The promises and unknowns of cannabidiol

By Christine Kilgore

credit: MysteryShot/Getty Images

Not too long ago, published research on cannabis-based therapies for patients with epilepsy consisted of a modest collection of retrospective reviews, case series reports, online patient/family surveys, and a handful of small, randomized controlled studies – not weighty by evidence-based standards.

A 2012 Cochrane review, in fact, determined that the efficacy of cannabidiol (CBD) – the cannabinoid of most interest for epilepsy – could not be confirmed, and a 2014 American Academy of Neurology (AAN) systematic review of the role of medical marijuana in various neurologic diseases concluded that data were inadequate to determine whether or not cannabinoids can reduce seizure frequency.

Today, the research field is elevated and seemingly energized. Three randomized, controlled, double-blind trials published in 2017 and 20181,2,3 – as well as another randomized, controlled trial (RCT) reported at AAN 2019 annual meeting in May – demonstrated that a purified, plant-derived oral formulation of CBD is efficacious and generally well tolerated for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome. Investigators reported median reductions in the frequency of convulsive seizures (Dravet) or drop seizures (Lennox-Gastaut) of 39%-49% in the CBD groups compared with 13%-27% in the placebo groups. Treatment periods with CBD serving as an add-on lasted 14 weeks, with outcomes compared to 4-week baseline periods.

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.

Alona Luckey, an Applied Behavioral Analysis tutor, works with Sophia, 5-year-old daughter of U.S. Army Sgt. David Hong, Fort Eustis chaplain assistant, on developmental skills at Fort Eustis, Va., Oct. 7, 2013. Because of Dravet syndrome, a rare form of epilepsy caused by gene mutations, Sophia has developed slower than her peers.

Credit: U.S. Air Force photo by Airman 1st Class Austin Harvill/Released

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.”

Credit: National Center for Biotechnology Information, U.S. National Library of Medicine

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).

In addition, at the AAN 2019 annual meeting in May, Dr. Patel reported sustained reductions in drop and total seizures through 72 weeks in the Lennox-Gastaut open-label extension cohort, with similar results when dropouts were accounted for in sensitivity analyses. (Patient retention was 80% at one year of treatment with Epidiolex.)

An expanded access program for Epidiolex carried out by Dr. Patel and other investigators across the U.S., independently of the manufacturer, is also yielding data on long-term safety and efficacy, Dr. Patel noted. Last year, physician investigators reported 48-week efficacy data on 4 other severe forms of childhood-onset epileptic encephalopathies (Epilepsy Behav. 2018 Sep;86:131-7), and more publications from the non–placebo-controlled compassionate access program are expected. “Some of these patients have been on the medication for 4-5 years,” he said.

Clinical trials in other uncommon epilepsies are underway; for instance, INSYS Therapeutics is testing a CBD oral solution as adjunctive therapy with vigabatrin as initial therapy for patients with infantile spasms.

Whether CDB can reduce seizures in more common forms of epilepsy such as focal epilepsy and idiopathic generalized epilepsy is a big question moving forward. Dr. Friedman points out that the initial open-label interventional study that preceded the pivotal phase 3 RCTs included children and young adults with various types of treatment-resistant epilepsies – not only Dravet and Lennox-Gastaut syndromes. “There didn’t appear to be any difference in terms of why they had epilepsy, and whether or not they responded” to add-on CBD, he said. 

Dr. Friedman said he expects to see chart review studies and retrospective reports as Epidiolex is used off label for adult patients who have been previously unrepresented or underrepresented in clinical trials. “As with any drug that’s been released, we’ll begin to understand more through practical experience … through reviews that aggregate patients’ experience,” he said.

At the same time, RCTs are critical. “We have proved that you can do [these trials],” said Dr. Patel, who serves as medical cannabis editor for the Epilepsy Foundation. The fodder for rigorous trials – a backdrop of knowledge sharing – has been growing during the past 5 years, he notes. During this time, he said, the number on publications on medical cannabis increased ninefold and the overall number of scientific publications on cannabis in PubMed increased 2.5-fold.

With the trials of Epidiolex completed, he said, “hopefully the path has been laid for more [randomized controlled trials] to be done” of various formulations of CBD, including synthetic versions that are currently being developed. 

Once the mechanisms of CBD’s antiseizure activity are identified, Dr. Friedman said, “medicinal chemists can create compounds that engage those targets much better, that penetrate the blood-brain barrier well, that absorb much better … that have all the properties of good CNS drugs.”

Current oral CBD treatment is challenged, he noted, by its substantial first-pass hepatic metabolism and resulting poor bioavailability (6%-19%). Transdermal delivery mechanisms for CBD have been developed to improve bioavailability and reduce variability in plasma concentrations, and are currently being tested – but with disappointing results thus far for epilepsy.

A synthetic transdermal CBD gel made by Zynerba failed to significantly reduce seizure frequency, compared with placebo in a 12-week, phase 2 double-blind RCT of patients aged 18-71 years with focal epilepsy (in either high-dose or low-dose groups), though a 24-month open-label extension study reported in late 2018 suggested that efficacy improves with continued use of the gel. 

Notably, there was a high rate of placebo response in the phase 2 trial of the CBD gel. Larger placebo effects seem more likely with cannabis-based preparations than with other epilepsy treatments, Dr. Friedman said, given abundant anecdotal reports and public attention paid to medical cannabis. “The placebo-associated response in the RCTs [on Dravet and Lennox-Gastaut syndromes] was generally what’s expected,” he said. “My worry is that when trials move to other groups and especially to adults, where the outcome is more dependent on patient report as opposed to observer report, it adds a little bit more subjectivity and more noise.”

Credit: MAURO FERMARIELLO/Science Source

Other compounds, other outcomes

Cannabidiol has long been the focus of cannabis-based research in epilepsy. It became well known among families affected by severe childhood-onset epilepsy when the parents of Charlotte Figi, a young girl with Dravet syndrome, sought out a high-CBD cannabis extract to help treat her seizures. Her remarkable improvements in seizure control and cognition were covered by Sanjay Gupta, MD, in a 2013 CNN documentary, “Weed.” 
CBD is just one of more than 100 different pharmacologically active molecules in the Cannabis sativa plant, however. Most of the National Institutes of Health–supported research on marijuana focuses on individual cannabinoid compounds, but Dr. Patel said that some scientists believe “there’s an ‘entourage effect’ – that you need more than just one chemical compound to have maximal benefit,” said Dr. Patel. “This is so theoretical, though, and represents a gap in our understanding. I’d like to see more research on it as it relates to clinical application.”

There is a lot of discussion on patient forums as well about combination therapy – particularly the combination of CBD and the psychoactive cannabinoid THC – and about whether various preparations sold in U.S. dispensaries are safe and effective for seizure control, Dr. Friedman said.

Cannabidiol, molecular model. Cannabidiol (CBD) is a cannabinoid chemical found in cannabis plants. 

Credit: KATERYNA KON/Science Source

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.

Dr. Debopam Samanta

Pivotal phase 3 trials of purified, plant-based CBD oral solution (Epidiolex)

  1. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome (N Engl J Med 2017;376:2011-20).
  2. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome (N Engl J Med 2018;378:1888-97).
  3. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome: A randomized double-blind, placebo-controlled phase 3 trial (Lancet 2018;391:1085-96).

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