4.4 Article

Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice

Journal

PSYCHOPHARMACOLOGY
Volume 238, Issue 3, Pages 833-844

Publisher

SPRINGER
DOI: 10.1007/s00213-020-05735-1

Keywords

Alcoholism; Alcohol dependence; Alcohol withdrawal; Anxiety-like behavior; Detoxification; Ethanol; Ketone bodies; Ketone monoester; Mice

Funding

  1. Mental Health Services-Capital Region of Denmark
  2. Research Foundation Mental Health Services in the Capital Region of Denmark
  3. NIH/NIAAA [R01AA025071, R01AA021984]
  4. Independent Research Fund Denmark [0134-00044B]
  5. Ivan Nielsen Foundation
  6. NIH/NIDDK [R01DK108283]

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The study tested the use of β-hydroxybutyrate and a ketogenic diet during alcohol withdrawal to alleviate acute withdrawal symptoms. Results showed that adding β-hydroxybutyrate to the diet was effective in reducing handling-induced convulsions and anxiety-like behaviors during early withdrawal.
Rationale After alcohol ingestion, the brain partly switches from consumption of glucose to consumption of the alcohol metabolite acetate. In heavy drinkers, the switch persists after abrupt abstinence, leading to the hypothesis that the resting brain may be starved when acetate levels suddenly drop during abstinence, despite normal blood glucose, contributing to withdrawal symptoms. We hypothesized that ketone bodies, like acetate, could act as alternative fuels in the brain and alleviate withdrawal symptoms. Objectives We previously reported that a ketogenic diet during alcohol exposure reduced acute withdrawal symptoms in rats. Here, our goals were to test whether (1) we could reproduce our findings, in mice and with longer alcohol exposure; (2) ketone bodies alone are sufficient to reduce withdrawal symptoms (clarifying mechanism); (3) introduction of ketogenic diets at abstinence (a clinically more practical implementation) would also be effective. Methods Male C57BL/6NTac mice had intermittent alcohol exposure for 3 weeks using liquid diet. Somatic alcohol withdrawal symptoms were measured as handling-induced convulsions; anxiety-like behavior was measured using the light-dark transition test. We tested a ketogenic diet, and a ketone monoester supplement with a regular carbohydrate-containing diet. Results The regular diet with ketone monoester was sufficient to reduce handling-induced convulsions and anxiety-like behaviors in early withdrawal. Only the ketone monoester reduced handling-induced convulsions when given during abstinence, consistent with faster elevation of blood ketones, relative to ketogenic diet. Conclusions These findings support the potential utility of therapeutic ketosis as an adjunctive treatment in early detoxification in alcohol-dependent patients seeking to become abstinent.

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