The effects of ketogenic diet on alcohol intoxication

PROJECT SUMMARY/ ABSTRACT The ketogenic diet (KD) has previously been shown to reduce alcohol withdrawal symptoms and cravings and emerged as a potential treatment option for alcohol use disorder (AUD). However, a preclinical study demonstrated higher blood alcohol concentrations in alcohol-administered rats maintained on KD compared to those on a standard chow diet. This raises concerns for heightened intoxication and associated risks for alcohol poisoning and reckless behaviors in individuals on KD. Furthermore, a previous study in our laboratory demonstrated elevated neurotransmitter glutamate in individuals adhering to KD compared to standard American diet (SA), and changes in levels of neurotransmitters glutamate and GABA may exacerbate the intoxicating effects of alcohol. Therefore, the overall objective of this proposed study is to examine the neuropharmacological effects of KD on alcohol intoxication. The K99 phase (Aims 1 and 2) will take advantage of cutting-edge magnetic resonance spectroscopy (MRS) methodologies to measure brain glutamate and GABA, as well as assess subjective and objective indices of alcohol intoxication in healthy individuals. Given previous evidence suggesting that chronic alcohol intake produces tolerance in individuals with AUD, the R00 phase (Aim 3) will focus on non- treatment-seeking individuals with AUD. We propose a randomized, cross-over design in which participants will receive a 2-week KD and a 2-week standard American diet in randomized order. Following the dietary intervention, participants will be assessed for brain levels of glutamate and GABA and responses to an alcohol challenge using breath alcohol concentration, motor and cognitive tests, and self-reports of intoxication on validated questionnaires. We hypothesize that adherence to a KD will elevate brain glutamate and GABA levels and slow alcohol metabolism, exacerbating alcohol intoxication symptomatology. The findings may have public health implications for better understanding factors mediating alcohol intoxication and identifying the safety of KD as a potential AUD therapy. The research outlined above will also provide the applicant with training to facilitate a successful transition from a mentored postdoctoral fellow to an independent researcher. Specifically, it will enable Dr. Li to achieve five training goals: 1) hands-on experience in the clinical and regulatory aspects of clinical research, 2) proficiency in MRS methodologies, 3) application of neuropsychiatric assessments and behavioral paradigm, 4) leadership skills, and 5) general independent research skills. Through a combination of didactic and hands-on activities, the project will fulfill Dr. Li’s training needs and enable her to transition to a successful and independent research career.