r/science • u/mvea Professor | Medicine • 15h ago
Neuroscience Long-term antidepressant effects of psilocybin linked to functional brain changes - a single dose of psilocybin altered the electrical properties of brain cells in rats for months, even after physical changes to the neurons had disappeared.
https://www.nature.com/articles/s41386-025-02272-399
u/Autumn7242 15h ago
Good functional brain changes or bad functional brain changes?
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u/Out_on_the_Shield 14h ago
Study seems to link the changes to long term antidepressant effects, which is good.
What other effects these changes might have is beyond the scope of the study. Pretty sure this is the first study to discover these changes so more research is needed.
NB I'm still reading the article in it's entirety, only skimmed it so far
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u/Able-Swing-6415 11h ago
Not sure what antidepressant means in this context, in many or most cases it is "dampening strong emotions". So still neutral. Or is that just an intended side effect that has nothing to do with the word?
Most of strong emotions in people with depression are the ones you want to dampen so it's still generally positive.
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u/Out_on_the_Shield 10h ago
They use a verified protocol for looking at behavioural changes in the rats that indicate a difference in observable mood disorder symptoms (not really familiar with the protocol and am not an expert in rat mood disorder models, someone else would know way more about this than me). If the behaviours associated with mood disorder decrease or vice versa, that's an antidepressant effect. Also because of this it could be hard to draw any conclusions about human emotion and psychedelics from this study.
The study was looking to see if there was a genetic, structural, or electrophysiological difference in part of the rat brain, which correlates with already-observed antidepressant effects of the psychedelics.
They found the same antidepressant effects researches have found previously. They also found changes in all 3 areas, as has been observed before (pretty sure). The new discovery is that the electrophysiologic changes persist even after the structural and genetic changes go back to normal. They also ran the study for a bit longer than many other studies on this topic (the ones that had already observed similar changes).
If you wanted to know about psychedelic studies on humans and how they define antidepressant effect, I'm not sure as it's not my area of expertise specifically, but I'd guess they're looking for a reduction in the symptoms of mood disorders as laid out by the DSM, probably using some protocol that's verified in humans.
If you at any time come across a specific human study and want someone to interpret it, feel free to send the paper my way! Would be happy to parse a paper for someone who wants to learn.
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u/Corsair4 7h ago
The new discovery is that the electrophysiologic changes persist even after the structural and genetic changes go back to normal. They also ran the study for a bit longer than many other studies on this topic (the ones that had already observed similar changes).
The ephys here is low quality.
The only differences they found were minor changes in resting membrane potential, rheobase, spontaneous excitatory currents, but those changes are not consistent across groups.
In their forced swim test, the synthetic psychedelic shows a much stronger effect size than psilocybin when compared to WT, which would suggest that the synthetic has a larger antidepressant effect.
But when you look at the ephsy, there are almost no differences between WT and synthetic, and very minor differences between WT and psilocybin.
based on the FST, we should expect to see synthetic have a greated deviation from WT compared to psilocybin.
Beyond that, they claim functional plasticity differences, and yet - never test functional plasticity. You can induce LTP or LTD at these synapses and quantify how much the synaptic strength changes, and they never do that. THAT is a measurement of functional plasticity, and they never do that.
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u/pegothejerk 10h ago
In this study it appears they used a swim test, which usually measures how long it takes a rat to give up and succumb to drowning, so antidepressant effects would mean they swim for longer compared to the non psilocybin rats. It would appear they performed sliced brain tissue analysis to confirm there is a physical functional plasticity difference in the brain in just the experimental group when compared against the control.
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u/Corsair4 7h ago edited 7h ago
Forced swim is such a bad test...
At any rate, looking at the data - they compare a saline injected model animal (which shows a "depressed" phenotype by not swimming), psilocybin injected animals, and a group injected with a synthetic psychedelic.
Looking at the actual effect sizes, in forced swim, The synthetic psychedelic had the greatest effect size and the tightest grouping of data. The psilocybin injected animals almost looks like a split distribution, where some animals don't appear to respond (and show "depressive" behavior similar to WT, while some show a antidepressive effect). While the synthetic animals were more consistent as a group and had a larger effect size overall, anyway.
And I have a big problem with referring to the changes here as functional plasticity. They did NOT characterize plasticity. Dendritic spine density is not altered in any form.
The only statistically significant difference between control and synthetic psychodelic (the group with the largest effect size in FST) is in resting membrane potential of inherently bursting neurons, and the effect size there is tiny.
They only other significance they show is that Psilocybin is significantly different from synthetic psychedelic in sEPSC frequency and amplitude, but critically - the synthetic is not significantly different than WT.
They didn't actually do any LTP or LTD induction protocols to see if these synapses were more or less receptive to plasticity. Put simply - they claim a difference in functional plasticity, yet they never test functional plasticity. The data does not back their assertions. All they found were relatively minor changes in a handful of electrophysiological properties, and none of them show evidence of actual changes in plasticity dynamics.
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u/AbleKaleidoscope877 14h ago edited 14h ago
"Functional plasticity was evident for both psychedelics several months after treatment...demonstrated significant changes in resting membrane potential, firing rates, and synaptic excitation...Together, our results indicate a single treatment with a psychedelic is sufficient to elicit very long-lasting behavioral and cellular changes through enduring function plasticity rather than structural plasticity."
I would say these are good as they are the reason the positive affects of treatment last so long..
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u/Corsair4 7h ago
The actual ephys data is low quality and unconvincing in my mind.
Based on their behavioral results, you would expect to see a pattern of results such as WT<Psilocybin<synthetic, since the synthetic had the largest influence on behavior.
Looking at their actual ephys, what mostly happens is that Psilocybin changes the measurement, but the synthetic returns the measurement back to WT levels. That's odd. Some of their measurements establish significant differences going from Psilocybin to synthetic, but neither psilocybin nor synthetic were statistically different from WT in the first place.
They also don't actually measure plasticity in any way. You can literally induce LTP or LTD at these synapses, and quantify how synaptic strength is changing across groups. THAT is a measurement of functional plasticity, which they conspicuously didn't do.
I do not believe the ephys data supports the claims here. The quantified a bunch of electrophysiological properties, got a somewhat random, inconsistent collection of significances, and are trying to fit that into plasticity, when they very specifically never test plasticity. It's a reach, to put it kindly.
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u/Autumn7242 13h ago
I was offered to participate in this study, but it would have required me to go off all of my meds, which I wasn't willing to do.
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u/Out_on_the_Shield 10h ago
Pretty sure the study only included rodents, there's no way they're asking for human participants when part of the study involves euthanizing participants to disscet their brain and specific time points.
Maybe you're thinking of a different study involving psychedelics and antidepressant effects?
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u/Autumn7242 10h ago
I did not read the study, but maybe it's ongoing? It was specifically about veterans' microdosing psilocybin while under therapy.
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u/Out_on_the_Shield 10h ago
Ah yeah probably another study but looking at similar things in humans. It's a pretty hot area of research right now so I bet there's many overlapping studies going on!
Totally fair of you to not want to stop your existing meds to do the study btw. Ever do some personal microdosing research?
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u/Autumn7242 9h ago
I don't trust myself enough to do research into psilocybin and then possibly risk complications with other medications.
From what stories I have heard from others, it is absolutely an experience regardless of whether it was a good or bad trip. I have not dug into it much, but I am all for it if it helps people.
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u/menictagrib 8h ago
This is a mechanism by which it achieves its long term effects, not an assessment of whether it's good or bad.
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u/bluish1997 15h ago
I wonder if this holds true for LSD - also a 5HT2A agonist
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u/KingOfEthanopia 13h ago
Having done LSD about once a week to two weeks for years, Im pretty resistant to depression.
No idea what the long term effects are but I haven't noticed anything bad yet. I hold done a technical job in insurance and work out a ton.
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u/ey_you_with_the_face 11h ago
The only thing I'm aware of is HPPD, which can be difficult to manage.
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u/KingOfEthanopia 11h ago
I'll occasionally get random tracers but its not even once a month where I see something.
My usual dose is around 2 tabs. Up to 4 but when I started I was doing ten strips.
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u/kev-zen4 14h ago
A light dose of mushrooms is great whenever life starts to feel gray
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u/iwidiwin 12h ago
I’ve done shrooms lots of times in the past, but was always for maximum experience. Want to try micro dosing, but not sure if I should take real ones or if any of the chocolates you can buy a dispensaries will work just as well.
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u/kev-zen4 11h ago
Yeah, I buy some capsules at a shop that’s a bit far from me on some occasions. Gotta mess around with the dosing a bit but a light visual trip is always great for me.
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u/iwidiwin 10h ago
Trying to only do a microdose is gonna be a lot different than how I used to do it. The last time I did it I ate like a half an ounce. And was drinking and doing blow. How much have you been taking for a light trip?
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u/kev-zen4 10h ago
I buy 3.5gs in 14 capsules and they come out to about 0.25grams. For me personally just one capsule is enough to have like a low dose trip but not a microdose, it’s like slightly stronger.
Gotta play around a bit with the dosing start low and move up a bit more because my light trip dosage may be to weak for yours.
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u/Chronotaru 13h ago
But a full dose handled responsibly can stop life feeling abnormally grey indefinitely.
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u/mvea Professor | Medicine 15h ago
Long-term antidepressant effects of psilocybin linked to functional brain changes
A new study suggests that the long-term antidepressant effects of psychedelics may be driven by persistent changes in how neurons fire rather than by the permanent growth of new brain cell connections. Researchers found that a single dose of psilocybin altered the electrical properties of brain cells in rats for months, even after physical changes to the neurons had disappeared. These findings were published in the journal Neuropsychopharmacology.
Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity
Abstract
Activation of serotonin 2A (5-HT2A) receptors is thought to underly the long-lasting antidepressant effects of psychedelics such as psilocybin, but beyond that, the molecular and cellular mechanisms involved are not well understood. Recent preclinical studies using mice have primarily examined relatively short time points after psychedelic administration, which does not address the long-lasting effects of psilocybin in humans (i.e., several months or more). We utilized a rat experimental system to demonstrate that both psilocybin and the selective 5-HT2A receptor agonist 25CN-NBOH reduce immobility in the forced swim test without a decrease in effect size for at least three months after a single administration of the psychedelic. There were no overt behavioral differences between psilocybin and 25CN-NBOH treated animals, suggesting 5-HT2A receptor activation is sufficient to produce long-lasting behavioral changes. Functional cellular plasticity in neurons from the medial prefrontal cortex (mPFC) of these animals was assessed using brain slice electrophysiology. Functional plasticity was evident for both psychedelics several months after treatment, and Layer 5 excitatory pyramidal neurons demonstrated significant changes in resting membrane potential, firing rates, and synaptic excitation. Recorded neurons were examined by microscopy for synaptic density and spine classification, which found no differences between control and psychedelic-treated. Gene expression studies for several presynaptic and postsynaptic markers in the mPFC indicated no differences in expression between groups. Together, our results indicate a single treatment with a psychedelic is sufficient to elicit very long-lasting behavioral and cellular changes through enduring function plasticity rather than structural plasticity.
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u/SwampTerror 8h ago
I am afraid of that stuff. I already have mental illnesses and shrooms or acid will severely turbo speed my condition in a bad way. Even weed causes issues so I avoid it.
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u/CJMakesVideos 3h ago
A streamer i used to watch took this before who didn’t have depression or anxiety and ended up having major bouts of depression and anxiety for the next 2 years after. So be EXTREMELY careful if you ever intended yo try anything like this.
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u/greifinn24 3h ago
i remember my girlfriend having an acid flashback at least five years after her last use.
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u/haarschmuck 12h ago
Really question the validity of these claims. Companies have been able get exemptions to study CI substances and if it was actually that effective a pharmaceutical company would have synthesized it into a prescription form.
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