The drug MDMA ('ecstasy') causes lasting damage to serotonin neurons in rats, partly through inflammation involving microglial activation and release of interleukin-1β. Cannabinoid CB2 receptors, which increase in microglia shortly after MDMA, can help control this inflammation. Giving rats a CB2 receptor agonist (JWH-015) before and after MDMA reduced microglial activation and interleukin-1β release, and slightly lessened the damage to serotonin neurons. Activating CB2 receptors thus partially protects against MDMA's neurotoxic effects.
A low dose of MDMA given to rats 96 hours before a neurotoxic dose reduces damage to serotonin transporters and lowers elevated interleukin-1β levels while increasing interleukin-1 receptor antagonist levels. The low dose itself raises IL-1β at 3 hours and IL-1ra at 96 hours, and increases soluble IL-1 receptor type I expression. Blocking IL-1 signaling with sIL-1RI prevents this protective effect, while injecting IL-1β alone mimics the preconditioning, indicating that IL-1β is key in developing tolerance to MDMA neurotoxicity.