THEORY - PAS and PSSD/Serotonin Theory - (Serotonin Overactivity - 5HT2C Receptors) - Plausible/Would be Treatable

flynn

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PAS and PSSD have remarkable similarities, both involve persisting sexual dysfunction along with other mental side effects such as depersonalisation, anhedonia, depression and apathy/emotional numbness. Both conditions appear to be fairly unresponsive to hormone therapy and dopamine agonists. This is unusual as both androgen therapy and dopamine agonists act directly on the dopaminergic system of the brain, which is thought to play a major role in sexual function, reward and pleasure. One possible reason for this, is a dysfunction with the dopaminergic system itself as in Schizophrenia, which is looked at in another thread. Another possibility is that there is an excessive inhibitory mechanism acting on the dopaminergic system to suppress dopaminergic activity in important regions of the brain leading to these symptoms.

For PSSD, it's thought that the sensitivity of serotonin (5HT) receptors specifically 5HT1A auto-receptors involved in modulating serotonergic activity, has been altered due to the excessive levels of serotonin produced by SSRI usage. These desensitised 5HT1A receptors lead to enhanced serotonergic activity which persistently dampens/suppresses dopaminergic activity.

Its possible that Accutane has altered serotonergic activity. One study has shown that Accutane significantly increases 5HT1A receptor expression, synthesis of serotonin and SERT protein levels in a rat cell line. This cell line specifically expressed 5HT1A receptors (1). Thus its possible Accutane causes PAS by changing the serotonin system through the 5HT1A receptor or by increasing the expression of other 5HT receptors. One such receptor is the 5HT2C receptor.

5HT2C receptors

5HT2C receptors are highly expressed throughout the mesocorticolimbic dopamine system of humans. This system is made up of dopamine releasing neurons of the ventral tegmental area (VTA) which projects to the nucleus accumbens and prefrontal cortex (PFC) (2). The mesocorticolimbic system plays a significant role in motivation, pleasure and reward seeking behaviour. There are strong reasons to suggest that most of the symptoms of PAS can be explained by a dysfunction of this brain region particularly the mesolimbic pathway.

5HT2C receptors have also been found in the striatum and appear to negatively regulate dopamine efflux and thus dopaminergic activity (3). Its been found that over-expression of 5HT2C receptors in the forebrain is associated with elevated anxiety and hypoactivity (4).

Studies in male mice also indicate that 5HT2C activation may have a suppressive influence on the control of male sexual behaviour (5).

There isn't much research concerning the effect of Accutane on 5HT receptors particularly 5HT2C receptors. However, one study showed that all-trans retinoic acid (metabolite of Accutane) significantly enhanced the expression of 5HT2C receptors in the early stages of differentiation of embryonal carcinoma cells. This has been proposed to occur as a result of epigenetic activation (6). Thus its possible Accutane could increase 5HT2C receptor expression in the adult brain.

Another interesting facet of 5HT2C receptors is that they can remain constitutively active, meaning they can have activity in the absence of a ligand/serotonin. They also undergo RNA editing, and there are several isoforms of the 5HT2C receptor meaning that some drugs which act as 5HT2C receptor antagonists don't necessarily act on all receptors. Agomelatine for example is a 5HT2C antagonist but it doesn't appear to work on the 5HT2C receptors in the mesolimbic pathway (7).

Given this, its possible that Accutane has substantially increased 5HT2C receptors in susceptible individuals resulting in greatly diminished dopaminergic activity in important brain regions such as the reward pathway. Reduced dopamine activity in the prefrontal cortex would also help to explain cognitive deficits which some users report.

Treatments and ways to investigate this

Given the constitutive activity of 5HT2C receptors, an inverse agonist would be more useful than antagonists. We would also need compounds which are capable of acting at 5HT2C receptors in the mesocorticolimbic pathway, which would exclude agomelatine. Here is a list of compounds I could find, unfortunately its difficult to find highly specific compounds which are in mass production. Thus several compounds which have a great activity profile are research chemicals and are incredibly expensive to buy. It's also best to avoid 5HT2A antagonism as it inhibits dopamine release. Here is a list in no particular order:

SB 242084 (This would be ideal) - Highly selective 5HT2C antagonist which appears to work on receptors of the mesolimbic system of rats. However it is currently a research chemical and so is very expensive.

5HT2C inverse agonists in order of strength - SB 206553 = Clozapine -> Mianserin -> Mesulergine = Ketanserin (8).

Sertindole - Antipsychotic - 5HT2C inverse agonist with high affinity to D2 and 5HT2A.

Pizotifen - Migraine pill with 5HT2C and 5HT2A antagonism.

Cyproheptadine - Strong antagonist of 5HT2A, 5HT2C and 5HT2B. However is also a strong antihistamine (sedative effect).

Metergoline - 5HT1B, 5HT2B, 5HT2C and dopamine agonist.

Buspirone - Reduces serotonin signalling by acting as an agonist at 5HT1A auto receptor. Also a weak 5HT2C antagonist. Well tolerated drug. Definitely worth trying, especially if you suffer from anxiety.

Other possible options worth trying

Bupropion - Inhibits dopamine re-uptake particularly in the prefrontal cortex, leads to enhanced dopaminergic neurotransmission in nucleus accumbens and prefrontal cortex.

Pramipexole - Activates D2/D3 receptors in prefrontal cortex, striatum, amygdala and thalamus. Helped some users on All Things Male forum but efficacy wore off eventually. Also some users have reported no benefit.

Berberine - Activates 5HT1A auto-receptors and inhibits post synaptic 5HT1A and 5HT receptors - Showed some efficacy in people with PSSD.

St Johns Wort - It has shown some effectiveness in people with PSSD.

Vraylar - weak 5HT2C inverse agonist (low affinity), 5HT2B antagonist, activity at dopamine receptors - Shown benefit for anhedonia.

Histidine - Helps regulate excess serotonin signalling.


(1) - https://www.ncbi.nlm.nih.gov/pubmed/17895527
(2) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422522/
(3) - https://www.ncbi.nlm.nih.gov/pubmed/15668911
(4) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777260/
(5) - https://www.ncbi.nlm.nih.gov/pubmed/12097814
(6) - https://www.ncbi.nlm.nih.gov/pubmed/15242780
(7) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128060/
(8) - http://molpharm.aspetjournals.org/content/55/5/863

- flynn
 
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CAn8tive

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May 22, 2018
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Just my two cents -
I take Bupropion and it does make a big difference in libido. Dr. Irwin Goldstein in San Diego was the person who brought it to my attention (Bupropion) for libido. It also improved social anxiety. Full disclosure I also take Buspirone and Lexapro. When I first started meds last year, I was only taking Buspirone 15mg and then added Bupropion 150mg a month or two after. I immediately noticed a boost in libido and energy and hanging flacid size from Bupropion. However my main focus/complaint was my general anxiety and I didn't feel Buspirone + Bupropion was helping enough for gen anxiety, plus I noticed I was getting easily irritated. So my Dr. added Lexapro 10mg (serotonin) to the mix. This helped substantially with anxiety and just feeling happier and less irritable/angry but the tradeoff is it did lower my libido and took away some energy Bupropion had given me.

May try in the future to reduce Lexapro dosage - in order to see if I get more energy and increase libido more.
 
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flynn

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Just my two cents -
I take Bupropion and it does make a big difference in libido. Dr. Irwin Goldstein in San Diego was the person who brought it to my attention (Bupropion) for libido. It also improved social anxiety. Full disclosure I also take Buspirone and Lexapro. When I first started meds last year, I was only taking Buspirone 15mg and then added Bupropion 150mg a month or two after. I immediately noticed a boost in libido and energy and hanging flacid size from Bupropion. However my main focus/complaint was my general anxiety and I didn't feel Buspirone + Bupropion was helping enough for gen anxiety, plus I noticed I was getting easily irritated. So my Dr. added Lexapro 10mg (serotonin) to the mix. This helped substantially with anxiety and just feeling happier and less irritable/angry but the tradeoff is it did lower my libido and took away some energy Bupropion had given me.

May try in the future to reduce Lexapro dosage - in order to see if I get more energy and increase libido more.

Thanks for your reply, thats very interesting.

So did Accutane give you sexual sid effects such as low libido? And bupropion directly helped the libido issues you had? Or did you just have low libido before accutane?

Also have you ever reported your sexual side effects anyway?
 

CAn8tive

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May 22, 2018
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Thanks for your reply, thats very interesting.

So did Accutane give you sexual sid effects such as low libido? And bupropion directly helped the libido issues you had? Or did you just have low libido before accutane?

Also have you ever reported your sexual side effects anyway?
Hello,

No problem thanks for posting on this site. You have a lot of really great info on here. Myself and I’m sure others appreciate it.

Yes, I do believe Accutane caused my sexual sides, though of course I can’t prove it.. I took it as a teen and had low libido and ED ever since. And Yes I noticed Bupropion does help me with libido and social anxiety. For me It has never been a complete absence of libido or not being able to perform at all. Just significantly reduced from what I would assume is “normal.” Especially when I was younger what teen or person in their 20’s has issues getting it up, that’s not normal imo and thats what I had. For the longest time I believed I may have a hormone imbalance, I’ve seen endocrinologists, internal medicine, Urologist’s, naturopaths and even just regular doctors over years and told them of my “issues.” They run standard male hormone tests, testorone etc. but my results always come back normal. Only 1 time a urologist said my testosterone was bordering slightly on lower end but it was a period of high stress and he said that could cause a drop. That was like 3 years ago, he gave me Clomid to try for a couple months but my results were - it slightly improved libido but made me very moody. Doc said that happens with Clomid and said I could try TRT, testosterone but I chose not to.

Also most docs when my hormone panel comes back normal say same thing.. oh your healthy you just need to relax.. heres a script for Cialis.. but I don’t agree I’m not nervous about the act of sex, never have been. Relaxing is not the issue... Its just a 50/50 if I will be able to perform or not. Plus with IBS-D and anxiety it matches many ppl symptoms here related to Accutane.
 
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flynn

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Hello,

No problem thanks for posting on this site. You have a lot of really great info on here. Myself and I’m sure others appreciate it.

Yes, I do believe Accutane caused my sexual sides, though of course I can’t prove it.. I took it as a teen and had low libido and ED ever since. And Yes I noticed Bupropion does help me with libido and social anxiety. For me It has never been a complete absence of libido or not being able to perform at all. Just significantly reduced from what I would assume is “normal.” Especially when I was younger what teen or person in their 20’s has issues getting it up, that’s not normal imo and thats what I had. For the longest time I believed I may have a hormone imbalance, I’ve seen endocrinologists, internal medicine, Urologist’s, naturopaths and even just regular doctors over years and told them of my “issues.” They run standard male hormone tests, testorone etc. but my results always come back normal. Only 1 time a urologist said my testosterone was bordering slightly on lower end but it was a period of high stress and he said that could cause a drop. That was like 3 years ago, he gave me Clomid to try for a couple months but my results were - it slightly improved libido but made me very moody. Doc said that happens with Clomid and said I could try TRT, testosterone but I chose not to.

Also most docs when my hormone panel comes back normal say same thing.. oh your healthy you just need to relax.. heres a script for Cialis.. but I don’t agree I’m not nervous about the act of sex, never have been. Relaxing is not the issue... Its just a 50/50 if I will be able to perform or not. Plus with IBS-D and anxiety it matches many ppl symptoms here related to Accutane.

Yes I felt it was important to try and aggregate some of the information about this in one place.

I completely understand when you say that something doesn't feel 'normal'. Hormone tests don't reveal anything and are the standard response of doctors, as in a normal situation, it would indeed be a hormonal issue. But as I've said before I've experimented with fairly high dosages of exogenous testosterone to no avail. I have also been in contact with numerous others, who also report no change in symptoms following the use of steroids and TRT. This is another reason I am becoming more and more convinced that the 5-alpha-reductase connection/theory is the true culprit here. As it explains why changing blood levels of androgens such as testosterone and having normal levels has little to no effect on these mental side effects despite producing effects in the body such as muscle growth.
 
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flynn

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CAn8tive

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Ok sounds good I reported my effects on there, thanks. I have an appt w Dr Irwin Goldstein Sexual medicine specialist in San Diego again this year. I saw him last year but I knew little about PAS (didn’t even know the name/acronym) any good feedback he gives me, I’ll share in this forum.
 
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flynn

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Feb 28, 2018
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Ok sounds good I reported my effects on there, thanks. I have an appt w Dr Irwin Goldstein Sexual medicine specialist in San Diego again this year. I saw him last year but I knew little about PAS (didn’t even know the name/acronym) any good feedback he gives me, I’ll share in this forum.
Thanks for reporting the side effects. That would be greatly appreciated. You might even want to share some of the info relating Accutane to 5 Alpha reductase and post Finasteride syndrome (PFS). In all honesty, most doctors have no idea what to make of this stuff as they haven't done any research into it and have no research to review. Fortunately, PFS is fast becoming a medically recognised condition.
 
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