Examination of Zinc, S-adenosylmethionine, and Combination Therapy Versus Placebo in Alcoholics (ExZACTO)

This is a randomized, placebo controlled trial of dietary zinc and S-adenosylmethionine (SAMe) in otherwise healthy alcoholic US Veterans. The primary goal is to determine if either dietary zinc or S-adenosylmethionine (SAMe) can augment lung immune defenses in alcoholics and thereby decrease the risk of lung injury and infection.

Alcohol abuse is a major burden on society and even more of a problem in the Veteran population. Chronic alcohol ingestion can have serious health consequences including pneumonia and acute lung injury, which can occur suddenly and without warning even in physically fit individuals without apparent signs of alcohol dependence. Therefore, it is vital for the health of our Veterans and indeed the entire population to identify effective treatments that can limit or even prevent these devastating consequences. The primary goal of this clinical research project is to determine if dietary zinc or supplements of the antioxidant S-adenosylmethionine (SAMe) can augment lung immune defenses in otherwise healthy alcoholics and thereby decrease the risk of lung injury and infection. There is already strong evidence from the investigators' experimental animal model that moderate daily alcohol ingestion for as little as six weeks causes oxidative stress and zinc deficiency in the lung. These derangements result insult in dysfunction of the alveolar macrophage, which is the resident immune cell, and predisposes animals to the development of pneumonia. Importantly, in this same animal model, the investigators found that adding either zinc or antioxidants to the diet prevents these problems and preserves lung health even during daily alcohol ingestion. This project will translate basic findings in the animal model to the clinical setting and determine whether or not zinc or SAMe supplements are effective in humans who pathologically consume alcohol. This project will enroll Veterans seen at the Atlanta Veterans Hospital in the Substance Abuse Treatment Program (SATP). Participants will be evaluated by undergoing a procedure to obtain samples of fluid from their lungs, measure zinc levels, redox potential, and assess how well their alveolar macrophages respond to bacteria (by determining phagocytic capacity). After completion of the initial evaluation, the participants will be randomized to receive standard treatment (placebo), zinc supplements, dietary SAMe, or the combination of zinc and SAMe for 14 days. All subjects will be evaluated for two weeks as they undergo treatment. At the end of this two week period, measurements of lung zinc, redox potential and macrophage function will be repeated and compared between the two groups. The hypothesis is that both dietary zinc and SAM supplements will improve the immune function of the alveolar macrophage. If this project is successful, it will lead to larger clinical trials to determine if either dietary zinc and/or SAMe supplements can be effective even in the acute clinical setting and improve outcomes in alcoholics who develop pneumonia or acute lung injury. Overall, both zinc and SAMe supplements are safe and inexpensive to provide, allowing these potential treatments to be easily implemented in the Veteran population as well as society in general. Given the significant burden of unhealthy alcohol use, the investigators need ways to limit the physical consequences of alcohol abuse while the investigators continue the efforts at public education and addiction treatment.

Involves flexible fiberoptic bronchoscopy with standardized bronchoalveolar lavage (BAL) technique (isotonic saline in a sub-segment of the right middle lobe or lingula) using standard conscious sedation techniques.

Improvement in alveolar macrophage phagocytic index. Phagocytic index will be measured before and after treatment phase. Phagocytic index is calculated using isolated alveolar macrophages from the bronchoscopy procedure such that phagocytic index = (total number of engulfed cells/total number of counted macrophages) x (number of macrophages containing engulfed cells/total number of counted macrophages) x 100.

Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment)

Improvement in alveolar macrophage intracellular zinc. Intracellular zinc will be measured before and after treatment phase using isolated alveolar macrophages. The units of measure are relative fluorescence units/cell (RFU/cell) and measured using confocal microscopy techniques.

Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment)

Improvement in redox potential in the alveolar space. Redox potential will be measured before and after treatment phase using lavage fluid and blood plasma.

Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment)

Improvement in alveolar macrophage granulocyte macrophage - colony stimulating factor (GM-CSF) receptor expression. GM-CSF receptor expression will be measured before and after treatment phase using isolated alveolar macrophages. The units of measure are relative fluorescence units/cell (RFU/cell) and measured using confocal microscopy techniques. Both alpha- and beta-subunits of the receptor will be measured.

Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment)

Improvement in serum zinc level. Serum zinc will be measured before and after treatment phase by collecting blood plasma. The units of measure are mg/dl.

Initial bronchoscopy to second bronchoscopy (Initial bronchoscopy performed prior to treatment and second bronchoscopy done 2-3 weeks after starting treatment)

Inclusion Criteria: Age 18-60 years Active alcohol use disorder Exclusion Criteria: Any active and uncontrolled medical problem(s) Known zinc deficiency Primary substance of abuse something other than alcohol Current abnormal chest x-ray HIV-positive Any disorder of blood coagulation Currently on medical treatment with anti-coagulants, including: warfarin heparin direct thrombin inhibitors anti-platelet agents (other than Aspirin) Daily use of vitamins or other nutritional supplements (unless taking as treatment for alcohol use disorder) Renal impairment (GFR < 60) Active bipolar disorder Active Parkinson's disease Current pregnancy Contraindication to treatment with zinc or S-adenosylmethionine Inability to give informed consent (i.e., limited cognitive capacity) Non-English speaking