Advancing Pregnenolone as a Novel Therapy for Co-Occurring Cannabis Use Disorder and Depression

About This Grant

Abstract Cannabis use and cannabis use disorder (CUD) are increasing in prevalence. When present, CUD exhibits relapse rates similar to those of other substance use disorders, making it a significant and growing public health concern. Notably, CUD is highly comorbid with depression. People with CUD are up to four times more likely to experience depressive symptoms than non-users. This comorbidity is associated with more severe clinical profiles, including earlier onset, greater functional impairment and poorer treatment outcomes. Despite this clinical need, there are currently no FDA-approved pharmacotherapies for CUD, particularly for those with co-occurring depression. Preclinical research demonstrates that the neurosteroid pregnenolone acts as a negative allosteric modulator of the CB1 receptor and inhibits many of the adverse intoxicating effects of cannabis. Our preliminary human studies found that pregnenolone also attenuates cannabis effects in the brain. Given the involvement of the endocannabinoid system in both mood regulation and cannabis reinforcement, pregnenolone may hold dual therapeutic potential, reducing cannabis use while alleviating depressive symptoms. Intravenous allopregnanolone is FDA-approved for postpartum depression. Our previous work showed that pregnenolone reduced alcohol use and depressive symptoms compared to placebo, in individuals with bipolar disorder and alcohol use disorder. Additionally, we reported improvements in depression and anxiety in placebo-controlled trials of pregnenolone in individuals with bipolar disorder or major depressive disorder (MDD). We hypothesize that targeting CB1 signaling through pregnenolone may reduce cannabis use and mitigate adverse cannabis effects, while the GABAergic properties of allopregnanolone will improve mood and anxiety. We propose examining pregnenolone as a treatment for individuals with both CUD and MDD. As a negative allosteric modulator of CB1 receptors, pregnenolone may regulate CB1R activity more subtly than receptor antagonists, potentially resulting in fewer side effects or withdrawal symptoms. Moreover, allopregnanolone may alleviate depressive and anxiety symptoms. The dual actions of pregnenolone and allopregnanolone make them well-suited to treating CUD, particularly in individuals with comorbid MDD. We propose a milestone-driven effort using the UG3/UH3 mechanism to advance pregnenolone as a treatment in this population. The UG3 phase will focus on obtaining regulatory approvals, refining the protocol and harmonizing procedures across sites. To determine optimal dosing frequency, we will conduct a pharmacokinetic study to establish pregnenolone's half-life in this population. A pilot safety and feasibility study will evaluate 12 weeks of pregnenolone treatment. The UH3 phase will incorporate lessons learned during the UG3 phase to conduct a multisite efficacy trial in individuals with CUD and MDD.