Cannabis

• How It Works

  Research shows that cannabis helps relieve pain, reduces chemo-induced nausea and vomiting, and decreases the number of seizures in rare forms of epilepsy. But non-medical use can result in addiction, side effects, and withdrawal syndrome that makes it difficult to stop use, ultimately leading to relapse.

  Cannabis sativa is an annual flowering herb native to East Asia, but is now cultivated around the world. Preparations made of flowers (marijuana) and leaves as well as hashish made from the resinous extract of the plant are taken orally; by smoking in cigarettes, cigars, pipes, water pipes, or “blunts” (cannabis rolled in the tobacco-leaf wrapper from a cigar); or by vaporizing. Cannabis tinctures, teas, ointments, and oil-based extracts that can be mixed into food products are also popular. It is currently the most widely used illegal agent by more than 147 million people worldwide, and most commonly consumed by inhaling.

  The biological effects of cannabis are mainly due to compounds called cannabinoids: Delta-9-tetrahydrocannabinol (THC) is the main psychoactive compound whereas cannabidiol (CBD) is non-psychoactive. Small studies suggest benefits of cannabis (includes smoked cannabis, oromucosal extracts of cannabis-based medicine, and the FDA-approved synthetic THC drugs dronabinol and nabilone) for pain due to neuropathy, fibromyalgia, rheumatoid arthritis and mixed chronic pain. An oral CBD solution known as Epidiolex was shown useful for decreasing the number of seizures in patients with either Lennox-Gastaut syndrome or Dravet syndrome, two rare forms of epilepsy. This is now an FDA-approved drug.

  Cannabinoids may also be useful for treating spasticity and neuropathic pain in multiple sclerosis patients. But there is not enough evidence to support their use for reducing symptoms of dyskinesia, Parkinson’s and Huntington’s diseases, irritable bowel syndrome, or addiction.

  Studies in laboratory and in animal models suggest cannabinoids can also kill cancer cells. Clinical studies indicate that patients who used cannabis-based products experienced less chemotherapy-induced nausea and vomiting compared to those on placebo or antiemetics. Although side effects including “feeling high” and dizziness were reported by patients, dronabinol and nabilone are recommended for controlling nausea and vomiting that do not respond to standard drugs. Dronabinol also helped reduce night sweats in some cancer patients.

  In addition, nabiximols (a cannabis extract) spray and THC (taken orally) were found useful in relieving pain in patients with advanced cancer. However, in an observational study, patients (with advanced melanoma, non-small-cell lung cancer, and renal clear cell carcinoma) who used cannabis during immunotherapy had reduced response to the treatment.

  Although some research shows benefits of cannabis, its use remains controversial because of the high risk of addiction, dependence, side effects and withdrawal syndrome. It is also important to note that synthetic cannabinoid drugs cause more serious side effects compared to natural cannabis. Despite the controversy, California became the first state to legalize it for “medical use” in 1996. As of February 2019, it was made available in 33 more states and the District of Columbia (DC) as a medicinal agent, with 11 states and DC also allowing recreational use. Medical cannabis may be used for cancer symptoms, non-cancer pain, glaucoma, AIDS, epilepsy, and multiple sclerosis, but cannabis use remains illegal under federal law.
  Further research is needed to fully understand the health effects of cannabis.

• Purported Uses
  • Pain
    Data from clinical studies show that cannabis helps relieve pain associated with neuropathy, fibromyalgia, and rheumatoid arthritis
  • Glaucoma
    Available data do not support cannabis use for glaucoma because its harmful effects outweigh the benefits in most glaucoma patients
  • Chemotherapy-induced nausea and vomiting
    Studies show that cannabis may help reduce chemotherapy-induced nausea and vomiting that do not respond to standard drugs.
  • Sleep
    Strong evidence is lacking to support cannabis use for sleep disorders
  • Appetite Stimulant
    Strong evidence is lacking to support cannabis use to stimulate appetite
  • Multiple Sclerosis
    Cannabinoids were shown to help reduce spasticity and neuropathic pain in multiple sclerosis patients
  • Spasticity
    Cannabinoids were shown to help reduce spasticity in patients with multiple sclerosis
  • Epilepsy
    Epidiolex, an oral CBD solution, reduced the number of seizures in patients with Lennox-Gastaut syndrome or Dravet syndrome, both rare forms of epilepsy.
  • Cancer treatment
    Cannabis has not been shown to treat cancer, but available data suggest that it may help control pain and night sweats associated with cancer.
• Do Not Take If
  • You have psychiatric, cardiovascular, kidney, or liver illness.
  • You are taking drugs that are substrates of Cytochrome P450 1A2: Smoking cannabis may make them less effective, and more so when smoked together with tobacco.
  • You are taking Immunotherapy drugs (nivolumab): Combined use with cannabis was associated with lowered response to treatment in patients with advanced melanoma, non-small-cell lung cancer, and renal clear cell carcinoma
  • You are taking warfarin: THC and CBD both increase INR levels, and may increase risk of bleeding
  • You are taking fluoxetine: Case reports show mania can occur when taken with cannabis
  • You are taking disulfiram: Delirium and hypomania can occur when taken with cannabis.
  • You are taking amphetamines, cocaine, atropine and sympathomimetic agents: Cardiotoxicity may occur with cannabis.
  • You are taking sedatives or hypnotics: The addition of cannabis can increase sedation.
  • You are taking clobazam: CBD increased clobazam levels in epileptic children, and may increase its side effects.
• Side Effects
  • Short-term side effects with use of medical cannabinoids include dizziness, dry mouth, nausea, fatigue, sleepiness, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination
  • Chronic bronchitis (inflammation of bronchial tubes that carry air to and from lungs) has been reported in regular users of cannabis products compared to non-users
  • Inhalation may cause heart attack, sudden cardiac death, disease of the heart muscle, stroke, transient ischemic attack (a brief stroke-like attack), and cannabis arteritis (inflammation of the lining of arteries)
  • Long-term cannabis use can harm the developing brain
  • Risk of addiction
  • Withdrawal syndrome (includes irritability, sleeping difficulties, dysphoria, craving, and anxiety) after stopping cannabis use
  • Cannabis hyperemesis syndrome (CHS characterized by frequent attacks of nausea and vomiting) in chronic cannabinoid users, has been associated with two deaths. In another case series, four patients were reported to experience relief from CHS following administration of benzodiazepines.
• Scientific Name

  Cannabis sativa

• Clinical Summary

  Cannabis sativa is an annual flowering herb native to East Asia, but is now cultivated around the world. Its uses as a source of industrial fiber, seed oil, and as a recreational agent date back thousands of years across cultures. It has also been employed in traditional medicine as an analgesic, hypnotic, and hallucinogenic, as a sedative, and for reducing inflammation. Preparations containing flowers (marijuana) and leaves; hashish derived from the resinous extract of the plant are consumed orally; by smoking in cigarettes, cigars, pipes, water pipes, or “blunts” (cannabis rolled in the tobacco-leaf wrapper from a cigar); or by vaporizing. Cannabis tinctures, teas, ointments, and oil-based extracts that can be mixed into food products are also popular. It is currently the most widely used illicit agent by more than 147 million people worldwide ⁽¹⁾, and the common route of consumption is via inhalation. Because of the potential for high abuse and dependence, and its classification as a Schedule I agent by the Controlled Substances Act in 1970, cannabis use is a controversial subject in the US.

  Pharmacologic investigations over the last few decades revealed cannabinoids (terpenoids) to be the active constituents. Delta-9-tetrahydrocannabinol (THC) is the chief psychoactive component whereas cannabidiol (CBD) is a major secondary non-psychoactive cannabinoid, and may modulate the effects of THC. It has antipsychotic, anticonvulsive, and anxiolytic effects. When co-administered, CBD was reported to mitigate the adverse psychotropic and cardiovascular effects associated with THC ⁽²⁾.

  Small studies have evaluated cannabis for its utility in treating pain, symptoms of neurological disorders, AIDS and cancer.
  A systematic review of 18 trials (766 subjects) reported significant relief from pain due to neuropathy, fibromyalgia, rheumatoid arthritis, and mixed chronic pain following cannabinoid use compared to placebo. The interventions included smoked cannabis, oromucosal extracts of cannabis-based medicine, synthetic THC agents dronabinol, nabilone (FDA approved), and a novel THC analogue ⁽³⁾. But a 4-year prospective study involving 1,514 patients with chronic non-cancer pain did not find evidence that cannabis use decreased pain severity or interference, or exerted an opioid-sparing effect ⁽⁴⁾.

  In a Cochrane review of four trials involving 48 epileptic patients, short-term CBD use was reported to be well tolerated with no adverse effects, but limited evidence precluded definitive conclusions to be reached on efficacy ⁽⁵⁾. Newer randomized studies of patients with either Lennox-Gastaut syndrome or Dravet syndrome, both rare forms of epilepsy, reported effectiveness of Epidiolex, an oral CBD solution, for reducing the frequency of seizures ⁽⁶⁾. This is now an FDA-approved drug ⁽⁷⁾. Additionally, data indicate benefits of cannabinoids for treating spasticity and neuropathic pain in multiple sclerosis (MS) patients ⁽⁸⁾. The American Academy of Neurology issued a Summary of Systematic Reviews for Clinicians indicating that oral cannabis extract is effective in reducing patient-reported spasticity scores and central pain or painful spasms associated with MS ⁽⁹⁾.

  Conclusions from a large, comprehensive review of 79 trials (6462 subjects) indicate low-quality evidence to address weight gain from HIV infection, sleep disorders, increasing appetite, and for Tourette syndrome, along with elevated risk of short-term adverse effects ⁽¹⁰⁾. The evidence for recommending cannabinoids to treat symptoms of dyskinesia, Parkinson’s and Huntington’s diseases, irritable bowel syndrome, and addiction has been deemed unavailable or insufficient ⁽¹¹⁾.

  In oncologic settings, preclinical findings from 34 studies suggest selective cytotoxic effects of cannabinoids against glioma cells (sparing normal brain cells) via apoptosis, toxicity, autophagy and necrosis ⁽¹²⁾. A single clinical trial of 9 patients with recurrent glioblastoma multiforme receiving chemotherapy did not find any benefit with intratumoral THC, but it was well tolerated ⁽¹³⁾. Data from another randomized study, involving 21 glioblastoma patients, in which oromucosal whole plant extract nabiximols (contains THC +CBD) was used, have yet to be published ⁽¹⁴⁾.

  For symptom management, systematic reviews ^(10) (15) show that patients who used cannabis-based products experienced less chemo-induced nausea and vomiting compared to those on placebo group or on antiemetics. The differences were not statistically significant and adverse effects including “feeling high,” dizziness, sedation, and dysphoria were reported, resulting in a high dropout rate.  Noteworthy are the 2017 American Society of Clinical Oncology (ASCO) guidelines on antiemetics that recommend dronabinol and nabilone for nausea and vomiting, which is resistant to standard therapy ⁽¹⁶⁾.

  Findings on effectiveness of cannabis against cancer pain are encouraging. Data from four trials indicate reductions in pain with orally administered THC and with nabiximols spray in advanced cancer patients ⁽¹⁷⁾. An earlier review concluded the evidence level of cannabinoids for alleviating cancer pain as moderate ⁽¹⁰⁾. Cannabis has also been investigated for its role in ameliorating cancer-related anorexia-cachexia syndrome (CACS), but neither cannabis extract nor THC were found effective in improving symptoms or quality of life in a randomized trial of patients with advanced cancer ⁽¹⁸⁾. Additional case reports suggest that dronabinol may be useful for managing persistent symptomatic paraneoplastic night sweats in cancer patients ⁽¹⁹⁾. In one patient with acute lymphoblastic leukemia, a cannabinoid resin extract was reported to affect dose-dependent disease control ⁽²⁰⁾. However, a retrospective observational study showed that concomitant use of cannabis during immunotherapy with nivolumab was associated with reduction in tumor response rate in patients with advanced melanoma, non-small-cell lung cancer, and renal clear cell carcinoma. Progression-free survival and overall survival remained unaffected ⁽²¹⁾.

  Although some data suggest potential benefits, cannabis remains a contentious issue because non-medical use is associated with high risk of addiction, especially when used from an early age ^(22) (23); dependence ⁽²⁴⁾; adverse effects ⁽²⁵⁾; and with withdrawal syndrome (irritability, sleeping difficulties, dysphoria, craving, and anxiety) ⁽²⁶⁾ that makes cessation tough, eventually leading to relapse.

  In a recent study of patients with cannabis dependence, nabiximols in combination with psychosocial interventions reduced cannabis use ⁽⁵⁸⁾; but an incentive-based intervention was ineffective in individuals with early psychosis and problematic cannabis use ⁽⁵⁹⁾.

  It is also important to note that synthetic cannabinoid drugs cause more serious adverse effects compared to natural cannabis, and include respiratory difficulties, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation and cognitive impairment ⁽²⁷⁾.

  Despite the controversy surrounding cannabis use, California became the first state to legalize it for “medical use” in 1996. As of February 2019, it was made available in 33 more states and the District of Columbia (DC) as a medicinal agent, with 11 states and DC also allowing recreational use. Current indications that qualify for medical cannabis use include cancer symptoms, non-cancer pain, glaucoma, AIDS, epilepsy, and MS. However, cannabis use remains illegal under federal law. Following a review of available scientific evidence, the Institute of Medicine ⁽²⁸⁾, and the National Academies of Sciences, Engineering, and Medicine recommend that further research be done to develop a comprehensive understanding of the health effects of cannabis ⁽¹¹⁾, which can inform medical cannabis policy. Barriers to research include regulatory issues that involve the FDA, Drug Enforcement Administration, National Institute on Drug Abuse, and Institutional Review Boards; procuring cannabis for studies; and methodological challenges of establishing an acceptable route of administration and standardized doses ⁽²⁹⁾.

• Purported Uses
  • Pain
  • Glaucoma
  • Chemo-induced nausea and vomiting
  • Mood Disorders
  • Sleep
  • Appetite stimulant
  • Multiple Sclerosis
  • Spasticity
  • Epilepsy
  • Cancer treatment
• Mechanism of Action

  Cannabinoids are the active constituents that mimic endogenous cannabinoids, and their activity is based on a receptor-mediated mechanism. THC exerts psychoactive and pain-relieving effects by acting as a partial agonist of cannabinoid receptors CB1 (predominantly expressed in the central nervous system) and CB2 (associated with the immune system). CB1 and CB2 are members of the G protein-coupled receptors ⁽³⁰⁾, and are activated through inhibition of adenylate-cyclase. The activation in turn inhibits the release of neurotransmitters acetylcholine and glutamate, while indirectly affecting opioid and serotonin receptors, gamma-aminobutyric acid and N-methly-D-asparate ⁽³¹⁾. The antiemetic effect of nabilone is due to its ability to activate CB receptors in the brain, which mediate nausea and vomiting ⁽³²⁾.

  Mechanisms by which CBD exerts its effects include activation of the serotonin receptor 5-HT_1A ⁽³³⁾; inhibition of reuptake and/or metabolism of anandamide, an endocannabinoid; activation of transient receptor potential vanilloid (TRPV1) channels; inhibition of adenosine reuptake; agonism of PPAR-gamma receptors; by intracellular increase in calcium ions; as well as via anti-oxidative activity ⁽³⁴⁾.

  After inhalation of cannabis, THC is detectable in plasma within seconds, with peak plasma concentration achieved within 3-10 minutes. The bioavailability of THC varies and depends on the depth of inhalation, puff duration, and breath-hold. The systemic bioavailability is estimated to be ∼23-27% for heavy users; and 10-14% for occasional users.
  Following onset of smoking (cigarette containing 15.8 or 33.8 mg THC), the maximum THC plasma concentration (84.3 and 162.2 ng/mL) is attained at about 8 minutes and within 3-4 hours, falls rapidly to 1-4 ng/mL ⁽³⁵⁾.
  When compared to smoking and inhalation, systemic absorption following oral ingestion was slower, with maximum plasma concentration (4.4-11 ng/mL for 20 mg; and 2.7-6.3 ng/mL for 15 mg) of THC attained in 1-2 hours.  Substantial metabolism in the liver, via microsomal hydroxylation and oxidation catalyzed by enzymes of cytochrome P450 complex, likely lowers oral bioavailability of THC by 4-12%.
  Much of the cannabis (80-90%) is excreted within 5 days in the form of hydroxylated and carboxylated metabolites (more than 65% of cannabis is excreted in the feces, with about 20% in urine). It is also important to note that residual THC levels have a half-life of 1.3 days in infrequent users compared to 5-13 days in frequent users ⁽³⁶⁾.

  Data on cannabidiol indicate the half-life to be between 1.4 and 10.9 h following oromucosal spray; 2–5 days following chronic oral administration; 24 h following intravenous administration; and 31 h following smoking. Bioavailability after smoking was 31%, but has yet to be determined with other routes. The maximum concentration is reached much faster following smoking and inhalation compared to oral and oromucosal routes. The Tmax has been reported to be achieved between 0 and 4 h ⁽³⁷⁾.

• Contraindications

  Cannabis products should not be used by patients with psychiatric, cardiovascular, renal, or hepatic illnesses ⁽³⁸⁾.

• Adverse Reactions
  • Short-term adverse effects following use of medical cannabinoids include dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination ⁽¹⁰⁾
  • Chronic bronchitis in regular users of cannabis products compared to non-users ⁽³⁹⁾
  • Inhalation is associated with myocardial infarction, sudden cardiac death, cardiomyopathy, stroke, transient ischemic attack, and cannabis arteritis ⁽⁴⁰⁾
  • Long-term cannabis use was shown to be detrimental to functional connectivity in the developing brain ⁽⁴¹⁾
  • Risk of addiction ^(22) (23)
  • Withdrawal syndrome (irritability, sleeping difficulties, dysphoria, craving, and anxiety) upon cessation ⁽²⁶⁾
  • Cannabis hyperemesis syndrome (CHS), characterized by cyclic attacks of nausea and vomiting in chronic cannabinoid users, has been attributed to two deaths (42). In another case series, four patients were reported to experience relief from CHS following administration of benzodiazepines ⁽⁶⁰⁾.
• Herb-Drug Interactions
  • Cytochrome P450 substrates: Smoking cannabis induces CYP1A2, with additive effects when smoked together with tobacco, and can affect the intracellular concentration of drugs metabolized by this enzyme ⁽⁴³⁾
  • Cytochrome P450 substrates: In vitro, CBD strongly inhibits CYP2C19 ⁽⁴⁴⁾and CYP2C9 ⁽⁴⁵⁾. Clinical relevance is not known.
  • Immunotherapy (nivolumab): Combined use with cannabis was associated with a reduction in treatment response rates in patients with advanced melanoma, non-small-cell lung cancer, and renal clear cell carcinoma (observational study) ^(21) (46)
  • Warfarin: THC and CBD both elevate international normalized ratio (INR) levels ^{(45) (47) (61)}
  • Fluoxetine: Case reports of mania resulting from co-administration of cannabis ⁽⁴⁸⁾
  • Disulfiram: Delirium and hypomania resulting from co-administration with cannabis ^(49) (50)
  • Amphetamines, cocaine, atropine and sympathomimetic agents: Cardiotoxicity may occur with cannabis via additive hypertension and tachycardia ^(51) (52)
  • Sedatives or hypnotics: Sedation and significant pharmacodynamic interactions when taken with cannabis via potentiation of central effects ⁽⁵³⁾
  • P-glycoprotein substrates: CBD inhibits P-glycoprotein and may influence metabolism of certain drugs ⁽⁵⁴⁾. Clinical relevance is not known.
  • Clobazam: CBD increased clobazam levels in epileptic children ⁽⁵⁵⁾
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