Cutting a path through the weeds with cannabis research

Medicinal cannabis

Dr Currien MacDonald, Medical Chair Director at WCG, discusses the challenges and opportunities presented by cannabis research.

The recent interest in cannabinoids as potential sources for medicinal use has been a long time coming. Advances in brain science and modern chemistry are supporting a new generation of investigation into cannabinoids, the active compounds in the cannabis plant. At the same time, the noise around legalisation in some US states focuses on the long history of drug problems and very real concern of addiction. It begs the question, is the attention better placed elsewhere? Is there a path through the weeds of hype and history?

With increasing understanding of the central nervous system’s use of the cannabinoid signaling pathway, the psychoactive substances produced by the cannabis plant could hold potential in areas that are increasingly recognised as unmet needs1. Current areas of attention include post-traumatic stress disorder (PTSD), palliative care, agitation in Alzheimer’s disease, spasticity in multiple sclerosis, inflammatory skin conditions, Tourette syndrome, idiopathic hypersomnia, and potential activation in immunotherapy treatments in oncology2,3. These investigations are being conducted with known cannabinoids. With many other phytocannabinoids existing, we may have barely touched the tip of their potential. In general, data support a therapeutic role for cannabis/cannabinoids in pain, seizure disorders, appetite stimulation, muscle spasticity, neurodegenerative diseases, adjunctive psychiatric treatment for resistant disease, and treatment of nausea/vomiting1.

Research support

Support for researching cannabidiol is expanding. The National Football League (NFL)granted $1M to study cannabis for reduction of concussion severity and pain4. More importantly, cannabis research received additional governmental support for continued investigation at the end of 2022 with H.R.8454, the Medical Marijuana and Cannabidiol Research Expansion Act becoming law. The law includes various provisions, including requiring the Drug Enforcement Administration (DEA) to assess whether there is an adequate and uninterrupted supply of marijuana for research purposes, prohibiting the Department of Health and Human Services (HHS) from reinstating the interdisciplinary review process for marijuana research, and allowing physicians to discuss the potential harms and benefits of marijuana and its derivatives (including cannabidiol) with patients. It also importantly requires HHS and the National Institutes of Health (NIH) to report on the therapeutic potential of marijuana for various conditions such as epilepsy, as well as its impact on adolescent brains and on the ability to operate a motor vehicle5. With an NIH directive, increased research attention is sure to follow. With many medical issues tied to political ones, the government support is a boon. 

The current legal situation with cannabis makes it imperative to conduct high quality research. In some states, cannabis is legal, but physicians are not able to prescribe it. They can provide recommendations, including dose and frequency, but with limited control. Additionally, the actual active dose can be variable depending on the source, further confounding a physician’s ability to provide appropriate treatment recommendations. 

Comparison with the standard of care

But is cannabis better than the standard treatment alternatives? Chronic pain is the most common symptom for which medical cannabis is prescribed, a large unmet need6. A reasonable number of studies into the effectiveness of cannabis for the management of chronic pain exist, but most of them are low or moderate quality due to small sample size, short follow-up periods, and a nonblinded or unrandomised study design7. How much better would it be to have good data showing what effect there is, who best might be served by what recommendation, and most importantly, how to reduce the risks from use? Moreover, with the legalisation of cannabis it can be no surprise that people are not just using the substances for recreation but also to self-medicate those ailments for which modern health care has not provided an adequate solution.

Even after high quality research is done, the US Food and Drug Administration (FDA) review of the data from rigorous clinical trials will be needed to ensure that those products are safe and efficacious for the various therapeutic uses for which they are being proposed. The FDA has received double the number of investigational new drug (IND)/pre-IND applications in the past 10 years, reflecting an increase in new types of cannabis products, and new routes of administration8,9. With such an imperative need, the FDA is committed to encouraging the development of cannabis-related drug products. It has encouraged cannabis-derived and cannabis-related drug teams to contact the relevant Center for Drug Evaluation and Research (CDER) review division and CDER’s Botanical Review Team (BRT) to answer questions related to their specific drug development programme. The BRT serves as an expert resource on botanical issues and has developed the Botanical Drug Development: Guidance for Industry to assist those pursuing drug development in this area. Due to the complexities, the FDA encourages development teams to request a pre-IND meeting to discuss questions related to the development of a specific cannabis-derived and cannabis-related drug product10.

Risk of addiction

One big boogeyman in this area is the idea of addiction being an intolerable significant risk. The risk of addiction is a serious one. However, for any of the indications being studied, there are a number of approved medicinal substances which have serious side effects but are commonly used. There are mechanisms to quantify addiction effects and ascertain whether that risk is appropriate for the level of benefits that go with it. Due to a high potential for abuse from the psychoactive intoxicating effects of tetrahydrocannabinol (THC), parts of the cannabis plant are listed as schedule I (no currently accepted medical use and a high potential for abuse). That is not to say that research on it isn’t worth pursuing. It’s possible to overcome this schedule with sufficient data. For example, a final order moved certain drug products, approved by the FDA, which contain cannabidiol, to schedule V, and dronabinol (which contains a specific amount of a synthetic THC-like compound) to schedule II. At this point, we just have insufficient data.

While there are additional steps to take when conducting research with schedule I drugs, such as having those studies conducted under a site-specific DEA investigator registration, there is also support. The National Institute on Drug Abuse (NIDA) Drug Supply Program provides research-grade marijuana for scientific study. Through registration issued by the DEA, NIDA is responsible for overseeing the cultivation of marijuana for medical research and has contracted with the University of Mississippi to grow marijuana for research at a secure facility. Marijuana of varying potencies and compositions along with marijuana-derived compounds are available. The DEA also may allow additional growers to register to produce and distribute marijuana for research purposes. Additionally, as the result of a recent amendment to federal law, certain forms of cannabis no longer require DEA registration to grow or manufacture.

There is a lot of work to be done before cannabinoids’ full potential can be realised. This research is important because cannabis is currently being used, but without the data and review to support its risks and benefits.

DDW Volume 25 – Issue 2, Spring 2024

References:

  1. Christopher A. Legare, Wesley M. Raup-Konsavage, Kent E. Vrana; Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals. Pharmacology 4 March 2022; 107 (3-4): 131–149.
  2. https://www.delveinsight.com/report-store/medical-marijuana-pipeline-insight Accessed 4 Jan 2024. 
  3. https://www.imperial.ac.uk/department-surgery-cancer/research/surgery/groups/medical-cannabis-research-group/ Accessed 4 Jan 2024.
  4. https://www.nfl.com/playerhealthandsafety/health-and-wellness/pain-management/nfl-awards-1-million-to-study-impact-of-cannabis-and-cbd-on-pain-management. Feb 1, 2022. Accessed 3 Jan 2024.
  5. https://www.congress.gov/bill/117th-congress/house-bill/8454
  6. McDonagh MS, Morasco BJ, Wagner J, Ahmed AY, Fu R, Kansagara D, Chou R “Cannabis-based Products for Chronic Pain: A Systematic Review.” Ann Intern Med. 2022;175(8):1143. Epub 2022 Jun 7.
  7. Whiting PF, et al. “Cannabinoids for medical use: A systematic review and meta-analysis.” JAMA. 2015;313(24):2456.
  8. Taylor CL, Pruyn SA. A U.S. Food and Drug Administration perspective on cannabis research and drug development. Explor Med. 2023;4:813–21. https://doi.org/10.37349/emed.2023.00179
  9. FDA 2023 guidance Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research. 
  10. https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process 2/24/2023. Accessed 4 Jan 2024.

Currien MacDonaldAbout the author:

Currien MacDonald, MD, CIP, is Medical Chair Director at WCG and contributes to biosafety reviews for WCG’s institutional biosafety committee. Prior to joining WCG, Dr. MacDonald served for four years as the Medical Director for Aspire IRB, and Vice Chair of Canadian REB. 

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