PROJECT SUMMARY In the midst of the opioid epidemic, the methamphetamine epidemic has devastated the Western United States, These twin epidemics have profoundly affected pregnant and postpartum women. Indeed, the majority of women receiving care at the University of Utah's Substance Use and Pregnancy – Recovery, Addiction, Dependence clinic have methamphetamine use disorder (MUD). Methamphetamine use (MU) frequently decreases during pregnancy. The hormonal changes of pregnancy, specifically the increased levels of progesterone and its metabolite allopregnanolone, may decrease craving and drug use among pregnant women. Conversely, the precipitous postpartum hormonal drop may increase the risk of return to use. Studies of progesterone supplementation in the postpartum period have shown promising results in reducing return to cocaine and tobacco use among postpartum women. Our long-term goal is to advance the understanding of how pregnant and postpartum women's unique physiology impacts the trajectory of MUD and to apply this knowledge to developing novel interventions aimed at reducing MU in this population. The objective of this R21 application is to test the feasibility, safety and preliminary efficacy of progesterone supplementation to reduce return to MU among postpartum women and to explore the association between allopregnanolone levels and methamphetamine craving. The rationale for this project is that progesterone will reduce return to MU among postpartum women. This research study will pursue two specific aims: (1) To assess feasibility, safety, and preliminary efficacy of micronized progesterone to decrease return to MU among postpartum women with MUD; (2) To evaluate the association between salivary allopregnanolone levels and methamphetamine craving in control and treatment groups. For Aim 1, we will randomize postpartum women with MUD who have achieved abstinence for at least one month prior to delivery to micronized progesterone, which metabolizes into allopregnanolone, or placebo and will assess MU over 12 weeks. We will track enrollment and retention of women with MUD, safety of this intervention and establish preliminary efficacy of progesterone to reduce return to MU. For Aim 2, we will test the hypothesis that increased allopregnanolone levels are correlated with reduced methamphetamine cravings among postpartum women. This project is innovative as it addresses a significant health issue facing this vulnerable population with a novel intervention. The proposed research is significant because of its potential to improve public health by decreasing MU among postpartum women and to advance scientific knowledge by investigating the association between allopregnanolone and methamphetamine cravings.