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A mediating influence behind symptom resolution is thought to be the personal insight \u2013 at times, bordering on the mystical \u2013 one acquires during the acute phase of a psychedelic session. Indeed, current clinical trials have found strong correlations between the acute subjective effects (ASE) under the influence of psychedelics and their enduring therapeutic properties. However, with potential barriers to widespread clinical implementation, including the healthcare resource-intensive nature of psychedelic sessions and the exclusion of certain at-risk patient groups, there is an active search to determine whether ASE elimination can be accompanied by the retention of persisting therapeutic benefits of these class of compounds. Recognizing the aberrant underlying neural circuitry that characterizes a range of neuropsychiatric disorders, and that classic psychedelics promote neuroplastic changes that may correct abnormal circuitry, investigators are rushing to design and discover compounds with psychoplastogenic, but not hallucinogenic (i.e., ASE), therapeutic potential. These efforts have paved the discovery of \u2018non-psychedelic\/subjective psychedelics\u2019, or compounds that lack hallucinogenic activity but with therapeutic efficacy in preclinical models. This review aims to distill the current evidence \u2013 both clinical and preclinical \u2013 surrounding the question: can the ASE of classic psychedelics be dissociated from their sustained therapeutic properties? Several plausible clinical scenarios are then proposed to offer clarity on and potentially answer this question.<\/jats:p>","DOI":"10.1007\/s00213-024-06599-5","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:17:00Z","timestamp":1715645820000},"page":"1481-1506","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Disentangling the acute subjective effects of classic psychedelics from their enduring therapeutic properties"],"prefix":"10.1007","volume":"242","author":[{"given":"Mazen A.","family":"Atiq","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L. 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