Mechanisms of cannabinoid tolerance

Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB₁R) that are responsible tolerance. CB₁R expression is downregulated in tolerant animals and humans while there is strong evidence of CB₁R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB₁R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB₁R desensitization and downregulation including the action of G protein-coupled receptor kinases, β-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB₁R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.