A landmark RCT in The Lancet confirmed CBD reduces the most dangerous seizure type (drop seizures) in Lennox-Gastaut syndrome by 43.9% vs 21.8% placebo — proving CBD's anticonvulsant effect isn't limited to Dravet and completing the evidence for Epidiolex's FDA approval.
Families with LGS patients, neurologists, and anyone following the clinical evidence for CBD in epilepsy.
43.9% vs 21.8% drop seizure reduction (p = 0.0135)
The Backstory
If Dravet syndrome is the disease that launched the CBD epilepsy movement, Lennox-Gastaut syndrome is the one that confirmed it wasn't a fluke.
LGS is rarer than Dravet, harder to treat, and in many ways more devastating. It doesn't just cause seizures — it causes multiple seizure types simultaneously, including "drop seizures" that send children crashing to the ground without warning. More than 90% of patients develop moderate to severe intellectual disability. Five percent die in childhood. At least 90% of adults with LGS still have seizures decades later.
The Devinsky Dravet trial had proven CBD could reduce seizures in one catastrophic childhood epilepsy. The question was whether it would work in a second, pharmacologically distinct form. If CBD's anticonvulsant mechanism was specific to Dravet's sodium channel dysfunction, it might not generalize. If it was broader — acting through mechanisms relevant to multiple seizure types — it would work here too.
It worked here too.
The Disease
The Trial
How They Did It
GWPCARE4: The Lennox-Gastaut Confirmation Trial
Design
Randomized, double-blind, placebo-controlled Phase 3 trial — the same gold-standard design used in the Dravet trial. 24 sites across the United States, Netherlands, and Poland.
ClinicalTrials.gov: NCT02224690
Population
171 patients aged 2-55 years with Lennox-Gastaut syndrome. All had documented slow spike-and-wave on EEG, at least 2 drop seizures per week at baseline, and had failed at least 2 anti-epileptic drugs.
86 randomized to CBD, 85 to placebo — added to existing medications
Intervention
Oral cannabidiol solution (Epidiolex) at 20 mg/kg/day or matched placebo for 14 weeks.
Same pharmaceutical-grade purified CBD used in the Dravet trial — no THC, no terpenes
Primary endpoint
Percentage change in monthly drop seizure frequency from baseline.
Drop seizures specifically — the most dangerous type, causing falls and injuries
Key secondary endpoints
Overall seizure frequency change, proportion achieving ≥50% reduction in drop seizures, and Caregiver/Patient Global Impression of Change.
Multiple outcome measures to capture the full clinical picture
Thiele et al. (2018), Lancet 391:1085-1096; NCT02224690
The Results
CBD Group (n=86)
- Median drop seizure reduction: 43.9%
- Significantly greater than placebo (p = 0.0135)
- Adverse events in 86% of patients
- Most common: diarrhea, somnolence, fever, decreased appetite
- 14% discontinued due to adverse events
- One death — deemed unrelated to treatment
Clinically and statistically significant seizure reduction
Placebo Group (n=85)
- Median drop seizure reduction: 21.8%
- Substantial placebo response — common in epilepsy trials
- Adverse events in 69% of patients
- 1% discontinued due to adverse events
- Demonstrates the importance of placebo control in seizure research
Meaningful placebo effect, but CBD still significantly better
Thiele et al. (2018), Lancet 391:1085-1096
43.9% vs. 21.8%
median reduction in monthly drop seizure frequency — CBD versus placebo. The between-group difference was 17.21 percentage points (95% CI: -30.32 to -4.09, p = 0.0135). In a patient population where nothing else had provided adequate control, CBD produced a clinically meaningful reduction in the most dangerous seizure type.
The placebo response (21.8%) is notable — placebo effects in epilepsy trials are well-documented and substantial. This is exactly why the Dravet trial used a double-blind design and why uncontrolled anecdotes about CBD for seizures, however compelling, can't substitute for RCTs.
Thiele et al. (2018), Lancet 391:1085-1096
Why This Trial Mattered Beyond Dravet
The Dravet result could have been a one-off. Dravet syndrome involves a specific sodium channel mutation (SCN1A). Maybe CBD's anticonvulsant mechanism was specific to that ion channel defect. If so, it wouldn't generalize.
Lennox-Gastaut syndrome has completely different and heterogeneous underlying causes. The fact that CBD worked here too meant its anticonvulsant mechanism was broader than any single ion channel. Whatever CBD does to reduce seizures, it works across different types of epilepsy with different etiologies.
This had two implications:
Process
What the LGS Trial Proved About CBD
CBD is not Dravet-specific
The anticonvulsant effect generalizes across at least two distinct epilepsy syndromes with different underlying causes, seizure types, and age ranges.
CBD reduces drop seizures specifically
Drop seizures (tonic and atonic) are mechanistically different from the convulsive seizures measured in the Dravet trial. CBD reduces both — suggesting multiple anticonvulsant mechanisms.
The placebo effect is real and large
21.8% drop seizure reduction in the placebo group. This is not nothing. It demonstrates why uncontrolled observations of CBD for seizures — however dramatic — cannot be taken at face value.
Adverse events are dose-dependent and manageable
86% adverse event rate is high but consistent with the Dravet trial. Most events were mild to moderate. The 14% discontinuation rate is higher than Dravet (3%) — possibly reflecting the older, more medically complex LGS population.
Thiele et al. (2018), Lancet 391:1085-1096
The Safety Profile
Myth vs. Reality
CBD is a natural supplement with no significant side effects.
At therapeutic doses for epilepsy (20 mg/kg/day), CBD has a real drug safety profile. In this trial, 86% of patients experienced adverse events. The most common were diarrhea, somnolence, fever, decreased appetite, and vomiting. Elevated liver enzymes occurred, particularly in patients taking valproate concurrently — requiring monitoring. 14% of patients discontinued due to adverse events. One patient died (deemed unrelated). CBD at these doses is a pharmaceutical with pharmaceutical risks — not a gentle supplement.
The Evidence
Thiele et al. (2018): 86% adverse event rate, 14% discontinuation, elevated liver enzymes requiring monitoring, one death. Devinsky et al. (2017): 93% adverse event rate in the CBD group of the Dravet trial.
Thiele et al. (2018), Lancet 391:1085-1096; Devinsky et al. (2017), NEJM 376:2011-2020
The liver enzyme elevation is worth understanding. CBD inhibits cytochrome P450 enzymes (particularly CYP3A4 and CYP2C19), which are the same enzymes that metabolize many anti-epileptic drugs. When CBD is added to valproate — a standard first-line drug for LGS — the combination can elevate liver transaminases. This isn't a reason to avoid CBD, but it's a reason it needs to be prescribed and monitored by a neurologist, not self-administered from a dispensary product.
The Path to Dual Approval
Together with the Dravet trial, this study completed the evidence package that the FDA required. In June 2018, Epidiolex was approved for both Dravet syndrome and Lennox-Gastaut syndrome in patients aged 2 and older — the first cannabis-derived drug ever approved by the FDA.
The approval was notable for what it wasn't: it wasn't for "epilepsy" broadly. It was for two specific, catastrophic, treatment-resistant syndromes where rigorous RCTs had demonstrated efficacy. The FDA approved the evidence, not the enthusiasm.
Research Timeline
The Second Confirmation
Devinsky open-label trial (Lancet Neurology)
214 patients with mixed treatment-resistant epilepsy — 36.5% seizure reduction
Devinsky Dravet RCT (NEJM)
First indication: CBD reduces convulsive seizures in Dravet syndrome (p=0.01)
Thiele LGS RCT (Lancet)
Second indication: CBD reduces drop seizures in Lennox-Gastaut syndrome (p=0.0135)
FDA approves Epidiolex for both indications
First cannabis-derived drug approved by FDA — for Dravet and LGS in patients ≥2 years
Epidiolex approved for tuberous sclerosis complex
Third indication added — CBD for seizures in TSC, another rare epilepsy
Multiple sources
Related Research
The CBD Epilepsy Evidence Base
This trial was the second pillar supporting Epidiolex's FDA approval. Together with the Dravet trial, it established CBD as a legitimate anticonvulsant.
Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial
Devinsky et al. (2016)
The open-label pathfinder + the NEJM Dravet RCT — the first indication that made Epidiolex possible
Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish
Gaoni & Mechoulam (1964)
THC isolation — CBD was first isolated even earlier (1940) but ignored for decades until epilepsy research revived it
A tale of two cannabinoids: THC and CBD therapeutic rationale
Russo & Guy (2006)
The paper that argued CBD had independent therapeutic value — Epidiolex vindicated that claim
The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids
Pertwee et al. (2008)
CBD's multi-target pharmacology — the mechanistic basis for why it works across different epilepsy types
What is Lennox-Gastaut syndrome?
Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy that typically begins between ages 3-5. It's characterized by multiple seizure types (especially "drop seizures" that cause sudden falls), a distinctive EEG pattern, and progressive cognitive impairment. More than 90% of patients develop intellectual disability. At least 90% still have seizures as adults. It's caused by diverse factors including brain malformations, injuries, and genetic conditions — unlike Dravet syndrome, which has one primary genetic cause. Treatment options before Epidiolex were limited and often inadequate.
How is this different from the Dravet trial?
Different disease, different seizure type measured, same result. The Dravet trial measured convulsive seizures in patients with a sodium channel mutation. This trial measured drop seizures in patients with heterogeneous causes. The fact that CBD worked in both — reducing seizures by ~39-44% versus placebo — proved its anticonvulsant mechanism is broad, not disease-specific. Both trials used the same drug (Epidiolex), same dose (20 mg/kg/day), and same gold-standard design (double-blind, placebo-controlled).
Why was the placebo response so high (21.8%)?
Placebo responses in epilepsy trials are notoriously high — typically 10-25%. Several factors contribute: natural fluctuation in seizure frequency (regression to the mean), the psychological effect of receiving treatment, increased compliance with existing medications during a trial, and caregiver reporting bias. This is exactly why placebo-controlled trials are essential for evaluating seizure medications. Without the placebo comparison, the 43.9% reduction in the CBD group would look impressive — but you'd have no way to know how much was drug effect versus context effect.
What the researchers found
Add-on CBD (20 mg/kg/day) reduced drop seizure frequency by 43.9% versus 21.8% with placebo (p=0.0135) in 171 patients with Lennox-Gastaut syndrome. This confirmed CBD's anticonvulsant efficacy in a second catastrophic epilepsy syndrome with different underlying causes than Dravet, establishing that CBD's mechanism is broad rather than disease-specific.
Why it matters
Together with the Dravet RCT, this trial completed the evidence package for FDA approval of Epidiolex — the first cannabis-derived prescription drug. It proved CBD's anticonvulsant effect generalizes across different epilepsy types and different seizure mechanisms, and it demonstrated that the most dangerous seizure type in LGS (drop seizures causing falls and injuries) specifically responds to CBD.
The numbers in context
171 patients (86 CBD, 85 placebo). Drop seizure reduction: 43.9% CBD vs 21.8% placebo (p=0.0135). Adverse events: 86% CBD vs 69% placebo. Discontinuation: 14% CBD vs 1% placebo. One death (unrelated).
How the study worked
Randomized, double-blind, placebo-controlled Phase 3 trial across 24 sites in USA, Netherlands, and Poland. Patients aged 2-55 with LGS, confirmed by EEG, ≥2 drop seizures/week, failed ≥2 anti-epileptic drugs. Oral CBD (Epidiolex) 20 mg/kg/day or placebo for 14 weeks. Primary endpoint: percentage change in drop seizure frequency.
Who was studied
Patients aged 2-55 with Lennox-Gastaut syndrome, ≥2 drop seizures/week, failed ≥2 anti-epileptic drugs
What this study cannot tell us
14-week treatment period may not capture long-term efficacy or safety. High adverse event rate (86%) including elevated liver enzymes, particularly with concurrent valproate. The 14% discontinuation rate in the CBD group is higher than in the Dravet trial. GW Pharmaceuticals funded the trial — standard for pharma but a conflict of interest.
How to read the evidence
Gold-standard Phase 3 RCT: randomized, double-blind, placebo-controlled, multi-site (24 centers, 3 countries), published in The Lancet. Strong evidence. Funded by GW Pharmaceuticals.
When this study was published
Published January 2018. Led directly to FDA approval of Epidiolex in June 2018 for both LGS and Dravet syndrome. A third indication (tuberous sclerosis complex) was added in 2020.
The bigger picture
This trial answered the critical question: is CBD's anticonvulsant effect specific to Dravet syndrome, or does it generalize? It generalizes. LGS has completely different underlying causes from Dravet, yet CBD worked in both. This means CBD's mechanism is broad — acting through pathways relevant to seizure activity in general, not just one ion channel defect.
Questions still open
- What is CBD's exact anticonvulsant mechanism? Would lower doses be effective with fewer adverse events? Can CBD help other epilepsy types beyond Dravet, LGS, and TSC?
Common questions
Read the original research
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial
Lancet
The Lancet — one of the world's oldest and most prestigious general medical journals, publishing landmark clinical trials since 1823.
Citation
Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, et al.. (2018). Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. https://doi.org/10.1016/S0140-6736(18)30136-3