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

Andrew M Novick, Korrina A Duffy, Rachel L Johnson, Mary D Sammel, Wen Cao, Andrew A Strasser, Mehmet Sofuoglu, Alexandra Kuzma, James Loughead, A Leslie Morrow, C Neill Epperson, Andrew M Novick, Korrina A Duffy, Rachel L Johnson, Mary D Sammel, Wen Cao, Andrew A Strasser, Mehmet Sofuoglu, Alexandra Kuzma, James Loughead, A Leslie Morrow, C Neill Epperson

Abstract

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://ichgcp.net/clinical-trials-registry/NCT01954966 \.

Keywords: Allopregnanolone; Neurosteroids; Progesterone; Sex-differences; Smoking.

Conflict of interest statement

CNE has served on advisory boards for Asarina Pharma and Sage Therapeutics and has been a consultant and received grant support from Sage Therapeutics. ALM is a consultant for Sage Therapeutics and Pure Tech health. ALM holds a provisional patent on the anti-inflammatory actions of allopregnanolone and related steroids on toll-like receptor pathways in the immune system and brain.

AMN, KAD, RLJ, MDS, WC, MS, AAS, AK, and JL reported no biomedical interested or potential conflicts of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Crossover study design. Functional magnetic resonance imaging (fMRI) scans measured neural activation in response to smoking and neutral cues. Participants completed measures of withdrawal symptoms, smoking urges, and mood states before each brain scan. Blood draws measured levels of neurosteroids, such as progesterone and allopregnanolone, after each brain scan. Smoking sessions measured change in carbon monoxide (CO) levels, number of cigarettes smoked, inhalation volume for the first cigarette, total inhalation volume during the session, and subjective nicotine effects at baseline and after a 4-day abstinence
Fig. 2
Fig. 2
Z-score map of functionally defined regions of interest (ROIs) for the contrast smoking cue minus neutral measured at the baseline session. ROI masks were created via voxel-wise correction at p = 0.05. Percent signal change was extracted from these ROIs for all 6 sessions for subsequent analysis. Specific details on ROIs, including voxels, coordinates, and specific z-score can be found in Additional file 1: Table S13
Fig. 3
Fig. 3
Significant interaction of allopregnanolone:progesterone ratio and sex on withdrawal symptoms and mood states. A Allopregnanolone:progesterone ratio and sex significantly interacted to predict nicotine withdrawal symptoms (p = 0.047) on the Nicotine Withdrawal Symptom Checklist. The simple slope for females was significant, such that having a higher ratio of allopregnanolone:progesterone was associated with lower withdrawal symptoms (p = 0.048). B Allopregnanolone:progesterone ratio significantly interacted with sex to predict fatigue on the Profile of Moods Scale (POMS) (p = 0.034). For females, a higher ratio of allopregnanolone:progesterone was marginally associated with lower reports of fatigue (p = 0.062). C Allopregnanolone:progesterone ratio significantly interacted with sex to predict confusion on the POMS. For females, higher ratios of allopregnanolone:progesterone were associated with lower reports of confusion (p = 0.008). For details see Table 4

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