Fernández-Borkel Tobías, Borkel Lucas F, Rojas-Hernández Jaime, Hernández-Álvarez Elisa, Quintana-Hernández Domingo J, Ponti Ludovica G, Henríquez-Hernández Luis Alberto
Center for MR Research, University Children's Hospital Zurich, 8032 Zurich, Switzerland.
Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College, London WC2R 2LS, U.K.
ACS Pharmacol Transl Sci. 2025 Jul 16;8(8):2839-2847. doi: 10.1021/acsptsci.5c00445. eCollection 2025 Aug 8.
The therapeutic potential of psychedelic substances, particularly psilocybin, for treatment-resistant depression (TRD) has garnered considerable attention. However, the necessity of subjective psychedelic experiences for therapeutic efficacy remains unclear, creating a critical gap in the field. To determine whether subjective psychedelic experiences induced by psilocybin are required for its antidepressant effects or whether these effects are mediated solely by neurobiological actions independent of consciousness. We propose a randomized controlled trial with three groups: (P) Psilocybin (25 mg oral dose with guided therapeutic integration), (P+A) Psilocybin under propofol-induced general anesthesia (eliminating subjective experiences), and (X+A) Propofol-induced anesthesia with placebo (with no psilocybin). Clinical assessments of depression and anxiety, combined with fMRI-based brain connectivity analysis (including fractal complexity, brain entropy, and network dynamics), will be conducted at baseline, postintervention, and during follow-ups. The proposed study protocol expects distinct therapeutic outcomes across groups. Superior improvements in depression and anxiety symptoms are anticipated in the conscious psilocybin group (P) compared to both anesthetized groups (P+A) and (X+A). Additionally, increased brain connectivity measures in fractal complexity and entropy are hypothesized to correlate positively with therapeutic improvements, particularly pronounced in the conscious condition. Isolating subjective experiences through anesthesia, aims to determine whether conscious psychedelic experiences play a causal role in therapeutic outcomes. Results have significant implications for clinical protocols, treatment guidelines, and the broader theoretical understanding of consciousness and its relationship to mental health.
迷幻物质，尤其是裸盖菇素，在治疗难治性抑郁症（TRD）方面的治疗潜力已引起广泛关注。然而，主观迷幻体验对于治疗效果的必要性仍不明确，这在该领域造成了关键的空白。为了确定裸盖菇素诱导的主观迷幻体验是否是其抗抑郁作用所必需的，或者这些作用是否仅由独立于意识的神经生物学作用介导。我们提出一项随机对照试验，分为三组：（P）裸盖菇素组（口服25毫克并进行引导性治疗整合），（P+A）在丙泊酚诱导的全身麻醉下使用裸盖菇素组（消除主观体验），以及（X+A）使用安慰剂的丙泊酚诱导麻醉组（不含裸盖菇素）。将在基线、干预后和随访期间进行抑郁和焦虑的临床评估，并结合基于功能磁共振成像的脑连接分析（包括分形复杂性、脑熵和网络动力学）。拟议的研究方案预计各小组会有不同的治疗结果。与两个麻醉组（P+A）和（X+A）相比，预计有意识的裸盖菇素组（P）在抑郁和焦虑症状方面会有更显著的改善。此外，假设分形复杂性和熵方面脑连接测量的增加与治疗改善呈正相关，在有意识的情况下尤为明显。通过麻醉分离主观体验，旨在确定有意识的迷幻体验是否在治疗结果中起因果作用。研究结果对临床方案、治疗指南以及对意识及其与心理健康关系的更广泛理论理解具有重要意义。
