Effect of progesterone administration in male and female smokers on nicotine withdrawal and neural response to smoking cues: role of progesterone conversion to allopregnanolone

Background Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the neurosteroid allopregnanolone is hypothesized to partly underlie the therapeutic effects of progesterone; however, this has not been investigated clinically. Methods Smokers ( n = 18 males, n = 21 females) participated in a randomized, double-blind, placebo-controlled crossover study of 200 mg progesterone daily across 4 days of abstinence. The ratio of allopregnanolone:progesterone was analyzed in relationship to nicotine withdrawal, smoking urges, mood states, subjective nicotine effects, and neural response to smoking cues. Results Allopregnanolone:progesterone ratio interacted with sex to predict withdrawal symptoms ( p = 0.047), such that females with higher allopregnanolone:progesterone ratios reported lower withdrawal severity ( b = − 0.98 [− 1.95, − 0.01]; p = 0.048). In addition, allopregnanolone:progesterone ratio interacted with sex to predict confusion ( p = 0.014) and fatigue ( p = 0.034), such that females with higher allopregnanolone:progesterone ratios reported less confusion ( b = − 0.45 [− 0.78, − 0.12]; p = 0.008) and marginally lower fatigue ( b = − 0.50 [− 1.03, 0.02]; p = 0.062. Irrespective of sex, higher ratios of allopregnanolone:progesterone were associated with stronger “good effects” of nicotine ( b = 8.39 [2.58, 14.20]); p = 0.005) and weaker “bad effects” of nicotine ( b = − 7.13 [− 13.53, − 0.73]; p = 0.029). Conclusions Conversion of progesterone to allopregnanolone correlated with smoking-related outcomes in both sex-dependent and sex-independent ways. Sex-dependent effects suggest that conversion of progesterone to allopregnanolone may contribute to greater therapeutic benefits in females but not males with TUD. Trial registration Clinicaltrials.gov registration, retrospectively registered: NCT01954966; https://clinicaltrials.gov/ct2/show/NCT01954966 \