The 5-HT2A receptor is one of the many receptors for serotonin (5-HT). A 2016 review reports a consensus that psychedelics act as agonists or partial agonists there, with particular importance for receptors on large layer V neurons of the cortex (Nichols, 2016).
The strongest human evidence comes from blocking studies. In 1998, ketanserin, a drug that blocks 5-HT2A, blocked psilocybin’s psychological effects in a dose-dependent way (Vollenweider et al., 1998), and in 2017 it fully blocked LSD’s general subjective effects (Preller et al., 2017). In a 2019 PET study of eight volunteers, how much of the receptor psilocybin occupied tracked how intense the experience was rated (Madsen et al., 2019). For pure DMT, no human blocking study has been published, though mouse and ayahuasca studies point the same way (Keiser et al., 2009; Valle et al., 2016).
It is not the whole story. A 2023 study found many of these receptors sit inside neurons (Vargas et al., 2023), and another reported plasticity effects of LSD and psilocin in mice that did not need 5-HT2A (Moliner et al., 2023). Which effects need the receptor is still debated.
Sources
- Nichols, 2016, Pharmacological Reviews: Psychedelics
- Vollenweider et al., 1998, NeuroReport: ketanserin blocks psilocybin
- Madsen et al., 2019, Neuropsychopharmacology: 5-HT2A occupancy and psilocin
- Vargas et al., 2023, Science: intracellular 5-HT2A receptors
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