Impact of Progesterone on Stress Reactivity and Cannabis Use

Participants will complete a screening visit to determine study eligibility. Eligible
subjects will be scheduled to begin 22 days of study participation. During the first week,
participants will be randomly assigned to take either progesterone or placebo (inactive
medication) twice a day, and to abstain from marijuana use. During this week, participants
will upload videos of themselves taking their medication and performing saliva drug tests.
They will collect and store additional saliva samples each morning for hormone testing. They
will also participate in "CREMA" sessions (Cue Reactivity Ecologic Momentary Assessment)
three times a day. These sessions include looking at stressful and neutral pictures and
rating stress and craving. At the end of this week, participants will return to the clinic
and participate in a stress task. For the next two weeks, participants will continue to
collect saliva samples and participate in CREMA sessions. They will return at the end of the
two weeks to return study supplies. Urine samples will be collected at each study visit.

Inclusion Criteria:

- 1. Able to provide informed consent and function at an intellectual level sufficient
to allow accurate completion of all assessment instruments.

2. Meet DSM-5 criteria for moderate or severe cannabis use disorder (within the past
three months) and report using cannabis at least five times weekly over the past
month. While individuals may also meet criteria for mild use disorders of other
substances, they must identify cannabis as their primary substance of abuse and must
not meet criteria for any other moderate or severe substance use disorder (except
tobacco) within the last 60 days.

3. Age 18-45. 4. For women, regular menses (every 25-35 days). 5. 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.

6. Women of childbearing potential must agree to utilize an effective means of birth
control.

7. Must consent to random assignment.

Exclusion Criteria:

- . Women who are pregnant, nursing or of childbearing potential and not practicing an
effective means of birth control.

2. Women who are amennorheic or using progesterone-based contraceptives. 3. Evidence
or 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 individual to be in the study.

4. History of or current psychotic disorder or bipolar affective disorder. 5. Current
suicidal or homicidal ideation/risk. 6. Known allergy to progesterone or peanuts
(vehicle for micronized progesterone).

7. 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.

8. Meet DSM-5 criteria for moderate or severe substance use disorder (other than
nicotine or cannabis) within the past 60 days.

9. Unable to comply with study procedures or pose threat to study staff.