Emerging Clinical Applications For Cannabis & Cannabinoids
A Review of the Recent Scientific Literature, 2000 — 2017
Humans have cultivated and consumed the flowering tops of the female cannabis plant, colloquially known as marijuana, since virtually the beginning of recorded history. Cannabis-based textiles dating to 7,000 B.C.E have been recovered in northern China, and the plant's use as a medicinal and mood altering agent date back nearly as far. In 2008, archeologists in Central Asia discovered over two pounds of cannabis in the 2,700-year-old grave of an ancient shaman. After scientists conducted extensive testing on the material's potency, they affirmed, "[T]he most probable conclusion ... is that [ancient] culture[s] cultivated cannabis for pharmaceutical, psychoactive, and divinatory purposes."
Modern cultures continue to indulge in the consumption of cannabis for these same purposes, despite a decades-long, virtual worldwide ban on the plant's cultivation and use. In the United States, federal prohibitions outlawing cannabis' recreational, industrial, and therapeutic use were first imposed by Congress under the Marihuana Tax Act of 1937 and then later reaffirmed by federal lawmakers' decision to classify the cannabis plant -- as well as all of its organic chemical compounds (known as cannabinoids) -- as a Schedule I substance under the Controlled Substances Act of 1970. This classification, which categorizes the plant alongside heroin, defines cannabis and its dozens of distinct cannabinoids as possessing 'a high potential for abuse, ... no currently accepted medical use, ... [and] a lack of accepted safety for the use of the drug ... under medical supervision.' By contrast, cocaine and methamphetamine -- which remain illicit for recreational use but may be consumed under a doctor's supervision -- are classified as Schedule II drugs. Both alcohol and tobacco are unscheduled.
Recent legal and administrative efforts to amend marijuana's scheduling under federal law have been unsuccessful. In July 2011, the Obama Administration rebuffed an eight-year old administrative inquiry seeking to reassess cannabis' Schedule I status, opining: "[T]here are no adequate and well-controlled studies proving (marijuana's) efficacy; the drug is not accepted by qualified experts. ... At this time, the known risks of marijuana use have not been shown to be outweighed by specific benefits in well-controlled clinical trials that scientifically evaluate safety and efficacy."
More recently, in April 2015, a federal judge upheld the constitutionality of cannabis' Schedule I classification in a case argued by members of the NORML Legal Committee. NORML's suit called for cannabis to be removed from the CSA so that states could regulate marijuana policy free from undue federal interference. Following one week of evidentiary hearings, the judge ruled that the federal law ought to remain in place as long as there remains any dispute among experts as to cannabis' safety and efficacy.
Most recently, in 2016, the US Drug Enforcement Administration rejected a pair of administrative petitions that sought to initiate rulemaking proceedings to reschedule marijuana under federal law. The agency opined, "[T]here is no substantial evidence that marijuana should be removed from Schedule I."
To the contrary, there exists ample scientific and empirical evidence to rebut the federal government's contention. Despite the nearly century-long prohibition of the plant, cannabis is nonetheless one of the most investigated therapeutically active substances in history. To date, there are more than 26,000 published studies or reviews in the scientific literature referencing the cannabis plant and its cannabinoids, according to a keyword search on the search engine PubMed Central, the US government repository for peer-reviewed scientific research, with over 1,000 new studies published annually. While much of the renewed interest in cannabinoid therapeutics is a result of the discovery of the endocannabinoid regulatory system (which is described in detail later in this publication), much of this increased attention is also due to the growing body of testimonials from medical cannabis patients and their physicians, as well as from state-level changes to the plant's legal status.
The scientific conclusions of the majority of modern research directly conflicts with the federal government's stance that cannabis is a highly dangerous substance worthy of absolute criminalization. For example, a summary of FDA-approved randomized clinical trials evaluating the safety and efficacy of whole-plant cannabis in various patient populations finds: "Evidence is accumulating that cannabinoids may be useful medicine for certain indications. ... The classification of marijuana as a Schedule I drug as well as the continuing controversy as to whether or not cannabis is of medical value are obstacles to medical progress in this area. Based on evidence currently available the Schedule I classification is not tenable; it is not accurate that cannabis has no medical value, or that information on safety is lacking."
More recently, a 2017 review of over 10,000 recent studies by the National Academies of Sciences, Engineering, and Medicine concluded that "conclusive or substantial evidence" exists in support of the clinical use of cannabis for the treatment of chronic pain and other conditions.
To date, over 140 gold-standard clinical trials exist examining the safety and efficacy of cannabis or individual cannabinoids in some 8,000 patients. By contrast, many FDA-approved drugs are subject to far fewer clinical trials involving far fewer subjects prior to market approval. In fact, according to a 2014 review paper published in the Journal of the American Medical Association, the median number of pivotal trials performed prior to FDA drug approval is two, and over one-third of newly approved pharmaceuticals are brought to market on the basis of only a single pivotal trial.
As clinical research into the therapeutic value of cannabinoids has proliferated so too has investigators' understanding of cannabis' remarkable capacity to combat disease. Whereas researchers in the 1970s, 80s, and 90s primarily assessed marijuana's ability to temporarily alleviate various disease symptoms -- such as the nausea associated with cancer chemotherapy -- scientists today are exploring the potential role of cannabinoids to modulate disease.
For example, scientists are investigating cannabinoids' capacity to moderate autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, as well as their role in the treatment of neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis (a.k.a. Lou Gehrig's disease).
Investigators are also studying the anti-cancer activities of cannabis, as a growing body of preclinical data concludes that cannabinoids can reduce the spread of specific cancer cells via apoptosis (programmed cell death) and by the inhibition of angiogenesis (the formation of new blood vessels).
Researchers are also exploring the use of cannabis as a harm reduction alternative for chronic pain patients. According to the findings of a 2015 study published by the National Bureau of Economic Research, a non-partisan think-tank, "[S]tates permitting medical marijuana dispensaries experience a relative decrease in both opioid addictions and opioid overdose deaths compared to states that do not." The NBER findings are similar to those published in 2014 in the Journal of the American Medical Association (JAMA) Internal Medicine which reported that the enactment of statewide medicinal marijuana laws is associated with significantly lower state-level opioid overdose mortality rates. "States with medical cannabis laws had a 24.8 percent lower mean annual opioid overdose mortality rate compared with states without medical cannabis laws," researchers concluded. Specifically, they determined that overdose deaths from opioids decreased by an average of 20 percent one year after the law's implementation, 25 percent by two years, and up to 33 percent by years five and six. (For a comprehensive summary of relevant studies finding that legal cannabis access is associated with decreases in opioid use, abuse, hospitalization, and mortality, please see NORML's fact-sheet, Relationship Between Marijuana and Opioids.)
Arguably, these recent discoveries represent far broader and more significant applications for cannabinoid therapeutics than many researchers could have imagined some thirty or even twenty years ago.
Cannabinoids possess a remarkable safety record, particularly when compared to conventional prescription drugs. Most significantly, the consumption of marijuana -- regardless of quantity or potency -- cannot induce a fatal overdose. States a World Health Organization review paper, "There are no recorded cases of overdose fatalities attributed to cannabis, and the estimated lethal dose for humans extrapolated from animal studies is so high that it cannot be achieved by ... users."
The use of cannabis for therapeutic purposes is also rarely associated with significant adverse side effects. A prominent review of clinical trial data "did not find a higher incidence rate of serious adverse events associated with medical cannabinoid use" compared to non-using controls over a four decade period. A more recent review of the relevant literature concludes that among the average adult user, the health risks associated with marijuana "are no more likely to be dangerous" than many other behaviors or activities, including the consumption of acetaminophen (the pain relieving ingredient in Tylenol).
That said, cannabis should not be viewed as a 'harmless' substance. Its active constituents may produce a variety of physiological and mood-altering effects. As a result, there may be some populations that may be vulnerable to increased risks from the use of cannabis, such as adolescents, pregnant or nursing mothers, and patients who have a family history of psychiatric illness or who possess a clinical high risk for developing a psychotic disorder. Patients with a history of cardiovascular disorders, heart disease or stroke may also be at an elevated risk of experiencing adverse side effects from marijuana, particularly smoked cannabis. As with any medication, patients should consult thoroughly with their physician before deciding whether the medical use of cannabis is safe and appropriate.
As states continue to approve legislation enabling the physician-supervised use of medical marijuana, more patients with varying disease types are exploring the use of therapeutic cannabis. Many of these patients and their physicians are now discussing this issue for the first time and are seeking guidance on whether the therapeutic use of cannabis may or may not be advisable. This report seeks to provide this guidance by highlighting some of the more relevant, recently published scientific research (2000-2017) on the therapeutic potential of cannabis and cannabinoids for a variety of clinical indications.
In some of these cases, modern science is now affirming longtime anecdotal reports of medical cannabis users (e.g., the use of cannabis to alleviate GI disorders). In other cases, this research is highlighting entirely new potential clinical utilities for cannabinoids (e.g., the use of cannabinoids to modify the progression of diabetes).
For patients and their physicians, this report can serve as a primer for those who are considering using or recommending medical cannabis. For others, this report can serve as an introduction to the broad range of emerging clinical applications for cannabis and its various compounds.
NORML | NORML Foundation
November 20, 2017
* The author would like to acknowledge Drs. Dale Gieringer, Estelle Goldstein, Dustin Sulak, Gregory Carter, Steven Karch, and Mitch Earleywine, as well as Bernard Ellis, MPH, former NORML interns John Lucy, Christopher Rasmussen, and Rita Bowles, for providing research assistance for this report. The NORML Foundation would also like to acknowledge Dale Gieringer, Paul Kuhn, and Richard Wolfe for their financial contributions toward the publication of this report.
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