“You can’t get at the truth by writing history.”
— Oxford History of Europe. In The Times Literary Supplement, November 28, 1986
The cannabis plant has been used for centuries by different ancient cultures as a remedy.1 Cannabis was introduced to Europe by Napoléon Bonaparte in 1799. In 1843, O’Shaughnessy2 published the first report on the use of Cannabis indica for multiple medical conditions, including catalepsy, rabies, cholera, tetanus, infantile convulsions, and delirium tremens. Queen Victoria may have used marijuana to treat her dysmenorrhea.3
The genus cannabis encompasses 3 species (Cannabis sativa, Cannabis indica, and Cannabis ruderalis) that vary widely in size and the cannabinoid content. Approximately 537 natural compounds, including 109 cannabinoids, have been identified in the cannabis plant.4 The primary psychoactive cannabinoid of marijuana, delta-9-tetrahydrocannabinol (Δ9-THC),5,6 acts as an agonist on the cannabinoid type 1 (CB1) receptors in the central nervous system (CNS).7 The other biologically active chemicals in marijuana have not been fully characterized. Marijuana is a crude preparation that mainly contains the dried buds of C sativa. Cannabis potency (the content of Δ9-THC) varies greatly with the strain, but it has increased approximately 30-fold since the 1970s through expert cultivation.8
The cannabinoid receptor family currently includes 2 cloned metabotropic receptors: CB1 (found predominantly in the brain)9 and CB2 (found primarily in the peripheral immune system10 and to a lesser degree in the CNS11 and microglia12). With the exception of a small population of neurons located in the brainstem and the cerebellum, healthy brain tissue does not express CB2 receptors.11 Rather, CB2 receptors are upregulated in reactive microglial cells in the CNS in neuroinflammatory disorders.13–15 Both cannabinoid receptors belong to the G-protein–coupled receptor superfamily coupled to Gi/o proteins and, under specific conditions, also to Gq/11. In addition to the 2 cannabinoid receptors, the endocannabinoid signaling system in the CNS includes 2 endogenous ligands (anandamide and 2-arachidonoglycerol), 2 enzymes responsible for synthesizing endogenous ligands (1,2-diacylglycerol lipase and phospholipase A), and 2 enzymes responsible for metabolism of endogenous ligands (fatty acid amide hydrolase and monoglyceride lipase). Anandamide and 2-arachidonoglycerol are arachidonic acid derivatives synthesized in the postsynaptic neuron. These endocannabinoids activate presynaptic CB1 receptors, inhibiting neurotransmitter release from the presynaptic neurons.16
Marijuana is currently classified as a schedule 1 substance in the United States, signifying “no accepted medicinal use.” This places marijuana in the same category as heroin and lysergic acid diethylamide. This classification was motivated by politics, not science. It was initially orchestrated by Harry Anslinger, the director of the Federal Bureau of Narcotics from 1931 to 1962. Despite the ongoing war on drugs, marijuana continues to be the most widely used illicit substance in the United States.17 The dawn of its legalization is breaking over the horizon. Twenty-three states currently have laws legalizing the medical use of marijuana, and 4 states (Alaska, Colorado, Oregon, and Washington) and the District of Columbia have legalized marijuana for both medical and recreational use. In 2002, the Ninth Circuit Court of Appeals affirmed, in Conant v. Walters, the right of physicians to recommend medical marijuana, regardless of its illegality under federal law, as well as the right of patients to receive accurate information. In May 2015, the U.S. Senate Appropriations Committee, in an unprecedented vote, allowed Veterans Administration physicians to recommend medical marijuana to their patients in states where medical marijuana is legal.
Anecdotal reports claim the efficacy of marijuana in medical conditions, including anorexia, neuropathic pain, spasticity, posttraumatic stress disorder, migraine, glaucoma as well as nausea and vomiting. In many instances, the evidence supporting its use in no better than that reported by O’Shaughnessy in 1843.2 Given the many claims of efficacy, and the frequently weak evidence for efficacy, is anecdotal evidence enough to support the use of marijuana as a medicine?
Several pharmaceutical drugs based on natural cannabis or synthetic cannabinoid compounds have been developed. Synthetic Δ9-THC in sesame oil (dronabinol, Marinol [Solvay Pharmaceuticals, Inc. Company, Marietta, GA]) was first licensed and approved in 1986 for the treatment of chemotherapy-induced nausea and vomiting. The neurocircuitry involved in nausea and vomiting includes the area postrema, the nucleus of the solitary tract, and the dorsal motor nucleus of the vagus.18,19 Cerebral, vestibular, area postrema, and gut afferent inputs for nausea and vomiting converge on the nucleus of the solitary tract in the caudal hindbrain.18 The area postrema and the nucleus of the solitary tract are relatively poor in CB1 receptor expression.20 Thus, there is little evidence to understand the mechanism by which a CB1 agonist might affect postoperative nausea and vomiting (PONV).
In this issue of Anesthesia & Analgesia, Kleine-Brueggeney et al.21 report, in a prospective, double-blind, randomized, placebo-controlled trial, that IV administration of Δ9-THC was not effective as an antiemetic in patients at high risk of PONV. Moreover, Δ9-THC was associated with substantial psychotropic side effects, prompting early termination of the study.
Previous studies on the efficacy of Δ9-THC in treating PONV were not optimal in design and unconvincing. In one report, the effects of 2 mg preoperative oral nabilone, a synthetic Δ9-THC, and oral metoclopramide on PONV were compared in a prospective, double-blind study in patients undergoing total abdominal hysterectomy. The incidence of PONV was found to be similar between the 2 groups.22 In another retrospective study, the authors reported that the preoperative treatment with 5 mg oral dronabinol and 25 mg rectal prochlorperazine significantly reduced the incidence of PONV.23 The doses of Δ9-THC used in the aforementioned studies seem to have been chosen arbitrarily because dose–response studies for Δ9-THC are lacking. In addition, the pharmacokinetics and bioavailability of Δ9-THC vary considerably in humans and depend on whether it is inhaled, injected, or swallowed. For example, when compared with oral administration, peak plasma levels of Δ9-THC after smoking marijuana occur more rapidly, and the bioavailability is substantially greater (18%–50% vs 6%–20%).24–26 To achieve constant bioavailability, Kleine-Brueggeney et al.21 administered Δ9-THC IV. However, the authors studied only one dose of Δ9-THC (0.125 mg/kg with a maximum of 10 mg), a dose chosen to target a maximum effect. It would have been more informative if the authors had established a dose–response relationship and included a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist in another group of patients who would have served as a positive control. This, of course, would have made the size and execution of the study significantly more challenging.
To understand the results of Kleine-Brueggeney et al.,21 we need to examine the evidence around the efficacy of Δ9-THC in treating nausea and vomiting. Several cannabinoids have been tested for the prevention of chemotherapy-induced nausea and vomiting. The emetogenic potential of antineoplastic drugs varies according to the drug used, ranging from cisplatin, which induces severe emesis in virtually all patients, to bleomycin, which seldom causes even minimal emesis.27,28 In one study, Δ9-THC was found to be superior to a placebo in patients receiving methotrexate, an agent of low intrinsic emetogenicity.29 In a systematic review of 30 randomized controlled trials, the effectiveness of cannabinoids (oral nabilone, oral dronabinol, and IM levonantradol) in chemotherapy-induced nausea and vomiting was evaluated in 1366 patients.30 Cannabinoids were found to be more effective antiemetics than prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, or alizapride in a medium emetogenic setting. However, cannabinoids did not show any efficacy in highly emetogenic chemotherapy settings.30 There were, however, no comparisons of cannabinoids with 5-HT3 receptor antagonists, the best comparator for the prevention of acute emesis in highly emetogenic chemotherapy settings. Patients given cannabinoids were more likely to withdraw because of side effects. Five percent of patients had paranoia, 6% had hallucinations, and approximately 13% had dysphoria or depression.30 This high incidence of psychotropic side effects casts great doubt on the ability of patients to report their experience. Furthermore, in this systematic review, the authors analyzed the incidence of complete control of nausea or vomiting only in the first 24 hours,30 although delayed nausea and vomiting are more likely to occur after chemotherapy.31 Therefore, relevance of their findings should be interpreted within these limitations.
A small pilot, randomized, double-blind, placebo-controlled phase II trial was conducted to investigate the whole-plant cannabis-based medicine containing Δ9-THC and cannabidiol (nabiximols, Sativex® [GW Pharmaceuticals PLC., Cambridge, UK]) added to standard antiemetics for the treatment of chemotherapy-induced nausea and vomiting.32 The overall observation included early (0–24 hours) and delayed (24–120 hours) phase periods. This study included a heterogeneous population in terms of type of cancer and the chemotherapeutic agents used. Seven patients were randomized to receive nabiximols and 9 received placebo. Complete response was noted in 5 of the 7 in the nabiximols group compared with 2 of the 9 in the placebo group. The incidence of adverse effects was higher in the nabiximols group (86% vs 67%) and 1 patient in the latter group was withdrawn because of adverse effects.
A recent meta-analysis of 28 randomized controlled trials examined the effectiveness of different cannabinoids, including Δ9-THC in chemotherapy-induced nausea and vomiting in 1772 patients. The risk of bias was found to be high for 23 or unclear for 5 studies.33 The authors concluded that the evidence suggesting the efficacy of cannabinoids in this setting was of a low quality.33
It is clear that antiemetic studies with cannabinoids have methodological difficulties and are inconclusive, and the evidence of efficacy is limited. In addition, the psychoactive effects of Δ9-THC represent a major challenge to blinding. At present, a more effective treatment is a combination of an oral 5-HT3 receptor antagonist with dexamethasone given during surgery or before chemotherapy.34,35 In addition, the high rates of side effects caused by cannabinoids including sedation, hallucinations, and mood change cast doubt on its clinical utility.
Cannabinoids have failed to support other claims of efficacy.33 For example, nabiximols when used as adjunctive treatment to optimize chronic opioid therapy in cancer pain did not meet the primary endpoint of demonstrating a statistically significant difference from placebo.a Nabiximols also failed when used in combination with an existing treatment regimen in ameliorating neuropathic pain in patients with multiple sclerosis.36
In 1992, the Food and Drug Administration approved dronabinol as an appetite stimulant for the treatment of acquired immune deficiency syndrome (AIDS)-related weight loss. Nevertheless, the evidence for the efficacy and safety of cannabis and cannabinoids as an appetite stimulant in patients with human immunodeficiency virus/AIDS is lacking.33,37 In contrast, the use of megestrol acetate, a synthetic derivative of progesterone that can stimulate appetite, resulted in substantial weight gain when given to patients with AIDS and was more effective than dronabinol in stimulating weight gain.38
Every study since O’Shaughnessy’s initial report has documented a high incidence (so to speak) of psychotropic effects. These range from excitement to sedation (even to the point of “cataleptic stupor”), disinhibition, and disorientation. Although a few patients may report some of these effects as acceptable to achieve relief of their symptoms, most patients have reported them as undesirable. In the current study, they were an important factor in the early cessation of the trial.
The legalization of medical marijuana, supported by ongoing anecdotal evidence widely reported on the Internet, and the support of patient advocacy groups continue to expand. However, making marijuana legal does not make it effective. Physicians, especially anesthesiologists involved in the management of pain and the side effects of analgesics, will be queried by our patients whether marijuana is right for them. We may be asked to provide prescriptions for medical marijuana. Even O’Shaughnessy concluded his article with the statement on his findings that “…be it true or false, I deem it my duty to publish it without any avoidable delay, in order that the most extensive and the speediest trial may be given to the proposed remedy.”
More than a century and a half after O’Shaughnessy’s report, we still have not documented the efficacy of marijuana for any medical indication other than as a transient treatment for sobriety.
Name: Mohamed Naguib, MB, BCh, MSc, FCARCSI, MD.
Contribution: This author helped write the manuscript.
Attestation: Mohamed Naguib has reviewed and approved the final manuscript.
Conflict of interest: Mohamed Naguib is named on several patents/patent applications submitted by the University of Texas MD Anderson Cancer Center and Cleveland Clinic that relate to CB2 modulators.
Name: Joseph F. Foss, MD.
Contribution: This author helped write the manuscript.
Attestation: Joseph F. Foss has reviewed and approved the final manuscript.
Conflict of interest: Joseph F. Foss is named on a patent application submitted by Cleveland Clinic that relates to a CB2 modulator.
a GW Pharmaceuticals and Otsuka announce results in first of three Sativex Phase 3 Cancer Pain Trials, January 8, 2015. Available at: http://www.gwpharm.com/GW%20Pharmaceuticals%20and%20Otsuka%20Announce%20Results%20in%20First%20of%20Three%20Sativex%20Phase%203%20Cancer%20Pain%20Trials.aspx. Accessed June 26, 2015.
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