Modeled Long‐Term Effects of Psilocybin on Dynamic Activity and Effective Connectivity of Fronto‐Striatal‐Thalamic Circuits

Summary & key facts

Researchers re-analyzed brain scans from people who had never used psychedelics, before and four weeks after a single high dose of psilocybin. They found that a set of brain circuits involved in goals and motivation became more flexible weeks after the dose. Computer models suggested this change came from weaker top-down control from the cortex and stronger bottom-up signals from deeper brain regions. These shifts were linked to brain maps of serotonin and dopamine receptors, and the authors say this re-organization might help explain why psilocybin has shown lasting benefits in conditions like depression and substance problems, but the results are tentative and come from healthy volunteers, not patients.

Key facts:

• The study looked at brain activity in the same healthy people before and four weeks after one full dose of psilocybin.
• Activity in the fronto-striatal-thalamic system — a brain network tied to motivation and goal-directed behavior — was more dynamic four weeks after psilocybin.
• Computer-based brain models suggested the increased flexibility was related to weaker top-down signaling from the cortex and stronger bottom-up signaling from subcortical and limbic areas.
• Cortical reductions in top-down signaling were linked to areas with more serotonin 5-HT2A receptors, while increased outflow from deeper regions was linked to areas with dopamine D2 receptors.
• The authors call their model-based explanations tentative, meaning they are plausible ideas supported by the data but not proven causes.
• The data come from psychedelic-naïve healthy volunteers, so the findings show brain changes in people without psychiatric disorders and not direct therapeutic effects in patients.

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.

Topics

Forensic Toxicology and Drug Analysis Paranormal Experiences and Beliefs Psychedelics and Drug Studies

Categories

Clinical Psychology Psychology Social Sciences

Tags

Anorexia Biological neural network Computational model Computer science Default mode network Flexibility (engineering) Functional connectivity Functional imaging Hallucinogen Limbic system Mechanism (biology) Modulation (music) Nerve net Neuroscience Psilocybin Psychology Receptor

Substances

Psilocybin

Conditions & symptoms

Depression Eating Disorder Substance abuse disorder Lack of energy or motivation Sadness or low mood