In a nonrandomized, open-label clinical trial, 74 adults with treatment-resistant depression received three intravenous ketamine infusions, with an additional four infusions for those who remitted. After the acute phase, 53% (39/74) experienced remission of depression symptoms. Higher baseline language domain scores on the RBANS cognitive assessment were associated with greater odds of remission. No significant association was found between remission and baseline immediate or delayed memory, visuospatial, or attention scores. During the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. The findings suggest cognitive improvement, not deterioration, with serial ketamine administration.
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.