Greater focus on clinical development can drive potential of cannabinoid medicine

Over the past few years, products based on CBD and medical marijuana have become widely available and accepted as treatments for various ailments.

However, despite their increase in popularity and legislative changes making access to these products much simpler, the science behind these treatments is lesser discussed and understood by consumers and health care practitioners.

Cannabinoids are natural or synthetic chemicals related to those produced by the cannabis plant (Pertwee R). Of the more than 120 known cannabinoids, only a small number are present in quantities easily characterized, such as THC and CBD (Morales P, et al; Ligresti A, et al). Few are associated with the euphoric “high” linked with cannabis use, including THC and cannabinol, which is brought about through activation of the CB1 receptor (Morales P, et al). The extent of the euphoric effects of these specific cannabinoids depends on the dose and route of administration (Huestis MA; Spindle TR, et al).

CBD, on the other hand, works at multiple receptor targets. While research has yet to determine which receptors are the most clinically relevant, CBD is believed to act mainly at targets outside the endocannabinoid system. What we do know is that CBD does not activate cannabinoid CB1 receptors and is not associated with euphoric effects, which may be an important factor for further investigation into its potential therapeutic effects.

Pharmaceutical-grade vs. unregulated products

Extracted from specific varieties of cannabis, there are a multitude of CBD oil products and other cannabis and hemp extracts readily available at dispensaries in many states or online. However, it is important to note that these unregulated products are not the same quality as purified pharmaceutical-grade formulation of CBD.

According to the Clean Label Project, more than 30% of unregulated products mislabeled CBD amounts by a notable level, and some products that claimed to contain CBD had absolutely no traces of CBD at all. Furthermore, unregulated CBD products can pose health risks to patients, as additional studies found that some CBD products contained heavy metals or pesticides, both of which are screened for and removed from pharmaceutical-grade formulations.

On the other hand, pharmaceutical-grade CBD studied as a treatment for certain medical conditions must undergo a robust scientific process, regulated by the FDA to protect patient safety and ensure product efficacy. Since the amount of CBD taken impacts clinical response and side effects, it is important that CBD products are regulated to ensure consistency and quality, so consumers and their physicians know exactly what is included in the product every time.

The value of evidence-based medicine

As the understanding of cannabinoids continues to grow, so, too, does the need for additional, high-quality evidence for their use as disease- and symptom-modifying treatments. Clinical evidence should be at the heart of how cannabinoids are used, to ensure they are effective and well-tolerated (Royal College of Psychiatrists, National Institute for Health and Care Excellence and Faculty of Pain Medicine).

Studies in animals have shown cannabinoids have therapeutic potential for a number of conditions (Ligresti A, et al), but few of these potential therapeutic benefits have been tested thoroughly in humans, and there is only limited high-quality evidence from advanced clinical trials (Royal College of Psychiatrists; Black N, et al; Pratt M, et al).

The value of evidence-based medicine cannot be overstated when it comes to cannabinoids. Medicines evaluated and approved by the FDA provide physicians with the security of knowing they can prescribe a treatment that has been rigorously studied and is backed by robust clinical evidence validating its safety and effectiveness.

Regulatory standards, approvals

FDA approval is a positive change to the cannabinoid landscape in the U.S. FDA-approved products are required to meet purification, content and dosing standards. They are rigorously tested in controlled clinical trials to understand the safety profile and efficacy, meet evidentiary standards for quality and stability and contain consistent concentrations of medicine across every batch. Therefore, establishing a regulatory review pathway and requiring FDA-approved cannabinoids to meet certain safety, efficacy and quality standards has permitted the safe and effective use of CBD as a medical treatment.

To date, the FDA has approved one cannabis-derived drug product, which contains a highly-purified form of CBD, for the treatment of seizures associated with LennoxGastaut syndrome, Dravet syndrome or tuberous sclerosis complex, and three synthetic cannabis-related drugs for nausea associated with cancer chemotherapy.

According to the FDA, one of the keys to advancing research and development lies in increasing our limited understanding of the safety profile of CBD and many other cannabis-derived compounds, including clear answers to questions around adverse events associated with CBD products and risks associated with long-term use. Better data in these areas will be needed for the FDA to make more informed decisions — backed by science —that could impact the health and safety of patients. The FDA also points to real-world data on CBD use and safety as having “a crucial role alongside data from other types of studies to fill in the current gaps in our understanding.”

Public interest in the use of cannabis-based therapies to manage symptoms of a diverse range of conditions — from chemotherapy-related nausea and appetite stimulation in HIV/AIDS to neurological disorders such as epilepsy, depression, anxiety, sleep disorders and more — is incredibly high. With an evolving landscape and greater focus on clinical development, the scientific community is finally moving closer to realizing the full potential of cannabinoid medicine and what it could mean for patients.

References:

• Better data for a better understanding of the use and safety profile of cannabidiol (CBD) products. https://www.fda.gov/news-events/fda-voices/better-data-better-understanding-use-and-safety-profile-cannabidiol-cbd-products. Published Jan. 8, 2021. Accessed March 2023.
• Black N, et al. Lancet Psychiatry. 2019;doi:10.1016/S2215-0366(19)30401-8.
• Cannabis-based medicinal products: NICE guideline. https://www.nice.org.uk/guidance/ng144. Published Nov. 11, 2019. Accessed March 2023.
• Clean Label Project CBD study results 2019. https://cleanlabelproject.org/wp-content/uploads/CBD-011.jpg. Accessed March 2023.
• Faculty position statement on the medicinal use of cannabinoids in pain medicine. https://fpm.ac.uk/sites/fpm/files/documents/2019-12/FPM-Cannabis-statement-2019-final_0.pdf. Accessed March 2023.
• FDA and cannabis: research and drug approval process. https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process. Published Feb. 24, 2023. Accessed March 2023.
• Huestis MA. Chem Biodivers. 2007;doi:10.1002/cbdv.200790152.
• Ligresti A, et al. Physiol Rev. 2016;doi:10.1152/physrev.00002.2016.
• Morales P, et al. Prog Chem Org Nat Prod. 2017;doi:10.1007/978-3-319-45541-9_4.
• Pertwee R (ed.). Handbook of Cannabis. Oxford University Press. 2014.
• Position statement PS05/19: Cannabis-based medicinal products. https://www.rcpsych.ac.uk/docs/default-source/improving-care/better-mh-policy/position-statements/ps05_19.pdf?sfvrsn=2db968d3_2. Published November 2019. Accessed March 2023.
• Pratt M, et al. Syst Rev. 2019;doi:10.1186/s13643-019-1243-x.
• Spindle TR, et al. JAMA Netw Open. 2018;doi:10.1001/jamanetworkopen.2018.4841.

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Farhad Sahebkar, MD, is executive medical director of research and development at Jazz Pharmaceuticals.