Sex and gender differences in behavioral, biological, and clinical correlates of substance use disorders are myriad, yet there exists a dearth of gender-informed treatment options. Ovarian hormones have been identified as potential mechanisms of these disparities , and recent clinical trials have begun to examine their utility as possible pharmacotherapeutic agents. The ovarian hormone progesterone has shown promise as a treatment for female cocaine and nicotine users, but has not yet been tested for cannabis. Gender differences in cannabis withdrawal, which is associated with relapse, are pronounced and several studies report more severe and impairing withdrawal symptoms in women compared to men. Developing pharmacological interventions for cannabis withdrawal remains an important priority given the significant cognitive, psychiatric, and physical consequences of heavy cannabis use.

Substantial evidence demonstrates sex and gender differences in the behavioral, biological, and clinical correlates of substance use disorders. Men tend to initiate use earlier and have higher lifetime prevalence rates of disorder, but women demonstrate more severe withdrawal, more rapid progression from first use to disorder, and greater likelihood of comorbid psychiatric disorder. A growing literature suggests that the ovarian hormones progesterone and estradiol may play a key role in these differences. Evidence from preclinical and clinical research suggests that estradiol enhances drug sensitivity and related behavior, while progesterone attenuates drug sensitivity and behavior. As such, recent clinical trials investigating exogenous progesterone as a potential pharmacologic intervention have shown attenuated subjective and physiological effects of cocaine and nicotine in drug-dependent women, and improved cognitive performance in female smokers. While progesterone has shown promise as a treatment for women with cocaine and nicotine use disorder, it has not yet been tested for cannabis.

To date, there are no approved pharmacologic interventions for cannabis use disorder (CUD) despite numerous clinical trials. Cannabis withdrawal is one potential target for CUD medication development research as withdrawal increases risk of relapse. Important gender differences in cannabis withdrawal have been identified warranting gender-based investigation. Several studies have found that women experience more severe and impairing withdrawal symptoms, primarily physiological (e.g. stomach aches, headaches, nausea) and mood-related (e.g. irritability, mood swings), compared to men. As a naturally occurring sex hormone, progesterone may effectively address these gender differences. The proposed pilot study investigates the feasibility and efficacy of exogenous progesterone administration for cannabis withdrawal among female cannabis users.

Specific Aim 1: Test the feasibility of exogenous progesterone administration among cannabis users.

Hypothesis 1: Exogenous progesterone administration will induce normative elevations in progesterone comparable to the luteal phase of female menstrual cycle and will be well-tolerated by participants.

Specific Aim 2: Examine the efficacy of exogenous progesterone on cannabis withdrawal.

Hypothesis 2: Compared to placebo, progesterone will attenuate withdrawal symptoms among heavy-cannabis-using women.

Exploratory Aim: Examine the effect of exogenous progesterone on cognitive functioning during cannabis withdrawal.

Exploratory hypothesis: Compared to placebo, progesterone will enhance cognitive functioning among heavy-cannabis-using women.

Inclusion Criteria:

1. Able to provide informed consent and function at an intellectual level sufficient to allow accurate completion of all assessment instruments and study procedures.
2. Age 18-45, with regular menses (every 25-35 days).
3. Report using cannabis at least 5 days per week, for at least the past year.
4. Consent to remain abstinent from alcohol for 12 hours prior to study visits, and all other drugs other than cannabis or nicotine for the duration of the study.
5. Consent to random assignment.

Exclusion Criteria:

1. Participants who are pregnant, nursing, amennorheic, or using oral contraceptives.
2. History of major medical illnesses; including liver diseases, abnormal vaginal bleeding, suspected or known malignancy, thrombophlebitis, deep vein thrombosis, pulmonary embolus, clotting or bleeding disorders, heart disease, diabetes, history of stroke or other medical conditions that the investigator deems as contraindicated for the patient to be in the study;
3. Regular use of psychotropic medication (antidepressants, antipsychotics, or anxiolytics) and recent/current psychiatric diagnosis and treatment for Axis I disorders including major depression, bipolar affective disorder, schizophrenia or panic disorder.
4. Current suicidal or homicidal risk. Any subject who endorses suicidal ideation will be seen by a licensed clinician in the Addiction Sciences Division who will determine the best course of action to ensure patient safety.
5. Known allergy to progesterone or peanuts (vehicle for micronized progesterone).
6. Unwilling or unable to maintain abstinence from alcohol 12 hours prior to study visits, and all other drugs other than cannabis or nicotine for the duration of the study.
7. Meet DSM-5 criteria for moderate to severe substance use disorder (other than nicotine, cannabis, or alcohol) within the past year.

Normally cycling menstruating females.

5 days