directly activated CB1 or CB2 or modulated the signaling of THC[76]. A study that included five common terpenoids fromCannabisalso found that none had direct interactions with CB1 or CB2[77].

Cannabis flavonoids are natural plant constituents also found in whole cannabis extracts. Beneficial activities from flavonoids include inhibition of TNF-αby apigenin, a potentially therapeutic mechanism in multiple sclerosis and rheumatoid arthritis; and PGE2 inhibition by cannflavin A, an action 30 times greater than PGE2 inhibition by aspirin[78]. One study evaluated the neuroprotective and anti-aggregative properties of cannflavin A and found that it demonstrated a neuroprotective role against the amyloidβ-mediated neurotoxicity associated with Alzheimer disease[79].

Phytosterols

A number of phytosterols are present in cannabis, with specific effects associated with each. For example, the cannabis phytosterol β-sitosterol was found to reduce topical inflammation by 65% and chronic edema by 41% in skin models[80]. Cannabis root contains significant amounts of β-sitosterol and other sterols that can be extracted by various methods[81]. Extracts of cannabis root have been used to treat pain and inflammation for millennia by various cultures, including the Romans as described by Pliny the Elder.

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].

Nabilone (Cesamet) is a Schedule II THC analog that is chemically similar but not identical to THC [37]. Approved by the FDA in 1985 for the treatment of chemotherapy-induced refractory nausea and vomiting and used off-label for analgesia, it is considered more potent than synthetic THC (e.g., dronabinol) [84]. It is administered (1 mg oral capsule) in doses of 1–2 mg twice daily for adults and 0.5–1 mg twice daily for pediatric patients [83].

Nabiximols (Sativex) is a botanically derived cannabis extract with a defined 1:1 ratio of THC to CBD (27 mg/mL THC + 25 mg/mL CBD) delivered as a metered buccal spray. This drug has regulatory approval for select pain indications in 20 countries (including Canada) and is currently undergoing advanced phase III trials in the United States for treatment of cancer pain refractory to optimal opioid therapy and for treatment of multiple sclerosis spasticity [83,85].

Cannador is an orally administered cannabis extract containing a 2:1 ratio of THC to CBD. It is under investigation in Europe by the Institute for Clinical Research for the treatment of anorexia/cachexia in patients with cancer [86].

Smoked cannabis here applies to the medicinal cannabis produced in Canada and the Netherlands, because the exceptional quality, purity, and consistency controls are in line with pharmaceutical-level standards. In both countries, cannabis for medical or research use is grown by a single contractor, licensed by the government, under exceptionally strict, controlled, and documented conditions. From "seed to smoke," the seedlings are grown, packaged, and distributed via a centralized supply chain.

In the Netherlands, cannabis with the following THC and CBD concentrations are available [87]:

In Canada, cannabis is available in potencies of [14]:

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].

THC is present in the living Cannabis plant as a mixture of monocarboxylic acids, and heating to greater than 120°C decarboxylates THC to promote biologic activity. THC decomposes from exposure to air, heat, or light, and oxidizes to cannabinol when exposed to acid [68,69]. THC binds to CB1 and CB2 receptors as a partial agonist, with preferential binding at CB1. The mechanism of action, transmitter system interactivity, and demonstrated and theoretical therapeutic utility of THC are complex and vast, and the following summary is limited to the area of pain.

Among natural cannabinoids, THC possesses the greatest psychoactive potency and also exhibits the greatest analgesic activity. Epidural (i.e., intrathecal, intraventricular) administration of THC produces antinociception similar in magnitude to that of opioid analgesics [90].

Analgesic mechanisms of THC include interaction with serotonergic 5-hydroxytryptamine (5-HT) systems. THC inhibits 5-HT release from platelet cells, increases cerebral production of 5-HT, and decreases synaptosomal uptake. These effects involve multiple trigeminovascular system mechanisms associated with migraine headache. Dopaminergic inhibition by THC may also contribute to analgesic benefits [31,91].

The glutamatergic system is foundational in chronic neuropathic pain and is causal in the development of secondary and tertiary hyperalgesia, via NMDA mechanisms, that characterize conditions such as migraine and fibromyalgia [92]. Cannabinoids inhibit pre-synaptic glutamate release, and THC reduces NMDA response by 30% to 40%. THC is also neuroprotective through antioxidant activity [93]. THC inhibits calcitonin gene-related peptide to reduce hyperalgesia, and preclinical studies show that THC blocks capsaicin-induced hyperalgesia at sub-psychoactive doses [94,95].

THC stimulates beta-endorphin production, and this important opioid system interaction partially accounts for the repeated findings of the opioid sparing effects with cannabis in clinical trials and preventing development of opioid tolerance and withdrawal and the reinstatement of analgesia when a prior opioid dosage has worn off in other studies [96,97,98].

THC also produces extensive anti-inflammatory activity through mechanisms that include inhibition of PGE2 synthesis, suppression of platelet aggregation, and stimulation of lipoxygenase. Studies have confirmed that THC produces 20 times the anti-inflammatory potency of aspirin and twice the potency of hydrocortisone, but unlike NSAIDs, it has not demonstrated COX inhibition [31,99].

11-hydroxy-THC is the primary metabolic product of THC. It is four times more potent in producing psychoactive and immunosuppressive effects than the parent compound [68,69].

Δ8-THC is aΔ9-THC isomer found in smaller amounts in the cannabis plant and has activity as a partial CB1 and CB2 agonist. In vitro assays have shown comparable efficacy and potency withΔ9-THC, and preliminary clinical results suggest greater antiemetic potency withΔ8-THC compared withΔ9-THC[100,101].Δ8-THC is psychoactive, but the effect is very weak and substantially overshadowed by THC due to its low concentration[8].

In 2022, the FDA issued a warning letter and consumer update regarding products containingΔ8-THC[102]. These products contain concentrated amounts ofΔ8-THC, typically manufactured from CBD. At the levels found in these products, the isomer induces significant psychoactive effects, and adverse effects have been reported, including hallucinations, vomiting, tremor, anxiety, dizziness, confusion, and loss of consciousness[102].

CBD has shown exceptional therapeutic promise as a single molecular entity. It is already in clinical use as a combination product with THC and in certain cannabis strains developed to overexpress CBD.

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].

Outside the United States, CBD is available in equal ratio to THC in the oromucosal spray nabiximols. In Canada and the Netherlands, some cannabis strains available for medicinal use have been bred to overexpress CBD, for a 1:1 ratio of CBD to THC. Pure (>99%) isolated CBD crystals, oils, waxes, and other extracts are available from many dispensaries.

In 2018, the FDA approved the first drug that contains purified CBD—a CBD oral solution for the treatment of seizures associated with Lennox-Gastuat syndrome and Dravet syndrome in patients 2 years of age and older[108].

Cannabinol is produced by THC oxidation and is most often found in aged cannabis products. Cannabinol shares some characteristics with CBD, such as anti-convulsant and anti-inflammatory activity. Adding cannabinol to THC does not significantly increase THC effect. It is a weak CB1 and CB2 partial agonist with approximately 10% of the activity of THC and appears to possess immunosuppressive properties. Potential therapeutic applications of cannabinol include diseases characterized by cannabinoid receptor up-regulation [72,104,109].

Cannabigerol possesses a broad mechanistic range, with activity as a partial CB1 and CB2 receptor agonist, a potent TRPM8 antagonist, an agonist at TRPV1and TRPA1, and also as an anandamide reuptake inhibitor in the low micromolar range. Other mechanisms of cannabigerol include 5-HT1A receptor antagonism andα2-adrenoceptor agonism[104,109]. Cannabigerol possesses anti-inflammatory and analgesic properties and also demonstrates anti-proliferative and antibacterial activity[104].

Tetrahydrocannabivarin is a CB1 receptor antagonist and CB2 receptor partial agonist. This effect is dose-dependent, as it shows THC antagonist activity at low doses while higher doses act as a CB1 agonist. Tetrahydrocannabivarin has shown anticonvulsant properties in in vitro and in vivo studies [110,111]. Other potential benefits of tetrahydrocannabivarin include its increase of central inhibitory neurotransmission, giving it therapeutic potential in epilepsy, and CB1 antagonism suggesting clinical benefit by decreasing food intake [104].

Cannabichromene, together with THC, is a major cannabinoid constituent in freshly harvested cannabis. It has activity as a potent TRPA1 agonist and weak anandamide reuptake inhibitor, and it is shown to exert anti-inflammatory, antimicrobial and modest analgesic activity. In preclinical animal studies, cannabichromene showed greater propensity than THC in producing adverse events, including hypothermia, sedation, and hypoactivity [104].

The rate of drug absorption is determined by the route of administration and drug formulation. Inhalation is the primary route of cannabis administration and provides rapid and efficient drug delivery from the lungs to the brain [68].

Smoked Cannabis

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].

Vaporized Cannabis

A study comparing smoked and vaporized administration found higher serum THC at 30 and 60 minutes post-inhalation with vaporization and comparable serum THC levels over the remaining six-hour period [115]. Vaporization was preferred by 80% of subjects, and as with smoking, vaporization was highly conducive to self-titration. The amount of THC delivery is influenced by the amount and type of cannabis, vaporizing temperature, duration of vaporization, and the balloon volume [116,117].

Oral Ingestion

The CNS and physiologic effects with oral ingestion are substantially delayed relative to inhalation, including slower onset of action, lower peak plasma levels, and longer duration of effect. With pharmaceutical cannabinoids such as dronabinol, 10% to 20% of ingested THC enters systemic circulation due to extensive first-pass metabolism. In healthy volunteers, a single 2.5-mg dose of dronabinol produces mean peak plasma THC at two hours, with a range of 30 minutes to four hours; these absorption and distribution kinetics are similar following a single 10-mg dose of dronabinol [118].

Plant cannabis can be mixed into brownies, cookies, or tea prepared from the flowering tops, but all result in unreliable absorption. In one study, oral ingestion of 20 mg THC in chocolate cookies resulted in only 4% to 12% of THC entering systemic absorption and peak plasma THC at one to two hours in most subjects and six hours in others, with some subjects showing multiple plasma peaks [68]. The bioavailability of THC from tea made of plant cannabis is lower than with smoking due to the poor water solubility of THC and the effect of hepatic first-pass metabolism [14].

THC distribution is time-dependent and begins rapidly after absorption. In plasma, THC is 95% to 99% plasma protein bound, primarily lipoproteins. The tissue distribution of lipophilic THC and its metabolites mostly involves uptake in fatty tissues and highly perfused organs such as the brain, heart, lung, and liver [59,68]. Whether THC accumulates in the brain with long-term use is unknown, due to limits in THC access and accumulation imposed by the blood-brain barrier [119].

Most cannabinoid metabolism occurs in the liver, with different metabolic byproducts predominating by route of administration. THC metabolism is complex and involves allylic oxidation, epoxidation, decarboxylation, and conjugation. THC is oxidized by the cytochrome P450 (CYP450) oxidases 2C9, 2C19, and 3A4 to produce the active metabolite 11-hydroxy THC and the inactive metabolite 11-nor-9-carboxy THC [120]. The 11-hydroxy THC plasma level parallels observable drug action [68]. Relative to inhalation, first-pass hepatic metabolism with oral ingestion yields a greater proportion of 11-hydroxy THC [59].

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].

Most patients in the RCTs discussed in this course were maintained on their pre-study medications for neuropathic pain, cancer pain, fibromyalgia, or multiple sclerosis. In these and other RCTs, patients smoked or ingested cannabis while taking their prescribed opioids, NSAIDs, muscle relaxants, ketamine, anticonvulsants, antidepressants, and benzodiazepines. Cannabis use with these other agents was well tolerated, and observed side effects did not differ from those expected with cannabis [14].

In theory, ingesting cannabis with drugs that alter its metabolic pathway should increase the risk of side effect enhancement or efficacy failure, but adverse drug-drug interactions of clinical relevance have not been reported to date. Cannabis should be used with caution by patients also using sedating substances such as alcohol or benzodiazepines [59].

Tolerance is defined as tissue adaptation resulting from repeated drug exposure, such that one or more drug effects diminish over time. Cannabis tolerance primarily results from pharmacodynamic mechanisms, including changes in CB1 signaling ability due to receptor desensitization and down-regulation. THC tolerance varies across different brain regions, possibly explaining why tolerance develops to some cannabis effects but not to others [122]. Tolerance to most THC effects develops after a few doses and then disappears rapidly following cessation, and pharmacodynamic tolerance can be minimized by combining a low dose of cannabinoid with one or more additional therapeutic drugs [123].

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.

Physician and patient concerns over pulmonary harm from cannabis smoking have been based on the known hazards from smoking tobacco, findings of carcinogenic compounds in cannabis smoke, and earlier epidemiologic studies associating long-term cannabis use with respiratory dysfunction [138]. This has contributed to reluctance over medical smoked cannabis use.

Although many carcinogens and tumor promoters are common to tobacco and cannabis smoke, differences in the active constituents result in different biologic outcomes. Molecules in tobacco smoke enhance carcinogenic pathways through several mechanisms, including circumvention of normal cellular checkpoint protective mechanisms; activation of respiratory epithelial cell nicotine receptors; promotion of tumor angiogenesis; stimulation of enzymes that convert polycyclic aromatic hydrocarbons found in smoke into carcinogens; and prevention of apoptotic cascades (cell death) in cells accumulating sufficient genetic damage. In contrast, molecules in cannabis smoke inhibit carcinogenic pathways through down-regulation of immunologically generated free radical production (the innate response to inhaled smoke and particulate); THC blockade of enzymatic conversion of smoke constituents into carcinogens; the absence of cannabinoid receptors in respiratory epithelial cells (which maintains DNA damage checkpoint mechanism integrity with prolonged cannabis smoke exposure); and the anti-angiogenic, tumor-retardant, and anti-inflammatory activity of many cannabinoid smoke constituents [139,140,141].

These factors appear in the results of a 20-year longitudinal study of pulmonary health in 5,115 participants who smoked cannabis [142]. The authors stated that pulmonary risks from cannabis smoking had been overstated and found that, unlike tobacco smoking, cannabis smoking had no effect on measures of pulmonary function. Medicinal use of smoked cannabis was also found to be very unlikely to produce adverse effects on pulmonary function [142]. In 878 Canadians 40 years of age and older, history of tobacco smoking or tobacco and marijuana smoking, but not marijuana-only smoking, significantly elevated the risk of respiratory problems or chronic obstructive pulmonary disease (COPD) relative to non-smokers [143]. In a 2022 study comparing 56 cannabis smokers and 33 tobacco-only smokers, the cannabis smokers showed higher rates of emphysema and airway inflammation than nonsmokers or tobacco-only smokers [144]. However, the researchers were careful to point out that high rates of concomitant tobacco smoking in the cannabis group made drawing firm conclusions difficult.

Vaporizing systems have been developed to further minimize pulmonary risks from smoked cannabis. These involve heating the plant material short of combustion and then inhaling the mist (instead of smoke). Vaporization may produce smaller quantities of the toxic smoking byproducts carbon monoxide, polycyclic aromatic hydrocarbons and tar, and compared with smoked cannabis, vaporization was found to significantly reduce carbon monoxide levels [115,116]. One study evaluated the subjective and physiologic effects and expired carbon monoxide in frequent and occasional cannabis users following placebo, smoked, vaporized, and oral cannabis [145]. Participants' subjective ratings were significantly elevated compared with placebo after smoking and vaporization; only occasional smokers' ratings were significantly elevated compared with placebo following oral dosing. Smoking produced significantly increased expired carbon monoxide concentrations post-dose compared with vaporization [145].

Concern was raised in the 1990s over the potential negative effects of cannabinoids on immune function in immunosuppressed patients, particularly those with HIV. Data from several studies have alleviated these concerns. In HIV patients randomized to placebo, dronabinol, or smoked cannabis for 21 days, both cannabinoid groups failed to show increased viral load or reductions in protease inhibitor levels or CD4 or CD8 cell counts. Both cannabinoid groups showed statistically significant weight increases, and the smoked cannabis group showed significantly increased CD4 and CD8 counts [146]. Supportive data include a study of primates injected daily with THC before and after infection with simian immunodeficiency virus (SIV). Contrary to expectations, chronic cannabinoid exposure did not increase viral load or diminish immune function. Instead, the primates given THC showed significantly decreased rates of early mortality from SIV infection, associated with attenuation of plasma and cerebrospinal fluid viral load and retention of body mass [147]. Other conformational findings include a 10-year follow study of HIV patients, which found that regular cannabis smoking had no effect on viral load or CD4 and CD8 cell percentages [148]. An exception comes from preclinical trial results suggesting that increased CB2 activity may impose risks in immunocompromised patients with specific infection, such as Legionella[59]. Further, results of a 2022 study found that THC, used for the treatment of chemotherapy-induced nausea, reduced the therapeutic effect of PD-1 blockade that impeded antitumor immunity, indicating an immunosuppressive role of the ECS [149].

There is abundant evidence from studies in adult subjects that smoking cannabis has an acute effect on motor coordination and impairs verbal and working memory for several hours after ingestion, an effect mitigated by several factors, including the degree of previous exposure to cannabis, the dose of THC, the ratio of THC to CBD, and genetic susceptibility [150]. These effects on cognition, mediated by THC, appear to resolve within hours to days after cessation of cannabis exposure.

The long-term effects of chronic cannabis use are more subtle and complex and involve multiple domains of cognitive function, as evidenced by psychologic testing and brain imaging studies. A growing body of evidence indicates that while significant neuropsychologic deficits may develop following chronic cannabis use, these deficits are largely reversible if chronic use did not commence until after one achieves adulthood (i.e., after full anatomic maturation of the brain). Early-onset (in adolescence) and long-term use of cannabis causes the greatest morphologic and functional impairments in the still-developing brain, and these deficits may not resolve completely after cessation of usage [150,151].

Results from the 2012 Dunedin study provide the most definitive data on neurocognitive effects from cannabis use [152]. This prospective study followed 1,037 individuals from birth in 1972/1973, assessed their cannabis use at ages 18, 21, 26, 32, and 38 years. Neuropsychologic testing was administered at 13 years of age, before cannabis use was initiated, and at 38 years of age, after persistent cannabis use patterns were established. Family member informants provided corroborating input. Among adolescent-onset, heavy cannabis users, there was an average decline in IQ of 8 points from 13 years of age to 38 years of age (impairment that was global and detectable across five domains of neuropsychologic functioning) and attention and memory problems observable by informants. Following cessation or infrequent use (median past-year use: 14 days) for one year, the IQ decline remained significant. In contrast, adult-onset heavy cannabis users did not exhibit IQ decline as a function of persistent cannabis use. The authors concluded that these findings suggest a neurotoxic effect of cannabis on the developing adolescent brain [152].

Observational studies suggest that THC may have psychotogenic effects while CBD may have antipsychotic effects. However, whether these effects on brain function are consistent with their opposing behavioral effects is unclear. One systematic review sought to identify the key brain substrates where these opposing effects can be observed [153]. Evidence suggests that the opposing effects may be present in the striatum, parahippocampus, anterior cingulate/medial prefrontal cortex, and amygdala, with opposite effects less consistently identified in other regions. Broadly, THC seems to increase brain activation and blood flow, while CBD seems to decrease brain activation and blood flow [153].

While cognitive function in long-term medical cannabis users has not been evaluated, a review of the published research on short- and long-term cognitive function in recreational users suggests that cognitive impairment is unlikely to persist beyond the acute intoxication state, even with high-THC cannabis, in late-onset users, short-term users, and occasional users [150].

Amotivational syndrome is not a medical diagnosis but a term used to describe adolescents and young adults who lose interest in and drop out from school, work, socializing, and other goal-directed activities. Cannabis has been cited as the cause when its heavy use accompanies these symptoms, but evidence of causality is lacking [8,126].

An acute psychotic reaction to cannabis has been described and is more likely to occur in young adults who are under stress and have a pre-existing vulnerability to psychoses or schizophrenia. An association has been found between cannabis use history and schizophrenia, but the causal direction of this link has not been established, with many studies suggesting causality showing instead a non-specific association between the most severe levels of cannabis use and a wide range of adverse psychosocial outcomes [126,154]. Furthermore, cannabis use in the general population soared between 1949 and 1995, while the population rates of schizophrenia remained stable [155].

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].

There are no cases in the literature of death due to toxicity following the maximum oral THC dose in dogs (up to 3,000 mg/kg THC) and monkeys (up to 9,000 mg/kg THC). In animals and humans, it is virtually impossible to induce fatal toxicity, and no human fatalities resulting from cannabis ingestion have been documented to date [37].

The side effect profile of medical cannabis is comparable to those produced by other medications tolerated by patients and approved for clinical use by the FDA [126,157]. The rare acute complications resulting in emergency department presentation, such as panic attacks, psychosis, or convulsions, can be managed with conservative measures such as reassurance in a quiet environment and IV administration of benzodiazepines if needed [14,158].

The greatest risk for toxicity and potential overdose is among children who may consume cannabis edibles, beverages, or candies inadvertently [159,160]. A concern with toxic reactions is self-harm. In 2014, a young man (19 years of age) from Colorado died after consuming an edible marijuana product (a cookie). The decedent initially ate only a single serving (one-sixth of the cookie), as directed by the salesclerk. Each serving contained approximately 10 mg of THC. Approximately 30 to 60 minutes later, after not feeling any effects, the decedent consumed the remainder of the cookie. For the next two hours, the young man exhibited erratic speech and hostile behaviors. About 3.5 hours following initial ingestion, he jumped off a fourth floor balcony and died from trauma [161]. In adults, most toxic reactions are mild, but in children, overdose can result in significant respiratory depression [160]. Signs can include somnolence, hallucinations, dyspnea, CNS depression, and even coma. Healthcare professionals should assess for availability of cannabis in the household if these signs present with no known explanation. If necessary, airway management and ventilation may be administered.

The sensationalized 1980s theory of marijuana as the gateway to hard drug use lacks empirical support. While heavy adolescent use is associated with risk of other drug abuse, there is no good evidence of causality or directionality, and the large majority of cannabis users do not progress to "hard" drug use [19,162]. Alcohol and nicotine use are more significant primers for hard drug use in many individuals [162]. Further research is necessary to clarify these points.

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].

The severity of cannabis withdrawal, and whether it develops at all in strictly medical users, is unknown. With cessation of regular medical use, the pharmacokinetics and possibly pharmacodynamics of THC, such as slow elimination, may diminish withdrawal symptom manifestation into the subclinical level of severity [28].

Roughly 9%, or 1 out of 11, who use recreational marijuana will develop an addiction syndrome; the figure increases to 17%, or 1 out of 6, who begin use in their early teens [19,165]. This compares with lifetime prevalence rates of 32% for nicotine, 23% for heroin, 17% for cocaine, and 15% for alcohol [19,166,167].

According to the Hartford Institute for Geriatric Nursing, little research on effective intervention for psychologic dependence on marijuana is available. Some guidance can be found in smoking cessation and self-help approaches.

(https://hign.org/consultgeri/resources/protocols/substance-misuse-and-alcohol-use-disorders Last Accessed: November 21, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

Addiction risk among medical cannabis users is unknown. Data on cannabis addiction and risk factors come primarily from recreational users who began during adolescence or early adulthood and used high-potency cannabis with great frequency and intensity in the absence of medical supervision. Whether these data apply to the typically older adult patient using smaller doses of medical marijuana for symptom control is not known [168].

The psychoactive effects and potential abuse liability of recreationally used cannabis are well known, but little is known of this potential with nabiximols spray (equal-ratio THC and CBD). A safety analysis using all published and unpublished nabiximols RCTs found that intoxication scores were low [166]. Euphoria was reported by only 2.2% of subjects, development of tolerance was not documented, abrupt cessation did not result in a withdrawal syndrome, and no cases of abuse or diversion were reported. An abuse liability study of nabiximols in experienced recreational cannabis smokers found some abuse potential at higher doses relative to placebo, but consistently lower abuse liability than equivalent doses of pure THC [166].

Although medical marijuana laws in some states have been anecdotally linked to increased recreational use among adolescents, a 2013 evaluation of the effects of these laws on adolescent marijuana use from 2003 through 2011 found that they had no measurable effect [169].

Cannabinoid hyperemesis syndrome (CHS) is characterized by severe cyclic nausea and vomiting in chronic (usually heavy) cannabis users [170]. It is a relatively rare adverse effect, but increasing case reports have been noted with the liberalization of cannabis in several states [171]. Individuals with CHS experience temporary relief of symptoms with hot baths or showers, and compulsive bathing is often an identifying feature (differentiating the condition from other causes of cyclic vomiting) [172,173]. Typically, patients begin with recurrent nausea and progress to intense, persistent vomiting with continued use of cannabis.

The underlying pathogenesis of CHS is unclear, although several theories have been presented. One theory is that the enteric emetic effects of cannabis (e.g., decreased gastrointestinal motility) may promote emesis by over-riding the antiemetic effects mediated by the CNS [172]. Symptoms resolve with cessation of cannabis use; relapse to use often results in a recurrence of the syndrome. Early recognition of CHS is essential to prevent complications related to severe volume depletion [173].

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: November 21, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

More than 2 million Americans currently suffer chronic and debilitating neuropathic pain from trauma or disease affecting the peripheral or central nervous system. These conditions include diabetic neuropathy, nerve compression syndromes, postherpetic or trigeminal neuralgia, stroke, multiple sclerosis, and spinal cord injury. Neuropathic pain is comprised of a sensory component of allodynia (pain response to benign stimuli) and hyperalgesia (exaggerated pain to mild provocation), and an affective component of prominent anxiety or depression, diminished motivation, and changes in motor control. Neuropathic pain is difficult to treat, and while the sensory and affective components may respond to opioid therapy, this drug class often produces intolerable side effects or fails to provide meaningful pain reduction. Earlier trials suggested effective analgesia with cannabis, and priorities in finding therapeutic alternatives to high-potency opioids prompted investigation of cannabis efficacy in neuropathic pain [176,177]. Finding even modest clinical benefit is important given the limited treatment options for these patients, and the RCTs uniformly found the number needed to treat to achieve 30% pain reduction was 3.5 for cannabis [178]. In one study, use of nabiximols was found to be the most effective cannabinoid for multiple sclerosis-associated central pain [177]. Unless otherwise noted, the RCT methods in the following sections were double-blinded and placebo-controlled with inert, non-active cannabis and/or pills.

HIV-Associated Distal Sensory Polyneuropathy

In a five-day trial of 55 patients with HIV-associated distal sensory polyneuropathy, overall daily pain levels were reduced by 34% with active cannabis vs. 17% with placebo, and pain reduction of more than 30% was attained by 52% with active cannabis vs. 24% with placebo; both differences in pain reduction were statistically significant. Cannabis was well tolerated and no safety concerns were raised. Cannabis produced more side effects than placebo, the most common being sedation, anxiety, and dizziness, all rated as "mild" in severity [179].

Another study titrated 34 patients with HIV-associated distal sensory polyneuropathy to individualized effective and tolerated inhaled cannabis doses. Titration started with 4% THC or placebo, with downward or upward adjustment for problematic side effects or incomplete pain relief, respectively. In five study phases over seven weeks, >30% pain reduction was attained by 46% with cannabis vs. 18% with placebo (statistically significant). Side effects were more frequent with cannabis, the most common being sleepiness or sedation, fatigue, and difficulty concentrating. Aside from acute psychotic symptoms developing early in the only cannabis-naïve subject, all side effects were "mild" and no safety concerns emerged [180].

Both of these studies restricted enrollment to patients with refractory pain despite optimal pharmacologic management, and all patients remained on their pre-study analgesic therapies. Of note, the significant magnitude of pain reduction in HIV neuropathy with cannabis therapy represents an important medical finding, because this type of pain has been notoriously resistant to standard treatment approaches [60].

Neuropathic Pain of Heterogeneous Origin

A trial of 38 patients with complex regional pain syndrome (Type I), physical trauma to nerve bundles, spinal cord injury, multiple sclerosis, or diabetes smoked a single high-(7%), low-(3.5%), or 0% THC (placebo) cannabis cigarette in three six-hour sessions [181]. Previous cannabis exposure was required. Low-and high-THC cannabis produced effective analgesia with comparability, suggesting a dose ceiling. Unpleasant side effects were more frequent with high-dose THC. Side effects were comparable between low-dose and placebo, and no subject terminated their involvement from side effects. Negative mood changes (e.g., sadness, anxiety, fearfulness) were not found. The authors stated the effects produced by cannabis were comparable to those observed with opioid analgesics, with pain relief resulting from equal alleviation of the affective and sensory component of pain but not resulting from a relaxing or tranquilizing effect [181].

Chronic Post-Traumatic or Postsurgical Neuropathic Pain

In an RCT with crossover, 23 subjects with chronic post-traumatic neuropathic pain smoked a single 25-mg dose of 0%, 2.5%, 6%, or 9.4% THC cannabis, three times daily over four 14-day periods alternating with 9-day washout [134]. The average daily pain intensity score was significantly lower with high-dose (9.4%) THC than with placebo. Intermediate potencies showed reduced but non-significant pain reduction vs. placebo. In addition, the 9.4% THC dose significantly improved ability to fall asleep and sleep quality compared with placebo. Side effects were more frequent with 9.4% THC cannabis and included headache, dry eyes, burning sensation in areas of neuropathic pain, dizziness, numbness, and cough. Most side effects were mild, and no serious or unexpected adverse events occurred. The authors concluded that single-inhalation 9.4% THC cannabis reduced pain intensity, improved sleep, and was well tolerated in these patients [134].

Vaporized Cannabis in Chronic Neuropathic Pain

In an RCT with crossover, patients with central or peripheral neuropathic pain resistant to conventional drug therapies received single-dose 3.53% THC, 1.29% THC, or 0% THC (placebo) cannabis [182]. Significant analgesic response was found with active but not placebo cannabis. Analgesia was equivalent with medium- vs. low-dose cannabis. Psychoactive effects were minimal and well tolerated, and neuropsychologic effects reversed within one to two hours. The authors state their findings of analgesic efficacy with low-dose cannabis in treatment-refractory neuropathic pain have large clinical value and that a negative impact on daily functioning is unlikely based on the observed side effects [182].

Experimental Neuropathic Pain

To examine the dose-by-time analgesic effect of cannabis, 19 healthy volunteers received capsaicin injection under the skin to simulate neuropathic pain and were administered in random sequence low-, medium-, and high-dose cannabis (2%, 4%, and 8% THC) or placebo cigarettes [183]. No effect on capsaicin-induced pain was found at any dose five minutes after smoking. At the 45-minute time point, there was a significant pain decrease with 4% THC, a significant pain increase with 8% THC, and no differences with 2% THC or placebo. A significant inverse relationship between pain perception and plasma THC was also found. The authors conclude a "therapeutic window" (or optimal dose) may exist for smoked cannabis with acute neuropathic pain, with low doses ineffective, medium doses efficacious, and higher doses pain-enhancing [183]. This biphasic dose-response effect of cannabinoids in acute neuropathic pain is consistent with the previous body of research [60].

Cannabis has not been found effective in acute nociceptive pain and has shown a biphasic dose-response effect with acute neuropathic pain [60]. However, chronic pain results from the development of abnormal sensory processing and other alterations in peripheral and CNS pain pathways [184]. The endocannabinoid receptor complex interacts with signaling pathways and pain circuitries expressing abnormal function in chronic pain, accounting for therapeutic effect not seen in acute pain [61].

Clinical trials of cannabinoids in patients with chronic pain due to rheumatoid arthritis, fibromyalgia syndrome, or cancer pain found statistically significant pain relief consistently around 30% in magnitude [185]. When considered alone, changes in pain scores understate the extent of overall relief in these patients, because improved mood, sleep, coping, and quality-of-life scores have been consistently reported with cannabis and cannabinoids. Patients with fibromyalgia and clinically relevant depression showed greater benefit from cannabinoids than non-depressed patients with fibromyalgia [60].

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].

Combining opioids and cannabis in pain therapy offers the added potential advantage of synergistic analgesic action that decreases the dosage requirements and side effects of both agents. Such an approach exploits the considerable functional interaction between endogenous opioid and cannabinoid systems and may also reduce the development of tolerance with both agents [176].

Spasticity is a core symptom of multiple sclerosis, is common after stroke and with other neurologic conditions, and greatly limits movement, activities of daily living, and participation in life by those afflicted. Oral antispasmodic agents are of limited effectiveness, and beneficial treatment options for spasticity have not significantly expanded since the late 1990s [191]. Consequently, many patients with multiple sclerosis have sought relief through cannabis use. The oromucosal cannabinoid spray nabiximols appears efficacious in multiple sclerosis but is not yet approved for clinical use in the United States [192]. Several clinical trials of cannabis in multiple sclerosis have been performed, and these studies have demonstrated cannabis efficacy in reducing spasticity and pain [193,194]. Cannabis-based medicine was effective in reducing pain and sleep disturbance in patients with multiple sclerosis and central neuropathic pain in one trial, while other RCTs demonstrated significant improvements in spasticity, disability, cognition, mood, sleep, and fatigue [195,196,197]. A 2004 study also found that cannabis helped alleviate bladder dysfunction, a problematic multiple sclerosis symptom [198]. A double-blind, placebo-controlled crossover study randomized patients with multiple sclerosis to smoke 4% THC or placebo cannabis cigarettes once daily for three days [194]. The findings of significant objective improvement in pain and spasticity differed from earlier trials showing significant improvement in patient perceptions but not objective measurements of spasticity [194]. Side effects have been acceptable to patients, and no serious safety concerns have emerged. Preclinical studies suggest a positive effect on the underlying disease processes in multiple sclerosis, evidence of an anti-inflammatory effect, and facilitation of remyelination and neuroprotection [199].

Numerous case reports describe substantial reduction in PTSD symptoms with cannabis use [200]. An open-label study of nabilone in 47 patients with treatment-refractory PTSD-associated nightmares found cessation or significantly reduced nightmare intensity in 72% of participants and diminished daytime flashbacks and night sweats and/or improved sleep duration and quality for some [201]. More robust research supporting the safety and efficacy of this use is lacking [202].

As noted, cannabis can be bred to overexpress CBD in order to avoid psychoactive effects. In one study, CBD-enriched cannabis was administered to 19 children with treatment-refractory epilepsy (after an average of 12 pre-study antiepileptic drugs) and their parents were interviewed to assess efficacy. Of the 19 patients, 84% showed reduced seizure frequency, 11% became completely seizure-free, 42% showed greater than 80% seizure reduction, and 32% showed a 25% to 60% seizure reduction. Other beneficial effects included increased alertness, elevated mood, and improved sleep, and side effects included drowsiness and fatigue. In 2018, the FDA approved purified cannabidiol for use in patients with Lennox-Gastaut and Dravet syndromes, but until recently, most published studies were relatively short-term (12 to 16 weeks) [83,203,204]. The objective of a 2019 study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy [204]. This open-label prospective study enrolled 26 children 1 to 17 years of age with refractory epilepsy, most with genetic epilepsies with daily or weekly seizures and multiple seizure types. All of the children were refractory to prior antiepileptic drugs and were, on average, taking two antiepileptic drugs. The duration of therapy ranged from 4 to 53 months (mean: 21 months). Adverse events were reported in 21 patients (80.8%) and included reduced appetite, diarrhea, and weight loss. Serious adverse events were reported in six patients (23.1%) and included status epilepticus, catatonia, and hypoalbuminemia. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy. At 24 months, 9 of the original 26 patients (34.6%) remained on cannabidiol as adjunctive therapy. Of these, seven reported a more than 50% reduction in motor seizures and three remained seizure free [204].

A matched case control study of medicinal cannabis use for symptom control in fibromyalgia found patient accounts of cannabis efficacy in alleviating pain, sleep disturbance, stiffness, problematic mood and anxiety, and headache, and objectively measured significant improvements in pain, stiffness, relaxation, and well-being [205]. An estimated 68% of participants experienced a reduction in standard therapies following cannabis initiation. Frequent side effects were somnolence, dry mouth, sedation, and dizziness. Significantly higher mental health-related quality of life scores were found in medicinal cannabis users compared with non-users [205].

In one study of patients with chronic irritable bowel syndrome, inhaled cannabis for three months led to improvements in quality of life, disease activity, and weight gain [206]. Observational study data in patients with Crohn disease suggest that cannabis helps alleviate disease symptom severity and reduces the requirements for other medications and/or the need for surgery [207].

Chemotherapy-induced nausea and vomiting was very difficult to manage before the introduction of 5-HT3 receptor antagonists. However, 5-HT3 antagonists are not very effective in blocking acute nausea and are ineffective in reducing delayed (24 hours or more) and anticipatory (conditioned) nausea and vomiting. The drugs of the NK1 receptor antagonist class are more effective with delayed as well as acute vomiting, although they are much less effective in reducing nausea. Nausea is the most distressing symptom experienced by chemotherapy patients because it is a continuous sensation, and as many as 20% of patients with cancer discontinue chemotherapy because current standard agents fail to control nausea[105,208]. A vast body of anecdotal evidence from the past 150 years as well as preclinical and clinical trial results strongly indicate a valuable role for cannabis in controlling nausea and vomiting caused by cytotoxic drug administration or secondary to another primary medical condition[105].

Most studies showing cannabinoid efficacy have used oral synthetics. The synthetic THC analogue nabilone and the synthetic THC dronabinol received initial regulatory approval for chemotherapy-induced nausea and vomiting based on improved outcomes over standard antiemetics used in the 1980s[105]. An older study ofΔ8-THC, a close but less psychoactive relative ofΔ9-THC, in pediatric patients with chemotherapy-induced nausea and vomiting found effective suppression of nausea and vomiting with negligible side effects[101]. More recently, an RCT with adults experiencing chemotherapy-induced nausea and vomiting found dronabinol comparable to the 5-HT3 antagonist ondansetron and superior to placebo[105,209].

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].

The potential role of smoked cannabis in rapidly alleviating breakthrough nausea and vomiting is especially promising given the findings of strong patient preference for smoked cannabis over oral therapies in a number of comparative clinical trials[3]. A study comparing 748 patients with cancer who smoked cannabis before and after chemotherapy with 345 patients using dronabinol found a reduction in nausea and vomiting of 70% to 100% with cannabis compared with 76% to 88% with dronabinol[212]. Oral cannabinoids may be less effective than sublingual or inhaled cannabis in chemotherapy-induced nausea and vomiting, and most patients prefer smoked marijuana over oral synthetic cannabinoids[213]. Several reasons account for this preference:

A meta-analysis of cannabinoid efficacy in chemotherapy-induced nausea and vomiting found superior antiemetic efficacy of dronabinol, nabilone, levonantradol (not approved for use in the United States), and smoked cannabis compared with conventional drugs and placebo [214].

Smoked cannabis has also been shown to improve non-chemotherapy medication adherence in which nausea and vomiting are common side effects. In a study of 258 patients receiving antiretroviral therapy for HIV infection, the subgroup of patients experiencing moderate-to-severe nausea who used marijuana were significantly more adherent to their regimen than non-marijuana users (75% vs. 48%). Alcohol use, the use of other illicit drugs, and marijuana use in those without nausea were associated with lower adherence [215].

Though it is often recommended in discussions of medical marijuana use, many healthcare professionals are not familiar with the process of administering cannabis through vaporizing. In essence, active cannabis ingredients can be vaporized if cannabis is heated and inhaled without combustion. The right temperature is reached when vapor is just visible as a light mist, but no smoke has formed, usually at a temperature of 180°C to 195°C. Using this method, the same cannabis can be used two to three times. In most cases, the recommended initial dosing is one to two times per day, with a minimum of 5 to 15 minutes between inhalations. Patients may need to inhale a few times, until the desired effect is reached or side effects occur. It may take up to two weeks to achieve steady-state THC concentrations and full therapeutic effect.

As discussed, a cannabis tea may be used to ingest medical marijuana, though the limited THC bioavailability and lack of water solubility make this a less attractive option in most cases. To brew the cannabis tea, 0.5 g cannabis is boiled in a pint of water for 15 minutes. The plant material is then strained out of the tea and sweeteners are added. The addition of a substance containing fat (e.g., milk powder) can improve the availability of THC in the tea. The tea may be kept refrigerated for up to five days. The usual initial dose is one cup in the evening, though if the effects are insufficient after two weeks, an additional cup (usually in the morning) may be added.