Low-carb diets, fasting and euphoria: Is there a link between ketosis and γ-hydroxybutyrate (GHB)?

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Summary

Anecdotal evidence links the initial phase of fasting or a low-carbohydrate diet with feelings of well-being and mild euphoria. These feelings have often been attributed to ketosis, the production of ketone bodies which can replace glucose as an energy source for the brain. One of these ketone bodies, β-hydroxybutyrate (BHB), is an isomer of the notorious drug of abuse, GHB (γ-hydroxybutyrate). GHB is also of interest in relation to its potential as a treatment for alcohol and opiate dependence and narcolepsy-associated cataplexy. Here I hypothesize that, the mild euphoria often noted with fasting or low-carbohydrate diets may be due to shared actions of BHB and GHB on the brain. Specifically, I propose that BHB, like GHB, induces mild euphoria by being a weak partial agonist for GABAB receptors. I outline several approaches that would test the hypothesis, including receptor binding studies in cultured cells, perception studies in trained rodents, and psychometric testing and functional magnetic resonance imaging in humans. These and other studies investigating whether BHB and GHB share common effects on brain chemistry and mood are timely and warranted, especially when considering their structural similarities and the popularity of ketogenic diets and GHB as a drug of abuse.

Introduction

Since recorded time, across many cultures, fasting has been used in rituals aimed at attaining a higher state of being. Fasting for religious and spiritual reasons has been mentioned in the Bible, both Old and New Testaments, the Koran and the Mahabharata [1]. Anecdotal feelings of well-being and mild euphoria also litter the popular literature on low-carbohydrate diets. For example, one diarist wrote after 2–3 days on the Atkin’s Diet: “It is not an unpleasant feeling, a sort of mild, foggy euphoria”. [2]. From an evolutionary perspective, mild euphoria associated with short-term fasting may ease anxiety and aid the search for food. Ketosis occurs during the first few days of fasting or a low-carbohydrate diet, when breakdown of fat (β-oxidation) outstrips breakdown of carbohydrate (glycolysis). Three ketone bodies are produced by the liver: acetone, acetoacetate and β-hydroxybutyrate (BHB). Whilst BHB is usually referred to as a ketone body, it should be noted that it lacks a ketone group and is in fact a short-chain hydroxy fatty acid. After 2–3 days of fasting BHB reaches millimolar levels in the blood and brain [3], and together with acetoacetate provides the brain with an alternative energy source to glucose. Several biochemical explanations have been proposed for the feelings of euphoria often associated with short-term total fasting or low-carbohydrate diets. Bloom [4] postulated that accumulation of acetoacetate produces a mild intoxication similar to ethanol. Phillips [5] speculated from his studies in dairy cows that the accumulation of isopropyl alcohol (a byproduct of acetone metabolism) in neural tissue might be responsible for fasting-induced religious, mystical or hallucinatory experiences.

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Hypothesis

Here I propose that diet-induced euphoria may involve production of BHB, and may be at least partially explained by the well-known psychological effects of its isomer, γ-hydroxybutyrate (GHB) (Fig. 1). Considering their structural similarities, it is perhaps surprising that no one has linked BHB and GHB before.

γ-hydroxybutyrate

GHB occurs naturally in the brain where it can undergo interconversion with the inhibitory brain neurotransmitter γ-aminobutyric acid (GABA) [6], [7]. However, in recent years, there has been burgeoning interest in GHB in relation to its potential as a treatment for alcohol and opiate dependence and narcolepsy-associated cataplexy. GHB has also gained notoriety as a major recreational drug of abuse and as a “date-rape” drug [6]. Sold illegally under a variety of names (including G, liquid

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