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

The takeaway

The cannabis terpene myrcene dose-dependently reduced pain sensitivity in a mouse neuropathic pain model, with greater potency in females, and the effect required CB1 cannabinoid receptors despite myrcene not directly activating them.

Cannabis pharmacology researchers, pain scientists, terpene researchers

CB1-dependent pain relief without direct CB1 activation

What the researchers found

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.

Why it matters

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 numbers in context

Myrcene tested at 1-200 mg/kg; CB1 antagonist blocked anti-allodynia; no direct CB1 activation in TRUPATH assay; females showed greater potency; no locomotion or temperature effects

How the study worked

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.

What this study cannot tell us

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.

How to read the evidence

Well-designed preclinical study with dose-response, sex comparison, and mechanistic dissection, but animal model results require human validation.

When this study was published

2025 publication

The bigger picture

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.

Questions still open

How does myrcene engage CB1 receptors without directly activating them? Would myrcene-enriched cannabis products provide better pain relief than THC alone in human trials?

Common questions

What is myrcene?

Myrcene is one of the most abundant terpenes found in cannabis. Terpenes are aromatic compounds that contribute to the plant's smell and may have independent biological effects beyond the cannabinoids THC and CBD.

Why was the effect stronger in female mice?

The study found myrcene was more potent at reducing pain in female compared to male mice, which may relate to known sex differences in the endocannabinoid system. However, female mice also showed aversion to the compound, suggesting a more complex response.

Read the original research

Elucidating interplay between myrcene and cannabinoid receptor 1 receptors to produce antinociception in mouse models of neuropathic pain.

Pain, 166(9), 2140-2151

View on PubMed ↗Publisher’s paper ↗

Citation

Alayoubi, Myra; Rodrigues, Akeesha; Wu, Christine; Whitehouse, Ella; Nguyen, Jessica; Cooper, Ziva D; O'Neill, Patrick R; Cahill, Catherine M. (2025). Elucidating interplay between myrcene and cannabinoid receptor 1 receptors to produce antinociception in mouse models of neuropathic pain.. Pain, 166(9), 2140-2151. https://doi.org/10.1097/j.pain.0000000000003558