Long-term effects of psilocybin on dynamic and effectivity 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
bioRxiv (Cold Spring Harbor Laboratory) November 7, 2024 preprint DOI: 10.1101/2024.11.06.622302 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Within-subject longitudinal trial |
|---|---|
| Population | Psychedelic-naïve healthy volunteers |
| Intervention | Psilocybin |
| Dose | full dose |
| Duration | Four weeks after dosing |
| Topics | Psilocybin |
| Keywords | Hallucinogen Term time Functional connectivity Biological neural network |
| Citations | 4 |
| Key findings | Psilocybin increases fronto-striatal-thalamic dynamic activity and flexibility four weeks after dosing, driven by reduced structural constraints and serotonergic- and dopaminergic-mediated changes in information flow. |
Abstract
Abstract Psilocybin has been shown to induce fast and sustained improvements in mental well-being across various populations, 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 apply empirical methods and computational modeling to resting-state fMRI data from a within-subject longitudinal psilocybin trial in psychedelic-naïve healthy volunteers. We first show increases in FST dynamic activity four weeks after a full dose of psilocybin. We then proceed to mechanistically account for these increased dynamics, by showing that reduced structural constraints underlie increased FST dynamic activity post psilocybin. Further, we show that these reduced structural constraints come along with increased bottom-up and reduced top-down modulation of FST circuits. While cortical reductions in top-down modulation are linked to regional 5-HT2A receptor availability, increased information outflow via subcortical and limbic regions relate to local D2 receptor availability. Together, these findings show that increased FST flexibility weeks after psilocybin administration 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 underling the potential clinical efficacy of psilocybin across various neuropsychiatric disorders including substance abuse, major depression, and anorexia. Significance Statement Fronto-striatal-thalamic systems, which underlie motivation and reward, go through profound functional and structural changes following psilocybin administration. We leveraged longitudinal fMRI data from a within-subject psilocybin trial in psychedelic-naïve healthy participants to show that psilocybin increases fronto-striatal-thalamic dynamic activity as well as flexibility four weeks after dosing. Computational modeling revealed that this increased flexibility is mechanistically caused by reduced structural constraints on functional dynamics. Further long-term changes included increased bottom-up and reduced top-down information flow mediated by the serotonergic and dopaminergic systems. This long-term functional re-organization of fronto-striatal-thalamic circuits may reflect a common mechanism underlying clinical symptoms improvements across diagnostic groups, such as increased openness, improved well-being, and reductions in anhedonia, apathy, and substance craving.
Comparable studies
Other non-randomized and open-label trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Patients with moderate-to-severe, unipolar, treatment-resistant major depression | 2016 | Open-label feasibility trial | n = 12 |
| Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Patients with severe, unipolar, treatment-resistant major depression | 2017 | Open-label trial | n = 20 |
| Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction Psychiatrically healthy nicotine-dependent smokers | 2014 | Open-label pilot study | n = 15 |
| Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Patients with treatment-resistant depression | 2018 | Clinical trial | n = 20 |
| Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder Subjects with obsessive-compulsive disorder (OCD) | 2006 | Controlled clinical trial |
Citations in the library
Cited by 4
- Perturbing whole‐brain models of brain hierarchy: An application for depression following pharmacological treatment Annals of the New York Academy of Sciences July 21, 2025
- Learning as the unifying mechanism of psychedelic action Journal of Psychopharmacology December 26, 2025
- Spiral brain dynamics track the temporal unfolding of subjective intensity during the N,N-dimethyltryptamine experience bioRxiv (Cold Spring Harbor Laboratory) September 28, 2026
- Cross-species mapping of psychedelic gene expression reveals links to the 5HT2A receptor, cortical layers, and human accelerated regions Research Square October 3, 2025
Cites 25
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- 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
and 20 more in the library