Ketosis decreases cocaine-induced reinstatement in male


A diet that is rich in fat, modest in protein, and very low in carbohydrates is typically referred to as a “ketogenic diet.” The formation of ketone bodies, which can be used as an alternative energy source by cells that cannot directly metabolize fatty acids, is the goal of this fuel combination, which tries to induce ketosis. Ketone levels in the urine are frequently used to gauge dietary compliance. When consuming fat as its primary fuel, the body naturally enters a state known as ketosis. This happens when eating a ketogenic diet with very few carbohydrates and frequently also when fasting intermittently. Fats break down and produce ketone bodies in the liver, such as β-hydroxybutyrate (OHB), which are signs of nutritional ketosis when carbs are lowered to less than 5–10% of the diet. Due to the unique metabolic state of the ketogenic diet, it has recently been used as adjunctive therapy for several neurological conditions, including epilepsy and neurodegenerative diseases. For example, the ketogenic, or “keto” diet (KD) was common to parents of epileptic children. The eating plan produces a rise in ketones in the bloodstream, which doctors discovered were useful in reducing the number of seizures patients endured. However, there are other conditions, such as drug addiction, where the impact of nutrition is just now being researched, but the ketogenic diet’s impact is barely touched upon.

Abuse-related drugs and palatable diets have an impact on common brain functions, specifically the reward system. Both increase the activity of dopaminergic neurons in the nucleus accumbens and stimulate common brain areas, including the lateral hypothalamus, ventral tegmental area, prefrontal cortex, or amygdala. They also decrease the density of active dopamine transporters. The brain circuits involved in motivation and reward are impacted by this dopaminergic activation brought on by tasty foods, including drug abuse. Recent research has shown that an intermittently delivered high fat diet (HFD), which does not affect body weight or metabolic indicators like ghrelin or leptin, can speed up the process of extinction and prevent the reinstatement of cocaine preference in adult male and female mice.

There is currently insufficient research conducted on the ketogenic diet’s potential therapeutic interactions with substance use disorders. In a recent study published in the journal Neuroscience Letters, Francisco Ródenas-Gonzalez, Dr. M. Carmen Blanco-Gandía, Professor Jose Miñarro and Professor Marta Rodríguez-Arias proposed that a ketogenic diet, which alters a person’s metabolic status, would prevent cocaine from inducing conditioned place preference (CPP) acquisition and hasten the erasure of cocaine-related memories in mice that had already developed CPP. The research sought to determine whether a ketogenic diet could alter cocaine’s conditioned rewarding effects at two key junctures: during acquisition and during extinction/reinstatement of the preference. The CPP technique, which assesses the contextual signals related to the rewarding effects of a medication, was used in their study.

The research team demonstrated that following the administration of 10 mg/kg of cocaine, all animals—whether given a KD or standard diet (SD) developed a place preference for the cocaine-paired compartment. However, both ketogenic diet-fed groups required fewer sessions throughout the extinction-reinstatement phase than the SD group did for the preference to disappear. Only the SD group showed a preference for the drug-paired compartment in the reinstatement test, which was produced by a priming dose of 5 mg/kg of cocaine (half the previously administered amount), demonstrating that being on a ketogenic diet prevented reinstatement with 5 mg/kg cocaine. The authors suggested a different explanation for how the ketogenic diet may affect addiction, including variations in βOHB blood levels. Animals in the ketogenic diet group did not grow more body weight than mice in the SD group, despite the ketogenic diet having more than twice as many calories as the SD.

One nutritional strategy for treating cocaine addiction may be the ketogenic diet. The diet may help to lessen the memories associated with cocaine use and the danger of relapse, even though it cannot be the only kind of treatment. In a statement to Medicine Innovates Professor Marta Rodríguez-Arias, the corresponding author said their study confirms what other research on various high-fat diets has revealed: nutritional treatments can influence the conditioned effects of drugs like cocaine, for which there is now no proven therapy.


Ródenas-González F, Blanco-Gandía MC, Miñarro J, Rodríguez-Arias M. Effects of ketosis on cocaine-induced reinstatement in male mice. Neuroscience Letters. 2022;778:136619.

Go To Neuroscience Letters.