The promises and unknowns of cannabidiol

The CBD formulation – named Epidiolex (GW Pharmaceuticals, Cambridge, England) and approved by the Food and Drug Administration in 2018 for patients with these two severe childhood-onset epilepsy syndromes – was recently found in a similarly rigorous phase 3 trial to be efficacious for patients with tuberous sclerosis–associated seizures, according to a company press release.

Maintaining momentum will be key, physician researchers say. These and other studies have only scratched the surface of an understanding of CBD’s mechanisms of action – knowledge that could lead to additional, more effective therapeutic compounds – as well as its pharmacokinetic interactions with other antiseizure drugs. Neurologist researchers also have questions about dosing, side effects, and long-term efficacy and safety – and importantly, whether it can safely and effectively reduce seizures in other types of epilepsy like focal epilepsy and idiopathic generalized epilepsy.

There is much more to learn, moreover, about the potential mechanisms and add-on value of dozens of other potentially biologically active compounds that have been isolated from the cannabis plant.

Understanding mechanisms, drug interactions

“We know there are many targets of cannabinoids in the central nervous system, but we don’t know which ones are critical for [the control of seizures],” said Daniel Friedman, MD, of New York University Langone Comprehensive Epilepsy Center, who coauthored a “personal viewpoint” on cannabinoids in neurological disorders in The Lancet.

Some animal models of Dravet syndrome suggest that the G protein–coupled receptor 55 – a protein on presynaptic neurons involved in regulating neurotransmitter release – is a target for CBD and possible mechanism for its antiseizure effect. But there are many other possibilities as well, Dr. Friedman said. Broadly speaking, plant-based cannabinoids are known to “bind to [various] receptors in the brain and to [influence] gene transcription, the metabolism of endogenous cannabinoids, and have myriad different effects,” he said. “They’re very promiscuous in their targets.”

While the body’s own cannabinoid signaling system plays some role in epilepsy – with endocannabinoids capable of acting as synaptic circuit breakers that set thresholds for neuronal excitability – it’s “not entirely clear whether or not elements of the endocannabinoid system are at all important for the therapeutic effect of CBD,” he said. Research has shown that CBD has limited activity at the cannabinoid receptor subtypes CB₁ and CB₂ that are central to tetrahydrocannabinol’s (THC’s) documented mechanism of action, he noted.

It’s also unclear after the published randomized, controlled trials of Epidiolex in patients with Dravet syndrome and Lennox-Gastaut syndrome how much of CBD’s benefit is because of a direct effect of the cannabinoid versus potential interactions with other drugs. CBD is known to inhibit several hepatic P450 enzymes, one of which metabolizes N-desmethylclobazam, an active metabolite of clobazam, and several studies have shown that CBD increases serum concentrations of N-desmethylclobazam.

Because patients in the RCTs were not stratified based on their clobazam use, it is not possible to know the contribution of higher N-desmethylclobazam levels to the efficacy of CBD, said Dr. Friedman, also associate professor in department of neurology at NYU Langone.

CBD also appears to interact with valproic acid another commonly used antiepileptic medication. Elevated transaminase levels – defined in the RCTs as of Epidiolex as elevations of three times or more the upper limit of normal – occurred in 13% of CBD-treated patients compared with 1% of placebo-treated patients across the three published trials, and most of these cases involved concomitant valproic acid. [Most cases resolved spontaneously or with dose modifications of CBD or concomitant medication.]

“I was very struck overall by the side effects in these trials … [especially] by the finding that a chemical compound that [the public presumes] is safe can increase liver enzymes,” said Anup D. Patel, MD, section chief of neurology at Nationwide Children’s Hospital and associate professor of neurology and pediatrics at the Ohio State University, both in Columbus. “It was super important for us to learn [about potential hepatotoxicity] because it is scary. Taking CBD without proper supervision and knowledge could really harm children.

“What I’d like to know now from a research perspective is, what type of patient is at risk for these [side effects]? Why did we not see them in everyone?” he said. “And secondly, what other antiseizure medications have a potential interaction with CBD or vice versa? I’m concerned that if CBD is paired with other medications that are metabolized in [the] liver, that potential harm could occur. We just don’t have the data now to know all this.”

Dr. Friedman and Dr. Patel were both involved in some of the pivotal multicenter research on Epidiolex, and Dr. Friedman was an investigator of the preceding open-label interventional trial that laid the groundwork for the RCTs.

Questions of durability and range of impact

Whether the effects of add-on CBD treatment are durable beyond the trials’ 14-week treatment periods – or whether patients “have a honeymoon period and eventually experience tolerance” to the CBD formulation – is something Dr. Friedman wonders about.

Thus far, an open-label extension study involving most patients enrolled in the Lennox-Gastaut syndrome RCTs indicates that efficacy continues and that safety profiles hold steady. An interim analysis of outcomes through 48 weeks of treatment reported sustained reductions in drop seizures – as well as total seizures – and similar side effects, with most of the 368 patients (92%) experiencing mild or moderate adverse events such as diarrhea and somnolence, and 10% having liver transaminase elevations (Epilepsia. 2019 Mar;60[3]:419-28).

Unfortunately, said Debopam Samanta, MD, a pediatric neurologist at the University of Arkansas for Medical Sciences, Little Rock, there have been no formal clinical studies of the efficacy of products sold in dispensaries, and most products are developed and sold without regulation, quality assurance, or accurate content labeling. “There’s no good quality control,” he said. “And we’re really not sure we can trust labeling.”

Yet patients and parents who cannot access or afford Epidiolex for conditions other than its approved indications are “still going to resort to CBD extracts bought online or from the stores to control seizures,” he said. Unregulated CBD extracts may have higher-than-expected levels of THC, which is concerning because THC can potentially aggravate seizures, he said, as well as impair cognition and alter structural and functional connectivity in the brain. 

Dr. Samanta became interested in CBD for epilepsy over the past several years as his patients’ families increasingly expressed interest. He got involved in manufacturer-sponsored research studies of Epidiolex, and recently wrote a review, published in Pediatric Neurology, of the clinical efficacy and safety of CBD in epilepsy (2019 Mar 22. doi: 10.1016/j.pediatrneurol.2019.03.014)

It’s not only seizure reduction that’s an important outcome for cannabis-based research in epilepsy, he notes, but also quality of life measures as well. “One thing I hear from my families is that they’re sleeping much better and are less irritable,” he said. Thus far, some of the research on Epidiolex has utilized the Subject/Caregiver Global Impression of Change scale, with some positive findings. 

Dr. Friedman disclosed that he serves on the scientific advisory board and holds equity interest in Receptor Life Sciences, which is developing cannabinoid-based therapies. He receives salary support for consulting and clinical trial related activities performed on behalf of the Epilepsy Study Consortium, a nonprofit organization. In the past 2 years, the consortium received payment for research services performed by him from Zynerba, GW Pharmaceuticals, and other companies.

Dr. Debopam Samanta disclosed that he has participated as an investigator in in two GW Pharmaceutical-sponsored studies involving Epidiolex. He did not receive any salary support for this participation.

Dr. Patel disclosed that he has served as an investigator and consultant for Greenwich Biosciences, the U.S. subsidiary of GW Pharmaceuticals, and that he has received research funding from this company as well as from the Pediatric Epilepsy Research Foundation and the NIH.