The serotonin-2A receptor (5-HT2AR) is a target for antidepressants that could work quickly or in treatment-resistant cases, but activating it can cause hallucinations. Recent research suggests certain partial agonists might produce antidepressant effects without hallucinations, though the molecular details are unclear. This study used molecular dynamics simulations of the receptor bound to two antipsychotics, three potential non-hallucinogens, and two hallucinogens. Findings suggest modest receptor activation yields only antidepressant effects, while hallucinations result from excessive activation. Modest activation via a sufficiently weak partial agonist may offer a viable drug development pathway, whereas microdosing may be problematic due to abuse potential and narrow therapeutic windows.
Activation of the serotonin 2A (5-HT2A) receptor suppresses fear expression but does not affect retention of fear extinction. Using the psychedelic DOI in mice, the authors found that 5-HT2A receptor activation reduced anxiety-like avoidance behavior and diminished fear expression in multiple tasks, including passive avoidance and auditory fear conditioning. The effect depended on 5-HT2A receptors in the amygdala: local infusion of a 5-HT2A antagonist into the amygdala reversed the effect, while local DOI infusion into the amygdala was sufficient to suppress fear expression. These findings clarify a neural mechanism by which psychedelics may reduce fear, but provide no evidence that they enhance fear extinction memory.