Influence of synthetic sex hormones on methamphetamine effects and self-administration in women

There are well-known sex differences in methamphetamine use disorder (MUD); women initiate use at an earlier age, transition to dependence faster, and exhibit a more severe course of addiction than men.

Historically, men have used methamphetamine (MA) at higher rates than women, however this is no longer true among young adults under age 25.

Data also show significant increases in MA use among women over age 25 and a five-fold increase in MA- associated overdose deaths in recent years. Thus, there is an urgent need to understand why women are vulnerable to MA use to improve women’s public health.

Cyclical fluctuations in female sex hormones are one factor that contributes to sex differences in MUD; estrogen (E2) promotes while progesterone (P4) dampens sensitivity of brain dopamine systems to dopamine agonists (MA).

So, clinical studies have probed the efficacy of P4 as a potential treatment for stimulant use disorders in women but with equivocal findings.

However, few studies have assessed the influence of synthetic ovarian hormones e.g., progestins, the active component of hormonal contraceptive medications, on sensitivity to stimulant drug reward.

This is surprising since a majority of US women use oral contraceptives (birth control pill, BCP) at some point in their reproductive life and the effects of E2 and P4 on brain neurobiology and drug effects are well documented.

The long-term goal of this research is to fill the knowledge gap of how synthetic ovarian hormones influence MA effects and use.

The first step toward this goal is to systematically determine how synthetic ovarian hormones influence the rewarding and motivational effects of MA in a controlled laboratory setting. The objective of this study is to determine how BCP influences MA subjective experiences and motivation for MA.

The rationale is that vital data of how synthetic hormones influence the abuse potential of MA will inform novel women-focused prevention and treatment approaches.

The working hypothesis is that progestin mimics the effects of P4 and blunts the rewarding subjective effects of MA and motivation to obtain MA.

This hypothesis is based upon the existing preclinical and clinical data of P4 effects on stimulant drug reward and also pilot data from the PI’s lab.

The specific aims are: 1) To determine the subjective rewarding effects of MA and motivation to obtain MA among women using BCP tested during active pill weeks vs. inactive pill weeks, in comparison to naturally cycling women tested at two phases of the menstrual cycle, 2) To determine how circulating natural and synthetic hormones are related to the rewarding subjective effects and motivational effects of MA.

This research is significant because it will provide fundamental knowledge of how synthetic ovarian hormones influence responses to MA in women.

The results will be clinically significant as they apply to a substantial proportion of US women who currently use BCP or cycle naturally.

This study is innovative because it is the first systematic study of how natural and synthetic ovarian hormones influence MA reward and motivation, and shifts the focus of clinical research on sex differences in MUD from the effects of natural hormones to synthetic hormones.

Finally, positive findings that high stable levels of synthetic progestin blunt MA reward will provide a framework for the development of therapies focused on female mechanisms.