Multi-scale effects of single-dose psilocybin in the macaque brain
Jiaojian Wang, Jin Chen, Wenjie Sun, Zeyuan Yang, Chengsi Luo, Futing Yang, Yu-Xuan Zhu, Hongshuang Wang, Xi-Han Zhang, Jamie C. Masthay, Soo-Ji Baek, Jie Li, Yan Zhuo, Xiaopeng Wang, Yashi Wu, Yingzi Ma, Qinyao Sun, Weizhi Ji, Steve W. C. Chang, Xiaohui Wang, Xiaona Zhu, Ji Hu, Yongchang Chen, Ti-Fei Yuan
Research Square October 29, 2026 preprint DOI: 10.21203/rs.3.rs-11081511/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study (non-human primate) |
|---|---|
| Population | Cynomolgus macaques |
| Intervention | Psilocybin |
| Dose | a single dose |
| Duration | Changes lasting 1 week |
| Measures | multimodal MRI, magnetic resonance spectroscopy (MRS), cerebrospinal fluid (CSF) proteomics and metabolomics, single-nucleus RNA sequencing (snRNA-seq) |
| Topics | Psilocybin |
| Key findings | A single dose of psilocybin in cynomolgus macaques increased frontoparietal network integration with default-mode and limbic networks, induced global network segregation, and produced some changes lasting one week. Cerebrospinal fluid shifted from acute prostaglandin-dominated inflammation to a sustained omega-3 fatty acid-associated anti-inflammatory state with extracellular matrix reorganization, and the dorsolateral prefrontal cortex showed sustained elevations of glutamate/glutamine and total creatine plus enhanced mitochondrial oxidative phosphorylation and HTR2A upregulation in deep-layer excitatory neurons. |
Abstract
Abstract Psilocybin holds strong therapeutic promise for treating major depressive disorder. However, the cellular and molecular substrates underlying its action have not been fully elucidated, especially in the primate brain. We combined multimodal MRI, magnetic resonance spectroscopy (MRS), cerebrospinal fluid (CSF) proteomics and metabolomics, and single-nucleus RNA sequencing (snRNA-seq) to map the multiscale temporospatial dynamics induced by a single dose of psilocybin in cynomolgus macaques. Psilocybin increased the integration of the frontoparietal network (FPN) with the default-mode and limbic networks, transiently reduced integration of the FPN with the somatomotor network, and induced global network segregation. Several regions in the cortex, striatum, and thalamus as well as certain of the frontoparietal white matter pathways showed persistent enhancement lasting 1 week. Notably, these changes were accompanied by a CSF multi-omics shift from acute prostaglandin-dominated inflammation to a sustained enrichment of an omega-3 fatty acid-associated anti-inflammatory state together with a bidirectional reorganization of extracellular matrix (ECM)-related signatures, characterized by increased CD44 and decreased fibulin-family proteins. In addition, we found lasting upregulation of TCA-cycle and NAD(P)-dependent redox enzymes. This was further supported by sustained elevations of glutamate/glutamine and total creatine in the dorsolateral prefrontal cortex (dlPFC), which was found using in vivo MRS. At the cellular level, psilocybin promoted HTR2A selective upregulation in deep-layer excitatory neurons along with a widespread enhancement of mitochondrial oxidative phosphorylation centered on the complex I subunit ND3 across diverse excitatory and inhibitory neuronal subtypes in the dorsolateral prefrontal cortex. Glial-state remodeling, including a shift of astrocytes toward ECM remodeling states and microglia toward an anti-inflammatory state, also occurred. Collectively, these findings provide evidence in the primate brain that psilocybin induces functional integration and segregation of brain networks, enhances energy metabolism and synaptic plasticity, and modulates neuroimmune signaling. All the data will be shared as an integrated resource for primate psilocybin research.