CBD may control seizures by regulating methionine through a previously unknown metabolic pathway

What the researchers found

Using the model organism Dictyostelium, researchers identified that CBD activity depends partly on the glycine cleavage system, linked to folate one-carbon metabolism (FOCM). CBD directly inhibited methionine synthesis. In a Dravet syndrome mouse model, one-carbon metabolism components including methionine were drastically altered. In an in vitro rat seizure model, methionine levels were elevated during seizures and reduced by CBD treatment.

Why it matters

Despite FDA approval of Epidiolex for Dravet syndrome, CBD mechanism of action was poorly understood. This study identifies an entirely new metabolic pathway (one-carbon metabolism/methionine) that may explain how CBD controls seizures.

The numbers in context

CBD activity dependent on GcvH1 (glycine cleavage system H protein); direct methionine synthesis inhibition; Dravet mouse brain showed altered one-carbon components; rat seizure model: elevated methionine attenuated by CBD.

How the study worked

Multi-model approach: unbiased screen in Dictyostelium to identify CBD-interacting proteins; validation in Dravet syndrome mouse model (brain tissue analysis); functional testing in acute in vitro rat hippocampal seizure model. Methionine and one-carbon metabolites measured across all models.

What this study cannot tell us

Initial discovery in a simple model organism (Dictyostelium); animal models only; mechanism not yet confirmed in human epilepsy tissue; does not establish dose-response in mammals; the multiple-model approach increases confidence but each individual model has limitations.

How to read the evidence

Moderate: novel mechanistic discovery validated across three model systems, but all preclinical/animal data.

When this study was published

Published 2020.

The bigger picture

One-carbon metabolism is fundamental to cellular function. If CBD anti-seizure effects work through this pathway, it opens entirely new drug targets for epilepsy treatment and may explain why CBD helps some seizure types but not others.

Questions still open

• Is methionine elevation a biomarker for seizure activity? Could directly targeting one-carbon metabolism be more effective than CBD itself?

Common questions

Read the original research

A new mechanism for cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.

British journal of pharmacology, 177(4), 912-928

Citation

Perry, Christopher J; Finch, Paul; Müller-Taubenberger, Annette; Leung, Kit-Yi; Warren, Eleanor C; Damstra-Oddy, Joseph; Sharma, Devdutt; Patra, Pabitra H; Glyn, Sarah; Boberska, Joanna; Stewart, Balint; Baldwin, Amy; Piscitelli, Fabiana; Harvey, Robert J; Harwood, Adrian; Thompson, Christopher; Claus, Sandrine P; Greene, Nicholas D E; McNeish, Alister J; Williams, Claire M; Whalley, Benjamin J; Williams, Robin S B. (2020). A new mechanism for cannabidiol in regulating the one-carbon cycle and methionine levels in Dictyostelium and in mammalian epilepsy models.. British journal of pharmacology, 177(4), 912-928. https://doi.org/10.1111/bph.14892

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