Glutamate, GABA and How Ketosis Helps Brain Activity

Ketogenic metabolic therapy works through several mechanisms at once. One involves the balance between the brain's two main chemical messengers. This article aims to explain how changing what someone eats can help two very different-seeming problems.

What glutamate and GABA do

Neurons talk to each other using chemicals called neurotransmitters. Glutamate is the main one that says go. When a cell releases glutamate, the next cell in the circuit becomes more likely to fire. GABA is the main one that says stop. When a cell releases GABA, the next cell becomes less likely to fire.

What matters is the ratio between the two, which we call the excitation and inhibition balance. A brain circuit works properly when the go and stop signals are matched closely enough to keep activity in a workable range. The comparison with an accelerator and a brake is rough but useful, because a car with either pedal stuck is undriveable for different reasons.

One further detail matters later. GABA is made out of glutamate by a single enzyme. The accelerator chemical is the raw material for the brake chemical, so anything that changes how a cell handles glutamate can also change how much GABA it has to work with.

The balance can fail in two directions

When the go signals run ahead of the stop signals, thoughts arrive faster than they can be finished. The ones that repeat or catastrophise turn up more often and carry more weight. Background noise feels intrusive, sleep gets shallow and small frustrations feel enormous. This overactive pattern shows up in anxiety, in obsessive and intrusive thinking, in mania and in the delusions that can come with psychosis.

When activity in part of the brain drops too low, the experience is closer to flatness. Motivation drains away. Thinking feels slow and effortful, which people usually call brain fog. Nothing seems worth starting and starting anything feels harder than the task warrants. This flat pattern fits apathy, the withdrawal and loss of drive that can come with schizophrenia and the trouble with thinking that often comes with depression.

There is good evidence that both patterns often come from the same underlying difficulty.

Energy is the thread connecting them

Research over the past twenty years keeps finding the same thing in serious mental illness: the brain has trouble turning glucose into usable energy. The technical name is cerebral glucose hypometabolism and it shows up alongside insulin resistance and problems with mitochondria, the parts of a cell that generate its power. This has been documented in bipolar disorder, in schizophrenia and in depression. It is also well established in Alzheimer's disease, where reduced brain glucose metabolism is one of the earliest changes visible on scans and can appear before symptoms do. Raised blood glucose and insulin resistance have been found in people in a first episode of schizophrenia who have never taken antipsychotic medication, which matters because it means medication cannot be the whole explanation. One recent framework proposes that what fails in schizophrenia is the brain's ability to switch fuel sources as demand changes.

An energy shortage produces the flat pattern in an obvious way. Cells that cannot make enough power do less work and areas running below capacity contribute less to thinking, motivation and drive.

How an energy shortage produces the overactive pattern is less obvious. Two things seem to happen.

The first is that glutamate can itself be burned for energy. Iain Campbell and Harry Campbell at the University of Edinburgh have proposed that a brain struggling to get energy from glucose starts drawing on glutamate as a backup fuel, so the go signal rises as a side effect of the brain trying to meet its energy needs. They put this forward as the mechanism behind mania.

The second involves the cells that supply the stop signal. GABA is released by a group of cells that fire very fast and use a lot of energy doing it, which makes them vulnerable when energy is short. Damage to these cells turns up repeatedly in research on schizophrenia and has also been linked to mood instability. When the cells supplying the brake are struggling, a circuit becomes overactive without anything having pressed the accelerator.

This is why one underlying difficulty can look like agitation in one person and apathy in another, occasionally like both in the same person at different times.

What ketones seem to do

When carbohydrate intake drops far enough, the liver starts making ketones out of fat. The brain takes them up and burns them. Two things follow that matter for the balance.

The first is that cells which were short of power have fuel again. That would be expected to lift the flat pattern on its own. Campbell and Campbell make a further point: once the brain has fuel it can use, it has less reason to draw on glutamate for energy, so the go signal has less reason to stay high.

The second is that ketones seem to quieten cells according to how hard those cells are working. In laboratory studies the slowing effect was strongest in the cells firing fastest and slight in cells that were already quiet. Ketosis also shifts the chemistry inside brain cells towards making more GABA and releasing less glutamate.

How the same change helps in both directions

You might think that anything reducing the go signal would flatten everybody and make apathy worse in the people who already have it. The evidence suggests the opposite. The effect depends on what each cell is doing at the time. Cells that are firing hard get slowed a good deal. Cells that are already quiet are barely touched.

At the other end, the improved fuel supply lifts cells that were short of power. So the overactive end comes down while the underactive end comes up. Researchers in this area increasingly describe the effect as network stabilisation.

What people notice

Two broad patterns come up. Some people describe a rapid lift in energy and motivation, arriving as an antidote to a long stretch of apathy, malaise, low energy and brain fog. Others describe feeling calmer, with intrusive, obsessive or negative thoughts turning up less often and carrying less force.

The reverse gets described too. When people come out of ketosis, deliberately or otherwise, some notice apathy returning, with motivation and energy falling away again. Others notice anxiety and dread returning, with overthinking and thoughts that race or intrude.

Which pattern a person notices may depend on where their own balance was sitting to begin with.

Why it can happen early

Ketones can appear in the blood within a few days of starting the diet, sometimes sooner. What is described above depends on ketones being present and on the shift in how cells make energy that follows. None of it needs weeks of structural change in the brain, so an early shift in how someone feels is what the biology would predict.

Where the evidence stands

The mechanism research described here comes mostly from epilepsy, from animal studies and from brain tissue in the laboratory. The clinical trials in psychiatry are more recent and smaller, with controlled trials in schizophrenia and bipolar disorder currently under way. Studies measuring glutamate and GABA directly in the brains of people using ketogenic metabolic therapy for a mental health condition are only starting to appear, so the link between the mechanism and the change people notice is still an inference.

What can be said is that the account is coherent, that it rests on findings demonstrated in the laboratory and that it explains a pattern which is otherwise hard to account for.

Perri Carlson-Hawke is a clinical psychologist and the Director of Metabolic Psychology. 

This article is general information and does not replace individual clinical advice. Do not alter prescribed medication without discussing it with your prescriber. 

Related References

Campbell, I. H., & Campbell, H. (2024). The metabolic overdrive hypothesis: Hyperglycolysis and glutaminolysis in bipolar mania. Molecular Psychiatry, 29(5), 1521–1527.

Juge, N., Gray, J. A., Omote, H., Miyaji, T., Inoue, T., Hara, C., Uneyama, H., Edwards, R. H., Nicoll, R. A., & Moriyama, Y. (2010). Metabolic control of vesicular glutamate transport and release. Neuron, 68(1), 99–112.

Lutas, A., & Yellen, G. (2013). The ketogenic diet: Metabolic influences on brain excitability and epilepsy. Trends in Neurosciences, 36(1), 32–40.

Ma, W., Berg, J., & Yellen, G. (2007). Ketogenic diet metabolites reduce firing in central neurons by opening KATP channels. Journal of Neuroscience, 27(14), 3618–3625.

Pinna, A., & Colasanti, A. (2021). The neurometabolic basis of mood instability: The parvalbumin interneuron link, a systematic review and meta-analysis. Frontiers in Pharmacology, 12, Article 689473.

Sarnyai, Z., & Ben-Shachar, D. (2024). Schizophrenia, a disease of impaired dynamic metabolic flexibility: A new mechanistic framework. Psychiatry Research, 342, Article 116220.

Sarnyai, Z., Kraeuter, A.-K., & Palmer, C. M. (2019). Ketogenic diet for schizophrenia: Clinical implication. Current Opinion in Psychiatry, 32(5), 394–401.

Steullet, P., Cabungcal, J.-H., Coyle, J., Didriksen, M., Gill, K., Grace, A. A., Hensch, T. K., LaMantia, A.-S., Lindemann, L., Maynard, T. M., Meyer, U., Morishita, H., O'Donnell, P., Puhl, M., Cuenod, M., & Do, K. Q. (2017). Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. Molecular Psychiatry, 22(7), 936–943.

Yudkoff, M., Daikhin, Y., Melø, T. M., Nissim, I., Sonnewald, U., & Nissim, I. (2007). The ketogenic diet and brain metabolism of amino acids: Relationship to the anticonvulsant effect. Annual Review of Nutrition, 27, 415–430.