Cannabidiol Reduces Drop Seizures in Lennox‑Gastaut Syndrome — Phase 3 Trial Results

Summary: A randomized phase 3 trial published in The Lancet found that adding a pharmaceutical formulation of cannabidiol to existing anti‑epilepsy treatments significantly reduced the frequency of drop seizures in people with treatment‑resistant Lennox‑Gastaut syndrome.

Source: The Lancet.

Key finding

Treatment with a standardized, pharmaceutical cannabidiol preparation given as an add‑on to existing anti‑epilepsy medications reduced the number of drop seizures — sudden falls caused by loss of muscle tone — in patients with Lennox‑Gastaut syndrome (LGS) who had been resistant to prior therapies. The results come from a 14‑week, randomized, double‑blind, placebo‑controlled phase 3 trial involving 171 participants.

Background

Lennox‑Gastaut syndrome is a severe, lifelong form of childhood‑onset epilepsy that accounts for roughly 1–4% of paediatric epilepsy cases. It features multiple seizure types, a characteristic slow spike‑and‑wave EEG pattern, and cognitive impairment. Many patients are treatment resistant: despite multiple drug and non‑pharmacological options (ketogenic diet, neurostimulation, or surgery), a minority achieve seizure freedom.

Trial design and participants

The international trial enrolled 171 participants aged 2–55 years across sites in the United States, the Netherlands and Poland. All participants had documented LGS, evidence of more than one type of generalized seizure for at least six months, and at least two drop seizures per week during a four‑week baseline period. Participants had a history of high treatment resistance: before enrollment the average patient had failed to respond to approximately six anti‑epileptic drugs and was taking an average of three concurrent anti‑seizure medications.

Participants were randomized 1:1 to receive oral pharmaceutical cannabidiol at 20 mg/kg per day (n=86) or matched placebo (n=85), added to their existing medication regimen for 14 weeks. Caregivers and investigators recorded daily seizure counts, medication use and adverse events throughout the study. The primary endpoint was percent change from baseline in monthly frequency of drop seizures during the treatment period. All participants who received at least one dose and had post‑baseline efficacy data were included in the primary analysis; safety analyses included all randomized patients.

Results

At baseline, participants averaged dozens of drop seizures per month. By the end of the 14‑week treatment period, the cannabidiol group experienced a median 43.9% reduction in monthly drop seizures (from an average of 71.4 to 31.4 per month), while the placebo group experienced a median 21.8% reduction (from 74.7 to 56.3 per month). The estimated median difference between groups was −17.21 percentage points (95% CI −30.32 to −4.09; p=0.0135).

Participants receiving cannabidiol also saw greater reductions in other seizure types. Monthly frequency of all seizures decreased by 41.2% in the cannabidiol group (average 144.6 to 83.8 per month) versus a 13.7% reduction in the placebo group (average 176.7 to 128.7 per month).

Safety and tolerability

Adverse events were more frequent in the cannabidiol group. Treatment‑related side effects were reported in 62% of cannabidiol recipients versus 34% of placebo recipients. When considering all adverse events recorded during the trial, 86% (74/86) of patients in the cannabidiol group experienced at least one event compared with 69% (59/85) in the placebo group; most events were graded mild or moderate.

The most commonly reported adverse events in the cannabidiol group were diarrhoea, drowsiness (somnolence), fever (pyrexia), decreased appetite and vomiting. Serious adverse events occurred more often in the cannabidiol arm; a total of 20 participants in that group experienced serious events. Temporary elevations in liver enzymes were observed in four participants receiving cannabidiol, with no evidence of lasting liver damage. Most adverse events resolved during the trial (61% in the cannabidiol group and 64% in the placebo group).

Withdrawals due to adverse events were higher with cannabidiol: 14% (12/86) discontinued for side effects compared with one withdrawal in the placebo group. One death occurred in the cannabidiol group but was judged unrelated to the study medication. There were no reported instances of abuse or misuse of the study drug during the trial.

Limitations and considerations

The authors underline several important limitations. This trial tested a single cannabidiol dose and did not assess multiple dosing strategies; therefore, optimal dosing remains to be defined. Potential pharmacologic interactions — notably with the anti‑epileptic drug clobazam — require additional investigation because combinations may affect both efficacy and adverse event profiles. The trial population was not ethnically diverse (approximately 90% of participants were white), so further studies should include broader populations. Finally, the reported results cover a 14‑week treatment period; long‑term efficacy and safety are being evaluated in the open‑label extension of this study.

Clinical implications

The trial provides evidence that a pharmaceutical formulation of cannabidiol used as add‑on therapy can significantly reduce drop seizures in patients with treatment‑resistant Lennox‑Gastaut syndrome over a 14‑week period. For a disorder with few reliably effective options, these findings are clinically meaningful and offer an additional treatment avenue. However, clinicians and families should weigh the benefits against the increased risk of adverse events and monitor for potential drug interactions and liver function changes.

Expert commentary

Lead author Dr Elizabeth Thiele (Massachusetts General Hospital) commented that these results are encouraging because they identify an additional option to reduce drop seizures when other treatments have failed. She stressed that the trial used a pharmaceutical cannabidiol preparation and not medical marijuana. In a linked editorial, clinicians highlighted the growing clinical interest in cannabidiol across pharmacoresistant epilepsy syndromes and noted ongoing trials in related conditions such as tuberous sclerosis complex and infantile spasms.

Trial registration, funding and publication

Funding for the trial was provided by GW Pharmaceuticals. The randomized, double‑blind, placebo‑controlled phase 3 study is registered with ClinicalTrials.gov under identifier NCT02224690. The full trial report and primary results were published in The Lancet.