International Review of Psychiatry
July 4, 2018
Thomas W. Flanagan, Charles D. Nichols
263 citations
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.
ACS Pharmacology & Translational Science
April 9, 2021
Thomas W. Flanagan, Gerald Billac, Alexus N. Landry et al.
50 citations
Psychedelic drugs can reduce inflammation, but this effect does not depend on their mind-altering properties. By testing 21 different 5-HT2A receptor agonists in a rat model of allergic asthma, the drug 2,5-dimethoxyphenethylamine (2C-H) was identified as the key structure for anti-inflammatory activity. Specific chemical modifications either enabled or blocked this effect. No link was found between a drug's ability to trigger calcium signaling (a standard measure of receptor activation) and its ability to prevent asthma symptoms or produce behavioral effects. This suggests that anti-inflammatory benefits arise from distinct receptor pathways, not the canonical signaling pathway. These findings could guide development of non-psychoactive anti-inflammatory drugs targeting the 5-HT2A receptor.
ACS Pharmacology & Translational Science
January 25, 2024
Thomas W. Flanagan, Timothy P. Foster, Thomas E. Galbato et al.
18 citations
Two psychedelic compounds, (R)-DOI and (R)-DOTFM, both activate the serotonin 2A receptor with comparable in vitro activity and behavioral potency, yet only (R)-DOI prevents inflammation and airway hyperresponsiveness in a mouse model of asthma. The compounds produce distinct differences in protein expression and inflammatory-related gene expression in lung tissue. The anti-inflammatory effects of certain psychedelics involve suppression of arginase 1 expression, revealing key mechanistic components of their anti-inflammatory action.
The FASEB Journal
April 1, 2017
Thomas W. Flanagan, Melaine N. Sebastian, Charles D. Nichols
2 citations
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.
The FASEB Journal
April 1, 2017
C. Nichols, Melaine N. Sebastian, Thomas W. Flanagan
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.