Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have partially overlapping neurophysiological effects, i.e., modulating the same neurotransmitter systems. Imaging data were obtained from the clinical trial NCT03019822, which explored the acute effects of lysergic acid diethylamide (LSD), d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers. The clinical trial employed a double-blind, placebo-controlled, crossover design. Herein, various resting-state connectivity measures were examined, including within-network connectivity (integrity), between-network connectivity (segregation), seed-based connectivity of resting-state networks, and global connectivity. Differences between placebo and the active conditions were assessed using repeated-measures ANOVA, followed by post-hoc pairwise t-tests. Changes in voxel-wise seed-based connectivity were correlated with serotonin 2 A receptor density maps. Compared to placebo, all substances reduced integrity in several networks, indicating both common and unique effects. While LSD uniquely reduced integrity in the default-mode network (DMN), the amphetamines, in contrast to our expectations, reduced integrity in more networks than LSD. However, LSD exhibited more pronounced segregation effects, characterized solely by decreases, in contrast to the amphetamines, which also induced increases. Across all substances, seed-based connectivity mostly increased between networks, with LSD demonstrating more pronounced effects than both amphetamines. Finally, while all substances decreased global connectivity in visual areas, compared to placebo, LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings advance our understanding of the distinctive neurobiological effects of psychedelics, prompting further exploration of their therapeutic potential.

致幻剂最近因其减轻各种精神疾病相关症状的潜力而引起了极大的关注。然而，造成这些影响的精确神经生物学机制仍不完全清楚。深入了解具体作用机制的一个有价值的方法是将致幻剂与具有部分重叠的神经生理学效应的物质进行比较，即调节相同的神经递质系统。影像数据来自临床试验 NCT03019822，该试验探讨了麦角酸二乙胺 (LSD)、d-苯丙胺和 3,4-亚甲二氧基甲基苯丙胺 (MDMA) 对 28 名健康志愿者的急性影响。该临床试验采用双盲、安慰剂对照、交叉设计。在此，检查了各种静息态连接性措施，包括网络内连接性（完整性）、网络间连接性（隔离）、静息态网络的基于种子的连接性和全局连接性。使用重复测量方差分析评估安慰剂和活性条件之间的差异，然后进行事后配对 t 检验。基于种子的体素连接的变化与血清素 2A 受体密度图相关。与安慰剂相比，所有物质都降低了多个网络的完整性，表明了共同和独特的影响。虽然 LSD 独特地降低了默认模式网络 (DMN) 的完整性，但与我们的预期相反，安非他明比 LSD 降低了更多网络的完整性。然而，LSD 表现出更明显的隔离效应，其特征仅在于减少，而安非他明也能引起增加。 在所有物质中，网络之间基于种子的连通性大多增加，LSD 表现出比两种安非他明更明显的效果。最后，虽然所有物质都会降低视觉区域的整体连接性，但与安慰剂相比，LSD 特别增加了基底神经节和丘脑的整体连接性。这些发现增进了我们对迷幻药独特的神经生物学作用的理解，促使进一步探索其治疗潜力。