Drinking, Acetate, and Stress
NCT Number: NCT06584448
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Alcohol Use Disorder|Alcohol Use, Unspecified|Heavy Drinker|Alcohol Use Disorder, Moderate, in Sustained Remission
Interventions: OTHER: Deuterium Metabolic Imaging with deuterated acetate tracer
Sponsor: Yale University
Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Sex: ALL
Age: ADULT
Enrollment: 50
Study Design: Allocation: NON_RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: BASIC_SCIENCE
Start Date: 2024-09
Completion Date: 2030-01
Locations: Yale University, New Haven, Connecticut, 06520, United States

Summary:
The purpose of this study is to learn how drinking alcohol affects how people experience stress and how that is affected by the body's chemistry. Specifically, the investigators will be studying relationships of drinking and a stress hormone called cortisol. The investigators believe that results will lead us to find more effective ways to help people stop or reduce drinking when participants are drinking at harmful levels.

Primary Outcome Measures: Rate of Conversion of Acetate to Glutamate + Glutamine (Glx) in the Brain, DMI data will be acquired during infusions of 2H-labeled Ac, using a 4-Tesla magnet. Deuterium flow from \[2,2,2-2H3\]Ac to glutamate (Glu) and glutamine (Gln). Ac forms AcetylCoA at a rate CMRAc and is oxidized by astroglia (VtcaA), labeling the small glial Glu pool (5-10% of the total Glu110).Astroglial Glu is converted to Gln and sent to neurons (Vcycle), where it is converted to labeled Glu. It mixes with the large neuronal Glu pool, fed also by unlabeled carbon mostly from glucose via neuronal oxidation (VtcaN), and the diluted Glu is released and taken up by glia for reconversion to Gln. With 2H, the sum of Glu and Gln is detected as \[2H\]Glx. The faster the rate of acetate consumption, the faster the appearance of \[2H\]Glx., Baseline and for TS, once within approximately one week and again at approximately one month|Concentration of [2H]Glx in the brain during administration of [2H]acetate, DMI data will be acquired during infusions of 2H-labeled Ac, using a 4-Tesla magnet. Deuterium flow from \[2,2,2-2H3\]Ac to glutamate (Glu) and glutamine (Gln). Ac forms AcetylCoA at a rate CMRAc and is oxidized by astroglia (VtcaA), labeling the small glial Glu pool (5-10% of the total Glu110).Astroglial Glu is converted to Gln and sent to neurons (Vcycle), where it is converted to labeled Glu. It mixes with the large neuronal Glu pool, fed also by unlabeled carbon mostly from glucose via neuronal oxidation (VtcaN), and the diluted Glu is released and taken up by glia for reconversion to Gln. With 2H, the sum of Glu and Gln is detected as \[2H\]Glx. The faster the rate of acetate consumption, the faster the appearance of \[2H\]Glx., Baseline and for treatment seekers, once after 1 month sober.
Secondary Outcome Measures: Rate of Cortisol Turnover, Plasma cortisol concentrations and enrichments will be measured in the Chemical Metabolism Core directed by Dr. Kibbey. Crashed plasma samples will be applied to a Phenomenex Kinetex F5 Core-shell LC column (100 x 2.1 mm, 2.6 µm), with 0.3 mL/min linear gradients from 100% aqueous phase (95% water, 5% acetonitrile and 0.1% formic acid) to 100% organic phase (95% acetonitrile, 5% water and 0.1% formic acid) in 20 min. Cortisol ions are measured in both positive and negative MS modes the Sciex TripleTOF 6600 using an information-dependent analysis (IDA) workflow consisting of a TOF MS scan (200 msec) and a high-resolution IDA experiment (70 msec each) monitoring 10 candidate ions per cycle. The ion source conditions are as follows; Ion spray voltage = 5000 V for positive mode and -4500V for negative mode, ion source gas 1 (GS1) = 50, ion source gas 2 (GS2) = 50, curtain gas (CUR) = 30, temperature (TEM) = 400 oC., Baseline and for treatment seekers, once after 1 month sober.
Other Outcome Measures: Change in Alcohol and Stress Measures, Measurements of stress and alcohol behaviors, based on questionnaires. Comparison of CMRac with baseline cortisol levels and measures of drinking and craving.Baseline cortisol levels will be compared among groups using a one-way ANOVA followed by post-hoc pairwise tests. Among AD subjects, differences between cortisol levels at 1 week, 1 month, and 3 months will be evaluated with linear mixed models using session (1 week vs. 1 month vs. 3 months). Correlation analysis will be used to examine associations between cortisol levels and levels of CMRac in HPA axis regions, drinking (e.g., # of drinks and drinking days in past 30 days, lifetime consumption), and craving. We will also consider multiple regression models to examine the independent and joint effects of group, cortisol levels, drinking, and craving in predicting CMRac., Baseline and for treatment seekers, once after 1 month sober.