Modeled Long-Term Effects of Psilocybin on Dynamic Activity and Effective Connectivity of Fronto-Striatal-Thalamic Circuits.
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs, Yonatan Sanz Perl, Adrián Ponce-Alvarez, Sebastián Idesis, Manesh Girn, Leor Roseman, Jennifer Mitchell, Adam Gazzaley, Morten L. Kringelbach, David Nutt, Taylor Lyons, Robin Carhart-Harris, Gustavo Deco
Human Brain Mapping July 1, 2026 DOI: 10.1002/hbm.70596 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of a within-subject longitudinal randomized trial Peer reviewed |
|---|---|
| Population | Psychedelic-naïve healthy volunteers |
| Intervention | Psilocybin |
| Duration | 4-week follow-up |
| Topics | Psilocybin Serotonin |
| Keywords | Thalamus Corpus striatum Frontal lobe Nerve net Neural pathways Humans Hallucinogens Magnetic resonance imaging Longitudinal studies Models, neurological Female Young adult Connectome Effective connectivity Dynamic brain activity Hopf model Fronto‐striatal‐thalamic circuits |
| Key findings | Dynamic fronto-striatal-thalamic activity increased four weeks after a full dose of psilocybin. The authors provide tentative model-based support that reduced structure-function coupling contributes to this increase, and report increased bottom-up and reduced top-down modulation of FST circuits, linked to 5-HT2A and D2 receptor availability. They suggest this long-term functional reorganization may be a common mechanism underlying psilocybin's potential clinical efficacy across psychiatric disorders. |
Abstract
Psilocybin has been shown to induce fast and sustained symptoms improvements across various psychiatric conditions, yet its long-term mechanisms of action are not fully understood. Initial evidence suggests that longitudinal functional and structural brain changes implicate fronto-striatal-thalamic (FST) circuitry, a broad system involved in goal-directed behavior and motivational states. Here, we performed secondary analyses and applied computational modeling to resting-state fMRI data from a within-subject longitudinal psilocybin trial in psychedelic-naïve healthy volunteers. We first showed that dynamic FST activity increased 4 weeks after a full dose of psilocybin. We then proceeded to mechanistically account for these changes by providing tentative model-based support that reductions in the structure-function coupling contribute to increased dynamic FST activity postpsilocybin. Finally, we used computational approaches to show that psilocybin induces longitudinal increases in bottom-up and reduced top-down modulation of FST circuits. We then used publicly available receptor maps to show that cortical reductions in top-down modulation are linked to regional 5-HT2A receptor availability, while increased information outflow via subcortical and limbic regions relates to local D2 receptor availability. Together, these findings suggest that increased FST flexibility weeks after a high dose of psilocybin is linked to serotonergic-mediated decreases in top-down information flow and dopaminergic-mediated increases in bottom-up information flow. This long-term functional re-organization of FST circuits may represent a common mechanism contributing to the potential clinical efficacy of psilocybin across various neuropsychiatric disorders including substance abuse, major depression, and anorexia nervosa.
Comparable studies
Other randomized controlled trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Hallucinogen-naïve adults reporting regular participation in religious or spiritual... | 2006 | Double-blind study | n = 36 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
Citations in the library
Cites 18
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 13 more in the library