Written by: Y. Tony Yang and Jerzy Szaflarski
Media contact: Bob Shepard, 205-934-8934
This editorial was originally published in the Journal of the American Medical Association on Nov. 19, 2018, by Y. Tony Yang, Sc.D., Center for Health Policy and Media Engagement, George Washington University School of Nursing, Washington, D.C.; and Department of Health Policy and Management, George Washington University Milken Institute School of Public Health; and Jerzy P. Szaflarski, M.D., Ph.D., Department of Neurology, University of Alabama at Birmingham School of Medicine; and University of Alabama at Birmingham Epilepsy Center.
Jerzy P. Szaflarski, M.D., Ph.D.On June 25, the United States Food and Drug Administration approved Epidiolex, the first cannabis-derived treatment, for two epilepsy syndromes, Lennox-Gastaut and Dravet. It contains cannabidiol, or CBD oil. While other drugs containing synthetic versions of tetrahydrocannabinol found in the cannabis plant have been previously approved by the FDA, Epidiolex is the first plant extract that will be available in the United States. This signifies that CBD has an accepted medical use, one of the requirements for moving it to a schedule higher than I under the Controlled Substances Act. The decision has significant implications for patients, regulations, and research.
Safety and efficacy
The approval by the FDA relied on data from clinical trials. Overall, the trials conducted in LGS and DS showed significant improvement of seizure frequency vs placebo in patients receiving 10 mg/kg/d or 20 mg/kg/d of CBD. Data from the randomized clinical trials are supported by several prospective, open-label, long-term observational studies indicating sustained long-term efficacy of CBD in the dose ranging from 5 mg/kg/d to 50 mg/kg/d and decrease in seizures ranging from 34.6 percent to 63.6 percent in patients with focal and generalized epilepsies.
The most commonly reported adverse effects were diarrhea and sedation; sedation was more common in patients taking concomitant clobazam. Increases in aspartate aminotransferase and alanine aminotransferase were mainly noted in patients taking concomitant valproate.
Several studies reported on interactions between CBD and other antiseizure medications. The interaction with clobazam resulted in significant increase in the levels of its active metabolite N-desmethylclobazam and resulted in excessive sedation. Interaction with warfarin was also reported. However, the risks associated with CBD were deemed generally acceptable; it was noted that the potential of liver injury could be appropriately treated by inclusion of relevant language in labeling, education of prescribers, and further characterization of the risk in the post market setting. Further, the FDA determined that the 10 mg/kg/d dose of Epidiolex did not have abuse potential.
Implications for patients
Lennox-Gastaut syndrome and DS are rare, severe, refractory epilepsy syndromes with early-childhood onset categorized as developmental and epileptic encephalopathies. They are characterized by multiple seizure types that are typically resistant to treatment, multiple seizures per day, and higher rates of mortality than the general epilepsy population. Most patients with LGS continue to have seizures despite using one or more of the six currently approved medications; prior to Epidiolex, no drugs were approved to treat DS.
At present, to obtain CBD, many parents and patients move to states with permissive cannabis laws to obtain various artisanal products, some of which with untested quality and composition. Unfortunately, self-medicating with artisanal products may expose patients to products with inaccurate labeling, containing impurities, underdosing or overdosing, insufficient supply and risk of adverse effects and drug-drug interactions without medical oversight.
Exposure to tetrahydrocannabinol, frequently present in artisanal cannabis products, may result in short-term and long-term negative developmental and cognitive effects, especially when given to children. Thus, having an approved pharmaceutical-grade product with known and stable content is critical to the treatment and survival of the thousands of children and adults with epilepsy.
Due to the severity of DS and LGS, the lack of effective treatments, and the resulting burdens placed on patients and their families, the implications of Epidiolex approval cannot be overstated. While initially Epidiolex will be approved for LGS/DS, we are likely to see its use in other types of epilepsies or other neuropsychiatric conditions that are in agreement with the results of numerous open-label studies. Such off-label use will likely face scrutiny of insurers; physicians and patients will face an uphill battle to obtain approval for off-label use.
Implications for regulations
Despite decriminalization of cannabis for medicinal use in most states, the federal government remains steadfast in its position that possession of marijuana is a federal crime. Approval of Epidiolex has potential for reshaping the federal scheduling of cannabis products and may encourage lawmakers to take a closer look at the utility of the cannabis plant. Both, the FDA and the Drug Enforcement Administration will play a role in the reclassification of cannabis after considering factors such as medical and addictive effects. Ultimately, on approval of Epidiolex by the FDA, the DEA will have to reschedule CBD to reflect the FDA’s conclusion of medical efficacy.
However, despite the changing societal and medical climate, the approval of Epidiolex may not affect rescheduling of the cannabis plant because the DEA could leave cannabis overall as a schedule I substance. Owing to the complicated and diverse nature of cannabis regulation, this reclassification could have wide-ranging societal implications.
For example, regulations compelling banks to disclose cannabis-related transactions as suspicious activities might be relaxed, making lenders less hesitant to work with those producing and selling cannabis. Restrictions on zoning and obtaining federal trademarks could also be reduced, making it easier for entrepreneurs to protect their intellectual property and conduct business. Provisions in the tax code preventing businesses that engage in illegal drug trafficking from receiving certain tax credits or deducting operational expenses from federal returns may no longer apply if cannabis is legalized, likely substantially improving companies’ ability to conduct business.
Also, employment related issues regarding cannabis drug testing will need to be addressed to set clear standards for the future. However, these potential regulatory changes could lead to increased cannabis use, which may be linked to addiction, increases in cardiovascular health issues, psychological and psychiatric issues, and motor vehicle accidents. Therefore, it is important that we develop appropriate policies and regulations preventing its negative public health effects.
Implications for research
The approval of Epidiolex will pave the way for further controlled clinical trials examining other uses of CBD, tetrahydrocannabinol, and other cannabinoids. Although the science on the effects of cannabis is emerging, more research is needed to address gaps in understanding how cannabis affects our bodies and public health. Owing to the current schedule I status, those wanting to research the effects of cannabis have to undergo a complicated approval process that typically involves the FDA, the DEA, and the National Institute on Drug Abuse within the National Institutes of Health. This red tape is prohibitive to all those lacking substantial resources, rendering it difficult to conduct cannabis research and development. In fact, the clinical trials testing the potential benefits of cannabis are scarce. While the FDA supports such research, it notes that it needs to plays the key role in fostering scientific research into the medical uses of cannabis and its constituents as part of the agency’s drug review and approval process. Therefore, to bring useful treatments, such as Epidiolex, to the market and to effectively realize the full medicinal potential of cannabis, regulatory barriers to research should be mitigated or removed. Approval of Epidiolex represents a significant step toward this goal.
Conclusions
Epidiolex authorization is a crucial new development, offering patients the first and only cannabis-derived, FDA-approved pharmaceutical for the treatment of severe, childhood-onset epilepsies. Based on the determination that plant-derived CBD is acceptable for medical use, the DEA should consider changing the overall classification of cannabis. Researchers should be able to take advantage of this development to advance and test further applications of cannabis.