By Attorney Richard M. Blau, Chair, Medical Marijuana Practice Group
A rare scientific clinical trial involving cannabis-related compounds has produced stark evidence suggesting the medicinal benefits to be gained through controlled use of medical marijuana. Recently published results from a scientifically-conducted clinical trial show that treating young patients suffering from epilepsy with cannabidiol ("CBD"), a compound derived from marijuana, can significantly reduce and in some cases eliminate seizures in children and young adults. The study was published on May 25, 2017 in the New England Journal of Medicine1. It is among the first yielding substantiated clinical evidence to support a form of treatment that is becoming fairly widespread with the advent of medical marijuana.
Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
The findings were derived from a double-blind, placebo-controlled study. "This study clearly establishes cannabidiol as an effective anti-seizure drug for this disorder and this age group," reports Dr. Orrin Devinsky, the director of the Comprehensive Epilepsy Center at New York University Langone Medical Center and a principal investigator of the study. The full slate of researchers includes: Orrin Devinsky, M.D., J. Helen Cross, Ph.D., F.R.C.P.C.H., Linda Laux, M.D., Eric Marsh, M.D., Ian Miller, M.D., Rima Nabbout, M.D., Ingrid E. Scheffer, M.B., B.S., Ph.D., Elizabeth A. Thiele, M.D., Ph.D., and Stephen Wright, M.D.
The study focused on 120 children and teenagers with Dravet syndrome, which is a rare disorder marked by drug-resistant seizures that can be nearly continuous in some cases. Dravert syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. Currently, there are no approved medications that can control completely seizures in children with Dravet syndrome, according to the Epilepsy Foundation.
1. Methods
The subjects were divided into an experimental group, which received the test drug, and a placebo group, which was given a medically inactive compound. In this double-blind, placebo-controlled trial, the researchers randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. As noted in the study’s abstract: "The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period."
2. Results
Over the course of 14 weeks, the participating subjects receiving CBD experienced a median number of 5.9 convulsive seizures per month (down from 12.4) compared with 14.1 convulsions per month (down from 14.9) for the placebo group. Results from the study also show that five percent (5%) of the subjects treated with the marijuana extract became seizure-free during the study period.2
3. Significance
The new findings are consistent with a less-stringent study from 2015 of a CBD compound called Epidiolex, made by the GW Pharmaceuticals company of Great Britain. That study, also led by Dr. Devinsky, suggested positive outcomes from the drug. However, unlike the recently-published research, the 2015 study did not use a placebo; its results, therefore, were vulnerable to a bias because patients and doctors could associate any progress to the drug. It should be noted that GW Pharmaceuticals funded the new Dravert Syndrome Study Group’s research. (ClinicalTrials.gov number, NCT02091375.3)
Interest in using CBD to treat epilepsy grew significantly in 2013 when an 8-year-old girl from Colorado with Dravet syndrome entered the public spotlight. Charlotte Figi, now 10, was having hundreds of seizures a month by age three when her parents decided to treat her with cannabidiol. The girl showed remarkable improvement after taking CBD administered by a Denver medical marijuana dispensary.
Dravet syndrome is rare, affecting 1 in 40,000 children. However, epilepsy is the fourth most common neurological condition and affects more than 65 million people worldwide, according to the Epilepsy Foundation. Research from April 2017 showed CBD to be effective in treating another relatively rare, but severe, form of seizure disorder called Lennox-Gastaut syndrome.4
Legal Status of CBD
CBD is one of dozens of compounds in marijuana called cannabinoids. Unlike tetrahydrocannabinol (THC), which is the main psychoactive chemical in marijuana, CBD does not get users "high." The compound is typically administered in an oil form and is thought to work by interacting with receptors on nerve cells.
Florida is one of twenty-nine states and the District of Columbia that have legalized marijuana for medical use. The conditions approved for treatment vary from state to state. In Florida, statutes provide for low THC medical marijuana to treat epilepsy and other specified diseases under the 2014 "Charlotte’s Web" law, while a 2015 statute allows terminally ill patients to use full-strength medical marijuana for palliative care. In 2016, Florida voters approved a constitutional amendment to expand the list of illnesses that qualify for treatment with medical marijuana; however, the Florida Legislature has not yet passed enabling legislation to implement the expanded scope of medical marijuana use by Floridians.
Sixteen states have laws that specifically allow the use of CBD to treat seizures. However, those laws have been called into question by rules recently issued by the federal Drug Enforcement Agency (DEA) which liberalized scientific research protocols, but clarified that the federal government considers any product containing THC to be illegal.
In late 2016, the DEA eased some of the regulatory requirements imposed by the Controlled Substances Act (CSA) for those who are conducting FDA-approved clinical trials on CBD. Federal Regulation (21 CFR 1301.18) requires researchers conducting CBD-based clinical trials under an FDA Investigational New Drug Application to have a DEA research registration. This registration permits the possession of an approved amount of CBD for a specific research protocol. Previously, researchers who expanded the scope of their studies and needed more CBD than initially approved had to request in writing a modification to their DEA research registrations – potentially delaying that research while the modification underwent an approval process that includes both the DEA and the Food and Drug Administration (FDA). Under DEA’s 2016 rule changes, a previously-registered CBD clinical researchers who are granted a waiver can readily modify their protocol and continue their research seamlessly. This waiver effectively removes a step from the approval process.
Yet, Marijuana remains a Schedule I controlled substance because of the presence of tetrahydrocannabinol (THC), marijuana’s psychoactive ingredient. Although CBD contains less than one percent (1%) THC and has shown some potential medicinal value, it nevertheless also is a Schedule I controlled substance as defined under the CSA. In its December, 2016 regulatory action, DEA reiterated that CBD is considered an illegal substance, just like other marijuana products.
Conflict between Federal and State Law
In many states with either legal marijuana systems or ones that allow for the possession of CBD products, there are thresholds for determining a CBD product. In a number of jurisdictions, it is a "CBD-only" product if it has less than 0.3 percent or 0.5 percent THC.
However, any product that contains THC, even in small amounts, is considered by the DEA to constitute marijuana under federal law and is illegal. This approach apparently is unlikely to change under the leadership of Attorney General Jefferson Sessions, III.
Courts have largely afforded DEA broad latitude in controlling substances derived from the cannabis plant. The DEA’s consistent position has been and remains that cannabinoids are marijuana and thus are a Schedule I substance and illegal in all circumstances. Marijuana reformers often point to Hemp Industries Association v. DEA.5 to say that non-psychoactive hemp is not a controlled substance. While the appellate judges in that case ruled that not all cannabis plants fall under the Controlled Substances Act, most courts, including the cases U.S. v. White Plume6, U.S. v. Proyect7, U.S. v. Rogers8, have held just the opposite.
Going Forward
GW Pharmaceuticals reportedly plans to seek FDA approval of Epidiolex in the next few months as a treatment for Dravet syndrome and Lennox–Gastaut syndrome. While scientific research has yet to explain how CBD works to reduces seizures in Dravet, Dr. Devinsky has described the leading theory as postulating that the CBD binds to a receptor in nerve cells called GPR55, modulating the calcium activity and excitability of the cells. He also says CBD has many other effects on nerve cells and that there is much to learn.
While DEA has relaxed protocols for much needed CBD and cannabis research, studies are projected to take years before results are compiled, analyzed and reported. In the meanwhile, the existing standoff between federal prohibition and state legalization of CBD and medical marijuana continues.
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[1] N Engl J Med 2017; 376:2011-2020 May 25, 2017 DOI: 10.1056/NEJMoa1611618.
[2] In the published article’s Abstract, the authors described their results as follows: "The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group."
[3] Additionally, Dr. Devinsky reported receiving grant support from Novartis, PTC Therapeutics, and Zogenix and holding equity interest in Rettco, Pairnomix, Tilray, and Egg Rock Holdings. Dr. Cross reports receiving grant support, paid to her institution, from GW Pharmaceuticals, Zogenix, Sanofi, and Vitaflo; fees for serving on an advisory board, paid to her institution, from Eisai; lecture fees, paid to her institution, from Shire and Nutricia; and consulting fees, paid to her institution, from Takeda. Dr. Marsh reports serving as a site primary investigator for a trial supported by Neuren Pharmaceuticals and receiving consulting fees from Stanley Brothers Social Enterprises. Dr. Miller reports receiving honoraria and travel support from INSYS Therapeutics. Dr. Scheffer reports receiving travel support and fees for serving on a scientific advisory board from GlaxoSmithKline; receiving travel support and lecture fees from UCB and Sanofi; receiving lecture fees from Eisai and Transgenomic; holding a patent on diagnostic and therapeutic methods for epilepsy and mental retardation limited to female patients, for which a single royalty payment has been made to University of Melbourne Commercial (WO2009086591); and holding a patent on methods of treatment and diagnosis of epilepsy by detecting mutations in the SCN1A gene, which has been licensed by Bionomics (WO2006133508). Dr. Thiele reports receiving consulting fees from Eisai, grant support and consulting fees from Zogenix Pharmaceuticals, and grant support from Courtagen. Dr. Wright reports being an employee of GW Pharmaceuticals, holding a pending patent on the use of cannabinoids in the treatment of epilepsy (WO2015193667), and holding a patent on the use of phytocannabinoids in the treatment of epilepsy (EP2448637). No other potential conflict of interest relevant to this article was reported.
[4] Two studies, GWPCARE3 and GWPCARE4, both are multicenter, randomized, double-blind, placebo-controlled trials that evaluated the safety and efficacy of cannabidiol in patients with Lennox-Gastaut syndrome who were taking other antiepileptic drugs The studies involved randomized, double-blind, placebo-controlled trial of patients between the ages of 2 years and 55 years that had a clinical diagnosis of Lennox-Gastaut syndrome and were on at least one or more anti-seizure medications. The researchers stratified the subjects in different arms, administering a 20 mg/kg per day dosing and a 10 mg/kg per day dosing, and then a placebo arm, so that subjects were randomized to one of those three administrations. Results of the experiments found that patients in the 20 mg/kg per day arm had a 47% median seizure reduction, and the 10 mg/kg per day arm had a 37% median seizure reduction, respectively, in contrast to 17% reduction seen in the placebo group. Those results, compared to subjects administered with a placebo in both arms, were statistically significant.
The studies’ secondary findings focused on the "responder rate," i.e., what percentage of patients achieved at least a 50% or more reduction of their seizures. Again in the 20 mg/kg per day arm, researchers reported 40% of the population had at least a 50% or more reduction; in the subjects receiving 10 mg/kg per day administrations, the resulting ratio was 34% compared to 15% in the placebo -- again demonstrating statistically significant differences.
Finally, with regard to safety, the researchers examined treatment-emergent adverse events. Results demonstrated over 90% of patients who received the 20 mg/kg per day arm administrations reported at least one event; over 80% was reported in the subjects administered with 10 mg/kg per day, but as compared to other studies with Lennox-Gastaut syndrome, there is a higher reported rate in the placebo arm as well as a study-generated rate of over 70% of patients in the placebo arm reporting at least 1 treatment-emergent adverse event. See, Patel A, Devinsky O, Cross JH, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a dose-ranging, multi-center, randomized, double-blind, placebo-controlled trial (GWPCARE3). Presented at: 2017 American Academy of Neurology Annual Meeting. April 22-28, 2017, Boston, MA; see also French J, Thiele E, Mazurkiewicz-Beldzinska M, et al. Cannabidiol (CBD) significantly reduces drop seizure frequency in Lennox-Gastaut syndrome (LGS): results of a multi-center, randomized, double-blind, placebo controlled trial (GWPCARE4). Presented at: 2017 American Academy of Neurology Annual Meeting. April 22-28, 2017; Boston, MA.
[5] 357 F.3d 1012 (9th Cir. 2004).
[6] 447 F.3d 1067 (8th Cir. 2006).
[7] 989 F. 2d 84 (2nd Cir. 1993).
[8] 549 F.2d 107 (9th Cir. 1976).