Classic psychedelics show therapeutic promise for neuropsychiatric disorders, partly through acute subjective effects (ASE) like mystical-type insights that correlate with long-term benefits. However, barriers such as high resource demands and exclusion of at-risk patients drive a search for compounds that retain therapeutic effects without ASE. Recognizing that psychedelics promote neuroplastic changes correcting aberrant neural circuitry, researchers are developing 'non-psychedelic' psychoplastogens that lack hallucinogenic activity yet show efficacy in preclinical models. This review examines clinical and preclinical evidence on whether ASE can be dissociated from sustained therapeutic properties and proposes clinical scenarios to clarify this question.
A healthy 35-year-old man experienced a rare hypotensive adverse event—neurocardiogenic syncope (fainting)—about 60 minutes after taking 25 mg of oral psilocybin in a clinical trial. His blood pressure dropped to 93/51 mmHg, with rapid heart rate and sweating, but he stabilized quickly with leg elevation and oral hydration. The episode may have been triggered by upright seated posture, restrictive EEG equipment, and anxiety about upcoming transcranial magnetic stimulation. Fewer than one-quarter of contemporary psychedelic trials report systematic adverse event assessment, highlighting the need for transparent documentation of both hypertensive and hypotensive events as psilocybin moves toward potential FDA approval.