Effect of Endotoxin on Alcohol Consumption

This pilot study is a double-blind, placebo-controlled design, which will compare endotoxin (0.4ng/kg i.v.) to placebo (0.0ng/kg) in non-treatment seeking adults meeting criteria for DSM-5 alcohol use disorders (n=32 total, n=16 per group).

Eligibility screening consists of an intake session and a physical exam. Participants meeting eligibility criteria will be randomized to receive a single dose of 0.4ng/kg i.v. endotoxin or placebo during a single laboratory session to evaluate ad-libitum alcohol consumption.

During the laboratory session, endotoxin (or placebo) administration will precede a 2-hour alcohol self-administration period.

Participants will be scheduled for a follow-up appointment to evaluate drinking behavior.

Adverse events are evaluated during the laboratory session and follow-up, and will be tabulated.

• Endotoxin (Drug), also known as Lipopolysaccharide: Endotoxin 0.4ng/kg i.v.

Primary outcomes

• Alcohol Consumption [120 minutes]: Mean mls of alcohol consumed for endotoxin and placebo groups during 120 minute alcohol self-administration session.

Sex: All, ages: 21 Years to 65 Years, accepts healthy volunteers

Inclusion Criteria:

1. Age 21-65;
2. Able to read and write English;
3. Meets DSM-5 criteria for current (past 6 months) alcohol use disorder;
4. Drinking criteria: Males - Drinks > 14 drinks per week and exceeds 4 drinks per day at least twice per week; Females -Drinks > 7 drinks per week and exceeds 3 drinks per day at least twice per week.
5. Must meet drinking criteria during a consecutive 30-day period within the 90 days prior to baseline;
6. Laboratory sessions will be scheduled such that subjects will not have major responsibilities on the following day which might limit drinking during the self-administration session (e.g., job interview, exam).
7. Negative urine pregnancy test for women.

Exclusion Criteria:

1. Participants with any significant current medical conditions (neurological, cardiovascular \[including hypertension or hypotension: sitting BP >160/100 or <90/60mmHg at baseline screening\], endocrine, thyroid, renal, liver), seizures, delirium or hallucinations, or other unstable medical conditions including HIV;
2. Current DSM-5 substance use disorders, other than alcohol or nicotine;
3. A positive test result at intake appointment on urine drug screens conducted for illicit drugs, excluding cannabis;
4. Past 30 day use of psychoactive drugs including anxiolytics and antidepressants;
5. Women who are pregnant or nursing, or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives \[oral, implant, injection, patch, or ring\], contraceptive sponge, double barrier \[diaphragm or condom plus spermicide\], or IUD);
6. Suicidal, homicidal or evidence of current (past 6-month) severe mental illness such as schizophrenia, bipolar disorder or major depression, or anxiety disorders;
7. Subjects treatment-seeking or who are currently in treatment for alcohol use;
8. Subjects with medical conditions contraindicating alcohol use (e.g., liver enzymes ≥3× normal);
9. Subjects likely to exhibit clinically significant alcohol withdrawal during the study. We will exclude subjects who a) have a history of perceptual distortions, seizures, delirium, or hallucinations upon withdrawal, or b) have a score of > 8 on the Clinical Institute Withdrawal Assessment scale at intake appointments;
10. Participation within the past 8 weeks in other studies that involve additive blood sampling and/or interventional measures that would be considered excessive in combination with the current application.
11. Subjects >38 on the Alcohol Use Disorders Identification Test (AUDIT)
12. Subjects with resting pulse >100 at challenge
13. Subjects with recent (past 2 weeks) acute illness or vaccination
14. Subjects with >Grade 2 laboratory abnormalities on screening

Participant flow

Outcome results

• Alcohol Consumption (Primary), Mean, Milliliters: Endotoxin 37.57 +/- 47.27; Placebo 50.08 +/- 37.58

Adverse events

Time frame: Lab session: +60, +75, +135, +165, +195, +225, +285, +345, +405, +450 minutes following endotoxin administration.

Limitations and caveats: Aims on this project were disrupted due to COVID-19 and supplier issues with endotoxin: Clinical research at Yale resumed as of August 1, 2021. Further, there was a significant delay in obtaining endotoxin for use in human subjects. The investigators supply from NIH was depleted and organizing and ordering additional endotoxin from List Laboratories (along with all the regulatory paperwork) took longer than expected. Investigators were without endotoxin from 5/2021 to 1/2023.

• Study Protocol and Statistical Analysis Plan (PDF, 2024-04-04)
• Informed Consent Form (PDF, 2024-04-04)

• Terril Verplaetse, PhD, Principal investigator, Yale University

NIH grants: R03AA028361