Turner Institute for Brain and Mental Health (D.S., G.F.E., A.R.) and Monash Biomedical Imaging (G.F.E., A.R.), Monash University, Clayton, Victoria, Australia; Wellcome Centre for Human Neuroimaging, UCL, London, United Kingdom (K.J.F., A.R.); and CIFAR Azrieli Global Scholar, CIFAR, Toronto, Canada (A.R.).
Turner Institute for Brain and Mental Health (D.S., G.F.E., A.R.) and Monash Biomedical Imaging (G.F.E., A.R.), Monash University, Clayton, Victoria, Australia; Wellcome Centre for Human Neuroimaging, UCL, London, United Kingdom (K.J.F., A.R.); and CIFAR Azrieli Global Scholar, CIFAR, Toronto, Canada (A.R.)
Pharmacol Rev. 2022 Oct;74(4):876-917. doi: 10.1124/pharmrev.121.000508.
Neuroimaging studies of psychedelics have advanced our understanding of hierarchical brain organization and the mechanisms underlying their subjective and therapeutic effects. The primary mechanism of action of classic psychedelics is binding to serotonergic 5-HT2A receptors. Agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy that can have a profound effect on hierarchical message-passing in the brain. Here, we review the cognitive and neuroimaging evidence for the effects of psychedelics: in particular, their influence on selfhood and subject-object boundaries-known as ego -surmised to underwrite their subjective and therapeutic effects. Agonism of 5-HT2A receptors, located at the apex of the cortical hierarchy, may have a particularly powerful effect on sentience and consciousness. These effects can endure well after the pharmacological half-life, suggesting that psychedelics may have effects on neural plasticity that may play a role in their therapeutic efficacy. Psychologically, this may be accompanied by a disarming of ego that increases the repertoire of perceptual hypotheses and affords alternate pathways for thought and behavior, including those that undergird selfhood. We consider the interaction between serotonergic neuromodulation and sentience through the lens of hierarchical predictive coding, which speaks to the value of psychedelics in understanding how we make sense of the world and specific predictions about effective connectivity in cortical hierarchies that can be tested using functional neuroimaging. SIGNIFICANCE STATEMENT: Classic psychedelics bind to serotonergic 5-HT2A receptors. Their agonist activity at these receptors leads to neuromodulatory changes in synaptic efficacy, resulting in a profound effect on information processing in the brain. Here, we synthesize an abundance of brain imaging research with pharmacological and psychological interpretations informed by the framework of predictive coding. Moreover, predictive coding is suggested to offer more sophisticated interpretations of neuroimaging findings by bridging the role between the 5-HT2A receptors and large-scale brain networks.
神经影像学研究表明，迷幻剂能够帮助我们深入了解大脑的层级组织，以及它们产生主观和治疗效果的作用机制。经典迷幻剂的主要作用机制是与血清素能 5-HT2A 受体结合。这些受体的激动作用会导致突触效能的神经调节变化，从而对大脑中的层级信息传递产生深远影响。在这里，我们回顾了迷幻剂对认知和神经影像学的影响的证据：特别是，它们对自我和主客体边界的影响，这些影响被认为是它们产生主观和治疗效果的基础。位于皮质层级顶端的 5-HT2A 受体的激动作用可能对感觉和意识产生特别强大的影响。这些影响在药物半衰期后仍能持续很长时间，这表明迷幻剂可能对神经可塑性产生影响，而这可能在其治疗效果中发挥作用。从心理学上讲，这可能伴随着自我的解除武装，从而增加感知假设的范围，并为思维和行为提供替代途径，包括那些支撑自我的途径。我们通过层级预测编码的视角来考虑血清素能调制与感觉之间的相互作用，这说明了迷幻剂在理解我们如何理解世界以及皮质层级中有效连通性的具体预测方面的价值，这些预测可以使用功能神经影像学进行测试。
