The Sigma1 receptor antagonist CM304 potentiates the antinociceptive effects of the cannabinoid receptor agonist delta9-tetrahydrocannabinol in rats and mice.
Pharmacological reports : PR April 1, 2026 Elmira Zolali, Mallory Burns, Sebastiano Intagliata et al.
Combining the sigma1 receptor antagonist CM304 with delta9-tetrahydrocannabinol (THC) enhances pain relief without worsening THC's side effects. In mice, CM304 increased the pain-blocking effect of THC and caused greater body temperature drops when combined. A high dose of CM304 alone reduced movement. In rats, CM304 made THC's pain relief more potent. CM304 did not produce THC-like effects in rats trained to recognize THC, nor did it amplify THC's subjective effects. The findings suggest sigma1 receptor antagonists could be safer adjuncts to cannabinoid-based pain treatments, offering pain relief without increasing adverse effects like sedation or abuse potential.