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