Psychedelics (Pharmacological Reviews, 2016)
David Nichols, one of the foremost medicinal chemists in psychedelic research, published this review in Pharmacological Reviews as a definitive summary of what is known about the pharmacology of classic serotonergic psychedelics. It covers LSD, psilocybin/psilocin, mescaline, DMT, and their structural analogs.
The paper synthesizes decades of research on 5-HT2A receptor agonism as the primary mechanism of psychedelic action, while also addressing the roles of other serotonin receptor subtypes. It explains structure-activity relationships — why small changes to a molecule's shape dramatically alter its psychoactive profile — and reviews the neuroscience of psychedelic-induced cortical activation patterns.
This is the paper most frequently cited as a starting point for anyone wanting to understand psychedelic pharmacology at a technical level. It is freely available and written to be accessible to readers with a basic biochemistry background.
Key takeaways
- –5-HT2A receptor agonism is necessary and sufficient for classic psychedelic effects; blocking this receptor eliminates the experience.
- –Psychedelics increase cortical glutamate release, suggesting they work partly by disrupting thalamic gating of sensory information.
- –Classic psychedelics show no evidence of neurotoxicity at standard doses, distinguishing them from stimulants and empathogens.
- –Tolerance develops rapidly (days) through receptor downregulation, which is why compulsive dosing patterns are rare.
- –The therapeutic window is unusually wide — the ratio between effective dose and lethal dose is among the largest of any psychoactive class.