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/
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.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.
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.
I've been taking a look at GAMSA drugs and there is golexanolone. https://en.wikipedia.org/wiki/Golexanolone6. 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 , and in vivo it
does not antagonize allopregnanolone-induced hyperphagia in
rats , or pregnanolone discriminative stimulus effects in
Rhesus monkeys . Similarly, in humans flumazenil does not
antagonize the reduction in saccadic eye velocity induced by
allopregnanolone . 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 .
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 .
However, in vitro the allopregnanolone potentiation of the GABAA
receptor current has been shown to be antagonized .
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
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)
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.
Golexanolone is in clinical trials for HE. https://www.globenewswire.com/news-rele ... olone.html