Drewko Adam J, Habets Ron L P, Brunt Tibor M
Molecular and Biophysical Life Sciences programme, Undergraduate School, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
PhD, Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
Mol Psychiatry. 2025 Aug 23. doi: 10.1038/s41380-025-03169-9.
Serotonergic psychedelics, including the recreationally used psilocybin and LSD, have become promising therapeutic agents for the treatment of treatment-resistant depression. While it is generally agreed that they exhibit their antidepressant effects by inducing rapid and sustained neuroplasticity, the molecular mechanisms responsible are widely debated. In particular, the role of the serotonin 5-HT receptor, known to mediate the hallucinogenic effects of psychedelics, is under scrutiny. However, many studies remain in conflict on whether action at the receptor is also required for neuroplastic effects. In this narrative review, we examine the available evidence for the involvement of the 5-HT receptor in neuroplasticity induction and the possibly antidepressant effects of psychedelics. Firstly, we review the role of decreased neuroplasticity in depression, the evidence for dendrito-, spino- and synaptogenesis promotion by psychedelics, and for its possible regional selectivity. We then discuss the current knowledge on psychedelic action at the 5-HT receptor, including its role in promoting hallucinogenic effects. Finally, we critically assess the studies testing the necessity for 5-HT signalling for neuroplastic effects and present a model of molecular mechanisms responsible for psychedelic-induced neuroplasticity.
血清素能迷幻剂，包括用于消遣的裸盖菇素和麦角酸二乙酰胺（LSD），已成为治疗难治性抑郁症的有前景的治疗药物。虽然人们普遍认为它们通过诱导快速且持续的神经可塑性来发挥抗抑郁作用，但相关的分子机制仍存在广泛争议。特别是，已知介导迷幻剂致幻作用的血清素5-羟色胺（5-HT）受体的作用正在受到审查。然而，关于受体作用对于神经可塑性效应是否也是必需的，许多研究仍存在冲突。在这篇叙述性综述中，我们审视了5-HT受体参与神经可塑性诱导以及迷幻剂可能的抗抑郁作用的现有证据。首先，我们回顾神经可塑性降低在抑郁症中的作用、迷幻剂促进树突、棘突和突触形成的证据及其可能的区域选择性。然后，我们讨论目前关于迷幻剂作用于5-HT受体的知识，包括其在促进致幻作用中的作用。最后，我们批判性地评估测试5-HT信号传导对于神经可塑性效应必要性的研究，并提出一个负责迷幻剂诱导神经可塑性的分子机制模型。
