Unlike other physiological fuel metabolites like glucose, ketones and fatty acids, there is a lack of homeostatic regulation of blood ethanol levels, which renders circulating levels to approach zero within a few hours after the cessation of drinking. Due to the diminished capacity for glucose utilization caused by metabolic reprogramming, a sudden abstinence from ethanol can result in significant energy depletion in neurons or other brain cells (Volkow et al., 2015). The resulting insufficiency of energy support likely explains many withdrawal symptoms, including dysphoria, tremor, anxiety, restlessness and insomnia (Muncie et al., 2013, Wilson and Matschinsky, 2020). Of course, association of withdrawal with this type of energy depletion may be due to effects in other CNS cell types including astrocytes. Indeed, impairment of brain energy production caused by reduced glucose uptake and usage in specific areas was found to be associated with diminished cognitive and executive functions (Volkow et al., 2015, Volkow et al., 2017). Many or most of these symptoms are likely results of changes in neuronal excitability.
