Imagine a future where the ketogenic diet—a well-known treatment for difficult-to-control seizures—could be replaced by a pill.

Such a pill would provide the same seizure-reducing benefits without the challenges of maintaining a strict diet or dealing with its side effects. Recent research suggests we may be one step closer to that goal¹.

Scientists have identified a specific receptor in the brain that is activated by the ketogenic diet and helps quiet brain activity that leads to seizures. This discovery was made using mouse models of epilepsy and provides new insight into how the diet works.

The ketogenic diet affects the body through many different biological pathways, which has made it hard to pinpoint exactly how it suppresses seizures. However, one key substance produced by the diet is beta-hydroxybutyrate (β-HB), a molecule made when the body burns fat for energy. β-HB activates a receptor called hydroxycarboxylic acid receptor 2 (HCAR-2).

HCAR-2 is found on many types of cells throughout the body, including fat cells and immune cells. Importantly, it is also present in the brain. The recent study focused on the hippocampus, a brain region where seizures often begin in people with temporal lobe epilepsy.

Using electrical recordings from brain cells in the hippocampus, researchers showed that β-HB reduced both the electrical activity of neurons and the communication between them—processes that are essential for seizures to occur. Crucially, these effects depended on HCAR-2. When the receptor was genetically removed, β-HB no longer reduced neuronal activity or seizures. This confirmed that HCAR-2 is required for these beneficial effects.

Because HCAR-2 is also present in the human brain, it has now become an attractive new target for developing drugs to treat drug-resistant epilepsy (DRE). Previous research already offers some encouraging clues. For example, niacin (vitamin B3) activates HCAR-2. In one observational study, higher dietary intake of niacin was associated with a lower prevalence of epilepsy. While this type of study does not prove cause and effect, it supports the idea that HCAR-2 may play a role in seizure control².

There are, however, important challenges to consider. HCAR-2 is found throughout the body, not just in the brain. Any drug designed to target this receptor for epilepsy would need to be carefully tested for effects on other organs, including fat tissue and the immune system. Some drugs that activate HCAR-2 already exist and are used to affect lipid metabolism. One example is MK-6892, an experimental HCAR-2 activator developed to lower blood lipids. There is currently no evidence that this drug reduces seizures. In fact, based on its chemical structure, it is unlikely to cross the blood–brain barrier, which would be necessary for anti-seizure effects.

Going forward, more research is needed to better understand how HCAR-2 influences brain excitability and seizure prevention. It may be possible to develop a drug that reaches the brain and selectively targets this receptor to treat drug-resistant epilepsy. At the same time, potential effects on the rest of the body would need to be carefully evaluated.

Even if HCAR-2 does not ultimately become the key to a new epilepsy treatment, this research sheds valuable light on how the ketogenic diet works. Most importantly, it moves us closer to the goal of developing new, more practical treatments for epilepsy in the future.

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1. Naderi et al., Hydroxycarboxylic Acid Receptor 2 Mediates β-hydroxybutyrate’s Antiseizure Effect in Mice. Annals of Neurology 2025;00:1–16 ↩︎
2. Ling K, He X, Yang Z. Dietary niacin intake and epilepsy: a cross-sectional study. Epilepsy Behav Rep. 2025 Aug 5;31:100814. doi: 10.1016/j.ebr.2025.100814. PMID: 40809740; PMCID: PMC12347950. ↩︎