Contradictory Effects of 5-HT2A Modulation

Recent research on 5-HT2A agonist compounds in mice indicates potential antidepressant effects without psychedelic experiences, highlighting a gap in human studies. Promising Phase II trials with psilocybin and LSD in conjunction with psychotherapy show rapid alleviation of anxiety and depression symptoms. This raises questions about the coexistence of effective antidepressants that are 5-HT2A antagonists, like gratazapine and tricyclic antidepressants, alongside the positive results from 5-HT2A agonists. Chronic antidepressant usage may downregulate 5-HT2A receptors, complicating our understanding of their mechanisms. Additionally, the off-target effects of psychedelics activate various neurotransmitters and receptors, such as dopamine and noradrenergic receptors, which may introduce further complexities in their therapeutic use.