Psilocybin For Treatment-resistant Depression: FMRI-measured Brain Mechanisms

Makrosky

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Recently published study : Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Abstract


Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
 
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Makrosky

Makrosky

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By the way cyproheptadine is an antagonist of 5ht2a among others. Has been used for relieving depression. Same with metergoline. The list of substances with 5ht2a antagonism used as antidepressants is large.
 

RedStaR

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By the way cyproheptadine is an antagonist of 5ht2a among others. Has been used for relieving depression. Same with metergoline. The list of substances with 5ht2a antagonism used as antidepressants is large.
That's funny since 5HT2a antagonists are used to nullify SSRI's neurogenesis and antidepressant effects.
 
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Makrosky

Makrosky

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That's funny since 5HT2a antagonists are used to nullify SSRI's neurogenesis and antidepressant effects.
There you have the answer on why theres much more to that than simply agonizing/antagonizing a single receptor.

A substance that agonizes 5ht2a is antidepressant.

A substance that antagonizes 5ht2a is antidepressant also.

And you think the mecahnism is only about a singlr receptor?
 

RedStaR

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There you have the answer on why theres much more to that than simply agonizing/antagonizing a single receptor.

A substance that agonizes 5ht2a is antidepressant.

A substance that antagonizes 5ht2a is antidepressant also.

And you think the mecahnism is only about a singlr receptor?
For SSRI's at least, this is the pathway of which it operates. I believe Ketamine also has NMDA/AMPA and 5-HT2 pathways for AD effects.

I do not know of antagonists of 5-HT2A that has AD effects, maybe you could share them.
 

Tarmander

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Jordan Peterson has talked about Mushrooms, and some interesting things about them. Personality wise, one use of psilocybin or DMT brings about a 1 standard deviation in openness that seems to be permanent. The data on alcoholism and other addiction is really great too.

I went through depression 5 years ago or so that was pretty intense, and part of how I found Peat and Matt. The interesting thing is that depression often has this aspect of over-responsibility. You take on too much on your shoulders and cannot bear the weight. I remember when reading depression forums how often depressed people loved movies and other escapes from life and responsibilities.

I wonder if using hallucinogens shows some deeper connection in the universe that allows a letting go of some of these impossible responsibilities that people place on themselves.
 

kyle

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Word to the wise - shrooms are not to be toyed with. Esp by depressives.
 
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Makrosky

Makrosky

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For SSRI's at least, this is the pathway of which it operates. I believe Ketamine also has NMDA/AMPA and 5-HT2 pathways for AD effects.

I do not know of antagonists of 5-HT2A that has AD effects, maybe you could share them.
There's another mechanism by which SSRIs might have AD effects. By increasing allopregnenolone levels in the brain. Probably a combination of different mechanisms. And also remember SSRIs don't have AD effects on some people and in others it worsens depression. But we are not talking about SSRIs, but psilocibe mushrooms. I don't understand why you still insist their AD mechanism is exclusively 5ht2a agonism. Whatever. I have mentioned you two substances that have 5HT2a antagonism and produce AD effects. If you look in the forum for 5ht2a you'll discover more.
 
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Makrosky

Makrosky

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Jordan Peterson has talked about Mushrooms, and some interesting things about them. Personality wise, one use of psilocybin or DMT brings about a 1 standard deviation in openness that seems to be permanent. The data on alcoholism and other addiction is really great too.

I went through depression 5 years ago or so that was pretty intense, and part of how I found Peat and Matt. The interesting thing is that depression often has this aspect of over-responsibility. You take on too much on your shoulders and cannot bear the weight. I remember when reading depression forums how often depressed people loved movies and other escapes from life and responsibilities.

I wonder if using hallucinogens shows some deeper connection in the universe that allows a letting go of some of these impossible responsibilities that people place on themselves.
Very interesting. Thanks for sharing this.
 

RedStaR

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There's another mechanism by which SSRIs might have AD effects. By increasing allopregnenolone levels in the brain. Probably a combination of different mechanisms. And also remember SSRIs don't have AD effects on some people and in others it worsens depression. But we are not talking about SSRIs, but psilocibe mushrooms. I don't understand why you still insist their AD mechanism is exclusively 5ht2a agonism. Whatever. I have mentioned you two substances that have 5HT2a antagonism and produce AD effects. If you look in the forum for 5ht2a you'll discover more.
5ht2a antagonists block SSRIs theraputic effects, which part of that didn't you understand?
 

johnsmith

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I wonder if using hallucinogens shows some deeper connection in the universe that allows a letting go of some of these impossible responsibilities that people place on themselves.

That alone was good to read.

Yes, this is starting to go into the subjective side of things. The subjective is not talked about too much around this forum, but it's definitely is an aspect of reality, and probably plays a role in our health as well.
 

alywest

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in my experience mushrooms completely take you out of clock-time and it also seems to open up the senses. I once watched a news segment with a woman undergoing deep brain stimulation and she remarked that the colors seemed to be more vivid around her and she immediately felt better. I have experienced that with psilocybin as well, the colors being extremely vivid, and seeing fractals move in perfect harmony, and feeling the sunlight and how incredible it is. Things we don't normally sense. Like, sure the sun feels nice normally, it's warming and all that. But you sense it in a totally different way, almost like a plant must feel when it gets the light it needs. At least that's what i experienced.

I think it can be dangerous if done alone in an environment that isn't conducive to positivity. For instance, I would guess that blue light is actually something that could trigger a bad trip. also music that has darker chord progressions and stuff. Ray has talked about the subtle influence that music has on our being, and when you're tripping you definitely see how that must be true but we block so much out when we are "sober." Also, definitely do not recommend smoking pot at any point when you are tripping. It is a bad combo. I think pot gives a numbing feeling that some people may need if they are dying of cancer or something, mushrooms really do open you up but you have to be conscious of environment.
 

Dhair

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5ht2a antagonists block SSRIs theraputic effects, which part of that didn't you understand?
"Estrogen has also been shown to increase the density of 5HT2A receptors in brain regions associated with mood (Fifa and Fillion, 1992)."
Sounds like you're reading propaganda.
The connection between estrogen and serotonin is well-established, and SSRIs are estrogenic. Big pharma has been pushing estrogen therapy for depressed women for decades, which has been a massive failure. So your statement regarding 5ht2a agonists being "therapeutic" is only accurate if you believe estrogen is beneficial for depression.
I'd like to see your sources.
 
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RedStaR

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"Estrogen has also been shown to increase the density of 5HT2A receptors in brain regions associated with mood (Fifa and Fillion, 1992)."
Sounds like you're reading propaganda.
The connection between estrogen and serotonin is well-established, and SSRIs are estrogenic. Big pharma has been pushing estrogen therapy for depressed women for decades, which has been a massive failure. So your statement regarding 5ht2a agonists being "therapeutic" is only accurate if you believe estrogen is beneficial for depression.
I'd like to see your sources.
It's the other way round. Estrogen is serotonergic.

I believe estrogen is necessary for good mental and physical health. I'm not sure why estrogen and serotonin get a bad rap on this forum. Perhaps you mean excess of both. Which applies to anything.
 

Dhair

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It's the other way round. Estrogen is serotonergic.

I believe estrogen is necessary for good mental and physical health. I'm not sure why estrogen and serotonin get a bad rap on this forum. Perhaps you mean excess of both. Which applies to anything.
Have you read any of Ray Peat's work?
 

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