Cannabis terpene myrcene reduced neuropathic pain in mice through CB1-dependent mechanism

Myrcene (1-200 mg/kg) dose-dependently increased mechanical pain thresholds in neuropathic pain mice, with greater potency in females than males. A CB1 receptor antagonist blocked myrcene's pain-relieving effect. However, in vitro experiments showed myrcene does not directly activate CB1 receptors or alter CB1 activity from cannabinoid agonists, suggesting an indirect mechanism. Myrcene did not cause the sedation or temperature changes typical of cannabinoids, but female mice showed conditioned place aversion.

Male and female mouse model of neuropathic pain plus in vitro experiments with HEK293T cells. Myrcene tested at 1-200 mg/kg intraperitoneally. Canonical tetrad outcomes (locomotion, temperature) assessed. CB1 antagonist used to test receptor dependence. TRUPATH assay tested direct CB1 activation by myrcene with agonists and endocannabinoids.

Myrcene is one of the most abundant terpenes in cannabis, and this study shows it contributes to pain relief through an unexpected mechanism: it requires CB1 receptors but does not directly activate them. This distinction matters for understanding how whole-plant cannabis produces effects beyond THC alone.

The "entourage effect" hypothesis proposes that cannabis components beyond THC contribute to therapeutic effects. This study provides mechanistic evidence that myrcene, a non-cannabinoid terpene, produces pain relief through the cannabinoid system without directly activating cannabinoid receptors, supporting but complicating the entourage concept.

Mouse model of neuropathic pain may not translate to human pain. Intraperitoneal injection does not reflect typical routes of cannabis exposure. The indirect mechanism by which myrcene engages CB1 receptors remains unknown. Female mice showed aversion to myrcene, raising questions about tolerability.