The study design consists of a randomized, double-blind, placebo-controlled study of low dose endotoxin. Individuals with current AUD (n=32) and matched controls without AUD (n=32) will be randomly assigned to receive a single intravenous (I.V.) infusion of either low dose endotoxin (0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline solution) to determine the acute and protracted role of inflammation in alcohol use.

Participants will be recruited from the community through campaigns in radio, buses, social media, and print publications. After a telephone interview, eligible individuals will complete in-person screening to assess for presence of DSM-5 alcohol use disorder and additional inclusion/exclusion criteria. Eligible participants will complete a physical exam to assess medical safety, including EKG and laboratory tests. Participants who pass the physical exam will then be randomized to an experimental condition (i.e., endotoxin vs. placebo). Randomization will be stratified by sex (male versus female) and AUD (moderate versus severe). Participants will complete an alcohol cue-exposure paradigm in the lab 2 hours post infusion, the time of peak cytokine response. Plasma levels of inflammatory cytokines (i.e., interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α)), mood, and alcohol craving, will be assessed at baseline and then hourly for six hours post infusion. Following the infusion, all participants will complete a 7-day follow-up phase consisting of daily diary surveys of mood, alcohol craving, and alcohol consumption. The adverse events will be managed by study nurse practitioners during the endotoxin challenge.

Inclusion Criteria (AUD Group):

1. Be between the ages of 21 and 65

2. Meet current (i.e., past month) DSM-5 diagnostic criteria for moderate to severe AUD

3. Be non-treatment seeking for AUD

4. Report drinking at least 28 drinks per week if male (21 drinks per week if female) in the 28 days prior to consent.

5. Must agree to one of the following methods of birth control (if female), unless she or partner are surgically sterile:

   • Oral contraceptives
   • Contraceptive sponge
   • Patch
   • Double barrier
   • Intrauterine contraceptive device
   • Etonogestrel implant
   • Medroxyprogesterone acetate contraceptive injection
   • Complete abstinence from sexual intercourse
   • Hormonal vaginal contraceptive ring

Inclusion Criteria (Control Group):

(1) The control group will be age-, sex-, smoking status-, and BMI-matched healthy individuals who drink at or below moderate drinking levels (≤1 drink/day for females, ≤2 drinks/day for males) and have no lifetime history of AUD.

Exclusion Criteria (All Groups):

1. Have a current (last 12 months) DSM-5 diagnosis of substance use disorder for any psychoactive substances other than alcohol and nicotine

2. Have a lifetime DSM-5 diagnosis of schizophrenia, bipolar disorder, or any psychotic disorder

3. Have current moderate to severe depression as indicated by a score of ≥ 21 on the Beck Depression Inventory - II (BDI-II)

4. Have current suicidal ideation or lifetime history of suicide attempt as reported on the Columbia-Suicide Severity Rating Scale (C-SSRS)

5. Have a positive urine screen for drugs other than cannabis;

6. Have clinically significant alcohol withdrawal symptoms as indicated by a score ≥ 10 on the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-R)

7. Have an intense fear of needles or have had any adverse reactions to needle puncture

8. Be pregnant, nursing, or planning to become pregnant while taking part in the study

9. Have a body mass index (BMI) greater than 30

10. Have a medical condition that may interfere with safe study participation (e.g., unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes, autoimmune or inflammatory disease)

11. Have clinically significant abnormal EKG

12. Have > Grade 2 laboratory abnormalities, based on FDA Guidance Document "Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials"

13. Have any other circumstances that, in the opinion of the investigators, compromises participant safety

14. To participate in the inflammatory challenge, participants must not show any of the following upon arrival to the inflammatory challenge study visit:

    1. BrAC > 0.000 g/dl
    2. clinical withdrawal (CIWA-R) score ≥ 10
    3. blood pressure ≤ 90/60 or ≥ 160/120
    4. resting pulse ≤ 50 beats/minute or > 100 beats/minute
    5. temperature ≥ 99.5°F
    6. recent (past 2 weeks) acute illness or vaccination
    7. score of 10+ on Physical Sickness Symptoms Assessment

The study investigator, medical personnel, and participants will be blind to drug condition.