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

Abstract

Rationale Preclinical studies support the hypothesis that endogenous neuroactive steroids mediate some effects of alcohol. Objectives 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. Methods 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. Results 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. Conclusions 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.

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

“…However, the possibility that ethanol may increase brain levels of 3α,5α-THP, without affecting its peripheral concentrations, remains open. In fact, some subjective effects of ethanol are diminished by prior administration of finasteride (199) or dutasteride (200), two inhibitors of 3α,5α-THP biosynthesis, suggesting that 3α,5α-THP may play a role in ethanol's actions in humans. Moreover, dutasteride reduced subsequent alcohol consumption in subjects classified as heavy drinkers (200).…”

Variation in AKR1C3, which encodes the neuroactive steroid synthetic enzyme 3α-HSD type 2 (17β-HSD type 5), moderates the subjective effects of alcohol

“…The moderation of only one of these three effects, sedation, by dutasteride blockade of 5AR (Covault et al, 2014) suggests that natural genetic variation in neuroactive steroid biosynthetic enzymes may provide tools to develop a more complete picture of the role of neuroactive steroids in alcohol’s effects in humans than is possible using pharmacological blockade of 5α-reductase. Interestingly, the pattern of genotype effects for each of the three measures was unique (HR moderation by both markers, AKR1C3*2 genotype effects on BAES stimulation in both lighter and heavier drinkers but genotype effects on BAES sedation only in heavier drinkers), suggesting that there is not a common neuroactive steroid compound and or locus of action that underlies neuroactive steroid effects for these different alcohol responses.…”

“…Because the allele frequency of the markers examined vary by race and have not been studied with respect to AD in non-Caucasians, we limited our examination of genotype effects on alcohol responses to the 65 Caucasian men who completed a 4-session alcohol/dutasteride study (Covault et al, 2014). Men were recruited by advertisement in the Greater Hartford, CT region, including at nearby colleges and universities.…”

“…Dutasteride, a 5AR inhibitor approved by the Food and Drug Administration to treat prostatic hyperplasia, inhibits both 5AR isoenzymes in humans at clinical dosages (Clark et al, 2004). Our group recently reported that dutasteride reduced sedative effects of alcohol in a clinical laboratory setting (Covault et al, 2014). …”

“…We hypothesized that the amino-acid coding AKR1C3*2 variant (His5Gln), which has been associated with reduced risk of both AD and bladder cancer, moderates the stimulant or sedative effects of alcohol. We examined this hypothesis using the self-reported Biphasic Alcohol Effects Scale (BAES; Martin et al, 1993) in a group of male participants in a recently completed human laboratory study of the combined effects of alcohol and dutasteride (Covault et al, 2014). Further, we examined whether the synonymous SRD5A1 SNP moderates subjective alcohol effects alone or in combination with the AKR1C3*2 variant and whether the moderating effects of the AKR1C3*2 variant on alcohol responses differ between lighter and heavier drinkers.…”