Nutrition Notes

Influence of Ketones and Ketogenic Diets on the Brain and Central Nervous System

In a previous article, we explored the use of ketogenic and carbohydrate restricted diets for improving blood glucose control and insulin levels in type 2 diabetes, metabolic syndrome and related conditions. This time, we’ll shift focus to other promising areas of therapeutic applications for this very low-carb, high-fat way of eating: neurological and neurodegenerative disorders, psychiatric conditions, and mood disorders.

Ketogenic diets have been used for therapeutic purposes since at least the 1920s, when they were developed as treatments for intractable epilepsy. Only recently, however, have scientists gained a better understanding of the mechanisms that explain the efficacy of this dietary intervention, and it’s probable there are still more to discover.

Ketogenic diets (KDs) induce a number of biochemical and physiological changes throughout the body. Although some of the beneficial effects may result simply from the presence of elevated ketones—which can be achieved through the use of exogenous ketones (usually as beta-hydroxybutyrate salts or esters)—others may not stem from the state of ketosis, per se, but instead may need to be induced by dietary carbohydrate reduction, which transitions the body from a primarily glucose-based metabolism to one where fatty acids predominate and ketones are generated endogenously.

For example, administering exogenous ketones in the absence of carbohydrate reduction would be unlikely to have a significant beneficial impact on chronic hyperglycemia or insulin resistance. On the other hand, exciting but small scale research suggests administration of exogenous ketones can have a substantial positive impact in certain conditions—such as Alzheimer’s disease—even when carbohydrate restriction is not implemented.   

To start with the somewhat obvious, KDs have a significant impact on normalizing hyperglycemia and hyperinsulinemia. To the extent that either or both of these may be causing or exacerbating neurological and neurodegenerative disorders (as is speculated for Parkinson’s disease and Alzheimer’s), correcting them may result in some improvement. Indeed, studies looking at nutritional ketosis for these conditions is promising so far, showing individuals with Parkinson’s to have improvements in both motor and non-motor symptoms, and for scores on a diagnostic tests for mild cognitive impairment (MCI, the precursor to Alzheimer’s) to improve from MCI to normal in at least one case study, albeit combined with other lifestyle changes.

Some of these results may be related to the reduction in blood glucose and insulin, but some are also likely due to the elevation of ketone levels. It has been shown in Alzheimer’s and  multiple sclerosis that neurons have impaired glucose uptake and metabolism, and there are metabolic abnormalities reminiscent of type 2 diabetes in Parkinson’s disease. In the case of Alzheimer’s, it’s been established that affected individuals are still able to properly metabolize ketones, so ketones may serve as an alternative fuel substrate to nourish otherwise starving neurons. (In addition to serving as an alternative fuel to glucose, ketones can be considered a better fuel, as they lead to “uniquely efficient” generation of ATP with fewer damaging reactive oxygen species than result from glucose metabolism.) The same may be true of other neurodegenerative disorders. A small feasibility study of a KD for Parkinson’s disease wherein ketosis was verified via urine testing (for the ketone body acetoacetate) showed the 5 participants having a mean improvement of 43% on the Unified Parkinson’s Disease Rating Scale (21-81%).

Beyond stimulating the production of ketones as a fuel source for the central nervous system, ketogenic diets induce several other effects that may explain their efficacy for diverse neurological and neurodegenerative conditions. One is greater production of GABA, and the resulting inhibitory activity in the brain to counteract increased excitatory stimuli, as is seen in epilepsy. Animal evidence shows that ketogenic diets increase production of norepinephrine. Increases in noradrenergic tone result in anticonvulsant activity, and noradrenergic receptor agonists generally induce anticonvulsant effects.

Another possible mechanistic explanation for the efficacy of the KD is that this nutritional state improves mitochondrial biogenesis and bioenergetics. Most neurodegenerative disorders are associated with mitochondrial dysfunction, decreased neuronal energy generation and increased oxidative stress, making the KD an attractive intervention. Some of these disorders—particularly different variants of epilepsy—are associated with defects in complex I of the electron transport chain. Metabolism of fatty acids and ketones results in fewer electrons passing through complex I, and in vitro evidence suggests the ketone bodies beta-hydroxybutyrate and acetoacetate mitigate decreases in ATP typically caused by complex I defects, as well as possibly promote repair of complex I. In other words, in conditions where cellular energy generation is impaired due to complex I defects, ketone metabolism and resultant ATP generation are not decreased.

Yet one more mechanism—one that is especially relevant for epilepsy but which may also play a role in migraine—is hyperpolarization or stabilization of neuronal membrane electrical potential. Proper balance of ion gradients and electrical charges must be maintained just inside and outside neuronal membranes to ensure healthy cellular function. This is typically disturbed in epilepsy patients and could also be a factor in other neurological conditions. Membrane hyperpolarization raises the threshold for seizure and may also do the same for migraine, such that the possibility of a seizure or migraine is still there, but it takes more of the stimulus to trigger the event.

Some of the effects mentioned above may explain why the KD has been shown to be beneficial in case reports of individuals with schizophrenia, including complete resolution of longstanding symptoms in a woman who’d experienced hallucinations for over 60 years. Individuals with bipolar II disorder may also benefit from a ketogenic diet, possibly for some of the reasons outlined here. A case report of two subjects with bipolar II noted that in following the KD, both subjects “experienced mood stabilization that exceeded that achieved with medication; experienced a significant subjective improvement that was distinctly related to ketosis; and tolerated the diet well,” with no significant adverse effects.

Changes in brain bioenergetics and neurotransmission—be it the presence of ketones, increased GABA, normalization/hyperpolarization of neuronal membranes, or some as-yet undiscovered factor—may explain anecdotal reports of individuals with depression or anxiety noticing improvements after adopting ketogenic diets, often for other purposes, such as blood sugar control or fat loss, as was the case for two individuals who tried keto for migraines. Their goal was fat loss; nearly complete resolution of high-frequency migraines was a happy unexpected bonus!

The numerous and diverse effects of ketogenic diets mean there will probably never be a “ketogenic diet in a pill.” It would be nearly impossible to develop a pharmacological agent to mimic these mechanisms, only a select few of which we’ve looked at here. For conditions that respond favorably to the presence of elevated ketones with or without a ketogenic diet, exogenous ketones, coconut oil or MCT oil may be beneficial. For conditions associated with chronic hyperglycemia or insulin resistance, dietary carbohydrate restriction may be required, although the addition of exogenous ketones on top of this may have an additive effect in some cases.