In an expanded access program, add-on CBD reduced major motor seizures by 50% at 12 weeks, with consistent reductions maintained through 96 weeks of treatment.
Families of children with severe epilepsy, neurologists, and anyone evaluating long-term CBD efficacy.
50% seizure reduction sustained 96 weeks
The Backstory
The randomized controlled trials proved CBD worked. The Dravet trial ran 14 weeks. The Lennox-Gastaut trial ran 14 weeks. The TSC trial ran 16 weeks. All demonstrated significant seizure reduction versus placebo.
But parents had an obvious question: does it keep working?
Epilepsy treatments famously lose effectiveness over time. A drug that works brilliantly for three months can stop working by six. Tolerance — the same phenomenon that cannabis users experience — is a constant threat in seizure management. Neurologists call it the "honeymoon effect": initial excitement followed by gradual return to baseline.
This study answered the tolerance question. For nearly two years. In 152 patients. In the closest thing to real-world clinical practice that a research program can produce.
The Expanded Access Program
Unlike the RCTs, this wasn't a controlled experiment. It was an expanded access program — a compassionate-use framework that gave patients access to Epidiolex before FDA approval. Since 2014, patients with severe treatment-resistant epilepsies had been enrolling at 25 sites across the United States. There was no placebo group, no blinding, no randomization. Everyone received CBD.
What this design loses in rigor, it gains in clinical relevance. These patients were on real-world medication regimens (median 3 concurrent anti-epileptic drugs, range 0-10). Their doses were titrated based on clinical response and tolerability, just as they would be in practice. They were followed for months and years, not weeks.
How They Did It
Long-Term CBD in Real-World Practice
Enrollment
607 total patients entered the expanded access program. Of these, 152 had confirmed Lennox-Gastaut syndrome (94) or Dravet syndrome (58). The remaining 455 had other treatment-resistant epilepsies.
Started 2014 — before any RCT had reported results
Treatment
Pharmaceutical CBD (Epidiolex) at 2-10 mg/kg/day, titrated up to 25-50 mg/kg/day based on response and tolerability. Median dose during maintenance: 21-25 mg/kg/day.
Consistent with the doses used in the RCTs
Follow-up
Patient visits every 2-4 weeks. Caregivers kept seizure diaries. Efficacy evaluated at 12-week intervals through 96 weeks. Safety monitored through 144 weeks (nearly 3 years).
Median treatment duration: 78.3 weeks (range 4-146 weeks)
Analysis
Percentage change in median monthly seizures from baseline, evaluated at each 12-week interval. Responder rates (≥50%, ≥75%, 100% reduction) tracked over time.
The critical question: do the numbers hold, or do they drift back toward baseline?
Laux et al. (2019), Epilepsy Res 154:13-20
The Numbers That Matter
50% reduction — sustained 96 weeks
Median monthly major motor seizures dropped by 50% at 12 weeks and stayed there through 96 weeks of continuous treatment. Total seizures (all types) dropped by 44% at 12 weeks with similar consistency. No evidence of tolerance development over nearly two years of daily CBD use.
For context, many anti-epileptic drugs show a 'honeymoon effect' where initial seizure reduction fades over months. CBD did not show this pattern. The reductions at week 96 were statistically indistinguishable from the reductions at week 12.
Laux et al. (2019), Epilepsy Res 154:13-20
The responder rates told the same story:
Major Motor Seizures
- ≥50% reduction: 53% at 12 weeks — consistent through 96 weeks
- ≥75% reduction: 23% at 12 weeks — consistent through 96 weeks
- 100% seizure-free: 6% at 12 weeks — consistent through 96 weeks
- No evidence of declining responder rates over time
Sustained response — no tolerance
Total Seizures (All Types)
- ≥50% reduction: 46% at 12 weeks — consistent through 96 weeks
- ≥75% reduction: 26% at 12 weeks — consistent through 96 weeks
- 100% seizure-free: 5% at 12 weeks — consistent through 96 weeks
- Broad seizure-type benefit maintained long-term
Similar sustained pattern across seizure types
Laux et al. (2019), Epilepsy Res 154:13-20
The Dropout Problem
Myth vs. Reality
CBD works for virtually everyone with treatment-resistant epilepsy.
In this expanded access program, 28% of LGS/DS patients withdrew — and 20% withdrew specifically because CBD wasn't working for them. This means roughly 1 in 5 patients did not benefit enough to continue treatment. The 50% seizure reduction reported at 96 weeks reflects the patients who stayed — those who responded. Including the non-responders who dropped out would lower the overall efficacy estimate. CBD is effective for many patients with severe epilepsy, but it is not effective for all.
The Evidence
Laux et al. (2019): 28% withdrawal rate, 20% due to lack of efficacy. Of those who remained, 53% achieved ≥50% reduction in major motor seizures. The persistence of response in those who stayed is genuine — but the selection effect must be acknowledged.
Laux et al. (2019), Epilepsy Res 154:13-20
This is an important nuance. The RCTs (which included non-responders through intention-to-treat analysis) showed 38-49% seizure reduction. This EAP showed 50% — slightly higher, likely because non-responders were more likely to withdraw, leaving a responder-enriched population in the long-term data. Both numbers are valid; they just measure different things.
No Tolerance
The most reassuring finding: no evidence of tolerance developing over 96 weeks of continuous daily CBD use.
This was not a given. The endocannabinoid system adapts to chronic cannabinoid exposure — that's the molecular basis of cannabis tolerance. CB1 receptors downregulate and internalize in response to sustained activation. If CBD's anticonvulsant mechanism worked primarily through cannabinoid receptors, tolerance would be expected.
The absence of tolerance supports the hypothesis that CBD's anticonvulsant mechanism involves non-CB1/CB2 pathways — TRPV1 channels, GPR55 antagonism, 5-HT1A agonism, adenosine reuptake inhibition, or T-type calcium channel modulation. These targets are less prone to the kind of receptor desensitization that drives cannabinoid tolerance.
Long-Term Safety
Through 144 weeks of safety monitoring:
- Somnolence: 30% — the most common adverse event
- Diarrhea: 24%
- Safety profile consistent with short-term RCT data — no new safety signals emerged with long-term use
- Serious adverse events were reported but consistent with the underlying disease severity in this population
The safety profile didn't worsen over time — an important finding for a drug intended for indefinite use in children.
Related Research
From Proof to Practice
This study bridges the gap between controlled trial evidence and real-world long-term use. It answers the question the RCTs couldn't: does CBD keep working?
Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
Devinsky et al. (2017)
The 14-week RCT. This EAP study shows the effect persists for 96 weeks.
CBD for Lennox-Gastaut syndrome (GWPCARE4)
Thiele et al. (2018)
The 14-week LGS RCT. Same story: works short-term. This study confirms long-term.
Add-on CBD for tuberous sclerosis complex
Thiele et al. (2021)
The TSC trial that also showed a dose ceiling — consistent with this EAP's finding of optimal doses around 21-25 mg/kg/day.
Chronic administration of cannabidiol to healthy volunteers and epileptic patients
Cunha, Carlini, Mechoulam et al. (1980)
The original 1980 trial ran 4.5 months and saw sustained benefit. Forty years later, this study confirmed the same pattern over 96 weeks.
Does CBD stop working over time for epilepsy?
Not in this study. Seizure reductions at 12 weeks were maintained consistently through 96 weeks of continuous daily CBD use — nearly two years. Responder rates (the proportion of patients achieving ≥50% seizure reduction) did not decline over time. There was no evidence of the "honeymoon effect" that plagues many epilepsy treatments. This suggests that CBD's anticonvulsant mechanism is not subject to the same tolerance that develops with chronic cannabis use for other purposes.
Does CBD work for everyone with severe epilepsy?
No. About 20% of patients in this program withdrew because CBD was not providing sufficient benefit. Among those who stayed, about 53% achieved a 50% or greater reduction in major motor seizures, and 6% became seizure-free. CBD is effective for a meaningful proportion of patients with treatment-resistant epilepsy, but it is not a universal solution. Predicting which patients will respond remains an area of active research.
What are the long-term side effects of CBD for epilepsy?
Through 144 weeks (nearly 3 years), the most common adverse events were somnolence (30%) and diarrhea (24%). No new safety signals emerged with long-term use — the side effect profile was consistent with what the shorter RCTs had shown. Liver enzyme monitoring remains necessary, particularly for patients also taking valproate. The overall safety profile was deemed acceptable for a population with severe, life-threatening epilepsy.
What the researchers found
At 12 weeks, CBD reduced median monthly major motor seizures by 50% and total seizures by 44%. These reductions remained consistent through 96 weeks. At 12 weeks, 53% of patients had 50%+ reduction in major motor seizures and 6% were seizure-free.
Why it matters
Clinical trials show efficacy under controlled conditions, but expanded access programs reveal how treatments perform in real-world clinical practice. These results confirm that CBD's seizure-reducing benefits persist long-term.
The numbers in context
607 total patients (152 with LGS/DS); median 3 concomitant AEDs; median treatment duration 78.3 weeks; 50% reduction in major motor seizures at 12 weeks; 53% achieved 50%+ reduction; 6% seizure-free; 28% withdrew (20% for lack of efficacy); somnolence 30%, diarrhea 24%.
How the study worked
Expanded access program (closely reflecting clinical practice) at 25 US sites. 152 patients with LGS or DS received pharmaceutical CBD (Epidiolex) at 2-10 mg/kg/day, titrated up to 25-50 mg/kg/day. Interim analysis through 96 weeks of treatment.
What this study cannot tell us
No control group (expanded access design). 28% withdrawal rate, with 20% leaving due to lack of efficacy, which could bias long-term results toward responders. Patients were on multiple concomitant medications.
How to read the evidence
Strong: large multi-site expanded access program with long-term follow-up, though lacking a control group.
When this study was published
Published in 2019.
The bigger picture
Sustained efficacy over nearly two years without apparent tolerance development is a critical finding. Many epilepsy treatments lose effectiveness over time, so this long-term data provides important reassurance.
Questions still open
- Does CBD maintain efficacy beyond 96 weeks? Could earlier initiation of CBD treatment improve long-term outcomes? What predicts which patients will not respond?
Common questions
Does CBD stop working over time for epilepsy?
What were the main side effects of long-term CBD use?
Read the original research
Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results.
Epilepsy research, 154, 13-20
Citation
Laux, Linda C; Bebin, E Martina; Checketts, Daniel; Chez, Michael; Flamini, Robert; Marsh, Eric D; Miller, Ian; Nichol, Kathryn; Park, Yong; Segal, Eric; Seltzer, Laurie; Szaflarski, Jerzy P; Thiele, Elizabeth A; Weinstock, Arie. (2019). Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results.. Epilepsy research, 154, 13-20. https://doi.org/10.1016/j.eplepsyres.2019.03.015
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