How CBD reduces seizures by blocking a vicious feedback loop in the brain

A new study in the journal Neuron has identified a previously unknown way that cannabidiol (CBD) – a substance found in cannabis – reduces seizures in people with epilepsy.

Scientists already knew that CBD blocks the ability of a molecule, called lysophosphatidylinositol (LPI), to amplify nerve signals in the hippocampus. Too much of this signal amplification promotes seizures.

But the exact mechanism was poorly understood. The new study suggests it blocks a “positive feedback loop” in the brain.

While LPI causes nerve signal amplification it also weakens signals that counter seizures, which likely encourages more seizures, which then increases levels of LPI and the protein it binds to (GPR55), and the cycle continues.

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“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” says Richard W. Tsien, chair of the Department of Physiology and Neuroscience at New York University in the US, and corresponding author of the new study.

“The study also clarified, not just how CBD counters seizures, but more broadly how circuits are balanced in the brain,” adds Tsien.

“Related imbalances are present in autism and schizophrenia, so the paper may have a broader impact.”

CBD disrupts a seizure-inducing positive feedback loop

In the brain, neurons communicate by “firing”. They send an electrical impulse from the dendrites to the soma, and down the axon to the end of the cell before the synapse – the junction between neurons. This triggers the release of neurotransmitters that float across this minuscule gap to either encourage the next cell to fire (excitation) or stop it from doing so (inhibition).

A balance between these two states is essential to normal brain function; too much excitation promotes seizures.

By genetically engineering mice the team successfully blocked the effects of LPI on excitation and inhibition.

They propose that CBD blocks a “positive feedback loop” where seizures increase the effect of LPI-GPR55 on excitation and inhibition, which likely encourages more seizures, which then increases levels of both LPI and GPR55.

This process could explain repeated epileptic seizures, although future studies are needed to confirm this.

The signalling network that LPI is a part of also includes “endocannabinoids” like 2-Arachidonoylglycerol (2-AG) that occur naturally in human tissues and respond to increases in brain activity by turning down the release of neurotransmitters from neurons.

LPI and 2-AG can be converted into each other by enzymes, so targeting this process could be a potential approach to controlling seizures.

“Theoretically, the brain could control activity by toggling between pro-excitatory LPI and the restorative actions of 2-AG,” explains Dr Evan Rosenberg, a post-doctoral researcher in the Tsein’s lab and first author of the study.

“Drug designers could inhibit the enzymes that underpin LPI production or promote its conversion to 2-AG, as an additional approach to control seizures.