Pharmacogenetics of Alcohol: Treatment Implications

Subjective and Physiological Effects of Alcohol: Role of Genetic Variation and Adrenal Hormones

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.

Study Overview

• Status: Completed
• Conditions: Alcoholism; Alcohol Related Disorders; Alcohol Abuse
• Intervention / Treatment: Drug: placebo medication + placebo alcohol; Drug: placebo medication + ethanol; Drug: dutasteride + placebo alcohol; Drug: dutasteride + ethanol

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).

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo medication + placebo alcohol	Drug: placebo medication + placebo alcohol; placebo medication administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
Experimental: Placebo Medication + 0.8 gr/kg Ethanol	Drug: placebo medication + ethanol; placebo medication administered 2-4 days prior to ingestion of 0.8 gr/kg ethanol divided between three drinks consumed over 36 minutes
Experimental: 4 mg Dutasteride + Placebo Alcohol	Drug: dutasteride + placebo alcohol; 4 mg dutasteride administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes; Other Names: Avodart
Experimental: 4 mg Dutasteride + 0.8 gr/kg Ethanol	Drug: dutasteride + ethanol; 4 mg dutasteride administered 2-4 days prior to ingestion of 0.8 mg/kg ethanol divided between three drinks consumed over 36 minutes; Other Names: Avodart

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breath Alcohol	Breath Alcohol level	40 minutes after beginning drink
BAES Sedation Response, Average of 6 Time Points	Biphasic Alcohol Effects Scale (BAES) Sedation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 sedation related questions regarding effects of alcohol. Total BAES sedation subscale score 0-70 with higher numbers indicating greater sedative effects of alcohol. [Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.]	40, 80, 120, 160, 210 and 240 minutes after start of drinking
BAES Stimulation Response, Average of 6 Time Points	Biphasic Alcohol Effects Scale (BAES)Simulation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 stimulation related questions regarding effects of alcohol. Total BAES stimulation subscale score 0-70 with higher numbers indicating greater stimulating effects of alcohol. [Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.]	40, 80, 120, 160, 210 and 240 minutes after start of drinking

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum 3a-androstanediol Glucuronide	Ratio of serum 3a-androstanediol drawn prior to alcohol administration (2-4 days after medication administration) compared to the baseline level prior to medication dose. The pharmacologic effect of dutasteride was measured by assay of serum 5a-androstan-3a,17b-diol,17-glucuronide (aka 3a-androstanediol glucuronide) as a biochemical measure of 5a-reductase enzyme inhibition. 3a-androstanediol glucuronide is the primary metabolic excretion product of 3a,5a-androstane neuroactive steroids. The	Baseline (pre medication administration) and 2-4 days post-medication (alcohol session)

Collaborators and Investigators

• Sponsor: UConn Health
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: July 31, 2008
• First Submitted That Met QC Criteria: August 13, 2008
• First Posted (Estimate): August 14, 2008

Study Record Updates

• Last Update Posted (Estimate): March 28, 2012
• Last Update Submitted That Met QC Criteria: March 26, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: dutasteride; steroid 5Alpha Reductase; neuroactive steroid
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Alcoholism; Alcohol-Related Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Steroid Synthesis Inhibitors; 5-alpha Reductase Inhibitors; Ethanol; Dutasteride
• Other Study ID Numbers: 06-218S-2; 5R01AA015606-02 (U.S. NIH Grant/Contract); 619 (GCRC)