Alcohol use disorder (AUD) is a chronic relapsing brain disorder that involves impairments in cognition, motivation and sleep. Globally, 5% of deaths can be attributed to alcohol consumption. There is an urgent need to test interventions that can promote long-term abstinence, reduce alcohol craving, and minimize withdrawal symptoms such as tremor, delirium and insomnia. Recent observations on brain energetics suggest a shift from brain glucose to acetate metabolism in AUD that persists beyond the acute intoxication state. During alcohol detoxification, brain acetate levels decrease, potentially leading to an energy-deficit state that contributes to neurotoxicity and withdrawal in AUD. A ketogenic diet (KD; high fat, low carbohydrate), increases ketone bodies including acetoacetate in plasma and brain (i.e., state of metabolic ketosis), which was shown to improve withdrawal in alcohol-drinking rodents during detoxification. For the K99 phase we propose a KD intervention study in AUD inpatients to test Aim 1: whether metabolic ketosis increases ketone bodies in the brain using 1H Magnetic Resonance Spectroscopy (MRS);
Aim 2 : the potential beneficial effects of metabolic ketosis on withdrawal symptoms, alcohol craving, sleep quality during alcohol detoxification. To this end, we randomize 50 AUD inpatients into a KD (n=25) or Standard American diet (n=25) for 3 weeks. Patients will undergo weekly MRS scans to quantify brain ketone bodies; and polysomnography to measure sleep quality. We hypothesize that: (1) we will be able to quantify ketone bodies in the brains of AUD patients on KD with MRS; (2) KD reduces withdrawal and craving in AUD patients, and improves sleep quality. For the R00 phase, we propose a 1-dose nutritional ketone ester (KE) intervention with a random 2-way crossover design in non-treatment seeking AUD outpatients (n=15) to test Aim 3: whether metabolic ketosis decreases alcohol consumption. KE is a safe, non-invasive method that increases ketone levels within 1 hr to concentrations similar to KD, and levels remain for 4 hrs. AUD outpatients consume a drink with either KE or isocaloric dextrose. Ketone bodies are measured in blood and brain (MRS), after which. participants perform a drink ?taste test? including alcohol and soft drinks to measure alcohol self- administration. KE is expected to decrease alcohol intake, craving, and increase brain ketone bodies. If beneficial clinical effects of metabolic ketosis can be documented in human AUD patients, e.g., on withdrawal, alcohol craving, sleep or alcohol consumption, then KD or KE could be targeted as a therapeutic intervention to enhance success in recovery from AUD. The K99 training proposal further aims to provide the PI Dr. Corinde Wiers with adequate research training and skills to transition from a mentored postdoctoral fellowship to an independent tenure-track research position. Dr. Wiers will gain technical competence on MRS, sleep polysomnography and biostatistics. She will further enhance her leadership and teaching skills via courses at the OITE and by giving lectures and talks at NIH, at universities and conferences. To accomplish these goals, Dr. Wiers has proposed a mentoring team with expert scientists from NIAAA and US universities: Dr. Nora Volkow (NIAAA), Dr. Thomas Ernst (University of Maryland), and Dr. Peter Morgan (Yale).
The proposed research is relevant to public health because understanding the effects of chronic alcohol use on brain functioning, withdrawal, craving, sleep, and alcohol consumption may help to prevent alcohol use disorder, which affects 10% of Americans throughout their life. Moreover, the proposed study directly aims to alleviate alcohol withdrawal symptoms during detoxification, which are distressing and can be life threatening. The proposed study is in line with NIAAA?s mission because it generates fundamental knowledge on the potentially beneficial effects of a novel ketogenic diet intervention on brain energetics, and alcohol withdrawal during alcohol detoxification, to improve the diagnosis, treatment, and ultimately the prevention of alcoholism.
