Cannabis use disorder (CUD) is a major problem in the United States. Over 37 million Americans used cannabis products last year and ~500,000 ER visits annually list cannabis as a probable cause. There is no FDA approved drug to treat CUD, making this an area of urgent need. Thus far, most medical strategies for CUD have resulted in little to no efficacy in patients. Clinical trials with rimonabant, however, indicate that antagonism of the type 1 cannabinoid receptor (CB1) is an attractive strategy for CUD. However, rimonabant and other first generation CB1 antagonists/inverse agonists with high brain penetration produced certain adverse effects in ~10% of clinical population. To de-risk this approach, we propose using a selective serotonin uptake inhibitor (SSRI) in tandem with an inverse agonist. This is based on preclinical observations that chronic inhibition of CB1 compromises serotonergic tone in rodents. To further de-risk this approach, we propose reducing excessive peak brain levels by using an inverse agonist with lower brain penetration. This is important because clinical trials with rimonabant, a first generation CB1 inverse agonist, indicated that lower levels of brain exposure eliminated adverse effects in patients while maintaining efficacy. Our group has developed and patented inverse CB1 agonists with lower brain penetration, allowing us to better control peak brain levels. Studies are proposed wherein we will first produce ADMET data to further characterize these novel compounds that have high potency and selectivity towards CB1. Compounds that demonstrate good drug-like properties will advance into in vivo pharmacokinetic studies to identify one advanced lead and a second backup compound. The advanced lead in tandem with fluoxetine, an SSRI, will be tested in a rodent model of anhedonia for efficacy. Finally, the therapeutic regimen will be assessed for activity in a model of cannabis induced drug discrimination in rats. Completion of these studies will lead to the identification of a novel inverse agonist for clinical development within a dual treatment modality in tandem with fluoxetine for safe and prolonged use in CUD.
The goal of this project is to develop a new therapy for cannabis/marijuana addiction and related disorders. A new blocker of CB1 receptor will be tested along with an antidepressant in cell and animal models of cannabis addiction.
