Cannabis

Scientific Name(s): Cannabis sativa L.
Common Name(s): Anascha, Banji, Bhang, Cannabis, Cannador, Charas, Dagga, Dimba, Esrar, Ganga, Ganja, Hashish, Hemp, Idrasil, Kief, Kif, Machona, Marihuana, Marijuana, Sawi, Shesha, Suma, Vingory

Medically reviewed by Drugs.com. Last updated on Nov 30, 2022.

Clinical Overview

Use

The efficacy of cannabis for the management of chemotherapy-induced nausea, spasticity in multiple sclerosis (MS), treatment-resistant seizures, and neuropathic pain has been clinically demonstrated to some extent. A bias towards reporting positive findings exists, both within individual clinical studies as well as within systematic reviews evaluating the role of cannabis in pain management. Undesirable adverse reactions, lack of data regarding long-term effects, and a general lack of comparison to standard treatments limit applications of cannabis; therapeutic use may be limited to either concomitant therapy or alternative therapy when conventional therapy has failed. Clinical studies in the United States have been limited by legal factors.

Dosing

Clinical studies use a wide range of preparations and usually allow dosage titration for effect. For more information regarding dosage recommendations for Cannabidiol (CBD) alone, see the Cannabidiol monograph.

Contraindications

Contraindications have not been identified. There is a risk of hypersensitivity to marijuana or other constituents of the plant. The benefits versus risks of cannabis use should be carefully weighed in individuals with psychosocial disorders.

Pregnancy/Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is limited. In retrospective studies, cannabis had a modest effect on fetal growth. THC crosses the placental barrier and is excreted in breast milk.

Interactions

Few case reports exist of interactions in which cannabis is solely implicated. Cannabis may interact with the following: alcohol, anticholinergic agents, CNS depressants, cocaine, cytochrome P450 (CYP-450) 1A2 substrates, CYP2C9 inhibitors, CYP3A4 inducers and inhibitors, St. John's wort, sympathomimetics, and warfarin.

Adverse Reactions

Use of medical cannabis or cannabis preparations is generally considered safe and is devoid of common major adverse reactions, although rare cardiovascular adverse effects and stroke have been noted. Tolerance and dependence have been documented. Major adverse reactions with recreational cannabis use occur more with increasing dosages and include cardiovascular effects, cannabinoid hyperemesis syndrome, psychosis, and others. When recreational use starts at an early age (ie, adolescence), brain development of functional connectivity can be impaired, resulting in declines in intelligence quotient (IQ). The risk of impairments in cognitive and motor function may limit applications of cannabis.

Toxicology

Increasingly potent, uncontrolled synthetic cannabinoids (ie, AMB- or EMB-FUBINACA) are being consumed via vapor pens, e-cigarettes, and herbal mixtures. These compounds mimic the effects of tetrahydrocannabinol (THC). They can be 85 times as potent as THC and their use has resulted in more frequent reports of fatal and non-fatal poisonings. Toxicities appear to be dose-dependent and most often manifest as agitation, anxiety, drowsiness, hallucinations, nausea, vomiting, and tachycardia. Seizures, loss of consciousness, cardiotoxicity, heart attack, renal toxicity, psychosis, and death are less common.

There is a lack of consensus regarding the risk of lung cancer from smoked cannabis or the risk of psychotic events from consumption of oral cannabis preparations. All risk factors should be considered in the context of applications for medical cannabis in intractable diseases. Toxicities due to long-term nonmedical (recreational) cannabis use include increased incidence of psychotic, respiratory, and cardiovascular events, as well as cancers of the lung, head and neck, brain, cervix, prostate, and testis.

Scientific Family

• Cannabaceae

Botany

Cannabis is a leafy annual, with some varieties attaining heights of more than 3 m. The stalk may grow 7.6 to 10 cm thick, is square and hollow, and has ridges running along its length. Each leaf has 5 to 11 soft-textured leaflets, 18 to 25 cm long, radiating from the top of the stalk. The leaflets are narrow and lance-shaped, with regular sawblade-like dentation. The plant is dioecious, with male or female flowers occurring on separate plants. The female plants have heavy foliage, whereas the male plants are sparser. The resinous mixture found in the glandular hairs of the leaflets and floral bracts is called "kief"; kief is collected, heated, and pressurized, resulting in hashish. Cannabis is cultivated worldwide for fiber, seed oil, and hashish.Cohen 2009, Cohen 2009, USDA 2018

Species ascribed to the Cannabis genus include C. sativa, Cannabis indica, and Cannabis ruderalis; however, disagreement exists regarding distinct classification of these species.Gloss 2015 Hemp, a fiber-producing genotypic variant of C. sativa, is botanically distinct from the non–fiber-producing parts of the cannabis plant. Cannabis and hemp variants differ in the amount of THC produced (1% to 20% vs less than 1%, respectively).Holler 2008

History

The use of cannabis in Asia, Africa, and South America dates back more than 5,000 years. Cannabis has been used for the treatment of catarrh, leprosy, fever, dandruff, hemorrhoids, obesity, asthma, urinary tract infections, loss of appetite, inflammatory conditions, and cough. Hemp has also been used as a source of fiber for rope and clothing. The plant's sedative effects were recognized by the ancient Chinese, but widespread use of the plant for its psychoactive effects began in the past century.Duke 1985, Fehr 1983

Cannabis is a controlled substance in the United States. Prescription synthetic cannabinoids and analogues that are registered for specific indications include dronabinol (THC; Schedule III substance), indicated as an antiemetic for chemotherapy-induced nausea and vomiting and for treatment of AIDS-related wasting syndrome; and nabilone (THC; Schedule II substance) used as an antiemetic in cancer patients.

THC/CBD ("nabiximols" [ie, Sativex]) as an orobuccal spray is approved for multiple sclerosis spasticity in more than 20 countries, including Canada and the United Kingdom, and is being studied in US clinical trials for relief of chronic pain in cancer patients. A pure CBD product (Epidiolex) has been approved in the United States for applications in pediatric treatment-resistant seizures.Bowles 2012, Cohen 2009, Epidiolex June 2018, NIH 2018, O'Connell 2017 For information on natural CBD preparations, see the Cannabidiol monograph.

Because of the previous illegality of cannabis possession and use in most jurisdictions in the United States, data from clinical trials have been limited, and much of the relevant documentation is based on retrospective data or case studies. However, the legislative shift in favor of cannabis use in some states and in other countries has led to an increase in the number of controlled studies. Most controlled studies compare cannabinoids to placebo, rather than to standard therapy.AMA 2010

However, the shift towards legal control of cannabis has led to an increasing trend in new, uncontrolled psychoactive synthetic cannabinoids that mimic the effects of THC. The first, JWH-018, appeared in 2008 with over 251 different cannabinoids that were reported to the United Nations Office of Drugs and Crime by 2017. Tolerance appears to develop quickly leading to the availability of increasingly potent compounds. Identified in 2014, AMB-FUBINACA is 85 times more potent than THC and 50 times more than JWH-018. Toxicity is a major concern as fatal and non-fatal poisonings are being reported more frequently. These products are smoked in vaporiser pens, e-cigarettes, or mixed with herbal products.Adamowicz 2019

Chemistry

More than 420 compounds have been isolated from cannabis and reported in the chemical literature. The most commonly described compounds are the cannabinoids THC and CBD. As interest in cannabis and its extracts is renewed, some of the less well-known of the more than 100 cannabinoids (tetrahydrocannabivarin, cannabigerol, cannabichromene, and others) and cannabis terpenoids (eg, limonene, linalool, myrcene, alpha-pinene, phytol) have more recently been highlighted in the literature.Russo 2011 In addition, cannabis contains alkaloids, steroidal compounds, and mixtures of volatile components.Baker 2003, Seamon 2006, Wilkins 2006 Synthetic cannabinoids include nabilone, ajulemic acid, HU-210, and WIN 55,212-2, some of which are nonpsychotropic agonists and antagonists of cannabinoid receptors.Burstein 2004, DiMarzo 2006, Russo 2011

The concentration of THC, the main psychoactive cannabinoid in cannabis, is maximized with increased light energy and varies in different parts of the plant, with higher concentrations in the bracts, flowers, and leaves, and lower concentrations in the stems, seeds, and roots.Andre 2016, Russo 2011 THC concentration varies from insignificant amounts in hemp varieties to 3% to 6% or more in smoked cannabis. Other preparations and concentrated extracts can contain as much as 80% THC. Different cultivation methods and varieties contribute to variations in potency, a point made most clearly by analysis of "black market" cannabis in the United Kingdom, continental Europe, and the United States; black market cannabis has become an almost exclusively high-THC preparation, with no significant CBD or other cannabinoid content.Cohen 2009, Cohen 2009, Russo 2011, Seamon 2006

Nonpharmaceutical, natural cannabis preparations typically consist of either fresh or dried leaves and/or flowers extracted with solvents or made into a paste or oil.

Pharmaceutical/approved preparations contain the synthetic cannabinoid nabilone alone, synthetic THC as dronabinol alone (or levonantradol, an analogue of dronabinol), or nabiximols (ie, THC with CBD in an approximately 1:1 ratio).Gloss 2015, Piomelli 2016 See the Cannabidiol monograph for information regarding natural CBD preparations.

Research is focused on finding cannabinoid derivatives devoid of psychoactive properties, such as ajulemic acid,Burstein 2004 and on breeding plant variants low in THC. CBD is often stated to be nonpsychoactive; however, it reportedly demonstrates antianxiety effects and thus cannot be considered entirely devoid of CNS properties.Leimuranta 2018, Piomelli 2016

Uses and Pharmacology

Cannabinoid receptors have been identified in human tissue. Cannabinoid type 1 (CB₁) receptors are found primarily in the CNS and peripheral nervous system; a key function of CB₁ receptors is to modulate release of the neurotransmitters glutamate and gamma-aminobutyric acid (GABA).(Grant 2018) CB₁ receptors are also found in the adrenal gland, bone marrow, and heart, liver, lung, reproductive, and vascular endothelial tissues. Type 2 receptors (CB₂) are found mainly in immune tissues but are also found in retinal, reproductive, and microglia cells.(Bari 2006, Grant 2018) CB₁ and CB₂ receptors respond to endogenous cannabinoids, the most prevalent of which are 2-arachidonoylglycerol and arachidonoylethanolamine (also termed anandamide).(Di Marzo 2006, Grant 2018) Natural (THC and CBD) cannabinoids act via the endocannabinoid system to suppress neuronal excitability and transmitter release, modulate cytokine release, and inhibit cyclooxygenase (COX) enzymes.(NCI 2017) The cannabinoid chemicals also act on cyclooxygenase, opioid receptors, adrenoreceptors, and voltage-gated potassium and sodium channels.(Gaston 2017)

Using functional magnetic resonance imaging (MRI), a randomized clinical trial in healthy volunteers demonstrated positive correlations between THC administration and reduced functional connectivity between the amygdala and primary sensorimotor areas of the brain.(Lee 2013) The dissociative effects of THC in the brain are likely to play an important role in human pain relief and may have relevance in interpreting outcome measures reported in other clinical studies.(Lee 2013)

Cancer

Animal data

Cannabinoids, including THC, have been studied in rodents for their potential to inhibit tumor growth via inducing apoptosis and inhibiting angiogenesis.(Blazquez 2008, Guindon 2011)

Clinical data

A specific role of cannabinoids in the management of prostate cancer has been postulated since the 1970s,(Guindon 2011, Ramos 2012) and clinical studies using adjuvant cannabinoids in glioblastoma and lung cancer are in progress.(NIH 2018)

CNS

Appetite stimulant effects

Clinical data

Studies evaluating the effects of synthetic and natural THC in cancer-associated anorexia have demonstrated increases in appetite and reductions in rate of weight loss.(Badowski 2018) One study evaluated the effects of cannabis extract and THC on appetite and quality of life in patients with cancer-related anorexia-cachexia syndrome. Patients were randomized to receive cannabis extract (standardized as THC 2.5 mg and CBD 1 mg), THC (2.5 mg), or placebo. Cannabis extract and THC were well tolerated, but there were no differences in appetite or quality of life with either treatment compared to placebo, or between the 2 treatments.(Strasser 2006)

Chemotherapy-induced and postoperative nausea and vomiting

Clinical data

The Society of Obstetricians and Gynaecologists of Canada guidelines for the management of postoperative nausea and vomiting (2008) note that cannabinoids have not been confirmed to be effective in the management of postoperative nausea and vomiting.(McCracken 2008) Likewise, the Society for Ambulatory Anesthesia consensus guidelines (2014) found cannabinoids (THC) to be ineffective prophylactic therapy for postoperative nausea and vomiting in adults at moderate risk.(Gan 2014) The American Society of Clinical Oncology (ASCO) updated clinical practice guidelines on antiemetics (2020) state that evidence is insufficient to recommend the use of medical marijuana for the prevention of chemotherapy- or radiation-induced nausea and vomiting or as a replacement for FDA-approved cannabinoids, dronabinol and nabilone.(Hesketh 2020)hesketh

Chemotherapy-induced peripheral neuropathy

Clinical data

The American Society of Clinical Oncology (ASCO) guideline update for prevention and management of chemotherapy-induced peripheral neuropathy (2020) recommends that clinicians not offer cannabinoids for the prevention of chemotherapy-induced peripheral neuropathy (CIPN) in adults with cancer undergoing treatment with neurotoxic agents (Intermediate; Moderate). For patients who have completed neurotoxic chemotherapy, no recommendations could be made for use of oral or oral mucosal cannabinoids in treatment of CIPN, outside the context of a clinical trial (Low; NA).(Loprinzi 2020)

Pain

Animal data

Results from experiments conducted in animals provide support for a therapeutic role for cannabinoids in the management of pain,(Comelli 2008, Costa 2007) and reviews of animal data have been published.(Lochte 2017, Mucke 2018, O'Brien 2018)

Clinical data

Clinical trials investigating the efficacy of cannabis and its derivatives have been conducted in both acute and chronic pain, and systematic reviews and meta-analyses of the data have been published. Few studies have investigated the effects of CBD alone on pain; most rely on high-CBD/low-THC plant-based preparations.(NIH 2018)

High-quality clinical evidence for the use of cannabis or its derivatives in neuropathic pain is lacking.(Mucke 2018) A Cochrane meta-analysis of 16 clinical trials reported in the literature up to November 2017 (N=1,750 participants) found that cannabis-based medicines may increase the number of those achieving 50% or greater pain relief compared to placebo (risk difference, 0.05 [95% confidence interval (CI), 0 to 0.09]). Number needed to benefit was 20 (95% CI, 11 to 100).(Mucke 2018) Other reviews report low to moderate evidence for cannabis-based preparations compared with placebo in patients with chronic pain, including that due to cancer.(Brown 2018, Darkovska 2018, Hauser 2018, Lochte 2017, Mucke 2018)

A bias towards reporting positive findings exists, both in individual clinical studies and in systematic reviews evaluating the role of cannabis in pain management.(Hauser 2018, Lochte 2017) Not all studies demonstrate efficacy over placebo,(Centonze 2009, DeVries 2017, Selvarajah 2010) and findings from other studies have not been published.(Mucke 2018)

A phase 2 clinical study (N=65) found THC 8 mg orally 3 times a day was no better than placebo for chronic abdominal pain.(DeVries 2017)

The value of trial results is limited by a simultaneous increase in adverse events,(Mucke 2018) with number needed for harm estimates between 5 and 8 on visual analog scales for cognitive and motor function adverse events.(Martin-Sanchez 2009, Richards 2012)

Seizures

THC's anticonvulsant activity appears to be mediated to an important extent by its partial agonist action at the CB₁ receptor. No effect, mixed effects, and proconvulsant effects of THC have also been demonstrated in acute seizure models, possibly because of activation of a diverse range of receptors, including both GABA and glutamate pathways. Findings with models of acute seizures may not translate well to chronic models because downregulation of receptor expression with chronic activation may alter drug targets or change the functional impact of THC.(Gaston 2017, Perucca 2017)

In contrast to THC, CBD has very weak affinity for the CB₁ and CB₂ receptors, indicating its antiseizure activity is mediated by other mechanisms; various targets have been investigated to explain CBD's anticonvulsant properties, including transient receptor potential channels, voltage-gated potassium and sodium channels, and certain G-protein-coupled receptors (GPCRs), such as GPR55, among others.(Gaston 2017, Perucca 2017)

Cannabidivarin, similar to CBD, has also been studied in vitro and in animal models, and may also act via transient receptor potential channels, although this is not considered the primary mechanism contributing to its anticonvulsant activity.(Gaston 2017, Perucca 2017) Other cannabinoids may also possess anticonvulsant properties.

Animal and in vitro data

Anticonvulsant properties of the various cannabinoids have been demonstrated in in vitro and in vivo studies of animal models, while other studies have demonstrated no effect, mixed effects, or proconvulsant effects; reviews of studies have been published.(Gaston 2017, Perucca 2017)

Clinical data

The majority of research on anticonvulsant activity has focused on CBD (see the Cannabidiol monograph).

Other CNS uses

Limited studies have evaluated the efficacy of cannabinoids in sleep disorders, depression, anxiety, and movement disorders, with mixed results. Studies are generally of lower quality or have potential for bias.(Whiting 2015) Evidence-based Canadian guidelines for pharmacotherapy of tic disorders (2012) determined that there is no evidence to support the use of cannabinoids in the management of tics in children and adolescents.(Pringsheim 2012) Low-quality evidence suggests modest benefits in adults with Tourette syndrome, and further clinical trials are being conducted.(NIH 2018, Pringsheim 2012, Whiting 2015) Low-quality evidence, based largely on case reports and case studies, suggests a role for cannabinoids in headache disorders, including migraine,(Leimuranta 2018, Lochte 2017) as well as in the treatment of cannabis dependence.(Trigo 2018)

The Veteran’s Affairs and Department of Defense (VA/DoD) clinical practice guideline for the management of major depressive disorder (MDD) (2022) recommends against the use of cannabis for MDD outside the research setting based on limited information for safety and efficacy (strong).(VA/DoD 2022)

Diabetes

The role of the endocannabinoid system in energy metabolism has been investigated, with emerging evidence showing CBD may slow beta-cell damage in type 1 diabetes mellitus.(DiMarzo 2011, Mastinu 2018)

Animal data

Limited experiments in rodents have been conducted.(DiMarzo 2011, Zuardi 2008)

Clinical data

The CB₁ receptor antagonist rimonabant has been evaluated in clinical trials of obese patients with and without comorbidities (dyslipidemia and/or type 2 diabetes) and has demonstrated reductions in hemoglobin A_1c (HbA_1c) levels; however, use was suspended in 2008 by the European Medicines Agency when documentation of psychiatric adverse effects (worsening anxiety and depression) showed that the benefits no longer outweighed the risks.(Di Marzo 2011, FDA 2007) Focus is now on cannabinoid CB₁ antagonists, including the less well studied tetrahydrocannabivarin (THCV), the propyl homologue of THC.

In one small randomized, double-blind, placebo-controlled study (N=62), patents with noninsulin–treated type 2 diabetes received CBD, THCV, a combination of CBD and THCV, or placebo for 13 weeks. CBD and THCV were well tolerated. THCV decreased fasting plasma glucose and improved pancreatic beta cell function, adiponectin, and apolipoprotein A. CBD decreased resistin and increased glucose-dependent insulinotropic peptide. However, the primary end point (change in high-density lipoprotein cholesterol) was not affected by treatment with CBD, THCV, or combination treatment.(Jadoon 2016) More research is needed.

Glaucoma

Clinical data

The few clinical trials of cannabis use in glaucoma conducted since the 1970s(Hepler 1971, Novack 2016, Whiting 2015) generally included very small sample sizes and produced no new findings. Proposed mechanisms of action include effects on the COX pathways(Green 2001) and mydriasis due in part to action via sympathomimetic pathways.(Korczyn 1982) Although reductions in intraocular pressure have been reported, the effect lasts only 3 to 4 hours, necessitating a dosing frequency of 6 to 8 times a day with a consequent risk of initiating substance abuse among users.(Sun 2015) Aside from unwanted neurological effects, an additional limitation is the reduction in ocular blood flow due to cardiovascular effects, which theoretically would limit the benefits of reduced intraocular pressure.(Novack 2016)

Inflammatory bowel disease

Animal data

In a mouse model of colitis, cannabinoids decreased macroscopic inflammation, myeloperoxidase activity, and peristalsis, and ameliorated inflammation.(Naftali 2017) A simple extract of medicinal cannabis promoted resolution of colitis upon intracolonic, but not oral, administration; improved diarrhea, weight loss, and healing of ulcerated GI tissue; showed a dose-dependent reduction in the severity of naproxen-induced gastric damage after oral, but not systemic, administration; and prevented gastric distention–induced visceral pain in rats.(Wallace 2013)

Clinical data

Limited clinical studies, generally including small numbers of participants, have been conducted. One study (N=13) showed improved inflammatory bowel disease outcomes with inhaled cannabis,(Lahat 2012) and another (N=21) reported safety but lack of efficacy with cannabis cigarettes, although improvements in Crohn disease measures were noted.(Naftali 2017) A phase 2 clinical study (N=65) found THC 8 mg orally 3 times a day was no better than placebo for chronic abdominal pain.(de Vries 2017)

A systematic review published in 2020 identified 20 studies in which cannabis and/or its cannabinoid derivatives were used for inflammatory bowel disease; 5 were randomized, placebo-controlled trials. Based on data pooled for meta-analysis from 4 of the randomized clinical trials (N=146; 3 full-study data and 1 conference abstract), cannabinoids were not effective for induction of remission; no heterogeneity was observed. Similarly, data pooled from 3 randomized clinical trials (N=86) found no significant effect of cannabis and/or cannabinoids on C-reactive protein; however, heterogeneity was very high. In contrast, post-treatment disease activity index scores were significantly reduced in the cannabis groups (4 studies, N=133; mean difference, 0.61; 95% CI, 0.24 to 0.99; P=0.001; minimal heterogeneity) as was the perceived efficacy by the participants, particularly for abdominal pain. In-hospital complications were significantly different only for parenteral nutrition with benefit favoring cannabis groups who were more likely to remain on oral nutrition, and were also likely to have a shorter hospital stay. Data for quality of life scores could not be pooled and were equivocal whereas no data were found for maintenance of remission; there was incomplete data on cannabis dosage and frequency of administration.(Doeve 2020)

Multiple sclerosis

Animal and in vitro data

Studies from in vitro and animal experiments support a role for cannabinoids in MS, demonstrating reductions in oligodendrocyte and neuronal cell death, influence on inflammation and microglial migration, and enhancement of remyelination.(Baker 2003, Teare 2005) The CB₂ receptor plays an important role in the regulation of inflammation in experimental MS animal models, with CB₂ deficiency associated with more severe disease.(Gowran 2011) Experimentally, it has been demonstrated that antagonism of CB₁ receptors (but not CB₂ receptors) inhibits spasticity but can sometimes transiently worsen it.(Baker 2003, Baker 2003) Increased CB₂ immunoreactivity has been observed in the spinal cord of MS patients.(Gowran 2011)

Clinical data

Despite the availability of data from clinical trials, there is no definitive role for cannabis extracts or cannabis analogues in MS, due in part to difficulty in obtaining objective clinical measures (ie, most trials use self-reporting as the primary outcome measure).(Nielsen 2018, Russo 2011, Whiting 2015) The 2014 American Academy of Neurology guideline on complementary and alternative medicine in MS advises that oral cannabis-based preparations can be used for reducing subjective spasticity symptoms and pain not classified as central neuropathic pain, and that oromucosal cannabinoid spray can be used for urinary frequency symptoms.(Yadav 2014)

Data from 10 moderate- to high-quality studies included in a quantitative review (up to 2016), suggest at least a trend towards reduced pain and spasticity with THC and THC/CBD.(Nielsen 2018) A meta-analysis of 6 studies (N=544) found that the cannabinoids evaluated showed a nonsignificant greater average improvement in spasticity (based on the Ashworth scale) compared with placebo (weighted mean difference, −0.12 [95% CI, −0.24 to 0.01]).(Whiting 2015)

Results for cannabinoid use in the treatment of ataxia are not very encouraging; however, studies often do not evaluate this outcome as a primary measure, with sample sizes likely underpowered to detect an effect.(Nielsen 2018) Evidence from smaller studies regarding effects of cannabinoids on bladder function in MS is generally not confirmed in larger, high-quality studies; however, some evidence suggests fewer voids, reduced frequency of nocturia, and improvements in other incontinence-related quality-of-life measures.(Nielsen 2018) Studies evaluating the effects of cannabinoid preparations on disability and disability progression have shown mixed results; use of different scales and outcome measures make consolidation of evidence difficult.(Nielsen 2018) Mixed results are also reported for overall quality-of-life measures.(Nielsen 2018)

Neurodegenerative diseases

Many neurological conditions, such as Alzheimer disease, MS, cerebral ischemia, Parkinson disease, and Huntington disease, exhibit a neurodegenerative component associated with excitotoxicity, oxidative stress, and inflammation.

Experimental and clinical evidence indicates that the endocannabinoid system is altered in these neurodegenerative conditions and that neuroprotection is afforded by cannabinoid molecules. CB₁ receptors occur in high density in the hippocampus and cerebral cortex, areas that exhibit preferential neuronal loss in Alzheimer disease.(Gowran 2011, Zuardi 2008) THC has been shown to affect brain-derived neurotrophic factor, which is involved in the health of neurons and is known to modulate neuroplasticity and adaptive processes underlying learning and memory.(D'Souza 2009) Data also suggest that cannabinoids have neuroprotective effects following brain injury. The CB₁ receptor antagonist rimonabant reduced hypokinesia in an animal model of Parkinson disease, and both THC and CBD have been found to protect nigrostriatal dopaminergic neurons. In models of Huntington disease, CB₂ receptor activation has been shown to be neuroprotective through reduction of microglial activation.(Gowran 2011, Zuardi 2008)

Clinical data

Clinical evidence is limited to case reports on 2 patients.(Mesiel 2012)

Dosing

Clinical studies use a wide range of preparations and usually allow dosage titration for effect, making standard dosage recommendations difficult to determine.

Estimate of relative efficacy for THC compared with codeine for pain is THC 10 mg to codeine 60 mg.Karst 2009

THC is distributed rapidly throughout the body, especially to tissues with high lipid content. Approximately 80% to 90% of an intravenous dose of THC is excreted in urine, and the remainder is excreted in feces via bile.Mason 1985

Pregnancy / Lactation

Avoid use. Information regarding safety and efficacy of medicinal cannabis in pregnancy and lactation is limited. In retrospective studies, cannabis use during pregnancy had a modest effect on fetal growth, with some studies demonstrating decreases in birth weight; because the maximal reported birth weight difference is on the order of about 100 g, the clinical significance of this decrease in birth weight is questionable.Merlob 2017 An increased risk of "small for gestational age" and neonatal intensive care unit admission was found in a large retrospective study that specifically excluded tobacco smokers.Grant 2018 Some minor developmental abnormalities were associated with maternal use during pregnancy but were not sustained in the long term (at 3 years of age), and no apparent differences in IQ were noted in some studies.Davies 2005, Hall 2003, Reece 2009 However, data are inconsistent, and other studies suggest that altered neurodevelopment can be present up to 14 years postexposure.Grant 2018, Merlob 2017 A case-control study reported increased rates of stillbirth among women using marijuana during pregnancy; however, confounders such as alcohol and tobacco use may have contributed to these findings.Merlob 2017

THC crosses the placental barrier and is excreted in breast milk.Baker 2018, Davies 2005 Data from the human milk biorepository (Mommy's Milk) revealed that delta-9-THC, 11-OH-THC, and cannabidiol were detectable in 63%, 9%, and 9%, respectively, of 54 samples from lactating women who reported recent marijuana use. Most of the women (88%) reported at least daily use via inhalation (64%) (other routes included ingestion or topical). Significant negative predictors of delta-9-THC concentrations were hours since last use, number of uses per day, and time lag between date of milk collection and date the sample was analyzed. Based on assumptions regarding breast-feeding frequency and 6% oral bioavailability, an estimated delta-9-THC level of 0.04 ng/mL was calculated for a 3-month-old infant weighing 6.1 kg; this would yield a dose ingested via breast milk approximately 1,000 times lower than that of an adult who consumed 10 mg delta-9-THC.Bertrand 2018 Lower baseline plasma prolactin levels have been demonstrated with frequent cannabis use.Ranganathan 2009

Because legalization of recreational and medicinal cannabis use is increasing in the United States, the American College of Obstetricians and Gynecologists encourages clinicians to specifically inquire into cannabis use in pregnant and/or breastfeeding women. Prescribing or suggesting use of cannabis during pregnancy or for women contemplating pregnancy is discouraged.ACOG 2017

Interactions

Few case reports exist of interactions in which cannabis is solely implicated. Additive effects may occur if nabilone or THC are taken with other CNS depressants, and decreased need for analgesics, dexamethasone, and ondansetron is possible with concomitant use.(Tran 2017) The cannabinoids THC and CBD are both metabolized by the CYP-450 enzyme system.(Gaston 2017, Tran 2017) CBD has been shown to inhibit CYP2C19, CYP2D6, CYP2C9, and CYP3 enzymes, and induce members of the CYP2B family in animal models.(Gaston 2017) CBD may also be an inhibitor of certain transporter systems.(Perucca 2017)

Alcohol (ethyl): Cannabis and THC may enhance the CNS depressant effect of alcohol (ethyl). Monitor therapy. This interaction is only expected when physiologically significant amounts of THC are introduced systemically. While this encompasses the vast majority of medical and recreational cannabis use, some cannabis strains, products, and routes of administration specifically (and often intentionally) minimize systemic THC exposure.(Chait 1994, Consroe 1979, Hollister 1986, Johnstone 1975, Perez-Reyes 1988, Reisfield 2010, Ronen 2010, Sativex December 2019, Siemens 1980, Worthley 2002)

Anticholinergic agents: Anticholinergic agents may enhance the tachycardic effect of cannabinoid-containing products. Monitor therapy.(Benowitz 1977, Cesamet December 2009, Freemon 1975, Williamson 2000)

Carbamazepine: Cannabis may increase the serum concentration of carbamazepine. Carbamazepine may decrease the serum concentration of cannabis. More specifically, THC and CBD serum concentrations may be decreased. Monitor therapy.(Ridout 2021, Stott 2013, Watanabe 2007)

CNS depressants: CNS depressants may enhance the CNS depressant effect of cannabinoid-containing products. Monitor therapy.(Belgrave 1979, Cesamet May 2006, Chait 1994, Consroe 1979, Dalton 1975, Epidiolex June 2018, Hollister 1986, Johnstone 1975, Macavoy 1975, Marinol July 2006, Perez-Reyes 1988, Reisfield 2010, Ronen 2010, Sativex March 2012, Sativex March 2015, Siemens 1980)

Cocaine (topical): Cocaine (topical) may enhance the tachycardic effect of cannabinoid-containing products. Monitor therapy.(Foltin 1987, Foltin 1990, Foltin 1995, Gash 1978, Lukas 1994, Williamson 2000)

CYP1A2 substrates (high risk with inducers): Cannabis may decrease the serum concentration of CYP1A2 substrates (high risk with inducers). Monitor therapy. This interaction has only been described with smoked cannabis herb (ie, marijuana).(Chetty 1994, Gardner 1983, Jusko 1978, Jusko 1979)

CYP2C9 inhibitors (moderate): CYP2C9 inhibitors (moderate) may increase the serum concentration of cannabis, CBD, and THC. More specifically, THC serum concentrations may be increased. Monitor therapy. This interaction is only expected when physiologically significant amounts of THC are introduced systemically. While this encompasses the vast majority of medical and recreational cannabis use, some cannabis strains, products, and routes of administration specifically (and often intentionally) minimize systemic THC exposure.(Marinol August 2017, Sachse-Seeboth 2009, Sativex December 2019)

CYP3A4 inducers (moderate): CYP3A4 inducers (moderate) may decrease the serum concentration of cannabis. More specifically, THC and CBD serum concentrations may be decreased. Monitor therapy.(Sativex December 2019, Stott 2013, Watanabe 2007)

CYP3A4 inducers (strong): Cannabis: CYP3A4 inducers (strong) may decrease the serum concentration of cannabis. More specifically, THC and CBD serum concentrations may be decreased. Monitor therapy.(Stott 2013, Watanabe 2007) Tetrahydrocannabinol and cannabidiol: CYP3A4 inducers (strong) may decrease the serum concentration of THC and CBD. Consider therapy modification.(Sativex December 2019, Stott 2013, Watanabe 2007)

CYP3A4 inhibitors (moderate): CYP3A4 inhibitors (moderate) may increase the serum concentration of cannabis. More specifically, THC and CBD serum concentrations may be increased. Monitor therapy. (Sativex December 2019, Stott 2013, Watanabe 2007)

CYP3A4 inhibitors (strong): CYP3A4 inhibitors (strong) may increase the serum concentration of cannabis. More specifically, THC and CBD serum concentrations may be increased. Monitor therapy. (Sativex December 2019, Stott 2013, Watanabe 2007)

Disulfiram: Disulfiram may enhance the adverse/toxic effect of cannabinoid-containing products. Specifically, the risk of a hypomanic episode may be increased. Disulfiram may also produce intolerance to the alcohol contained in the dronabinol oral solution. No action needed. Use of the dronabinol oral solution with disulfiram is contraindicated, but this interaction does not apply to the dronabinol capsules or other cannabinoid-containing products.(Cesamet May 2006, Lacoursiere 1983, Mackie 1994, Marinol July 2006, Syndros July 2016)

Fluoxetine: Cannabinoid-containing products may enhance the adverse/toxic effect of fluoxetine. Specifically, the risk of a hypomanic episode may be increased. No action needed.(Anderson 2022, Cesamet May 2006, Cornelius 2010, Marinol July 2006, Stoll 1991)

Grapefruit juice: Grapefruit juice may increase the serum concentration of THC and CBD. Avoid combination.(Sativex December 2019, Stott 2013)

Hormonal contraceptives: THC and CBD may decrease the serum concentration of hormonal contraceptives. Consider therapy modification.(Sativex December 2019)

Lumacaftor and ivacaftor: Lumacaftor and ivacaftor may decrease the serum concentration of CYP2C9 substrates (cannabis, CBD, THC) (high risk with inhibitors or inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 substrates (high risk with inhibitors or inducers). Monitor therapy.(Orkambi August 2018)

Naloxone: Naloxone may enhance the therapeutic effect of cannabinoid-containing products. Naloxone may also decrease effectiveness of cannabinoids. These effects may depend on naloxone dose and frequency, cannabinoid dose and route of administration, and prior cannabinoid exposure. No action needed.(Cooper 2010, Greenwald 2000, Haney 2007, Haney 2003, Haney 2015, Ranganathan 2012, Wachtel 2000)

Naltrexone: Naltrexone may enhance the therapeutic effect of cannabinoid-containing products. Naltrexone may also decrease effectiveness of cannabinoids. These effects may depend on naltrexone dose and frequency, cannabinoid dose and route of administration, and prior cannabinoid exposure. No action needed.(Cooper 2010, Greenwald 2000, Haney 2007, Haney 2003, Haney 2015, Ranganathan 2012, Wachtel 2000)

Nicotine: Nicotine may enhance the stimulatory effect of cannabis. Nicotine may enhance the tachycardic effect of cannabis. No action needed.(Penetar 2005)

Propofol: Cannabis may diminish the therapeutic effect of propofol. Monitor therapy.(Flisberg 2009, Imasogie 2021)

St. John's wort: St. John's wort may decrease the serum concentration of cannabis, CBD, and THC. Monitor therapy when given with cannabis, and consider therapy modification if given with THC and CBD. This interaction is mainly expected to reduce systemic concentrations and effects of THC and CBD. Patients using a cannabis strain, product, or route of administration that does not introduce physiologically significant amounts of these compounds may not be affected. UK product labeling for THC/CBD oromucosal spray recommends avoiding use of this product in combination with strong CYP3A4 inducers and St. John's wort. Labeling in other areas may differ (eg, Canadian labeling gives no specific management recommendation).(Sativex February 2014, Sativex December 2019, Stott 2013, Watanabe 2007)

Sympathomimetics: Cannabinoid-containing products may enhance the tachycardic effect of sympathomimetics. Monitor therapy.(Benowitz 1977, Foltin 1987, Foltin 1990, Foltin 1995, Gash 1978, Lukas 1994, Williamson 2000)

Tacrolimus (systemic): Cannabis may increase the serum concentration of tacrolimus (systemic). Monitor therapy.(Cunetti 2018, Hauser 2016, Leino 2019, Moadel 2019)

Warfarin: CBD is a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2C9. S-warfarin is metabolized by CYP2C9, while R-warfarin is metabolized by CYP1A1, 1A2, and 3A4. In vitro studies suggest that THC may also inhibit CYP2C9. Four cases of increases in otherwise stable international normalized ratios occurring after smoking cannabis, ingesting cannabis, and oral administration of CBD oil have been reported as a probable interaction between warfarin and cannabis. Symptoms of bleeding occurred in some but not all patients.(Damkier 2019, Hsu 2019)

Adverse Reactions

In clinical studies, short-term adverse effects of cannabinoids included effects on the CNS (including confusion, dizziness, disorientation, issues with balance, euphoria, hallucination, and somnolence) dry mouth, nausea, and vomiting.(Mucke 2018, Whiting 2015, Wong 2017) Case reports of other, more diverse adverse events exist. Moderate-quality evidence shows more people withdraw from studies due to adverse events with cannabis-based medicines than with placebo.(Mucke 2018) A meta-analysis of 62 studies reported more events with cannabinoids than with placebo. The summary OR was 1.41 (95% CI, 1.04 to 1.92) for serious adverse events and 2.94 (95% CI, 2.18 to 3.96) for study withdrawal due to adverse events compared to placebo.(Whiting 2015) Seizure aggravation leading to treatment withdrawal has been reported in studies conducted in treatment-resistant seizure syndromes.(Perucca 2017)

Results of a 2011 to 2018 US National Health and Nutrition Examination Survey that included responses from 12,543 adults with a mean age of 39 years demonstrated significantly increased odds of coronary artery disease in participants who "ever used (even once)" cannabis or hashish compared to those who "never used" it (adjusted odds ratio [OR], 1.9; 95% CI, 1.24 to 2.93; P=0.003). The odds increased by 68% for those who used at least once per month for at least 1 year (OR, 1.63; 95% CI, 1.02 to 2.77; P=0.04), by 98% for "current users (within the last 30 days)" (OR, 1.98; 95% CI ,1.11 to 3.54; P=0.02), and by 99% for "heavy users (at least 5 times/month)" (OR, 1.99; 95% CI, 1.02 to 3.89; P=0.045). Results were consistent among all sub-groups (ie, race, gender, hypertensive, obese, COPD, hyperlipidemic, tobacco smoking status, diabetic). Overall, respondents were 48.8% male and 34.3% Caucasian.(Skipina 2022) Increased heart rate accompanied by slight increases in supine blood pressure is commonly observed with inhaled cannabis, probably due to vasodilation and reflex tachycardia.(Goyal 2017) A review of the cardiovascular effects of inhaled cannabis (THC/CBD) notes an association between ventricular tachycardia and an increased risk of atrial fibrillation and myocardial infarction.(Goyal 2017) A case of complete heart block was reported in a 51-year-old female chronic marijuana smoker (1 to 2 bags 4 to 5 times/week for years) with no significant medical history. She presented with bradycardia and 3rd degree AV block, which was treated with implantation of a permanent pacemaker. A 3-month follow-up revealed persistent underlying complete heart block.(Mithawala 2019) Tolerance to cardiovascular responses has been noted with long-term cannabis use. A temporal relationship between recent cannabinoid use (largely as inhaled cannabis) and the occurrence of stroke has been suggested, with cerebral vasoconstriction as a possible mechanism. Causality, however, has not been established.(Tsivgoulis 2014, Wolff 2017)

Cannabinoid hyperemesis syndrome is being reported more frequently and generally occurs in the context of long-term recreational use of large dosages.(Chang 2009, Iacopetti 2014, Mahmad 2015) Various skin eruptions have also been reported in long-term users.

The endocannabinoid system plays a role in the regulation of fertility; cannabis use and/or disruptions to the endocannabinoid system have been shown to have negative effects on reproduction.(Dekker 2012, Karasu 2011, Lewis 2012)

No serious adverse events were reported in a 12-month study evaluating use of cannabinoids in MS patients(Zajicek 2005); however, studies evaluating long-term adverse effects of medicinal cannabis use are generally lacking.(Mucke 2018, Whiting 2015) Evidence suggesting long-lasting cognitive impairment with long-term recreational use of cannabis exists, but is marked by debate; more research is needed.(Volkow 2014) Tolerance to some neurocognitive impairment effects of cannabis has occurred in heavy cannabis users, and frequent use of low doses can rapidly induce tolerance to the subjective "high."(Theunissen 2012) Cannabis withdrawal syndrome, recently classified in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5), is an underrecognized syndrome of heavy cannabis users (especially adolescents) that should be considered in patients presenting with eating disorders and complaints of food avoidance, weight loss, and GI symptoms.(Chesney 2014)

Long-term cannabis use has been associated with gingival enlargement (clinically similar to phenytoin-induced enlargement) and cannabis arteritis, which may initially appear as Raynaud phenomenon and intermittent claudication.(Rawal 2012, Tennstedt 2011)

Candidiasis of the tongue related to smoking cannabis has been reported in 2 young males and treated successfully with miconazole gel.(Faustino 2020)

Cannabis-induced acute pancreatitis has been reported in 2 cases: subsequent to a period of heavy use in a young adult, and 3 occurrences in 1 young male over an approximate 6-month period during chronic recreational use.(Pagliari 2019)

Toxicology

In 2014 and 2015, the uncontrolled synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA appeared, respectively, on the grey market with the former shown to be 85 times more potent than THC and 50 times more than JWH-018 introduced only 6 years earlier. Toxicity appears to be dose-dependent and is a major concern, as fatal and non-fatal poisonings are being reported more frequently. The most common adverse effects are agitation, anxiety, drowsiness, hallucinations, nausea, vomiting and tachycardia. Seizures, loss of consciousness, cardiotoxicity, heart attack, renal toxicity, psychosis, and death are less common. In 2016, AMB-FUBINACA was associated with a massive outbreak of 33 cases of "zombie-like" intoxication in New York, characterized by strong CNS depression and slow, mechanical arm and leg movements. Analysis of samples seized in New York contained an average of 16 mg/g of AMB-FUBINACA whereas preparations related to several deaths in New Zealand in 2017 and 2018 were found to contain an average of 59 mg/g. The parent substance (ie, AMB- or EMB-FUBINACA) may not necessarily be present in postmortem blood samples but may be found in other bodily fluids and tissues (ie, urine, kidney, liver, stomach) as indicated in a fatal case of a 27-year-old male.Adamowicz 2019

Despite a plausible biological rationale and epidemiological data, no consensus exists regarding the risk of lung cancer from smoked medical marijuana. All risk factors should be considered in the context of applications in intractable diseases.Hall 2003, Mehra 2006 Likewise, the potential for addiction and risk of inducing mental illness continues to be debated.Degenhardt 2008 A systematic review found an increased risk of psychotic outcomes with the use of cannabis (OR, 1.41; 95% CI, 1.2 to 1.65).Moore 2007 Another systematic review of MRI and postmortem studies found that patients with schizophrenia and those at genetically high risk for psychosis might be particularly vulnerable to volume loss of brain structures upon exposure to cannabis.Rapp 2012 Data from a large, population-based, case-control study confirmed the results of 2 prior epidemiologic studies demonstrating a positive association between recreational marijuana use and an increased risk of testicular cancer.Lacson 2012 Although there is little direct evidence that cannabinoids are carcinogenic, cannabis smoke was carcinogenic in animal studies and mutagenic according to the Ames test. Cannabis smoke contains many of the same carcinogens found in tobacco smoke at up to 50% higher concentrations, with 3 times the tar per cigarette.Bowles 2012

Systematic reviews of toxicity due to long-term nonmedical (recreational) cannabis use found increased risks for psychotic, respiratory, and cardiovascular events, as well as for cancers of the lung, head and neck, brain, cervix, prostate, and testis.Ferretjans 2012, Rapp 2012, Reece 2009 Cannabis use has been identified as an independent risk factor for human papilloma virus–positive (HPV+) head and neck squamous cell carcinoma due to the effects of cannabinoids on CB₂ receptors in tonsillar tissue.Cardesa 2011 A rare case of small-cell lung cancer was reported in a 22-year-old male cannabis user with a negative history for cigarette smoking, and eosinophilic pneumonia was described in a 60-year-old male with recreational exposure to cannabis from a different source than usual.Kothadia 2012, Liebling 2013 Additionally, evidence of bone toxicity associated with long-term cannabis use exists, and cannabis has been linked in a dose-dependent manner with effects on bone metabolism.Reece 2009 Cannabis use during teenage years, when development of frontal lobe functioning is vulnerable, has been associated with psychosis, depression, and abnormal development of cognition and brain function, including working memory function.Jager 2010 Delayed-onset cannabis-induced psychosis was reported in a young adult with symptoms that manifested 3 months after he experimented with smoking cannabis.Perera 2017

Index Terms

• Cannabidiol
• CBD
• Tetrahydrocannabinol
• THC

References

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