The history of serotonin research is closely tied to hallucinogenic drugs that activate serotonin-2A receptors. Early discoveries of LSD, psilocybin, and serotonin led to the idea that psychotic states in disorders like schizophrenia may involve abnormalities in serotonin systems. Sixty years of study have confirmed a significant relationship between serotonin and both drug-induced and disorder-based psychotic states. Modern biochemical, pharmacological, behavioral, neuroimaging, genetic, and molecular biological sciences are converging to understand how serotonin systems interact with other monoaminergic and glutamatergic systems to modulate consciousness and contribute to psychotic disorders like schizophrenia. This review summarizes experimental assessments of the serotonergic hallucinogen model psychosis in relation to the serotonin hypothesis of schizophrenia.
The noetic (insightful) quality of mystical-type experiences in psychedelic-assisted therapy may arise from changes in metacognition—the ability to monitor and evaluate one's own thoughts. Drawing on existing metacognition models, the authors propose that psychedelics activate procedural, performance-based metacognitive feelings, producing an 'Aha!' experience interpreted as a feeling of epistemic gain. This framework could help explain therapeutic mechanisms such as intention setting, music's role, traumatic memory recall, and spiritual bypassing. The paper reviews theoretical links between metacognition and altered states like meditation and lucid dreaming, then outlines future research directions.