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.
Psychedelic medicine (New Rochelle, N.Y.)
March 1, 2024
Meghan Hibicke, Gerald Billac, Charles D Nichols
2 citations
In male Wistar-Kyoto rats, intravenous psilocin (the active form of psilocybin) produced persistent antidepressant-like effects, reducing immobility in the forced swim test at both 3 and 14 weeks after a single dose. When lorazepam was given 30 minutes before psilocin, the antidepressant-like effect was present at 3 weeks but absent by 14 weeks, and the effect at 14 weeks was weaker than in rats given psilocin alone. Lorazepam therefore reduced both the magnitude and longevity of psilocin's antidepressant-like effects in this animal model.
Research Square
June 15, 2021
D. Parker Kelley, Katy Venable, Gerald Billac et al.
1 citation
In a rat model of post-traumatic stress disorder (PTSD), N,N-dimethyltryptamine (DMT) and the combination of DMT with the monoamine oxidase inhibitor harmaline (pharmahuasca) reduced reactive oxygen species (ROS) production in the prefrontal cortex and hippocampus, while harmaline alone had mixed effects. RNA sequencing of the prefrontal cortex showed that DMT and pharmahuasca altered expression of genes related to ROS production, inflammation, neurotransmission, and neuroplasticity. DMT, but not harmaline, showed both affinity and efficacy at the human 5HT2A receptor. The findings suggest DMT and pharmahuasca may help treat PTSD by reducing oxidative stress and inflammation and promoting neuroplasticity.
The FASEB Journal
April 1, 2019
Gerald Billac, Charles D. Nichols
1 citation
Classical serotonergic psychedelics are being re-examined as treatments for various diseases. While most research focuses on their central nervous system effects, previous work suggests that serotonin 2A receptor (5-HT2AR) agonists can modulate TNF-alpha-mediated inflammatory responses in the periphery. This study characterizes signaling pathway activation for a panel of 5-HT2AR ligands from three chemical classes: tryptamines, ergolines, and phenethylamines. Initial results examining the canonical Gαq pathway and β-arrestin2 recruitment showed no significant correlation between potency or efficacy and anti-inflammatory activity in vivo. Ongoing studies are examining additional GPCR-mediated signaling via cAMP accumulation to understand the structural basis for biased signaling and inform drug design.
SSRN Electronic Journal
January 1, 2026
Dennis Parker Kelley, Gabriel Sturm, Katy Venable et al.
Serotonergic psychedelics show therapeutic effects across diverse neuropsychiatric, inflammatory, and cardiometabolic disorders, effects mediated largely by the serotonin 5-HT2A receptor. These drugs are exceptionally context-dependent, able to be anti-inflammatory or pro-inflammatory depending on setting. Each target pathology is linked to elevated stress exposure, which drives mitochondrial and allostatic dysregulation. The authors propose that psychedelics act as super-normal stimuli for the adaptive 5-HT2A receptor stress response, inducing a process called allostatic recalibration (AR). AR involves three phases: destabilizing, recalibrating, and consolidating updated allostatic programs. This recalibration replaces entrenched pathological allostatic programs with ones tuned to the safe context of psychedelic therapy, explaining their transdiagnostic effects.
The FASEB Journal
April 1, 2017
Gerald Billac, Charles D. Nichols
A panel of 5-HT2A receptor ligands, including the psychedelic drug (R)-DOI, shows superpotent anti-inflammatory effects in mouse models of asthma and atherosclerosis. The ligands exhibit differential activation of signaling pathways, with (R)-2C-BCB strongly biased toward the Gq pathway as measured by calcium mobilization. Ongoing studies examine β-arrestin signaling, receptor internalization, and other GPCR pathways. The goal is to use structure-activity relationships to develop novel therapies targeting specific effector pathways for inflammation-based diseases.