Mechanisms by which cannabidiol promotes peripheral nerve regeneration.

Li J.; Xin Y.; You W.; Zhou J.; Wu Z.; Fang X.; Zhang W. · Neural regeneration research · 2026

**Background & Methods** This review study utilized a sciatic nerve crush injury model in mice combined with multi-omics analyses and molecular validation to investigate cannabidiol's mechanisms in promoting peripheral nerve regeneration. The research focused on the gut-microbiome-nerve axis pathway, employing both in vivo and in vitro experimental approaches with transcriptomic sequencing and biochemical analysis. **Key Findings** • Cannabidiol oral administration restored abundance of the probiotic bacterium *Akkermansia muciniphila* following peripheral nerve injury, which was significantly depleted after nerve damage. This restoration correlated with improved nerve morphology, increased static sciatic index scores, and reduced gastrocnemius muscle atrophy in treated mice. • Cannabidiol treatment elevated serum and local sciatic nerve levels of 3-hydroxyphenylacetic acid (3-HPA), a microbial metabolite that inhibited MAPK signaling activation in Schwann cells, thereby reducing inflammatory factor secretion and creating a favorable microenvironment for nerve repair. • The therapeutic efficacy of cannabidiol was dependent on intact microbiota, as antibiotic-induced dysbiosis significantly attenuated its neuroregenerative effects. Conversely, direct *Akkermansia muciniphila* supplementation and exogenous 3-HPA administration independently promoted peripheral nerve injury recovery, establishing a causal relationship in the proposed pathway. **Dosage & Administration** Not reported. The abstract does not specify cannabidiol doses, treatment duration, or administration schedules used in the experimental model. **Safety & Adverse Effects** Not reported. No adverse effects or safety concerns were documented in the provided abstract. **Evidence Quality** This is a mechanistic review/research study with significant limitations regarding clinical translation. The evidence derives from animal models (mice) rather than human subjects, limiting direct applicability to clinical peripheral nerve injury management. While the multi-omics approach and identification of a novel "cannabidiol-*Akkermansia muciniphila*-3-HPA-MAPK axis" represent novel mechanistic insights, these findings require validation in human clinical trials. The study's strength lies in its comprehensive molecular pathway elucidation and experimental verification through multiple approaches (microbiota depletion and supplementation experiments), though the relevance of specific findings to different types of peripheral nerve injuries remains unclear.

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