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Dutasteride reduces alcohol's sedative effects in men in a human laboratory setting and reduces drinking in the natural environment.

ABSTRACT: Preclinical studies support the hypothesis that endogenous neuroactive steroids mediate some effects of alcohol.The aim of this study was to examine the effect of dutasteride inhibition of 5?-reduced neuroactive steroid production on subjective responses to alcohol in adult men.Using a within-subject factorial design, 70 men completed four randomly ordered monthly sessions in which pretreatment with 4 mg dutasteride or placebo was paired with a moderate dose of alcohol (0.8 g/kg) or placebo beverage. The pharmacologic effect of dutasteride was measured by an assay of serum androstanediol glucuronide. Self-reports of alcohol effects were obtained at 40-min intervals following alcohol administration using the Biphasic Alcohol Effects Scale (BAES) and the Alcohol Sensation Scale (SS). We used linear mixed models to examine the effects of dutasteride and alcohol on BAES and SS responses and the interaction of dutasteride with the GABRA2 alcohol dependence-associated polymorphism rs279858. We also examined whether exposure to dutasteride influenced drinking in the weeks following each laboratory session.A single 4-mg dose of dutasteride produced a 70 % reduction in androstanediol glucuronide. Dutasteride pretreatment reduced alcohol effects on the BAES sedation and SS anesthesia scales. There was no interaction of dutasteride with rs279858. Heavy drinkers had fewer heavy drinking days during the 2 weeks following the dutasteride sessions and fewer total drinks in the first week after dutasteride.These results provide evidence that neuroactive steroids mediate some of the sedative effects of alcohol in adult men and that dutasteride may reduce drinking, presumably through its effects on neuroactive steroid concentrations.

SUBMITTER: Covault J

PROVIDER: S-EPMC4181572 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Dutasteride reduces alcohol's sedative effects in men in a human laboratory setting and reduces drinking in the natural environment.

Covault Jonathan J Pond Timothy T Feinn Richard R Arias Albert J AJ Oncken Cheryl C Kranzler Henry R HR

Psychopharmacology 20140221 17

<h4>Rationale</h4>Preclinical studies support the hypothesis that endogenous neuroactive steroids mediate some effects of alcohol.<h4>Objectives</h4>The aim of this study was to examine the effect of dutasteride inhibition of 5α-reduced neuroactive steroid production on subjective responses to alcohol in adult men.<h4>Methods</h4>Using a within-subject factorial design, 70 men completed four randomly ordered monthly sessions in which pretreatment with 4 mg dutasteride or placebo was paired with ...[more]

PMID: 24557088

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Project description:Excessive consumption of alcohol is a major problem in the United States and abroad. Despite many years of study, it is unclear why some individuals drink alcohol excessively while others do not. It has been postulated that either lower or greater acute responses to alcohol, or both, depending on the limb of the breath alcohol concentration curve, contribute to propensity for alcohol misuse.To prospectively assess the relationship of acute alcohol responses to future binge drinking.Within-subject, double-blind, placebo-controlled, multidose laboratory alcohol challenge study with intensive follow-up. Each participant completed 3 randomized sessions examining responses to a high (0.8 g/kg) and low (0.4 g/kg) alcohol dose and placebo, followed by quarterly assessments for 2 years examining drinking behaviors and alcohol diagnoses.Participants recruited from the community.High-risk heavy social drinkers aged 21 to 35 years who habitually engage in weekly binge drinking (n = 104) and light drinker controls (n = 86).We conducted 570 laboratory sessions with a subsequent 99.1% follow-up (1506 of 1520).Biphasic Alcohol Effects Scale, Drug Effects Questionnaire, cortisol response, Timeline Follow-Back, Drinker Inventory of Consequences-Recent, and DSM-IV alcohol abuse and dependence.Alcohol produced greater stimulant and rewarding (liking and wanting) responses and lower sedative and cortisol responses in heavy vs light drinkers. Among the heavy drinkers, greater positive effects and lower sedative effects after alcohol consumption predicted increased binge drinking frequency during follow-up. In turn, greater frequency of binge drinking during follow-up was associated with greater likelihood of meeting diagnostic criteria for alcohol abuse and dependence.The widely held low level response theory and differentiator model should be revised: in high-risk drinkers, stimulant and rewarding alcohol responses even at peak breath alcohol concentrations are important predictors of future alcohol problems.clinicaltrials.gov Identifier: NCT00961792.

Project description:RATIONALE:Drug-related cues evoke craving and stimulate motivational systems in the brain. The acoustic startle reflex captures activation of these motivational processes and affords a unique measure of reactivity to drug cues. OBJECTIVES:This study examined the effects of cannabis-related cues on subjective and eye blink startle reactivity in the human laboratory and tested whether these effects predicted youth's cue-elicited cannabis craving in the natural environment. METHODS:Participants were 55 frequent cannabis users, ages 16 to 24 years (M?=?19.9, SD?=?1.9; 55% male; 56% met criteria for cannabis dependence), who were recruited from a clinical trial to reduce cannabis use. Eye blink electromyographic activity was recorded in response to acoustic probes that elicited startle reactivity while participants viewed pleasant, unpleasant, neutral, and cannabis picture cues. Following the startle assessment, participants completed an ecological momentary assessment protocol that involved repeated assessments of cue-elicited craving in real time in their real-world environments. RESULTS:Multilevel models included the presence or absence of visible cannabis cues in the natural environment, startle magnitude, and the cross-level interaction of cues by startle to test whether cue-modulated startle reactivity in the laboratory was associated with cue-elicited craving in the natural environment. Analyses showed that cannabis-related stimuli evoked an appetitive startle response pattern in the laboratory, and this effect was associated with increased cue-elicited craving in the natural environment, b?=?- 0.15, p?=?.022, 95% CI [- 0.28, - 0.02]. Pleasant stimuli also evoked an appetitive response pattern, but in this case, blunted response was associated with increased cue-elicited craving in the natural environment, b?=?0.27, p?<?.001, 95% CI [0.12, 0.43]. CONCLUSIONS:Our findings support cue-modulated startle reactivity as an index of the phenotypic expression of cue-elicited cannabis craving.

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Dutasteride reduces alcohol's sedative effects in men in a human laboratory setting and reduces drinking in the natural environment.

Publications

Dutasteride reduces alcohol's sedative effects in men in a human laboratory setting and reduces drinking in the natural environment.

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