Similarities between PAS and PSSD

[Flynn]

It seems that PAS and PSSD share many of the same symptoms. I've seen on several forums, that many blame the 5HT1A receptor for PSSD. As the auto-receptor version of 5HT1A becomes desensitised due to SSRI use, which persists after stopping the SSRI. As a result there is an excess of 5HT1A signalling post-synaptically. Predominantly in the raphe nucleus which leads to a suppression of dopaminergic activity/function.

Interestingly, the only major study I could find that has looked into accutane and serotonin, showed that accutane increased 5HT synthesis, increased SERT expression and increased expression of 5HT1A receptors in a rat cell line. Note that this cell line only expressed this receptor type, so its possible that accutane also increases expression of other 5HT receptors.

Given this, is it possible that PAS is caused by the same underlying mechanism of PSSD. As if 5HT1A expression is increased to such an extent that persists after treatment, we may have an excessive amount of post synaptic 5HT1A activity leading to a reduced dopaminergic activity. Unfortunately no 5HT1A antagonists are on the market but these would be well worth trying.

@Ghost You seem like the person to ask:
1. Have you found that most people with PSSD also have symptoms such as depression, anhedonia, loss of motivation, emotional blunting?

2. Have I interpreted this info correctly or am I wrong? Can you see how increased 5HT1A expression from accutane could lead to PSSD like symptoms?

3. Has there been any explanation on your forum as to why dopamine agonists aren't very effective for treating PSSD? They don't seem to work much in PAS. Does the 5HT system have such a strong effect on the dopamine system, that it can inhibit/negate the effect of dopamine agonists on dopamine activity.



If any PAS people have experience with SSRI's or tried anything like inositol? or any of the substances which have helped PSSD people, please let me know

 

[Ghost]

@Flynn

1) Yea most people do. It's a spectrum though. I have some degree of it, but there are others who have it really bad. I can still feel all the emotions, but maybe they are a bit dulled. It's hard to tell these days because it's been 3.5 years. But yes, I'd say over 1/2 of people have it as a symptom. In 2016 I conducted a survey, and over 85% of respondents rated their emotional capacity as under 5/10 (10 being original/normal) (n = 19)

2) It depends on where the receptors are. If they are in the RN, then yes, that's good. If they are in the projection areas, then that's bad. I think you understand it well. 3 years ago, I actually thought Accutane might help PSSD. PSSD Collaborative Research • View topic - 13-cis-Retinoic Acid (Accutane) . I've changed my thinking since then, but they do seem quite related. The projection areas are where the downstream problems are. Looking up a map of these projections will help show you where the downstream problems will happen.

3) They do work wonders for some people, but do little for others. I think it depends on the serotonin dominance, but also about the bursting patterns of the dopamine neurons and not just the amount of dopamine. If 5HT is inhibiting dopaminergic transmission, an agonist will do less than it would for a healthy person. Also, if you need a flood of dopamine for something like a sexual event, you won't get this because the bursting of dopamine is being inhibited.

 

[Flynn]

@Flynn

1) Yea most people do. It's a spectrum though. I have some degree of it, but there are others who have it really bad. I can still feel all the emotions, but maybe they are a bit dulled. It's hard to tell these days because it's been 3.5 years. But yes, I'd say over 1/2 of people have it as a symptom. In 2016 I conducted a survey, and over 85% of respondents rated their emotional capacity as under 5/10 (10 being original/normal) (n = 19)

2) It depends on where the receptors are. If they are in the RN, then yes, that's good. If they are in the projection areas, then that's bad. I think you understand it well. 3 years ago, I actually thought Accutane might help PSSD. PSSD Collaborative Research • View topic - 13-cis-Retinoic Acid (Accutane) . I've changed my thinking since then, but they do seem quite related. The projection areas are where the downstream problems are. Looking up a map of these projections will help show you where the downstream problems will happen.

3) They do work wonders for some people, but do little for others. I think it depends on the serotonin dominance, but also about the bursting patterns of the dopamine neurons and not just the amount of dopamine. If 5HT is inhibiting dopaminergic transmission, an agonist will do less than it would for a healthy person. Also, if you need a flood of dopamine for something like a sexual event, you won't get this because the bursting of dopamine is being inhibited.

Thanks for such a thorough response. Great to get your opinion on this.

Slightly confused with 2) So are you saying that if 5HT1A receptor expression has been excessively increased in the RN due to accutane, then this is likely to be same problem as PSSD? Can you just explain this a little more.

 

[Flynn]

I just posted this on acne.org but thought I'd repost here:

The only study I could find on accutane and serotonin, found that it increase 5HT1A (serotonin) receptor expression and affected serotonin production and SERT expression - 13-cis-Retinoic acid alters intracellular serotonin, increases 5-HT1A receptor, and serotonin reuptake transporter levels in vitro. - PubMed - NCBI

Note also that if accutane can affect 5HT1A receptor expression, there is no reason to think it couldn't affect the expression of other serotonin receptors.

Many of the mental side effects people with PAS report, are similar/identical to people with PSSD. Emotional blunting, anhedonia, loss of personality, loss of sex drive/libido, feel disconnected from reality. Much of this, is indicative of reduced/dampened dopaminergic signalling. This is almost a definite, given that drugs which act directly on the dopamine system (dopamine agonists, steroids) have a dampened or reduced effect compared to healthy people.

Now from my research, there are only a few ways accutane could have plausibly done this.

1. It's altered the dopamine system directly by altering the expression of D2R's
(dopamine receptors) etc. in regions of the brain like the striatum which completely messes with normal dopamine reward circuitry as in schizophrenia. This is worst case scenario. But it seems unlikely to me as I would expect that if this was the case, we would be more sensitive to dopaminergic drugs and they would be likely to send us into manic states or have more pronounced effects. It's also strange that nobody with PAS reports psychosis or hallucinations etc.

2. The dopamine system has been affected by changes in the activity/expression of receptors/hormones in the brain such as progesterone and cortisol which can affect dopamine signalling. This is why it's still well worth, PAS people doing RU trials. Maybe use different doses. We may need to try 100mg versus 50mg as @B_D_Acc hasn't had much success.

3. A very plausible explanation of this, would be that accutane has altered our serotonergic signalling in a way that has persisted. It may have left us with a kind of hypersensitive serotonin signalling. Its possible that accutane use may lead to increased 5HT1A receptor expression, post-synaptically (resulting in increased serotonin signalling). Or its affected some other kind of serotonin receptor.

4. Alternatively SERT may have remained up regulated leading to a serotonin deficiency and they is insufficient serotonin activity. I know that I have noticed improvements in mood and personality when experimenting with drugs which affect serotonin but never really gain improvement in sexual side effects.

Remember that, people with PSSD don't always respond to dopamine agonists and testosterone levels don't seem to matter as in PAS (correct me if I'm wrong).

Right now, the serotonergic system seems like the only plausible candidate capable of doing this with such a strong inhibitory effect (please correct me if I'm wrong here). It's also a coincidence that SSRI's which also affect serotonin system can produce an almost identical persisting problem for people.


I am slowly starting to run out of explanations or ideas for PAS and I don't see many people helping to make them. Do any of you guys have any experience with SSRI use post accutane. If RU cycles don't work. It may be worth trying some of the protocols which have helped PSSD people such as St. Johns Wort and inositol. Hell I'm even tempted to try low dose SSRI.

@Lost @Willylong98 @cnb30 @B_D_Acc @Namelk @tanedout @Dasjes @Orion @CrazyPickles @vicecaz

 

[PAS]

Hey bro, dont get discouraged!!!! Me and many others appreciate every idea, iam just too ignorant to suggest anything .

I have taken 50 mg RU for 4 days now. Everybody says the effect comes 3 4 days later. Lets see what happens.

 

[tanedout]

@Flynn Good work on the theories! Dopamine is definitely effected. I know some people have had benefits from St Johns Wort, but usually it doesnt last. I've tried it with no benefits. I did get some improvements in sensitivity from Choline & Inositol, but only very slight. There are definitely guys on acne.org who've been on/are on SSRI's post accutane, but I don't believe any get benefits.

Weed is supposed to boost domaine, and that is one thing that I've found restores sensitivity and orgasm a fair bit - but only when stoned. Just found this when I tried vaping weed, but it;s not something I've done for a few years, or intend to try again.

I'm pretty keen to give RU a go, and with my cortisol always being very high I might have a shot at getting some on prescription. I'm going to discuss next time I speak to my doctor, but it would likely first require a referral to an endo and additional bloods taken by them, so would be some months away.

 

[vicecaz]

Thanks for all your theories Flynn. Trying to understand the specific mechanism that created this condition in us is extremely difficult, because we were affected differently; there is people who took accutane and are just fine, some got dry eyes and pain in the body, some got sexual sides, emotional sides..A theory might fit your case but not mine for example . The whole body is affected, not only the brain or the gut. Trying to understand with certainty where it all started is nearly impossible to me.
We can picture what happened, interpret our symptoms, absorb the information . Next step is to focus on the solution rather than the how of the problem

With time I'm sure we'll get closer from the truth but it the meantime there's so much experiment and protocol to be done, and I'm sure doing with consistency, adjustment, listening/interpreting our reaction, we'll heal . We already have all we need to
Recovery stories stand as proof

 

[PAS]

If this helps any theory, I dont feel good when I am normal. And i dont feel good at all on weed. So it probably has something to do with dopamine receptors instead of amount since weed doesnt let dopamine get reabsorbed, so even the increased amount of dopamine doesnt make me feel good.

Erections are affected by weed in some strange way that I dont feel horny but i do feel more driven, if anybody can make sense of that.

 

[Flynn]

@Flynn Good work on the theories! Dopamine is definitely effected. I know some people have had benefits from St Johns Wort, but usually it doesnt last. I've tried it with no benefits. I did get some improvements in sensitivity from Choline & Inositol, but only very slight. There are definitely guys on acne.org who've been on/are on SSRI's post accutane, but I don't believe any get benefits.

Weed is supposed to boost domaine, and that is one thing that I've found restores sensitivity and orgasm a fair bit - but only when stoned. Just found this when I tried vaping weed, but it;s not something I've done for a few years, or intend to try again.

I'm pretty keen to give RU a go, and with my cortisol always being very high I might have a shot at getting some on prescription. I'm going to discuss next time I speak to my doctor, but it would likely first require a referral to an endo and additional bloods taken by them, so would be some months away.

Thats useful to know. I will be tempted to try St Johns Wort. Again most of these protocols haven't helped people with PSSD. So its still possible that a treatment which works in PSSD, would work for PAS. It would be useful to try a 5HT1A receptor antagonist. Have you ever tried things which affect acetylcholine?

 

[Flynn]

Thanks for all your theories Flynn. Trying to understand the specific mechanism that created this condition in us is extremely difficult, because we were affected differently; there is people who took accutane and are just fine, some got dry eyes and pain in the body, some got sexual sides, emotional sides..A theory might fit your case but not mine for example . The whole body is affected, not only the brain or the gut. Trying to understand with certainty where it all started is nearly impossible to me.
We can picture what happened, interpret our symptoms, absorb the information . Next step is to focus on the solution rather than the how of the problem

With time I'm sure we'll get closer from the truth but it the meantime there's so much experiment and protocol to be done, and I'm sure doing with consistency, adjustment, listening/interpreting our reaction, we'll heal . We already have all we need to
Recovery stories stand as proof

Yes but I think it's more useful to focus on the mental sides as these are the worst to live with and have the biggest impact on peoples quality of life.

Trying to work out a theory is useful as it provides new potential treatments to try.

I hope you're right and we get there soon.

 

[Flynn]

If this helps any theory, I dont feel good when I am normal. And i dont feel good at all on weed. So it probably has something to do with dopamine receptors instead of amount since weed doesnt let dopamine get reabsorbed, so even the increased amount of dopamine doesnt make me feel good.

Erections are affected by weed in some strange way that I dont feel horny but i do feel more driven, if anybody can make sense of that.

Did you ever smoke weed before accutane? Was there a difference in the way it affected you?

In what way, dont you feel good on weed?

 

[tanedout]

Have you ever tried things which affect acetylcholine?

Such as? I can't think of any examples

 

[Flynn]

piracetam but I've just read that it may not actually effect acetylcholine.

 

[tanedout]

piracetam but I've just read that it may not actually effect acetylcholine.

Nope never tried it, I'm pretty wary of any pharmaceuticals now for obvious reasons! I've got stuff like pramipexole and noopept in my supplements arsenal, but have never actually used them.

The only pharma drug I'm aware of which has resulted in temporary remission of PAS sides is prednisone which is a powerful anti-inflammatory, but not something you want to be taking long-term. Others have taken it with no success however.

 

[MNK99]

@tanedout
"Such as? I can't think of any examples"
Also nicotine. Don't start smoking obviously. Vaping maybe. It attaches to the brain's acetylcholine receptors and mimics it.

 

[Flynn]

Nope never tried it, I'm pretty wary of any pharmaceuticals now for obvious reasons! I've got stuff like pramipexole and noopept in my supplements arsenal, but have never actually used them.

The only pharma drug I'm aware of which has resulted in temporary remission of PAS sides is prednisone which is a powerful anti-inflammatory, but not something you want to be taking long-term. Others have taken it with no success however.

Can you remember which PAS sides it helped? did it help sexual sides at all? Interesting that prednisone is a corticosteroid and essentially acts like cortisol. Makes some sense in relation to this study - All-trans retinoic acid-induced hypothalamus–pituitary–adrenal hyperactivity involves glucocorticoid receptor dysregulation I still think its possible that PAS is related to a dysregulation of progesterone and/or cortisol receptor expression. I guess if receptor are significantly downregulated leading to insufficient glucocorticoid activity, then increasing glucocorticoid activity through prednisone could help.

 

[vicecaz]

That's why Licorice and cordyceps are really interesting as they act on the glucocorticoid/adrenocorticoid/mineralocorticoid activity
As tanedout stated it's helped some, I remember reading their posts, but others didn't have the same success
Tubzy was about to try prednisone as well for pfs but I don't know if he tried it yet, probably not since he's into the electrolyte protocol

 

[tanedout]

Can you remember which PAS sides it helped? did it help sexual sides at all? Interesting that prednisone is a corticosteroid and essentially acts like cortisol. Makes some sense in relation to this study - All-trans retinoic acid-induced hypothalamus–pituitary–adrenal hyperactivity involves glucocorticoid receptor dysregulation I still think its possible that PAS is related to a dysregulation of progesterone and/or cortisol receptor expression. I guess if receptor are significantly downregulated leading to insufficient glucocorticoid activity, then increasing glucocorticoid activity through prednisone could help.

Pretty sure he said it resolved all sides, but I can't find the post - I know he had sexual sides, but can't remember the others. I've tried supplementing with licorice and cordyseps before (although not together) and didn't notice any benefits that I remember

 

[Flynn]

OK. I still think people need to try RU at higher doses.

 

[Flynn]

@Ghost I was just wondering man, from your forum which substances have helped reverse PSSD in people? Even if the result couldn't be replicated in everybody else.Are St johns wort? Berberine? or Inositol worth trying?