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Updated: Jun 17, 2026
Oromucosal as an Alternative Method for Administration of Cannabis Products in Rodents
Published on: August 22, 2025
Evidence that MDMA ('ecstasy') increases cannabinoid CB2 receptor expression in microglial cells: role in the
Elisa Torres1, Maria Dolores Gutierrez-Lopez, Erika Borcel
1Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
Abstract:
3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') produces selective long-lasting serotonergic neurotoxicity in rats. The drug also produces acute hyperthermia which modulates the severity of the neurotoxic response. In addition, MDMA produces signs of neuroinflammation reflected as microglial activation and an increase in the release of interleukin-1beta, the latter of which appears to be a consequence of the hyperthermic response and to be implicated in the neurotoxicity induced by the drug. Over-expression of the cannabinoid CB2 receptor in microglia during non-immune and immune pathological conditions is thought to be aimed at controlling the production of neurotoxic factors such as proinflammatory cytokines. Our objective was to study the pattern of CB2 receptor expression following MDMA and to examine the effect of JWH-015 (a CB2 agonist) on the MDMA-induced neuroinflammatory response as well as 5-hydroxytryptamine (5-HT) neurotoxicity. Adult Dark Agouti rats were given MDMA (12.5 mg/kg, i.p.) and killed 3 h or 24 h later for the determination of CB2 receptor expression. JWH-015 was given 48 h, 24 h and 0.5 h before MDMA and 1 h and/or 6 h later and animals were killed for the determination of microglial activation (3 h and 24 h) and 5-HT neurotoxicity (7 days). MDMA increased CB2 receptor expression shortly after administration and these receptors were found in microglia. JWH-015 decreased MDMA-induced microglial activation and interleukin-1beta release and slightly decreased MDMA-induced 5-HT neurotoxicity. In conclusion, CB2 receptor activation reduces the neuroinflammatory response following MDMA and provides partial neuroprotection against the drug.
Insights
Cannabinoid CB2 receptor activation mitigates MDMA-induced neuroinflammation and offers partial neuroprotection. JWH-015, a CB2 agonist, reduced microglial activation and interleukin-1beta release, lessening serotonin neurotoxicity.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- 3,4-Methylenedioxymethamphetamine (MDMA) causes long-lasting serotonergic neurotoxicity and neuroinflammation in rats.
- Hyperthermia induced by MDMA exacerbates neurotoxicity, linked to increased interleukin-1beta release and microglial activation.
- Cannabinoid CB2 receptors on microglia are implicated in regulating neuroinflammatory responses.
Purpose of the Study:
- To investigate CB2 receptor expression patterns after MDMA administration.
- To evaluate the neuroprotective effects of JWH-015, a CB2 agonist, against MDMA-induced neuroinflammation and 5-hydroxytryptamine (5-HT) neurotoxicity.
Main Methods:
- Adult Dark Agouti rats were administered MDMA (12.5 mg/kg, i.p.).
- CB2 receptor expression was assessed at 3 and 24 hours post-MDMA.
- JWH-015 was administered before and after MDMA to assess microglial activation (3, 24 hours) and 5-HT neurotoxicity (7 days).
Main Results:
- MDMA administration led to increased CB2 receptor expression, primarily in microglia.
- JWH-015 treatment significantly reduced MDMA-induced microglial activation and interleukin-1beta release.
- JWH-015 administration resulted in a slight decrease in MDMA-induced 5-HT neurotoxicity.
Conclusions:
- CB2 receptor activation effectively dampens the neuroinflammatory cascade triggered by MDMA.
- Targeting CB2 receptors offers a potential therapeutic strategy for mitigating MDMA-induced neurotoxicity.
