The Promises And Unknowns Of Cannabidiol

BY CHRISTINE KILGORE


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 child-hood-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.]


Dr. Daniel Friedman











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

“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 superimportant 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.


Dr. Anup D. Patel

 


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 under-standing. 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.

Image 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 re-search 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 re-search 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 dou-ble-blind, placebo-controlled phase 3 trial (Lancet 2018;391:1085-96).

Additional resources:

Epidiolex prescribing information.
The Health Effects of Cannabis & Cannabinoids: The Current State of Evidence and Recommendations for Research, National Academies Press, 2017.
American Academy of Neurology Position Statement (2018): Use of medical marijuana for neurologic dis-orders.
Cannabinoid dose and label accuracy in edible medical cannabis products (JAMA. 2015 Jun 23-30;313[24]:2491-3).
“Evidence for cannabis and cannabinoids for epilepsy: A systematic review of controlled and observational evidence” (J Neurol Neurosurg Psychiatry. 2018 Jul;89[7]:741-53).
“Historical perspective on the medical use of cannabis for epilepsy: Ancient times to the 1980s” (Epilepsy Behav. 2017 May;70[Pt B]:298-301).