The cannabis industry is a booming economic force across the nation as states increasingly legalize the sale of medical and/or recreational marijuana. It remains on the national Schedule I list of drugs that are not acceptable for legal sale.
But what do healthcare providers really understand about the drug’s safety, risks, and benefits? Not enough, human research protection professionals say.
“Cannabis research is important, but its legal status impedes that research,” said Amanda Higley, PhD, CIP, IRB chair for Advarra in Seattle. Higley spoke about cannabis research at a recent teleconference.
“This is a pivotal time in the world,” she said. “We’re addressing research gaps and quality.”
While there is a need for clinical trials to assess safety and treatment use of cannabis, such research is hindered by the federal government listing it as an illegal drug, Higley said. The FDA recognizes the pressing need to conduct research about circumstances for which cannabis might be used as a medication, she added.
Without ample cannabis clinical trials, healthcare practitioners and the public rely on anecdotal, weak evidence, or studies with indirect ways of obtaining evidence. For example, a recently published review of cases involving marijuana and violence combined information from news media accounts, journal articles, and anecdotal clinical experience. The study makes the case that people with pre-existing medical conditions use marijuana to alleviate their symptoms although it can worsen their conditions over time. It also discusses the link between aggression and the use and potency of tetrahydrocannabinol (THC). (The study is available at: https://www.mdpi.com/1660-4601/17/5/1578.)
“I got cases from the internet and different news organizations. The scientific discussion and rationale mostly came from journal articles, and putting it together came from my clinical experience,” said Norman S. Miller, MD, JD, chief executive officer of Health Advocates in East Lansing, MI. “Good research should be done to show what marijuana is and what it is not.”
The FDA has not approved cannabis to be marketed for treatment of any disease or condition. But it has approved Epidiolex (cannabidiol) and three synthetic cannabis-related products (Marinol, Syndros, and Cesamet). These are available only through prescriptions. (For more information, visit: https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process.)
Although marijuana is a Schedule I drug that has no currently accepted medical use in treatment in the United States, researchers and sponsors can submit an investigational new drug application to the FDA for a clinical trial. They also must register with the Drug Enforcement Administration.
The FDA supports researchers who intend to study cannabis by providing information on the clinical research process and support through meetings and information from the FDA Center for Drug Evaluation and Research (CDER) Small Business and Industry Assistance group, according to testimony given Jan. 15, by Douglas Throckmorton, MD, deputy director for regulatory programs — CDER, before the U.S. House Committee on Energy and Commerce, Subcommittee on Health. (The testimony is available at: https://www.fda.gov/news-events/congressional-testimony/cannabis-policies-new-decade-01152020.)
Of the four drugs containing marijuana derivatives that were approved by FDA for treatment, there is reasonable evidence for efficacy in treating neuromuscular disorders, sleep disorders, and Tourette syndrome. There is not good evidence for efficacy in treating depression, anxiety, psychosis, and glaucoma, Higley said. “The studies to date have a number of limitations,” she said.
For instance, there are design elements that are important for IRBs to consider when reviewing these protocols. “A cannabis protocol should include as much information as possible about the chemical agent,” Higley explained.
Studies involving marijuana should include plant characteristics, including species, variety, strain, how it is harvested, how much of the plant is used, extraction methodology, and concentrations of relevant chemicals. “We believe if sponsors of principal investigators fail to provide this information, then it is within the purview of the IRB to require it,” Higley said.
IRBs also should ensure investigators list all potential risks in informed consent documents for studies of marijuana or any of its derivatives, including cannabidiol (CBD) products.
“There also are many unanswered questions about the science, safety, and quality of products containing CBD,” Throckmorton told Congress. “The agency is working on answering these questions through ongoing efforts, including feedback from a recent FDA hearing and information and data-gathering through a public docket.”
Throckmorton listed these potential risks associated with using CBD products:
• Liver damage. “We are concerned about potential liver injury associated with CBD use that could go undetected if not monitored by a healthcare provider,” Throckmorton testified.
• Drug interactions. Drug interactions were seen in CBD studies. For example, Epidiolex studies show a risk of CBD affecting a patient’s other medicines.
• Male reproductive toxicity. Laboratory animal studies show male reproductive toxicity, including a decrease in testicular size, inhibition of sperm growth and development, and decreased circulating testosterone, Throckmorton said.
When IRBs review studies involving THC-containing products, they should be aware of the risk that a research participant might drive under the influence.
IRBs also might ask questions about any placebo-controlled design, Higley noted. “Cannabis studies can show a high response rate in a placebo group,” she said. “The pros and cons of providing a placebo group should be evaluated.”