Anti-inflammatory properties of 5-HT2A receptor agonists
Psychedelics activate the target receptor differently than serotonin. This phenomenon is called functional Selectivity. For example, the ability of psychedelics to recruit Gi signaling pathways compared to serotonin may be related to their behavioral effects. We believe that another pathway is recruited to the receptor by psychedelics that produces anti-inflamamtory effects.
We are currently performing classic receptor pharmacology experiments to identify potentially relevant functionaly selective pathways for not only behavioral effects, but anti-inflammatory effects.
Studies in our lab several years ago discovered that the drug (R)-2,5-dimethoxy-4-iodoamphetamine, a selective 5-HT2 receptor agonist, has potent anti inflammatory activity to prevent TNF-alpha mediated inflammation both in cell culture, and in whole animal models. We subsequently translated these findings to rodent models of human inflammatory diseases. For example, levels of (R)-DOI below those necessary for behavioral effets can fully prevent the development of allergic asthma and its symptoms in mice and rats. These include prevention of pulmonary inflammation, mucus over production, eosinophilia, and airways hyperresponsiveness. We are continuing our study of this class of drug in asthma models, as well as other models of inflammatory disease.
Significantly, we have found that (R)-DOI inhibits the development of asthma through modulation of both inate and adaptive immune processes. It prevents the activation and recruitment of Th2 cells, and blocks secretion of proinflammatory cytokines and chemokines in pulmonary tissues. Unlike corticosteroids, (R)-DOI is not a broad spectrum immunosuppressant and selectively blocks only a subset of inflammatory pathwyas that together are enough to prevent pathology. Therefore, we propose that 5-HT2A receptor agonist molecules represent a new class of anti-inflammatory that is small molecule, highly bioavailable, and steroid sparing.