While an increasing number of states have legalized the use of marijuana for medicinal or recreational purposes, the US Drug Enforcement Administration (DEA) has yet to change its designation as a Schedule I substance under the Controlled Substances Act.1 As a result, researchers have largely been hindered from conducting adequate trials on the use of cannabis-derived agents for the treatment of various disorders.

However, in 2018, the US Food and Drug Administration (FDA) approved the cannabis-based drug Epidiolex (GW Pharmaceuticals) for the treatment of seizures in patients aged 2 years and older with Dravet syndrome and Lennox-Gastaut syndrome (LGS). Epidiolex, which contains only cannabidiol (CBD), the nonpsychoactive compound found in the Cannabis sativa plant, is the “first FDA-approved drug that contains a purified drug substance derived from marijuana,” according to the press release announcing its approval.2

Subsequently, the DEA initially changed the designation of Epidiolex from a Schedule I to a Schedule V substance before ultimately removing it from the list of controlled substances altogether in 2020. This latest change reduces physician barriers in prescribing the drug, as it removes the requirement of reporting such prescriptions to the DEA.3


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The FDA approval was based on findings of randomized controlled trials (RCTs) demonstrating the efficacy of Epidiolex (CBD) compared to placebo in the treatment of drug-resistant seizures in Dravet syndrome and LGS. Following promising results from a range of nonrandomized studies, several multinational, double-blind, placebo-controlled trials further supported the efficacy of CBD for this indication.

In a study published in 2017 in the New England Journal of Medicine (NEJM), investigators compared the efficacy of CBD (20 mg per kilogram of body weight daily) with that of placebo, along with standard antiepileptic drug (AED) therapy, in children and young adults with Dravet syndrome. The sample consisted of 120 patients aged 2 to 18 years (boys, 52%) who had previously tried a median of 4 antiepileptic drugs.4

Over the 14-week treatment period, the median monthly frequency of convulsive seizures decreased from 12.4 to 5.9 in the CBD, compared to a reduction from 14.9 to 14.1 in the placebo group (adjusted median difference in change in seizure frequency, -22.8 percentage points; 95% CI, -41.1 to -5.4; P =.01).

The findings further revealed that 43% of patients in the CBD group showed at least a 50% reduction in the frequency of convulsive seizures compared with 27% in the placebo group (odds ratio, 2.00; 95% CI, 0.93-4.30; P =.08). 

A greater number of adverse events occurred in patients receiving CBD vs placebo, including “diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests.”

In a trial published in NEJM in 2018, children and adults aged 2 to 55 years with Lennox-Gastaut syndrome were assigned to a 20-mg CBD group (n=76), a 10-mg CBD group (n=73), or placebo (n=76), in addition to standard AED therapy.5 Compared to a 28-day baseline period in which patients experienced 2 or more drop seizures per week, seizure frequency decreased by a median of 41.9%, 37.2%, and 17.2% in each group, respectively, during the 14-week treatment period (P =.005 for 20-mg CBD vs placebo, and P =.002 for 10-mg CBD vs placebo).

Common adverse events in the CBD groups included somnolence, decreased appetite, and diarrhea, with greater frequency in the 20-mg group. Elevated liver aminotransferase concentrations were observed in 14 patients in the CBD groups. Discontinuation of the trial medication due to adverse events occurred in 6 patients in the 20-mg CBD group and 1 patient in the 10-mg CBD group.

A trial published in the Lancet in 2018 also investigated the use of adjunctive CBD for the treatment of drop seizures in patients aged 2 to 55 years with LGS who had experienced at least 2 drop seizures per week during a 4-week baseline period. Participants were assigned to receive either 20 mg/kg oral CBD daily (n=86) or placebo (n=85) for 14 weeks.6

During the treatment period, the CBD group showed a median percentage reduction in monthly drop seizure frequency from baseline of 43.9% (IQR, -69.6 to -1.9), compared to 21.8% (IQR, -45.7 to 1.7) in the placebo group, with an estimated median between-groups difference of -17.21 (95% CI, -30.32 to -4.09; P =.0135).

Adverse events similar to those noted in the other LGS trial affected 86% of patients in the CBD group and 69% of patients in the placebo group, and 14% and 1% of patients in these respective groups withdrew from the trial due to adverse events.

In a systematic review of 35 studies that was published in February 2020, Elliott et al concluded that data from both randomized trials and nonrandomized studies “suggest that cannabidiol reduces seizure frequency and increases treatment response; however, there is an increased risk of gastrointestinal adverse events.”7

In 2020, Epidiolex was also approved for the treatment of seizures in tuberous sclerosis complex (TSC). Studies are currently underway to explore the efficacy of the drug in patients with infantile spasms, Rett syndrome, and other disorders.8

For a clinician’s perspective on the topic, we interviewed Charuta Joshi, MBBS, professor of pediatric neurology and regional director of neurology services at Children’s Hospital Colorado, Anschutz Medical Campus in Aurora.

Since Epidiolex was approved for the treatment of seizures associated with Dravet syndrome, LGS, and TSC, what has been observed thus far regarding its impact on these patients?

We have not done a systematic study to determine how many patients with Dravet, LGS, and TSC in our clinic have responded to Epidiolex. However, this is certainly a welcome addition to the armamentarium of medications available to these patients with difficult-to-treat seizures. Since we do not have a good way to know which of these patients will respond to Epidiolex, we do offer it to all who may avail of it. The GW Company is also quite helpful to patients and physicians in navigating the specialist pharmacy requirements in getting the medication to patients.

What are important considerations for clinicians regarding the use of this drug?

We offer it to patients aged 2 or older with Dravet syndrome, LGS, or TSC. It is important to know that although “natural,” Epidiolex has a lot of interactions with different antiseizure medications – not just clobazam.9 It can increase levels, to a small extent, of commonly used medications like topiramate, oxcarbazepine, zonisamide, etc. However, major interactions are for medications like stiripentol, clobazam, valproic acid, everolimus, and thus dose adjustments may be necessary.

Additionally, co-medication with valproic acid requires liver function test monitoring because it can cause an increase in enzyme levels aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Complete blood count (CBC) changes with the combined use of valproic acid and Epidiolex have also been reported.9

What are other emerging areas of research pertaining to the use of cannabis-based therapies in epilepsy or other neurological disorders?

We have a study at Children’s Hospital Colorado where Epidiolex is being used in patients with autism. Dr. Nicole Tartaglia heads that study.10

What are remaining concerns or questions regarding the use of such therapies for these disorders?

I think the remaining concerns are the same with most new antiseizure medications, such as the fact that many are not “antiepileptogenic.” They target broad mechanisms, and therefore are not exactly selective for the disease state or do not prevent seizures. Thus, it becomes easier to understand why they are not always 100% effective in treating seizures, and some patients find no benefit from their use.

References

1. Drug Enforcement Administration. Drug fact sheet: marijuana/cannabis. April 2020. Accessed online May 31, 2021. https://www.dea.gov/sites/default/files/2020-06/Marijuana-Cannabis-2020.pdf

2. US Food and Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. Published online June 25, 2018. Accessed online May 31, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms

3. MJBizDaily. DEA removes cannabis drug Epidiolex from controlled substances list. Published online April 7, 2020. Accessed online May 31, 2021. https://mjbizdaily.com/dea-removes-cannabis-drug-epidiolex-from-controlled-substances-list/

4. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618

5. Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378(20):1888-1897. doi:10.1056/NEJMoa1714631

6. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-1096. doi:10.1016/S0140-6736(18)30136-3

7. Elliott J, DeJean D, Clifford T, et al. Cannabis-based products for pediatric epilepsy: An updated systematic review. Seizure. 2020;75:18-22. doi:10.1016/j.seizure.2019.12.006

8. Golub V, Reddy DS. Cannabidiol therapy for refractory epilepsy and seizure disorders. Adv Exp Med Biol. 2021;1264:93-110. doi:10.1007/978-3-030-57369-0_7

9. Gaston TE, Szaflarski JP. Cannabis for the treatment of epilepsy: an update. Curr Neurol Neurosci Rep. 2018;18(11):73. doi:10.1007/s11910-018-0882-y

10. McNamara NA, Dang LT, Sturza J, et al. Thrombocytopenia in pediatric patients on concurrent cannabidiol and valproic acid. Epilepsia. 2020;61(8):e85-e89. doi:10.1111/epi.16596

11. Cannabidiol Study in Children With Autism Spectrum Disorder (CASCADE). ClinicalTrials.gov Identifier: NCT01550003. Accessed online May 31, 2021. https://clinicaltrials.gov/ct2/show/NCT04520685