Mechanisms of cannabinoid tolerance.
Level 5 - mechanism / opinion, no new human data
Narrative review of preclinical and mechanistic studies
PubMed 37348821 · doi:10.1016/j.bcp.2023.115665
What was done
This narrative review synthesized evidence across rodent, non-human primate, and human studies regarding cannabinoid tolerance. It evaluated neuroadaptations at the cannabinoid type 1 receptor (CB1R), sex differences in tolerance development, underlying intracellular signaling pathways (including G protein-coupled receptor kinases, beta-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and receptor trafficking), and potential strategies to mitigate tolerance.
What was found
The abstract reports no quantitative values or statistical metrics. Qualitatively, it reports that CB1R expression is downregulated in tolerant animals and humans, CB1R desensitization occurs in tolerant rodent models, and prominent sex differences exist in acute cannabinoid response and tolerance profiles.
Why it matters
Understanding the molecular mechanisms of CB1R desensitization and downregulation provides a foundation for developing strategies to prevent or reverse tolerance, potentially sustaining the therapeutic benefits of cannabinoids while lowering the risk of cannabis use disorder.
Limits
As a narrative review, it lacks systematic search criteria and quantitative synthesis. Much of the mechanistic signaling detail is derived from animal models rather than direct human experimentation, and human assessment remains constrained by the lack of imaging probes capable of measuring CB1R desensitization in vivo.
Cited by
- contradicts When a drug is introduced to the body, the brain responds by upregulating the receptors for that drug.