Why we don't react to psychedelics anymore (Allopregnanolone)

This is for hypothesis and even educated speculation.
cdraham
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Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by cdraham »

Hello guys, as many of you know especially in the severe PSSD sufferers our reaction to many (recreational) drugs is very blunted or non existent. I've been thinking about this for a while.

Lately I've been reading some posts here about Allopregnanolone and PSSD.

There is this study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23979/
The efficiency of the enzyme, the ratio of Vmax to Km, then was calculated. The enzymatic efficiency of rat 3α-HSD, in the conversion from DHP to allopregnanolone, was 3.7 and was 0.003 in the conversion of allopregnanolone to DHP. The enzyme efficiency of the reductive reaction increased ≈46-fold in the presence of fluoxetine. Fluoxetine did not alter the oxidative reaction. Thus, fluoxetine dramatically enhances the efficiency of the enzyme, but only in the conversion of DHP to allopregnanolone.
If there is chronic high Allopregnanolone in PSSD, this would shift the brain to a more inhibitory dominant tone, as Allopregnanolone is a potent positive allosteric modulator of GABA. Even if Allopregnanolone levels returned to normal after SSRI cessation, there is evidence that 5a-DHP can have genetic effects on GABA receptors.

How is this connected to psychedelics?


We know psychedelics work by increasing glutamate along many other reactions (simplification), what if Allopregnanolone and high GABA signalling is blocking glutamate function from working?

It's known that benzodiazepines, which are also positive allosteric modulators of GABA, just like Allopregnanolone is, can stop psychedelic trips. This is also true if you take a high dose of a benzodiazepine and then do the psychedelic later. The trip will be very blunted or not work.

In contrast to PFS, they are suspected to have low Allopregnanolone. Ive been taking a look at their forum and it seems like many report having benefits from psychedelics there.

I've been checking TBI subreddits and even those with "real" brain damage seem to respond fine to psychedelics.

So what is it in us thats blocking the psychedelics effects? I think it is chronic high Allopregnanolone leading to a strong inhibitory GABA signal. This would also explain why we don't feel anxiety anymore. It's like were on a benzodiazepine 24/7.

High allopregnanolone would also prevent neurogenesis from happening, aswell as LTP because glutamate function is needed for LTP.

What could we try to reverse this?


The only thing that could inhibit this potent GABA signalling would be so called GAMSAs. If the GABA potentiation is coming from neurosteroids, regular GABA antagonists won't work.
6. Not all antagonists at GABAA receptors antagonize
allopregnanolone and THDOC
Several studies have found that the benzodiazepine antagonist
flumazenil does not antagonize steroids that positively modulate
the GABAA receptor. For example, it has no effect on allopregnanolone’s potentiation of the GABAA receptor current according
to patch-clamp studies of hippocampal cultures [3], and in vivo it
does not antagonize allopregnanolone-induced hyperphagia in
rats [56], or pregnanolone discriminative stimulus effects in
Rhesus monkeys [26]. Similarly, in humans flumazenil does not
antagonize the reduction in saccadic eye velocity induced by
allopregnanolone [5]. However, at least one study has reported an
antagonistic effect: that flumazenil antagonizes allopregnanolonedecreased probe-burying in female Wistar rats, and thus apparently counters allopregnanolone’s anxiolytic effect in them [25].
The ethanol antidote Ro15-4513 is a weak benzodiazepine
antagonist that in vivo does not antagonize the contextual learning
disruption caused by allopregnanolone in C57Bl6 mice [22].
However, in vitro the allopregnanolone potentiation of the GABAA
receptor current has been shown to be antagonized [3].
In contrast, GABAA receptor antagonists directed against the
GABA site, like bicuculline, or chloride channel blockers such as
picrotoxin, or the GABAA receptor negative allosteric modulator
pregnenolone sulfate block both the effect of GABA and
allopregnanolone/THDOC potentiation of the receptor [45,42,29].
Use of such substances in vivo is dangerous as blockage of the GABA
effect at the GABAA receptor leads to over-excitation with
induction of seizures. This highlights the need to use GAMSAs,
i.e. specific neurosteroid antagonists that do not affect GABA
responses, when attempting to inhibit cognitive deficits or other
adverse conditions mediated by allopregnanolone, for safety
reasons.
I've been taking a look at GAMSA drugs and there is golexanolone. https://en.wikipedia.org/wiki/Golexanolone

Unfortunately these drugs are RCs, some of them in human trials and not really available for the public.

Here are some more studies of golexanolone (GR3027)

https://pubmed.ncbi.nlm.nih.gov/26138462/
https://pubmed.ncbi.nlm.nih.gov/29492615/

There is hepatic encephalopathy which can cause similiar neurological symptons seen in PSSD. A popular hypothesis is the GABA hypothesis: https://www.researchgate.net/publicatio ... phalopathy
Furthermore, increased ammonia concentrations upregulate the peripheral-type benzodiazepine receptor in the outer membrane of astroglial mitochondria, thereby enhancing astrocytic mitochondrial synthesis and release of neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA(A) receptor complex, on which there are specific binding sites for neurosteroids, that are distinct from those for BZs and barbiturates. Tetrahydroprogesterone and tetrahydrodeoxycorticosterone levels were found to be increased in a mouse model of acute liver failure, and, when THP or THDOC was injected into normal mice, sedation and Alzheimer type II astrocytic changes in the cortex, striatum, and hypothalmus were induced. Each of these direct or indirect effects of ammonia on the GABA neurotransmitter system has the potential of increasing inhibitory neurotransmission, and, hence, contributing to the manifestations of HE.
Image

Golexanolone is in clinical trials for HE. https://www.globenewswire.com/news-rele ... olone.html
PsychoGenesis
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by PsychoGenesis »

me and others like ghost still respond to psychedelics

we know PSSD is an endocrine fuckery beyond what neurotransmitters can do

but the psychedelic blunting is much simpler than that
IMHO

https://pubmed.ncbi.nlm.nih.gov/1973935/
cdraham
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by cdraham »

PsychoGenesis wrote: Fri Oct 16, 2020 12:35 pm me and others like ghost still respond to psychedelics

we know PSSD is an endocrine fuckery beyond what neurotransmitters can do

but the psychedelic blunting is much simpler than that
IMHO

https://pubmed.ncbi.nlm.nih.gov/1973935/
Thanks for that study
JakeLawe
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by JakeLawe »

I offer the following perspective, acknowledging it's opposite exists:

Severe depression gets in the way.

One may feel "normal" but the depression is there, possibly even "resurfaced" or "transfered" by means of coping mechanisms of the mind that takes the opportunity to do so after ingesting of "antidepressants", hence psychedelics can't "get past through" the depression.

Another view is that even psychedelics are placebo of sorts or entirely.. like.. it's us tripping balls, not really by the chemical reactions per se but by means of our own minds. If one's depressed as fuck the placebo effect is bound to be weaker.

Why do people don't get high the first times with weed? was my experience and of many more.. it took about four-five times of smoking before i could say i got high, i felt literally not anything the first times.

Same with cigarettes.. first times one does it one can't feel anything except bad smell and bad throat but one kept at it because was "cool".. (in the 80's, 90's at least), then.. suddenly one felt it made something for concentration etc..or that one got irritable, got a headache without it

Same with ssri's.. placebos to me..

IF they're not placebos.. then i still go with depression gets in the way.. but may be both.. In short, according to this perspective: 'fixing" deep sadness (by any means and assuming there's something to "fix" since feeling sadness is part of being human) should reverse this and, once happier, the subject can now get high as fuck and trip balls as desired.
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Delfador
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by Delfador »

I still react to psychedelics just the same. I'm not saying this to disregard your theory though. Just reporting a case .
Naczoz
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by Naczoz »

Me too, maybe Im not that happy and euphoric, but most of acid trip remains the same.
cdraham
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by cdraham »

PsychoGenesis wrote: Fri Oct 16, 2020 12:35 pm me and others like ghost still respond to psychedelics

we know PSSD is an endocrine fuckery beyond what neurotransmitters can do

but the psychedelic blunting is much simpler than that
IMHO

https://pubmed.ncbi.nlm.nih.gov/1973935/
Thanks for the study, did u take a look at this: https://watermark.silverchair.com/9-2-1 ... POOt-q2opw
In conclusion, the present experiments show thatboth 3a,5a-THP and ganaxolone increase the firingactivity of 5-HT neurons, and that they both can pre-vent the citalopram-induced reduction of this activity.This not only offers a biological basis for the anti-depressant-like effect of 3a,5a-THP but also supportsthe hypothesis that ganaxolone might have such ben-eficial properties. Furthermore, our data suggest that3a,5a-THP or ganaxolone could constitute good can-didates as adjuvants to reduce the delay before thera-peutic onset, seen with SSRIs. Since naturallyoccurring neuroactive steroids might not be suitablefor chronic treatments (due to their very short half-life and side-effects profile) (Gasior et al., 2000),if ganaxolone had antidepressant properties, it couldbe especially promising as a treatment or as anadjuvant in the treatment of mood disorders in femaledepressed patients.
cdraham
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by cdraham »

Delfador wrote: Wed Oct 21, 2020 12:44 pm I still react to psychedelics just the same. I'm not saying this to disregard your theory though. Just reporting a case .
Thanks. How bad are your symptoms?
Knifli
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by Knifli »

I still react to psychedelics, but i don't get very emotional anymore eversince PSSD. In the earlier days of PSSD i almost didn't react at all to psychedelics, just some mild visuals.

Before pssd psychedelics used to make me very emotional for everything. Now i just get the trippy visuals, more philosophy and observing of things.

Not sure what caused this.
Sertraline jan-jul 2018
silentpain89
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Re: Why we don't react to psychedelics anymore (Allopregnanolone)

Unread post by silentpain89 »

I think i have a combination of PFS/PSSD, since i took both and i have worst sides of both spectrums (Numb skin, loss of taste and smell senses, ofcourse the fun complete impotence and sexual dysfunction etc........)..
Mushrooms were like a bad joke at normal doses..I literally felt nothing..I tried to double it...I was bit happy for few hours and then it passed..
Then i went ahead and took what is considered a heroic dose almost 6 g (Equivalence in magic truffle 60g)...and OMG i saw and felt what heaven must be like (Although im an atheist)..But if heavens existed,it must feel the same...After That dose i felt immense improvement and relief from my depression and negative thoughts...My worst sides which are severe dry eyes and skin improved immensely and i felt and measured an increase in my testicular volume (Yes the shrank to two little grapes since i got this)..I was willing and wanting to live even if i got stuck with this disease forever (Those thoughts before that dose usually end up in suicide Planing)...
BUT this honeymoon phase didnt last sadly...Im feeling after 2,5 weeks that im deteriorating again...I wish i could follow up with another dose or microdose or whatever...
Ofcourse our shitty Gouvernements is willing to „protect“ me from those evil mushrooms by banning them but to the criminals in the Pharma industry they are free to kill us around with no punishment. What a world we are living in.
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