The 5‐HT2A receptor is the most widely expressed serotonin receptor in mammals. While distribution occurs largely in the central nervous system, the 5‐HT2A receptor has been detected in platelets, endothelial and epithelial cells, and lymphatic tissue. Most commonly viewed as the classical target of psychedelic compounds, our lab has made significant progress in understanding how activity at the 5‐HT2A receptor profoundly activates anti‐inflammatory pathways. Here we have generated a chronic asthma model to examine the therapeutic potential of 5‐HT2A receptor activation in persistent allergic airways disease. Our studies show that nasal administration of the 5‐HT2A agonist (R)‐DOI attenuates the elevated airway responsiveness, goblet cell hyperplasia, collagen deposition, and airway structural remodeling that accompanies persistent allergen challenge. Additionally, we have used an acute model in rodents to interrogate structural components of known psychedelics most critical for their anti‐inflammatory effects. Our studies indicate that the 4 position of 5‐HT2A structural agonists contains the chief mediator for reducing bronchial hyperresponsiveness in asthma. This ultimately suggests that a blood‐brain inpenetrant molecule can be developed that lacks the psychoactivity of classical psychedelics but maintains therapeutic efficacy.Support or Funding InformationThis work was supported, in part, by research funds from the American Asthma Foundation Scholar Grant Award to C.N., The Betsey Gordon Foundation, and the Eleusis Benefit Corporation, PBC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.