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.

Fig. 1

Pharmacokinetic comparison of 2-, 3-, or 4-mg single doses of dutasteride in 24 healthy men. Change relative to predrug baseline for serum 3α-diol G, a measure of relative 5AR activity, at 1, 3, 7, 14, 21, 28, and 42 days after drug administration (mean±SEM)

Fig. 2

Serum 3α-diolG (ng/ml) before and 2–4 days following placebo or 4 mg dutasteride (mean±SEM) for the 280 laboratory sessions completed by 70 participants in the dutasteride/ alcohol laboratory study. Comparison of results for sessions with no dutasteride exposure during the prior month (a) or for sessions with 4 mg dutasteride during the prior month (b)

Fig. 3

a Breath alcohol concentration (mean±SEM) as a function of time relative to beginning the first drink. BrAC peaked at the first time point, 40 min following initiation of drinking, and was not affected by dutasteride pretreatment. b Change in heart rate (mean±SEM) as a function of time relative to the beginning of drinking. Heart rate significantly increased following alcohol administration (p<0.001); there was no effect of dutasteride pretreatment on heart rate change following alcohol

Fig. 4

Acute alcohol effects displayed as the sum (mean± SEM) of the seven BAES stimulation (a) and sedation (b) items. Dutasteride pretreatment significantly reduced BAES sedation following alcohol, p<0.001, in a mixed model that included all time points following alcohol. Post hoc testing *p<0.05 for 0 vs. 4 mg dutasteride in the alcohol condition for individual time points

Fig. 5

Sum of response to four alcohol sensation anesthesia subscale drowsy/relaxed items (mean±SEM). Dutasteride pretreatment reduced the alcohol-associated increase in response for these items, p<0.001, in a mixed model that included all time points following alcohol. Post hoc testing **p<0.01 for 0 vs. 4 mg dutasteride in the alcohol condition for individual time points

Fig. 6

Weekly TLFB data following laboratory sessions with dutasteride or placebo pretreatment for heavy vs. light male drinkers. a, b Heavy drinking days per week (mean± SEM) were significantly reduced in the heavy drinking group for 2 weeks following dutasteride pretreatment but not placebo pretreatment, paired t test for post-laboratory drinking compared with 90-day TLFB baseline data, ***p≤0.001; **p<0.01. c, d Total standard drinks per week (mean±SEM) were significantly reduced for the heavy drinking group during week 1 following dutasteride but not placebo, ***p≤0.001