Clinical trial NCT00734656: Pharmacogenetics of Alcohol: Treatment Implications
Official title: Subjective and Physiological Effects of Alcohol: Role of Genetic Variation and Adrenal Hormones
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alcohol Related Disorders
Alcoholism
Alcohol Abuse
Keywords: steroid 5Alpha Reductase
dutasteride
neuroactive steroid
Lead sponsor: UConn Health
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2008-08-14
Enrollment: 94
Sex: MALE
Minimum age (years): 21
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL

Brief summary: This study will explore the hypothesis that effects of alcohol are in part mediated by increased production of neuroactive steroids, which interact with GABAA-receptors. We propose to study non-dependent drinkers using a 4-session within-subjects design in which alcohol / placebo is paired with dutasteride / placebo pretreatment. Dutasteride is a 5-alpha steroid reductase (5AR) inhibitor that limits the production of dihydrotestosterone and the 5a-reduced neuroactive steroids allopregnanolone, pregnanolone and 3a,5a-androstanediol.

Detailed description: Alcohol has multiple pharmacological effects, though which of these effects relate to the risk of alcohol dependence is not clear. Animal studies indicate that the neuroactive steroid allopregnanolone is an alcohol-modulated endogenous agonist at GABAA receptors and that genetic variation in steroid 5a-reductase type I gene which generates neuroactive steroids, may moderate alcohol effects. To better define the role of neuroactive steroids we will conduct a laboratory study of non-alcohol dependent drinkers using a 4-session design in which alcohol/placebo beverage is paired with dutasteride/placebo pretreatment. Dutasteride, an inhibitor of both type I and type II 5a-reductase enzymes, blocks the production of 5a-reduced neuroactive steroids. This study will extend our preliminary findings with finasteride by including a) a placebo control for alcohol, b) a more specific inhibitor of both 5a-reductase isoenzymes, c) a larger group of subjects (including both light and heavy drinkers).

Eligibility criteria: Inclusion Criteria:

* Main Study: Subjects will be healthy volunteers with or without parental history of alcoholism who are 21-45 years old and who have a BMI \>18.5 and \<32.5. Drinking history: All subjects must report at least one occasion in the prior month of drinking at least 3 drinks on a single day; additionally, LD subjects will be selected if they drink 1-3 drinks, 1-3 times per week (up to 5 drinks per week on average), with no more than one occasion in the past 2 months on which they drank \>4 drinks. HD subjects will be selected if they report drinking at least 10 drinks per week, with at least one episode per week of heavy drinking.

Exclusion Criteria:

* Main Study: Subjects cannot have a current or past DSM-IV diagnosis of alcohol or drug dependence, current or past 24-months diagnosis of alcohol or drug abuse or another major psychiatric disorder, neurological illness, have had a hypersensitivity reaction to dutasteride, evidence of liver dysfunction, currently be using benzodiazepines, other psychotropic medications or medications that are known to influence steroid hormone levels or metabolism or modify the effects of alcohol. Nicotine-dependent subjects will be excluded to avoid the confounding effects of nicotine withdrawal during day-long laboratory sessions. Women are not allowed to participate. Subjects anticipating moving from the area during the period of their planned study participation will be excluded from study entry.

Primary outcomes:
measure: Breath Alcohol
timeFrame: 40 minutes after beginning drink
measure: BAES Sedation Response, Average of 6 Time Points
timeFrame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking
measure: BAES Stimulation Response, Average of 6 Time Points
timeFrame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking
Secondary outcomes:
measure: Change in Serum 3a-androstanediol Glucuronide
timeFrame: Baseline (pre medication administration) and 2-4 days post-medication (alcohol session)
Other outcomes:
Locations:
city: Farmington
country: United States
facility: University of Connecticut Health Center
state: Connecticut
Study officials:
affiliation: UConn Health
name: Jonathan Covault, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: