Progesterone for Cannabis Withdrawal
Condition: Cannabis Use Disorder; Cannabis Withdrawal
MeSH terms: Marijuana Abuse
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Progesterone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Progesterone capsule; Placebo capsule. Manufactured to mimic progesterone 200mg capsule.
Other intervention name(s): Prometrium; Inactive comparator
Intervention MeSH terms: Progesterone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Progesterone; Ovarian hormones; Gender; Cannabis; Withdrawal; Cognitive functioning