Serotonin 5-HT2A receptor agonists, including psychedelics like psilocybin, show promise as anti-inflammatory agents beyond their known effects on anxiety, depression, OCD, and addiction. Activation of 5-HT2A receptors produces potent anti-inflammatory effects in animal models of human inflammatory disorders at sub-behavioral levels. This review discusses the role of the 5-HT2A receptor in inflammation, highlights studies using the agonist (R)-DOI in cellular and animal models, and examines potential mechanisms. Psychedelics regulate inflammatory pathways through novel mechanisms, potentially offering a new treatment strategy for inflammatory disorders.
Activating the 5-HT2A receptor with the agonist (R)-DOI before allergen exposure reduces airway hyperresponsiveness in a chronic mouse model of allergic asthma, suggesting a potential new treatment for inflammatory airway diseases. The authors previously showed that (R)-DOI prevents asthma symptoms in an acute ovalbumin-induced model, and here they extend those findings to a persistent asthma model. They also report testing psilocybin and other tryptamines for effects on airway hyperresponsiveness in rodents. The overall goal is to develop 5-HT2A receptor agonism as a therapy for asthma and related inflammatory disorders.
Activating the serotonin 5-HT2A receptor with the psychedelic (R)-DOI reduces inflammation in a mouse model of atherosclerosis. In ApoE-deficient mice fed a high-fat diet, (R)-DOI treatment slowed atherosclerotic plaque development. The anti-inflammatory effect was specific to certain inflammatory pathways in innate and Th2 cells, not a generalized immune suppression. These findings suggest that 5-HT2A receptor activation may offer a novel therapeutic strategy for atherosclerosis, though the work was conducted only in mice.