One in Four Epilepsy Patients Developed Tolerance to CBD Treatment | Research

The takeaway

Among 92 patients with treatment-resistant epilepsy using CBD-enriched oil, 25% developed tolerance (reduced effectiveness) after an average of 7.3 months, with patients who had shorter epilepsy duration more likely to develop tolerance.

Epileptologists, CBD prescribers, epilepsy patients on long-term CBD

25% of patients developed tolerance to CBD after an average of 7.3 months

What the researchers found

Of 84 patients analyzed for tolerance (treated at least 3 months), 21 (25%) developed tolerance after a mean of 7.3 months. Overall responder rate was 54% (>50% seizure reduction), and 9% became seizure-free. Shorter epilepsy duration was negatively correlated with tolerance development (p=0.038).

Why it matters

This is the first study to systematically report tolerance to CBD in epilepsy patients. If one in four patients loses treatment benefit over time, it has significant implications for long-term seizure management.

The numbers in context

92 patients; mean age 11.8 years; mean follow-up 19.8 months; mean CBD dose 11.3 mg/kg/day; 31% discontinued; 51% had adverse reactions; 54% responder rate; 9% seizure-free; 25% developed tolerance at mean 7.3 months; shorter epilepsy duration associated with tolerance.

How the study worked

Prospective study of 92 consecutive patients (age 1-37, mean 11.8 years) with treatment-resistant epilepsy treated with CBD-enriched oil (CBD:THC 20:1), with tolerance defined as either need for >30% dose increase or >30% increase in seizure frequency after at least 3 months of stable treatment.

What this study cannot tell us

Single-center study; open-label design without placebo comparison; tolerance definition was operationalized rather than biologically confirmed; variable CBD-enriched oil formulations.

How to read the evidence

Prospective open-label study providing moderate evidence of tolerance development, limited by lack of placebo control and single-center design.

When this study was published

Mean follow-up of 19.8 months (range 3-45 months).

The bigger picture

Tolerance development could limit the long-term clinical utility of CBD for epilepsy, suggesting that dosing strategies, drug holidays, or combination approaches may need to be developed to maintain efficacy over time.

Questions still open

Can tolerance be overcome with dose adjustments or treatment breaks? Does tolerance to pharmaceutical-grade CBD (Epidiolex) develop at similar rates?

Common questions

Does CBD stop working over time?

In this study, 25% of epilepsy patients showed signs of tolerance to CBD after an average of 7.3 months, meaning the treatment became less effective. This is the first systematic report of CBD tolerance in epilepsy.

Who is more likely to develop tolerance?

Paradoxically, patients with shorter epilepsy duration were more likely to develop tolerance. The reasons for this are unclear and require further investigation.

Read the original research

Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist?

Brain & development, 43(1), 89-96

View on PubMed ↗Publisher’s paper ↗

Citation

Uliel-Sibony, Shimrit; Hausman-Kedem, Moran; Fattal-Valevski, Aviva; Kramer, Uri. (2021). Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist?. Brain & development, 43(1), 89-96. https://doi.org/10.1016/j.braindev.2020.06.018