Long-term CBD treatment sustained seizure reductions for up to 96 weeks in children and adults with severe epilepsy

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.

The Numbers That Matter

The responder rates told the same story:

The Dropout Problem

Myth vs. Reality

✕Myth

CBD works for virtually everyone with treatment-resistant epilepsy.

✓Reality

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.

Frequently Asked Questions

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.