Pharmacogenetics of Alcohol: Treatment Implications

Study Overview
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Brief Summary
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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
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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).

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

Conditions
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Alcohol Related Disorders, Alcoholism, Alcohol Abuse

Intervention / Treatment
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* Drug: dutasteride + ethanol
* Drug: placebo medication + ethanol
* Drug: dutasteride + placebo alcohol
* Drug: placebo medication + placebo alcohol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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steroid 5Alpha Reductase, dutasteride, neuroactive steroid