Health Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks

[perpetualdawn]

Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin’s effect on connectivity is network specific, strengthening the routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.

https://www.cell.com/cell/fulltext/S0092-8674(25)01305-4

tl;dr:
The medial frontal cortex supports decision making and executive function. This study looked at how psilocybin alters post-acute structural connectivity; the actual rewiring, not the acute “tripping” phase. They found that inputs from perceptual regions and the mouse equivalent of the DMN were strengthened, while inputs from cortico-cortical recurrent loops (the circuits that stabilize top-down predictions and habitual patterns) were weakened.

Psilocybin opens an activity-dependent plasticity window: the circuits that are active during the drug state are the ones that get strengthened. This suggests that psychedelic-evoked plasticity can be intentionally guided, consistent with the idea that what the mind engages with during a session shapes the long-term effects.

This confirms some things that psychedelic enthusiasts have known intuitively for a long time, and also spells out more concretely what the science has been alluding to lately.

 

[iom]

It is my understanding that physical exercise induces neuroplasticity as well. I'm very curious as to how this compares, quantitatively and qualitatively, with the action of psychedelics. Certainly exercise has been shown to have anti-depressant effects at least as good as the usual pharma drugs, but I don't think it's clear how much increased neuroplasticity has to do with the anti-depressant effect of exercise.

At the same time, I remain cautious and skeptical about many of the claims of how psychedelics exert their actions. For one thing, I think the brain gets way more attention than it deserves, being that 5-HT2A and 5-HT2B receptors are all over the body. Also by studying action in the body, one might get better insight into actions in the brain in so far as such actions may be analogous. I suspect psychedelics will some day be understood to have a very broad spectrum of activity, and effects on mental well-being may be the product of many different actions.

 

[perpetualdawn]

@iom It would be really interesting to directly study and compare how psychedelics and excercise affect neuroplasticity. It would really take the wind out of the sails of the psychedelic exuberance if it ended up that a jog does just as good a job as a magic mushroom session. Good of you to bring that up, good reminder.

My expectation is that they're not the same, overlapping, but not the same, and that they can be synergistic. Personally, I try to get a lot of exercise (a bit out right now with an injury, but normally) and I see psychedelics as a great adjunct to a healthy lifestyle.

When you think about it, our modern society is radically under-exercised and that this should probably be the first thing to look at for anyone who is feeling in the dumps. Our species evolved to be far more active than what a typical modern lifestyle promotes. It's just not healthy sitting on a chair barely moving in front of a computer or phone or whatever. Even most people who are considered "active" are only marginally so compared to our ancestors who were out in the fields every day, or living nomadically on the land even further back, or swinging in the trees if you go back deep in our evolutionary history millions of years ago.

If you made a sort of Maslow's Heirarchy of well-being, exercise and diet should probably be lower towards the base of the pyramid, and psychedelics higher up.

 

[Leprechaun]

It is my understanding that physical exercise induces neuroplasticity as well. I'm very curious as to how this compares, quantitatively and qualitatively, with the action of psychedelics. Certainly exercise has been shown to have anti-depressant effects at least as good as the usual pharma drugs, but I don't think it's clear how much increased neuroplasticity has to do with the anti-depressant effect of exercise.

At the same time, I remain cautious and skeptical about many of the claims of how psychedelics exert their actions. For one thing, I think the brain gets way more attention than it deserves, being that 5-HT2A and 5-HT2B receptors are all over the body. Also by studying action in the body, one might get better insight into actions in the brain in so far as such actions may be analogous. I suspect psychedelics will some day be understood to have a very broad spectrum of activity, and effects on mental well-being may be the product of many different actions.

Anecdotally almost the same. If I want to change habits. A good 2 hour run and imaginative narration throughout the run has very powerful habit and internal process alteration for the positive, same level as psilocybin.

just my personal experience.

 

[Leprechaun]

@iom It would be really interesting to directly study and compare how psychedelics and excercise affect neuroplasticity. It would really take the wind out of the sails of the psychedelic exuberance if it ended up that a jog does just as good a job as a magic mushroom session. Good of you to bring that up, good reminder.

My expectation is that they're not the same, overlapping, but not the same, and that they can be synergistic. Personally, I try to get a lot of exercise (a bit out right now with an injury, but normally) and I see psychedelics as a great adjunct to a healthy lifestyle.

When you think about it, our modern society is radically under-exercised and that this should probably be the first thing to look at for anyone who is feeling in the dumps. Our species evolved to be far more active than what a typical modern lifestyle promotes. It's just not healthy sitting on a chair barely moving in front of a computer or phone or whatever. Even most people who are considered "active" are only marginally so compared to our ancestors who were out in the fields every day, or living nomadically on the land even further back, or swinging in the trees if you go back deep in our evolutionary history millions of years ago.

If you made a sort of Maslow's Heirarchy of well-being, exercise and diet should probably be lower towards the base of the pyramid, and psychedelics higher up.

I did some anecdotal studies on running on psychedelics.

I noticed psychedelic effects quite muted and more pleasant after finishing the run.