Effects of daily exogenous pregnenolone on downstream neuroactive steroids and their effects on drinking in individuals with alcohol use disorder

Introduction

Alcohol use disorder (AUD) prevalence and relapse rates remain high despite currently available pharmacotherapies and there is an urgent need for more effective treatments. Dysregulation of neuroactive and related sex and stress steroids has been linked to increased craving, problematic drinking, and relapse risk, demonstrating that neuroactive steroids may play an important role in AUD. Specifically, potentiation of neuroactive steroids shows promise as a treatment target for stress-related adaptations in alcohol use disorder. For example, daily administration of the neuroactive steroid precursor pregnenolone (PREG) resulted in normalizations in hypothalamic-pituitary-adrenal (HPA) axis response to stress provocation, decreased craving, anxiety, depression and alcohol use in individuals with AUD. However, whether pregnenolone’s effects are related to the synthesis of downstream neuroactive steroid metabolites needs to be examined. Therefore, here we assessed levels of a panel of neuroactive steroids and their effects on drinking outcome in treatment seeking men and women with AUD who received daily exogenous pregnenolone.

Methods

Seventy five treatment seeking individuals (65.3% male; 46.2 ± 12 years old) meeting diagnostic criteria for AUD participated in a pilot 8 week double blind randomized controlled trial of daily PREG doses (PREG300: 300 mg/day, N=27 or PREG500: 500 mg/day, N=25) vs placebo (PBO, N=23). In approximately weeks 2, 5 and 7 of the trial blood samples were collected to assess levels of pregnenolone, progesterone, testosterone, estradiol, DHEA, DHEA-S, and allopregnanolone using ELISA assays. Drinking was measured throughout the study using daily smartphone ecological momentary assessment (EMA) diaries and weekly timeline follow back. Linear mixed effects models assessed treatment effects on levels of these neuroactive steroids and their relationship to drinking during the trial.

Results

There were no effects of PREG treatment on testosterone, estradiol, DHEA and DHEA-S levels (p’s>0.05). PREG treatment increased plasma levels of pregnenolone (F[2, 71.4]=6.78, p<.002, PREG300>PBO, p<.03; PREG500>PBO, p<.000), progesterone (F[2,68.11]=4.91, p<.01, PREG300>PBO, p<.008; PREG500>PBO, p<.007) and allopregnanolone (F[2,66.1]=3.25, p<.045, PREG300>PREG500, p<.013). Higher pregnenolone and progesterone levels during treatment were associated with lower alcohol intake outcomes (p’s<0.05).

Conclusions

We found selective effects of exogenous pregnenolone treatment on the downstream neuroactive steroid metabolites progesterone and allopregnanolone, but not on testosterone, estradiol, DHEA, or DHEA-S levels, suggesting selective biosynthesis pathway effects. While plasma pregnenolone and progesterone levels were increased in both the PREG300 and PREG500 doses across the trial, allopregnanolone increases were only found with the PREG300 group, suggesting potential dose-specific effects in the biosynthesis pathway and conversion of exogenous pregnenolone to allopregnanolone. Moreover, levels of pregnenolone and progesterone were associated with lower drinking outcomes, suggesting that neuroactive steroid levels have clinical relevance in AUD.Future research is needed to further understand alcohol effects on neuroactive and peripheral steroids and their relationship to drinking outcomes, while considering both sex and menstrual cycle phase variables.

References

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