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Clinical Research on Cannabis

Author: Sterling Scott and Brent Cahill

Scope of Active Research

Research organizations worldwide are engaged actively in the study of specific cannabinoids, combinations of cannabinoids, and delivery systems for controlled dosing of cannabinoids. As this article is being written, there are nearly 200 worldwide clinical trials underway focusing on cannabinoids. For every clinical trial, there are typically ten or more pre-clinical investigational studies underway in Universities and in public and private companies.

Conservatively estimated, including formally registered clinical trials and counting the number of pre-clinical trials, it is likely that more than 1000 studies are currently underway focusing on specific cannabinoids, combinations of cannabinoids, and delivery systems for cannabinoids.

It is unlikely that there has ever been a time when more research has been dedicated to unraveling the complexity of cannabis flowers and the estimated 108 different cannabinoid compounds, 66 terpenoids, and 23 flavonoids. 

Current active research focuses mainly on Cannabidiol (CBD) and -9-Tetrahydrocannabinol (THC), although research is also being conducted on other cannabinoids including 9-Tetrahydrocannabivarin (THCV), Tetrahydrocannabinolic acid (THCa), and Cannabidivarin (CBDV) as treatments for cancer, chronic pain management, epilepsy, and PTSD, among others. In addition, there are both current and completed clinical trials evaluating the efficacy of flavonoids such as apigenin, beta-caryophyllene, quercetin, beta-sitosterol, for conditions ranging from insomnia and hypercholesterolemia to cancer and anemia.

Some speculate that cannabis compounds delivered in a controlled-dose, time-delayed method as a clinically validated therapeutic medicine would be revolutionary and lead to a broader recognition of complex botanical medicines. That is uncertain. We do know that early findings are confirming demonstrable therapeutic benefits to cannabinoids.

Early Findings of Demonstrated Therapeutic Benefits of Cannabis

Cannabinoids, dosed in double-blind, randomized clinical testing (in some cases, utilizing synthetic cannabinoids) have, in fact, demonstrated quantifiable therapeutic benefits for certain common relatively common human conditions, such as treatment of chronic pain, insomnia, anxiety, as well as for much more specific identifiable disorders, such as PTSD. This article describes the validated therapeutic benefits and the clinical findings on which the findings are based.

Treatment of Chronic Pain in Adults

Clinical trials have demonstrated that “cannabis is an effective treatment for chronic pain in adults,” according to the National Academies of Sciences, Engineering, and Medicine. This finding, regarded as “substantial evidence,” is perhaps the most critical research-based conclusion of this past decade involving cannabis. 

Chronic pain is a recurring issue for an estimated 30% of the adult population in the United States and likely a similarly large portion of communities worldwide. Age is a factor because chronic pain conditions typically present with increasing severity and frequency as the population ages.

The most comprehensive published review of cannabinoid use in the treatment of chronic pain is Whiting et al. (2015) (involving a review of 28 randomized studies, 2,454 participants, and a wide range of chronic pain sources). Other reviews of particular note summarized by the National Academies in their seminal 2017 publication include Andreae et al. (2015), Wallace et al., 2015 and Wilsey et al. 2016.

Regulatory authorities in many countries already expressly recognize cannabinoids for the treatment of chronic pain in adults. In Canada, although “it does not currently have an approved Health Canada indication,” the government acknowledges that “medical cannabis may be used to alleviate symptoms for a variety of conditions. It has most commonly been used in neuropathic pain and other chronic pain conditions.” In Mexico, a 2017 congressional decree declared that “pharmacological derivatives of sativa, indica, and American cannabis or marijuana, among which is tetrahydrocannabinol, its isomers, and stereochemical variants” were legal for medical use, although those derivatives had to contain less than 1% THC at the time of writing. In 2013, Uruguay became the first country to legalize the recreational use, sale, and cultivation of Cannabis, and direct-to-consumer sales via pharmacies began in mid-2017. Unfortunately, these strains of cannabis also contained relatively low THC, and therefore, medical research is slow. Colombia has quickly become a significant player in the international medical cannabis market, with companies exporting to Canada and the UK after legalization in 2016. Germany has begun a rapid increase in medical cannabis import in the past quarter, indicating a surging demand and rapid adoption of the treatment.

Most of the state-regulated medical cannabis programs in the United States allow it to be prescribed for the treatment of chronic pain in adults. The U.S. Food and Drug Administration (“FDA’) has approved the use of the synthetic cannabinoids dronabinol and nabilone to treat nausea during chemotherapy, as well as the cannabidiol-based Epidiolex for the treatment of seizures resulting from Lennox-Gastaut and Dravet syndromes, two severe forms of epilepsy. It has not, however, identified any medical uses of the cannabis flower in and of itself. 32 Individual states have expressly defined chronic or other pain, either on its own or as a result of another illness as a qualifying condition for the prescription of cannabis. These states are Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Iowa, Maryland, Michigan, Minnesota, Missouri, Montana, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Dakota, Ohio, Oregon, Pennsylvania, Rhode Island, South Carolina, Utah, Vermont, Washington, and West Virginia. It is important to note that laws vary widely throughout these states on exactly how the medicine can be consumed, and at what potency of THC.

Cannabis products for the treatment of chronic pain in adults are widely predicted to increase substantially over the next decade, as is research to evaluate dose-response, delivery methods, and combinations of cannabinoids and side effects.

Improving Short-term Sleep Outcomes

Clinical trials also support, with moderate but not conclusive evidence, that cannabinoids are “an effective treatment to improve short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis.” Like chronic pain conditions, sleep-related disorders are pervasive and affect a large cross-segment of the population. Approximately 50-70 million adults in the US report some type of sleep disorder.

The most comprehensive published review of cannabinoids and sleep outcomes is Whiting et al. (2015).

Decreasing Anxiety Symptoms

Clinical trials also provide “limited evidence that cannabidiol is an effective treatment for the improvement of anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders.”

Cannabidiol, which is frequently referred to as “CBD,” is one of the significant cannabinoids typically present in hemp species and “marijuana” types of the Cannabis sativa species. CBD, of course, has received particularly widespread attention in most of the western world, after many countries have acted to remove cannabidiol from controlled substances lists, thereby encouraging both research and worldwide commerce.

Ongoing research is particularly intensive with cannabidiol. Whiting et al. (2015) provide what is generally regarded as the first clinical review of randomized clinical trials in which Cannabidiol has been assessed to improve anxiety symptoms.

Improving symptoms in Posttraumatic Stress Disorder (“PTSD”).

There is “limited evidence (a single, small fair-quality trial) that nabilone is effective for improving symptoms of posttraumatic stress disorder.”

PTSD is commonly understood to be a disorder arising from exposure to a traumatic event(s), especially within groups that are subjected to extreme stress environments, such as military combat veterans. Medications to treat PTSD are generally limited to antidepressants and demonstrate very low effective response rates.

It is likely that recently completed clinical trial programs will further our understanding relatively quickly as the medical community is closely anticipating publication of results from two recently completed clinical trial programs at the same time as there are additional 5 studies of cannabinoids and PTSD symptoms.

In one such recently completed study, a triple-blind, crossover, placebo-controlled trial investigates smoking four different types of cannabis with various tetrahydrocannabinol and cannabidiol concentrations on PTSD symptoms in veterans (M. Bonn-Miller, study director; ClinicalTrials.gov: NCT02759185). The study, funded by the Colorado Department of Public Health and Environment, was registered as completed in April 2019.

In another prominent randomized controlled trial, the University of British Columbia (Eades et al, study director; ClinicalTrials.gov: NCT02517424) is evaluating 42 adults with PTSD administered different amounts of two most common cannabinoids, tetrahydrocannabinol and cannabidiol (in high–low, high–high, and low–low dose forms) to measure PTSD symptoms as well as other health assessments.

The Path Forward

It is almost certain that clinical investigations of cannabis compounds through all phases of the process of drug review for cannabinoids will continue to increase in scale and funding worldwide over the next decade. Importantly, some of the artificial clinical have been lowered in the face of strong public and academic interest. Recently, even the US FDA, arguably one of the gold standards for strict science and investigational research, has provided a mid-summer 2019 consumer update to indicate that it is considering regulatory reforms that may allow the use of certain cannabinoids like cannabidiol (CBD) in dietary supplement and/or nutrition supplement forms in advance of full drug approvals.

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