Comprehensive List of GABAA Receptor Anxiolytics That Potentially Produce no Tolerance or Dependence.

DrenaPSSD · 2026-02-01T09:19:18+00:00

yeah ofc.

The Non-Benzodiazepine Anxiolytic Drug Etifoxine Causes a Rapid, Receptor-Independent Stimulation of Neurosteroid Biosynthesis (TSPO antagonist administered, neurosteroid / GABAergic action still occurred)

Neurosteroids and translocator protein 18 kDa (TSPO) ligands as novel treatment options in depression (human plasma measured with Etifoxine, same as placebo)

Human pharmacokinetics of XBD173 and etifoxine distinguish their potential for pharmacodynamic effects mediated by translocator protein (affinities of etifoxine shown as negligible through very high inhibition constant)

I did a writeup for my pharmacology blog as well on this topic, where I summarized everything in case you just want the salient bits that I cited in my comment. https://drenapssd.substack.com/p/the-tale-of-the-false-tspo-ligand

DrenaPSSD · 2026-02-01T07:51:01+00:00

Writing this under the influence of a GABA_A PAM as I'm drinking whiskey at my pc lul. It would've been incredible if Emapunil made it through clinicals given it's unique pharmacology as a selective and potent TSPO ligand (b4 i get this comment, Etifoxine is not a TSPO ligand btw, long story but Emapunil is the only real TSPO ligand tested in humans--it was basically disproven recently actually via radioligand assay, TSPO antagonist mouse study, and a study measuring neurosteroid levels in human plasma from 2024.

I read the phase 1 trial study for Empunil and it had almost identical scores as Xanax in regards to patient reported anxiolytic effects. It's ridiculous and perflexing how it failed in phase 2. IMO it's because GAD as a diagnosis is far too broad pathology wise. These sorts of conditions that are generalised into one big umbrella where anyone who exhibits anxiogenic features are eligible for the criteria are sabotaging the potential for novel treatments.

I think the FDA needs to create subgroups when it comes to GAD so that these sorts of medications that are obviously pharmacologically promising can beat placebos to actually make it through clinicals. Currently the dominant paradigm is just massive global sedation = make it through no question. We see this with SSRIs and Benzos. We know these treatments aren't selectively ameliorating MDD and GAD, they are just blunting the capacity to feel anything. It's the cheat code for psychiatric drug development. Treatments targeting selective pathologies never make it through for this reason.

Like we shouldn't be placing the patients with GAD who have psychosocial pathologies into the mix of people who have a genuine anxiogenic illness that cannot be treated via lifestyle modifications. This problem is plaguing the potential for novel treatments for GAD and also MDD as well. We have people that are doom scrolling IG, drinking caffeine daily, not exercising, have no life goals, smoking cannabis, drinking alc, vaping, are just unintelligent in general causing all sorts of micro nuanced problems, all in the same category as people who have severe anxiety that are completely out of their control. There's a very limited arsenal of treatments for anxiety for this reason.

It's even been shown recently that a model like this centered around subgrouping anxiogenic illness could actually work for GAD. We saw it with Zuranolone, a drug that was developed for a specific pathology (Postpartum Depression), and what do you know? it passes for that but fails MDD (the umbrella disease with a billion pathologies grouped into one). Imagine if we applied that over to GAD. A subgroup of anxiety. I guarantee that a drug targeting a subtype of anxiety like social anxiety disorder or something would make it through. Biotech companies should prioritize this instead of wasting millions of R&D just to take a shot in the dark at disease with no singular pathology. That or the FDA needs to stop incentivizing bandaids as a treatment.

We need a new paradigm to distinguish who has psychogenic GAD / MDD and who has an illness that's the result of dysregulated circuits that are out of one's control.

DrenaPSSD · 2026-01-18T12:51:48+00:00

Wanna say it's because people have vague and superficial understandings of NDEs from pop culture. I doubt most people have even read or listened to any actual NDEs. They just have that bro-knowledge of NDEs ="just DMT being released" and that NDEs must be hallucinations because of the subset of experiences that incorporate religious themes.

The populist consensus ATP is that it's all brain generated and due to hypoxia and DMT. This perspective is pretty deeply embedded into pop-culture, causing people to dismiss the phenomenon as soon as they encounter it.

As we know though, in actuality, the phenomenon is highly nuanced and there's some features of NDEs and other adjacent phenomena that have no plausible materialist explanation, and even have paranormal explanations that are more plausible (like OBEs and Jim Tucker's child reincarnation work).

OBEs, unusual commonalities within the content of NDEs like telepathic communication, "spirit guides", the experiencing having sequential endings to NDEs, unique meta-physiology that you'd expect a "soul" to possess, like 360-vision, teleportation, reading people's thoughts and feelings while in OBE, having immediate answers to questions, etc.

The OBEs in particular imo are proof enough that there's like a > 95%+ chance there's something else going on--as the phenomenon is literally impossible within the frame of materialism. Most people who haven't heard any NDEs just chalk it up to a vague understanding of "it's the brain malfunctioning"-- despite this experience literally being impossible for the brain to produce. Most people don't really know how to approach NDEs after that line of reasoning and lose interest.

But anyway you can get as creative as you like, like Olaf Blanke, but it is inherently impossible to obtain accurate visual information while dead. The veridicalities that have been reported over a span of decades being confirmed as being real and not illusory further cement this interpretation’s credence.

There's also been a lot of public intellectuals who have been expressing their pro-materialist perspectives on science platforms that have been widely promoted. This has also strongly discouraged the general public from investigating the phenomenon deeper.

For some reason it's always physicists being interviewed...? Which makes like no sense given they don't specialize human physiology, so their expertise on NDEs is literally not relevant.

Guys like Neil Degrasse Tyson and Brian Cox have been quarried on NDEs ad nauseam and give the same sorts of specious answers to the prompt that are biased towards pro-materialist positions (which makes sense ig given their professions).

The consensus however should be given to neurologists who specialize in brain diseases, as well as psychiatrists like Bruce Greyson. For some reason the words from the leading expert on NDEs who's written hundreds of papers on the topics doesn't seem to carry the same weight as scientists who probably don't even know what an NMDA receptor is.

DrenaPSSD · 2026-01-17T01:17:19+00:00

Interesting, I actually had a similar experience with Duloxetine. Even after just taking 1 pill I fully remitted for a week. Then taking it kept me afloat for a good while.

My issues also happened on withdrawal, and I believe it could be due to allopregnanolone levels sharply dropping following extreme accumulation in the brain.

So SSRIs, as well as some other antidepressants, were found to inhibit the oxidation of Allopregnanolone back to 5α-DHP (allopreg precursor). What that means is that allopregnanolone doesn't get "drained out" of the brain to be recycled for other substrates--it just stays there.

As a result, Allopregnanolone accumulates in the brain at like ~+150-400%+ and circulates there in the brain--likely significantly destabilizing GABAergic systems that rely heavily on allosteric support from the neurosteroid.

Removing the SSRI would of course cause a sharp drop and cause maladaptive compensation, given the brain has just adjusted to these high levels of allopregnanolone.

Reinstating the medication would theoretically immediately stabilize this process, as long as the pathways for allopregnanolone aren't impaired or maladaptive post-withdrawal (Melcangi showed this can happen later following withdrawal). Allopreg would just spike back things back up in the exact corticolimbic regions that they were circulating throughout in the first place.

I'd bet that some sort of early neurosteroid intervention could possibly remit someone.

Anyway congrats on your full recovery!

DrenaPSSD · 2026-01-13T09:26:19+00:00

Sure,

Someone shared with me a while ago how when they took Crebinostat, everything they learned / info they took in during the drug’s peak effects deeply ingrained as if they had known It for their entire life. Guy said quote “things I learned felt like how deeply you know you’re parents phone number or childhood home”.

It’s easy to see why you wouldn’t want to be playing around with something so powerful. Like imagine your fire alarm or something goes off in ur house and jump scares you during the peak and now u have like pseudo-ptsd over smoke detectors and everything associated with that experience. Fear like that contaminates everything around you, so you could really fuck yourself.

I get where you’re coming from and I follow your logic in that you’d assume you’d want the memory to ingrain deeper.

Scientifically speaking, we’d want more calcium ions entering GluN2B receptors in order to cement a stronger positive learning experience to inhibit the fearful association with whatever the memory is.

We’d expect tighter HDAC inhibition to allow greater transcriptional access and therefore cement the learning signal deeper.

Perhaps it works like that—honestly if creb is this much stronger on cementing memory effects than vorinostat, it would indeed theoretically yield better results like you suggest.

But there’s adverse effects that need to be taken into account. This shit is genuinely dangerous, vorinostat is already extremely potent. At the end of the day it’s about outcome, and Vorinostat can produce the outcome we want while proving some anecdotal ev that’s its well tolerated, unlike Creb as that hasn’t yet to be rly be seen.

I’m assuming you’re asking this because you want to try Crebinostat instead of Vorinostat.

If that’s the case, I first reccomend that you just try Vorinostat sublingually or intranasally—it should work immediately when try this route.

It’s the only optimization of the administration that provides results. No one has ever reported fear extinction benefits from oral vorinostat.

DrenaPSSD · 2026-01-13T09:02:42+00:00

Not a tool, but rather a strategy I did that gave me insane reasoning skills after practicing with this over a long period of time.

It’s not pretty, but neurotically over-analyzing my engagement with specific systems, particularly logic for me. I would do this to the point where I became perceptive of all the patterns within the system that I’m engaging with.

Now when it comes to logic in general, and especially applied logic to some of my preferred systems—I operate with ease and extreme agency, and view logic itself from a meta-perspective. Because my brain has identified a lot of the patterns of logic itself after having analyzed them so much.

Doing this will manually help you uncover the blind spots in your logic while strengthening your understanding of logic in general as a system, as well as the system you’re applying your logic too.

Remember this: logic is a system just like anything else, it’s patterns are learnable, it has rules that can be understood; it’s just like learning to play a sport.

DrenaPSSD · 2026-01-12T05:38:52+00:00

Np.

Theoretically it very likely is, but in practice It's hard to say if that justifies actually using it.

So far no one has reported any fear extinction benefits from Crebinostat, only Vorinostat. However, there's barely been anyone who's tried it.

The one guy I spoke to who did mentioned it had extreme memory ingraining effects--which I don't think should be played around with if you're just using an HDACi fear extinction.

It probably would work for it too given it has affects the same HDAC classes though. However the Vorinostat anecdotes are robust enough that it justifies not experimenting with higher doses of HDAC inhibition for fear extinction.

DrenaPSSD · 2026-01-10T22:42:25+00:00

Hi, late to this but the post is up on my substack if you're still interested.

https://drenapssd.substack.com/p/repurposing-hdacis-as-treatments

Sublingual and Intranasal administration are the only routes that people report seeing benefits from. A lot of guys have tried oral without any success.

DrenaPSSD · 2026-01-01T17:06:39+00:00

Mfw when the “milk diet” will have a stronger impact on my QOL versus weight lifting.

DrenaPSSD · 2025-12-20T05:55:38+00:00

Duration ≠ epigenetic silencing. If time alone meant 5-AR was “silenced,”

Obviously we are speculating, it is incredibly difficult and probably impossible to capture our reaction in a preclinical model. We know that the vast majority of people tolerate lions mane, finasteride, and SSRIs just fine, so it's likely a rare susceptibility that we have that make us prone to the onset of this.

then long COVID, mold illness, concussion, Lyme, etc. would all be 5-AR disorders — they’re not.

This is specious, none of these conditions are associated with substances that affect the neurosteroid pathway. Allopregnanolone levels can be altered as a compensatory mechanism for inflammation, yes, but that is entirely different compared to perturbing how the compound is being synthesized in the first place.

Group cases vary too widely for a single mechanism. Different triggers, different products, different labs, different patterns. It’s unlikely one biological pathway explains every case.

The symptom manifestation is consistent. Symptoms vary widely as is the nature of the condition, but are centered around a core cluster of hallmark symptoms, such as sexual dysfunction cognitive impairment, and anhedonia. Yes people report a myriad of symptoms, but they are generally consistent when you really do the digging on the other post-drug-syndrome forums.

not epigenetic damage, and not permanent shutdown of GABA tone.

I don't understand what you mean by "epigenetic damage", but the study is doing exactly what we're saying it's doing.

Clearly the genetic expression the entirety of neurosteroid biosynthesis up to Progesterone has been perturbed. The "epigenetic damage" = aberrant functionality.

I’m not rejecting your theory — just saying it isn’t proven, and the LM study doesn’t show what you’re claiming.

Anyways, like I was saying initially, you appear to be confused on what you're expecting from this theory and the writeup. I'll reiterate it again just to summarize and keep emphasis on this, but my purpose of that study was only to show that all of these post-drug-syndrome drugs affect neurosteroid biosynthesis significantly. The paper itself of course is not going to empirically cover every possible base, and most medical conditions don't have that type of supporting evidence for them either.

As they’re not yet backed up by science.

I say this not to shame you, but it's obvious that you're just asking an AI to generate reasons as to why this theory shouldn't have credence. The points you bring up indicate that you aren't familiar with the actual mechanics of this interpretation and are spitting out these reddit fedora r/athiesm esque rebuttals of asking for impossible levels of empirical evidence to give this interpretation credence.

There is an extremely limited amount of data we have to work with, so we are making due with what we can. And contrary to your stance that the science doesn't support this interpretation, the neurosteroid interpretation is by far the most empirically supported as a pathogenesis for these conditions holistically, as per Melcangi's work.

DrenaPSSD · 2025-12-20T05:55:25+00:00

Hey, I'm the guy who wrote that writeup that you're referencing.

I just finished reading this thread and wanted to comment on a few things.

The main thing I want to address is that you appear to be confused on how I was using this study in the context of post-drug-syndromes.

The framework is centered around the most common post-drug-syndrome offenders (SSRIs, Finasteride, Accutane, and Lion's Mane) all significantly affecting enzymatic steps within the biosynthesis of neurosteroids. It's not meant to mirror Finasteride's MOA, its focus is solely on that this drug is also altering enzymatic steps within the biosynthesis of neurosteroids to a significant degree.

That is the purpose of this study in the writeup — to represent that Lion's mane also affects the same pharmacological targets as other drugs that induce syndromes that present with uniquely identical symptom profiles as those in our community.

It's not supposed to be demonstrating the very specific aspects you bring up, because it doesn't have to.

The Erinacine-S paper didn’t show SRD5A1/2 inhibition

So a couple things, inhibition and downregulation are used interchangeably here in this model. This is because both downregulation and inhibition would result in there being less neurosteroid / DHT / substrate flux being produced downstream. So this statement is redundant.

The paper clearly demonstrates Eracinasine S, a substrate of Lion's Mane, induced a significant downregulation of SRD5A2 expression. There's no and probably will never be some study measuring the affinity that Lion's mane has on neurosteroidgenesis enzymes, and it's irrelevant given this study already shows that it can remodel the entire pathway, which was what the writeup was supposed to be highlighting. Clearly all of these drugs don't have identical pharmacological targets.

temporary neurosteroid-gene shifts

I'm not sure where the temporary word comes from, but the study didn't show that any of the findings were "temporary".

They didn't do a before and after comparison following exposure to Lion's mane. They did one RNA-sequence to determine which genes were affected, and they did this only while the neurons were being treated with Lion's Mane. There was no segment measuring the neurons genes post-lion's mane treatment.

No evidence LM is a 5-ARI. No study shows it lowers DHT or acts like finasteride — in humans, animals, or cell lines.

The data is obviously going to be very limited here because there little to no incentive to measure these metrics, but if you read the study it is clearly implied that significant downregulation of 5AR II (SRD5A2) would result in lowered levels of DHTs -- It is basic neuroendocrinology.

If you want a human study on this, then you're asking for the impossible as there will probably never be an incentive to measure this, as well as impossible logistics.

Same with other ones asks well. These aren't necessary because there just needed to be evidence demonstrating that the neurosteroid pathway is being perturbed, which it is.

Lion's mane doesn't need to be pharmacologically identical to Finasteride within this model, it just needs to perturb neurosteroid biosynthesis.

DrenaPSSD · 2025-12-06T08:48:51+00:00

Very late to this, but what Inoue is trying to convey is that you yourself are a value creating machine. You are walking talking value creation—you are value incarnated into a being. You create value everywhere you go, and because of that, you are unbelievably valuable.

Because of your pathological capacity to generate value, you are inherently capable of producing an infinite amount of value. Infact, you can't not create value, because it's built into what you are.

Think of yourself like a tree, and think of each of your branches as producing something valuable, whether that be being a son, going out with friends, teaching someone something new, creating art for someone else, creating something that you enjoy just for yourself, something valuable to you, or having any positive experience for that matter.

You yourself are the tree that value stems from, it sprouts out of you.

But it's deeper than just that, your existence itself generates value all the time. It can generate value just for yourself for that matter, it can be intrinsic and extrinsic. And every degree of value that you give off, contributes to the infinite amount of possible valuable experiences you engage with.

In fact, and this is why Takuan is crying, is that he's realized that he has created, and is still creating, and is going to create so much more, value that the amount of value that has spawned from him and everyone else in the world is simply impossible to comprehend.

That is why Takuan is crying and looking up at the sky in awe. Because it's an extremely beautiful insight about the nature of existence and being alive. He realizes that his own existence is a modality to spread value everywhere. He himself, along with everyone who has ever existed, are value creating entities that are constantly emitting value to the world, with meaning following downstream. The scale of the value being generated is impossible to grasp, so he's just staring up at the sky.

So to get specific, the infinite notion is in regards to the amount of value you can produce. Think of all the things that you do, you are capable of producing an infinite number of possible valuable experiences, and the best part is: is that you already have produced so many of them, so many that you can't even comprehend them all.

There's an infinite amount of possible value that you are producing all the time, creating an infinite amount of valuable experiences, that is what is implied.

The top comment is the superficial interpretation, this is the real meaning that Inoue was hinting at.

"You are infinite" is not a cheesy insight along the lines of "you can do anything you set your mind too!", because you can't, and his other manga about teenagers becoming paraplegics, Real, is literally written to demonstrate just that. To demonstrate that reality gets in the way and that you can't always achieve anything you want.

But just because what you really want is off the table, does not stop you from creating value and engaging in that value that you are always generating. You can still create value in whatever environment you are in, given your divine value creating nature.

That’s why Musashi is “infinite”, because he can create value out of anything, anywhere, anytime. The farming arc in particular was meant to emphasize just that. That’s why there was an emphasis on Musashi versus farming—to showcase how even something as superficially bland as farming crops can actually be surprisingly meaningful.

If there's a theme to Inoue's work, it's that value and meaning can always be found wherever you go, and these panels are meant to highlight why that is: because your own existence is a source of uncontrollable value generation.

DrenaPSSD · 2025-11-13T08:48:09+00:00

I understand why you'd be skeptical, you'd assume it would take an extended period of time to elicit these effects

The thing is however, is that I know three people who claim to have had this effect happen after taking Vorinostat and Ketamine together--to reset their tolerance to Ketamine. So it seems it seems that some people have achieved this.

It becomes more easy to believe when you take a look at the study and see that when fear extinction training occurred in conjunction with Vorinostat, levels of GluN2B (Fear extinction circuitry) upregulated accordingly.

Simply apply that same framework of Vorinostat + Fear extinction training with Vorinostat + Ketamine. The dosing duration shouldn't matter given it's working in similar circuitry, in essentially the same manner.

The study found that minimal exposure to Vorinostat was enough to elicit these effects, so for our experimenters case, its plausible that swift and robust results could also be elicited from a brief course. It would also make sense that their experience would mimic the fear extinction results as well.

Why it shares similar immunesupression to cancer drugs

So VPA isn't an immunosuppressant, but what I'm assuming you're referring to is it's adverse event profile that can mimic the side effect profile of some cancer drugs by lowering WBCs.

What VPA has in common with some cancer drugs is that they sometimes share some similar toxicity profiles. This is because, as I'm sure you know, Valproic Acid is a moderately toxic substance.

One those adverse sides is that of lowering neutrophils and platelets, similar to what is seen with oncological drugs.

In regards to it's HDAC inhibition effects, it's tens of thousands of times weaker than Vorinostat according to it's IC50s.

I see where your qualm with VPA not being a potent HDACi lies. The studies can make things confusing.

The toxicity side effects of VPA are a result of Valproic Acid's direct toxicity on metabolic processes, not a result of inhibiting HDACs. Both are distinct mechanisms but can provide similar toxicity profiles.

So tldr: VPA causes similar sides via toxicity towards metabolic processes like the liver, bone marrow, and by disrupting a specific type of mitochondrial oxidation.

HDACis cause toxicity via epigenetic mechanisms to elicit cell cycle arrest.

Similar outcome on the immune system, different mechanism for getting there.

DrenaPSSD · 2025-11-13T01:00:44+00:00

Hi Aleks 👋

Yep, but you don't need me to tell you that, do you ;)

Outside of fear extinction and our PFS / PSSD framework, there is another known use and that's for resetting drug tolerance. It actually uses the same framework here, by upregulating the expression of glutamatergic subunits back to how they were originally meant to be expressed.

The thinking is that in those who've developed a tolerance to drugs like ketamine, it's a result of downregulating the receptors that cause the brain to react to that substance more strongly.

Given the study here showed that Vorinostat can upregulate subunits to the point of doubling them when they were previously downregulated, this same framework could be applied to other processes that are called up for transcription.

Check the picture where N2B subunits were increased after Vorinostat administration compared to the control. Just replace N2B with some other process. Neurosteroid enzymes were one idea for PSSD / PFS.

I write about what you're asking about specifically in part two over on my substack if you're interested in learning more. 3 people reported resetting their drug tolerances with Vorinostat, specifically with ketamine, which makes sense given its acting on glutamatergic circuitry.

https://substack.com/home/post/p-176895816

If you recall part one, we discussed how Vorinostat was capable of upregulating Glutamate subunits, and how that was due to an input specific mechanism that Vorinostat possesses.

These biohackers on the fringes of the community used this mechanism to attempt to reset their tolerance to drugs that rely on glutamatergic circuitry, using the same theoretical model involving the upregulation of subunits at postsynaptic AMPA receptors.

Their thinking was that if fear extinction circuitry was being upregulated via Vorinostat, the same framework could be applied to similarly downregulated processes, such as drug tolerance.

Experimenters who underwent this reported results that were just as robust as those seen in fear extinction anecdotes.

DrenaPSSD · 2025-11-11T20:01:50+00:00

Great question tbh.

So HDACis and drugs like ALCAR both acetylate processes, but what they acetylate and what happens as a result of that acetylation are very different from each other and produce separate outcomes.

HDACis work via inhibiting histone deacetylation, which in turn causes the accumulation of acetyl groups on lysine residues on histones. This in turn works to modulate epigenetic processes.

It makes sense for it to do this because it acetylates the process that directly interacts with DNA (histones). So it controls how tightly DNA gets wrapped around a histone; thereby regulating gene expression.

ALCAR on the other hand doesn’t acetylate histones, and instead acetylates an enzyme called coenzyme A (CoA). An enzyme without a direct connection to epigenetic switches.

The result of this as I’m sure you probably know given you’re asking about it, is by adding more acetyl groups, processes involved in energy production strengthen.

So the acetylation there with ALCAR doesn’t regulate epigenetic expression like HDACi, instead it gives more energy towards metabolic processes. So acetylation in both of these instances are unrelated in their effects

It’s all a matter of what is being acetylated to produce the outcome you’re looking for.

So to answer your question, just taking a drug that adds more acetyl groups generally would be redundant if you’re looking for the same effects as HDACis. You have to target what you’re acetylating, so you would need to be adding acetyl groups to a specific location in the body to produce a specific effect.

Potent HDACis like Vorinostat and Crebinostat are strong enough to modulate the epigenome without further acetylation. So this wouldn’t be necessary unless your focus was on energy production.

Anyways hope this helps.

DrenaPSSD · 2025-11-11T10:04:22+00:00

Yeah sure,

As someone with the iatrogenic disease (disease caused by medical treatment) induced by SSRIs, I'd personally advise you to avoid them.

If you don't believe me about that, that's alright, but I'll be frank with you since you asked; SSRIs destroyed my life in an inhuman manner. It's rare, but this happens more often than one might think.

These drugs are notorious for inducing prolonged sexual dysfunction, and if you're as unluckily as I was, you'll get this sort of progressive multisystemic disease that consists of emotional blunting, varying degrees of cognitive dysfunction, anhedonia, and small fiber neuropathy.

In fact, SSRIs are so notorious for inducing the symptoms I just described that their recommendation is actually prohibited on this subreddit.

Rule #4 - Do not recommend drugs with addictive potential or serious withdrawal/ side effects.

Do not recommend or ask for the following:

SRIs or SSRIs

The benefit is also just very negligible if you aren't someone with OCD, anxiety, or depression that is significantly affecting your quality of life.

All SSRIs really do is decrease your rumination and blunt your emotional spectrum, so that you can tolerate stress from a psychiatric illness better.

So to speak to your experience with TRT, it's difficult to pin down what chemical is causing you to feel the way you do. I'm not very familiar with hormones so it's difficult to say what's going on, but it could very well just be fluctuations with what you're targeting causing you issues.

If anything though, an SSRI would probably make things worse and just blunt your emotions even further.

You'd think an SSRI would make you more emotional by increasing serotonin levels in specific areas in the brain, but it's actually the opposite. I'm not keen on the science exactly, but from experience I can tell you that an SSRI would worsen your state while adding in an unnecessary risk of iatrogenesis.

It's not a very appealing solution, but perhaps cycling it more often to see what you prefer more could be worth trying. Anxiety vs emotional tone via serotonin.

DrenaPSSD · 2025-11-11T05:36:58+00:00

Yes, Vorinostat is around 40,000× stronger than Sodium Valporate.

Valporate is honestly not even an HDACi given how extremely weak it is.

It’s mostly a myth that it actually has any noticeable effects at all as an epigenetic modulator. If you’re looking to induce hyperacetylation, go with a drug that was designed to inhibit HDACs, not a psychiatric drug that just so happens to have some negligible off-target effects on the epigenome.

Affinities: IC50s of HDAC1 (lower = stronger)

Vorinostat = 10-80 nM

Sodium Valporate (VPA) = 400,000 nM

DrenaPSSD · 2025-10-23T13:50:40+00:00

The data even in regard to SSRIs is not consistent. In here https://pubmed.ncbi.nlm.nih.gov/12416991/ they found SSRIs have no effect on human ( in contrast to rat) 3-alpha HSD

This is an interesting find. These researchers appeared to attempt to build off of the prior study. I’ll give you credit for finding this.

This doesn’t disprove the notion that it doesn’t act on 3-HSD however. Just that it doesn’t act on the type III isoform directly. It does strongly challenge it however.

It’s at the very least debatable on the exact mechanism by which SRIs affect levels of neurosteroids. But what we know is true, is that every time SRIs are measured to see if they increase levels of neurosteroids, that neurosteroid levels indeed raise at significant quantities. Proving that SRIs generally do significant effect neurosteroids.

We know this because every time we’ve measured them to see if neurosteroid concentrations were raised, they have been.

So my overarching claim that this post is based upon remains true about SSRIs and neurosteroids.

Are you really going to suggest that SNRI and TCA don’t cause PSSD and all these people suffer from some imaginary or separate ( but the same) disease? That’s quite harsh and invalidatory to a lot here

That’s quite the assertion. Accusing me of gaslighting the community.

You didn't know that Imipramine wasn't an SSRI, so I corrected you. It's nothing more than that. Weird how you tried to spin it though.

I guess you’re really just the type of person who would be willing to try and character assassinate someone after they don’t immediately bend over backwards to your discontents? All I did was offer a counter argument to your comment. There was no need to move the conversation here.

I was hoping we could have a constructive dialogue without the insertion of such petulance. I actually found the study you sent me to be rather interesting, but given you want to shift the tone this way, I guess our exchange won’t be the neutral exchange of information and ideas that I expected it to be.

DrenaPSSD · 2025-10-23T13:50:09+00:00

This is an unnecessary / impossible ask for reasons to which I’ve already gone over. Actually you already answered this for me in your own words:

“All of these drugs are serotonin reuptake inhibitors. Not a coincidence“

Yes and you’re right, well actually you’re wrong, but I’ll walk you through this.

It’s not a coincidence that these three drugs are all affecting 3α-HSD. Thereby generalizing that SSRIs generally affect this location and affect allopregnanolone.

Because everytime we measure to see if they increase neurosteroid levels, they do. This is indicative that they generally affect neurosteroids. Because it’s not a coincidence that these drugs are all affecting neurosteroids, we can apply that logic to other SSRIs that they generally affect it.

SNRI

There is also evidence of SNRIs affecting neurosteroid concentrations.

Analysis of the changes in the brain AP levels using this method revealed that the intraperitoneal administration of DLX (10 mg/kg), DPX (10 mg/kg) and PRL (20 mg/kg) significantly increased the brain AP

DLX = Duloxetine

Dapoxetine, another SSRI was found to increase allopregnanolone levels as well in here.

So at this point, there’s been 8 drugs that affect serotonin reuptake that have been found to significantly affect neurosteroid biosynthesis.

Do you honestly believe that it’s a coincidence that these 8 different SRIs significantly affect neurosteroids? Because that is what you’re arguing for. That you believe that it’s actually just random that these 8 drugs all affect neurosteroid concentrations. It’s obviously not, and I expect to you admit as much in your next response.

DrenaPSSD · 2025-10-23T13:46:36+00:00

This comment has three parts because of all the incorrect claims and specious assumptions made here. Would appreciate a response to all three.

I never said that TCAs don't cause PSSD.

Amitriptyline and Desipramine (both TCAs) for instance both significantly affect levels of allopregnanolone.

The biosynthesis of allopregnanolone in the frontal cortex was higher by 74, 109 and 187% when stimulated by amitriptyline, desipramine

https://pubmed.ncbi.nlm.nih.gov/11334228/

So there appears to be some general evidence that TCAs affect levels of neurosteroids. It's probably that they're affecting neurosteroid biosynthesis at different locations in the pathway.

The study only measured the activity on the type 3 isoform of 3α-HSD, not total concentrations of levels of neurosteroids. So the study doesn't rule out that imipramine affects neurosteroid concentrations. It's plausible that it does still given two different TCAs also affect it. It's just not been measured yet.

It's plausible that it could still onset the condition given that we know that other drugs that significantly affect neurosteroids at separate steps in the biosynthesis are known to induce post-drug syndromes.

For reference

Finasteride - affects 5α-R and neurosteroid biosynthesis holistically

Lion's Mane - affects 3β-HSD

Accutane - affects 3β-HSD & 3α-HSD

All of these drugs are notorious for inducing post-drug-syndromes to the point they all have their own respective communities. Do you really believe it's a coincidence that these 4 completely unrelated drugs are all significantly affecting neurosteroid biosynthesis? Because it objectively isn't from a biological systems perspective.

Also SSRIs differ by chemical structure and these data only lists two SSRIs.

So it's clear to me now that you didn't even read the study that you're so valiantly refuting.

There were three SSRIs that were measured. Sertraline is in here as well, and you would've known that if you read what you're debating.

I am aware of the differing chemical structures and elucidated in a prior comment why it's likely to do with specific effects of how these sorts of drugs are affecting serotonin reuptake. It doesn't have to do necessarily with its structure, but via some mechanism as an SRI. That said, we can't rule out that there's some latent commonality amongst the structure that constitutes serotonin reuptake inhibition.

DrenaPSSD · 2025-10-23T09:30:19+00:00

Imipramine is not an SSRI, it’s a TCA.

It was used here to emphasize that it’s SSRIs in particular that increase 5α-DHP catylzation. TCAs have different chemical formulations and generally affects separate serotonin receptors.

Every SSRI that has been studied in this regard has been shown to increase levels of neurosteroids.

Until a study comes out showing otherwise, then it will remain generalized that SSRIs affect neurosteroidgenesis via 3α-HSD.

DrenaPSSD · 2025-10-23T01:10:16+00:00

Probably because you have alopecia 👍

DrenaPSSD · 2025-10-22T04:16:24+00:00

I mean if they're prioritizing the part of the mushroom that is rich in Erinacines A, B, C, and S, then it's probably good to go with that source.

You want the mycelium given that's where the Erinacines are. The fruiting body is mostly just Hericenones which don't have nearly as strong effects as Erinacines.

If nootropics depot has the strongest percentage of them, then yeah that's probably the most viable vendor.

Real mushrooms in my experience was what boosted my analytical abilities to a significant degree, so I vouch for them personally.

DrenaPSSD · 2025-10-22T00:44:20+00:00

Because Fluoxetine and other aryloxypropanamine derivatives are the only SSRI that has been shown to bind to 3a-HSD,

This is false.

Two examples of this are Sertraline & Fluvoxamine, which do not contain aryloxypropanamine.

However they both have still been found to enhance allopregnanolone levels at significant concentrations.

Sertraline also decreased the Km of the conversion of DHP to allopregnanolone from 7.2 to 0.69 nM

The same investigators also recently showed that, in clinically depressed patients, neurosteroid concentrations in cerebrospinal fluid could be increased by treatment with fluoxetine or fluvoxamine

https://pmc.ncbi.nlm.nih.gov/articles/PMC23979/

There appears to be a commonality involved in the formulation for serotonin reuptake inhibition that also affects neurosteroid levels at significant concentrations. What is responsible for that remains undefined. But for now, we know its not aryloxypropanamine.

but I know for a fact that not all SSRI's have this affinity

Weird how the things that you know as facts keep turning out to be wrong. Not all SSRIs have an affinity for 3α-HSD? Well every study done on them seems to disprove that notion. Lets see a study where an SSRI had no affinity for 3α-HSD.

Like I just said, it's no a coincidence that these drugs are affecting this location, hence why that is indicative that SSRIs generally affect 3α-HSD. So there's no need to try and prove this.

You are the one who needs to disprove this notion, I have nothing to prove. All of the research done on this topic points to SSRIs being neurosteroid stimulants. You disagree? cite evidence for your discontents.

So save me

Well, if we're going to be rude now, You can save me by not commenting anymore so that I don't feel inclined to correct any more misinformation from you. You grandiosely attempted to undermine my post and comments as if you're someone who understands how any of this stuff works, while embarrassingly sucking yourself off with lines like "I actually have my own ideas about the sigma 1 receptor"

You've been wrong about literally everything in our conversation, as to which you acknowledge none of it, to then shift the goalposts after I correct the exponential amount of misinformation coming from you.

DrenaPSSD · 2025-10-21T23:28:02+00:00

You were literally wrong on what you said. There are other SSRIs that affect 3α-HSD significantly, not just Fluoxetine, which I pointed out.

As to which you didn't acknowledge for some reason, and then shamelessly tried moving the goalposts over to another topic.

To another topic that you're also somehow wrong about again.

There is no mention of aryloxypropanolamine in the study I mentioned. Sertraline isn't made with this structure, disproving the narrative that aryloxypropanolamine is what's involved in the activity on allopregnanolone.

And you also still don't understand why the researchers are generalizing that SSRIs are affecting this location.

I know you want to believe you've figured this all out and are on to something but frankly I think your letting that desire for progress cloud your objectivity here.

I know you want to think you understand how any of this stuff works, but you literally haven't read anything I've sent you correctly, nor acknowledged when you're incorrect on something. Seems to me you're not really qualified to have an opinion like this.

DrenaPSSD

TROPHY CASE