Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

This is for hypothesis and even educated speculation.
taarn
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by taarn »

I was just searching for the effects of bupropion on cortisol and found this interesting paper.

Effect of bupropion on nocturnal urinary free cortisol and its association with antidepressant response.
https://www.ncbi.nlm.nih.gov/pubmed/15589567
The study examined the relationship between pre-treatment nocturnal hypothalamic-pituitary-adrenal (HPA) activity, as reflected by nocturnal urinary free cortisol (NUFC) response to a single-dose of sustained-release bupropion, and the antidepressant effect of the drug. NUFC changes in response to treatment with bupropion also were assessed. NUFC was measured in 20 patients with unipolar major depressive disorder before and after initiating treatment with sustained-release bupropion. Prior to treatment, subjects were studied on two separate sessions, one week apart. On the morning of each session, the participants received bupropion (150 mg, PO) or placebo using a randomized, double-blind procedure. Following the second session, subjects then received open-label treatment with bupropion for 8 weeks. NUFC sampling was repeated at the end of treatment. There was a significant interaction between NUFC concentration in response to single-dose bupropion and its antidepressant effect. Treatment non-responders showed a significant increase in NUFC in response to a single-dose of bupropion, whereas responders showed no such change. In addition, the NUFC response to bupropion challenge correlated significantly with the change in depression ratings as a result of treatment. In contrast to many other antidepressants, treatment with bupropion for 8 weeks did not reduce HPA activity in either responders or non-responders. These findings suggest that the NUFC response to a test-dose of bupropion might be helpful in predicting its antidepressant effect. One possible mechanism for the association between the NUFC response to acute bupropion challenge and antidepressant efficacy might be linked through dopaminergic and/or noradrenergic mechanisms.
To me it suggests that when AD meds cause cortisol spikes it's not too beneficial for patients, and people who tolerate them more or get benefits out of them don't get that cortisol response. Probably for those who have bad reactions to antidepressants like developing PSSD symptoms the meds elicited an above average cortisol response.

Furthermore this paper shows that bupropion doesn't alter the HPA axis. Could it be partly responsible for that bupropion is less likely to cause PSSD?
iull1k
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by iull1k »

Ok but we still have guys with PSSD because of Bupropion, or got worse with it. There is another mechanism involved in my opinion.
Jaxx
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Jaxx »

This was posted on the PSSD facebook page
As I promised at the first PSSD group, I am going to release some of the information that belongs to my scientific work. It would not have the scientific structure and would not be as near to be complete or anything like that. I would answer only questions that I’m allowed to answer and that would be done after a while.
In this post I’ll present the medications and supplements I have used that brought me some relief in symptoms.

Until April 2018 every supplement or medications I have tried completely failed to help my PSSD symptoms. At April 2018 I started taking addy. I felt clear improvements with all aspects of my PSSD at the second night. The improvements disappeared the day after for another 5 days at my PSSD baseline. After another 5 days I had at least 7 days of dramatic improvements in all aspect (I have them all except of genital numbness). After those few days I came back to my baseline for several days and then a dramatic worsening appeared. It is clear to me that my 5ht1a auto receptor was desensitized after it was agonized by addyi. Once the 5ht1a autoreceptor is activated the serotonin released from the presynaptic neurons are reduced and thus the dopaminergic activity at the pleasure centers is disinhibited. I tapered addyi off for at least one month and I was in bad PSSD shape.
I tried CBD oil the day after completely stoping addyi (3-30 mg a day). It took me few days to notice a clear improvement after about 2.5 months of addyi which were terrible except of the early clear success from it. CBD oil is 5ht1a partial agonist so it let the autoreceptor to slowly up-regulate while still activating it. I had moderate improvement which was definitely above my PSSD baseline before addyi. That lasted for a month and a half.
I then moved to ropinirole (0.5 mg a day). That is a postsynaptic dopamine agonist. It had good results too while I wasn’t using CBD oil alongside it. CBD oil was actually destroying the ropinirole effects whenever I mixed them. Ropinirole bypasses the serotonin issues and directly activates the dopamine receptor. I only figured that CBD blocks the ropinirole effect after I mixed them at the second time. At that point I decided to stop using drugs as I saw the dangers of permanently messing my self up. There are many people who are trying to manage their PSSD symptoms but ending up with extreme worsening. I explain this issue in my hypothesis which I can’t reveal right now. Afterward I tried CBD again but it had no effect. It seems it has its effects only after using serotonergic drugs that wore the 5ht1a auto receptor out. I moved to NADH (5-20 mg a day) That is the antioxidant form of vitamin B3. It actually increases the biosynthesis of dopamine. I had great results with it. Actually on of my friend too. she had tremendous results with it too and much better then the results she had on CBD oil (she tried those supplements only) She suffers from mild form of PSSD. I have found out that demiana and avina sativa extracts helped me too for some extent.
I see that some supplements have an effect on me while others completely don’t (ginkgo, bacopa, Muira puama, mucuna, maca , fu ti, and many other supplements had completely no effect on me) . I may add that i tried Wellbutrin, amantadine, bremelanotide , testosterone, HCG, clomid, oxytocin and proviron with absolutely no benefits and the hormones were actually destroying my HPTA axis.
Overall I see PSSD as a result of extremely low dopaminergic activation at the pleasure centers that is caused mostly due to high levels of serotonin at the limbic system and hyperreactivity of all the receptors towards downregulation/de sensitization which prevents us to maintain the benefits from any supplements or drugs that can help. Cycling drugs is extremely risky so I prefer cycling the supplements.
In my research I am working on ways to heal this condition and not managing its symptoms. I cant reveal information about that yet as it would give you nothing at this point and would harm my research.
This is serious research with psychiatric, neurologist and urologist departments managers that are giving me there support. I can tell you that there is definitely hope and it would take several years till we get that thing solved !
I do not give advice in this post to anyone to try what I have tried as I’m not a doctor !!! So be very cautious about what you try on your own risk !!!
taarn
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by taarn »

iull1k wrote:Ok but we still have guys with PSSD because of Bupropion, or got worse with it. There is another mechanism involved in my opinion.
Yes I'm aware of that, it is only less likely to cause PSSD, not totally safe. It is not serotonergic anyway. (Although desensitizes DRN 5-HT1A by another mechanism) I pointed out leaving the HPA axis intact can be partly responsible for this reduced likeliness of causing long lasting issues.

Sure other mechanisms are also involved but I think messing with cortisol and the HPA axis plays an important role in the pathology of PSSD. If someone who is predisposed to cortisol spikes and getting into high-glutamate overexcited states takes a few pills of bupropion it can still lead to long lasting changes and probably PSSD. This is still in accord with Mesolimbo's proposed mechanism of how a few pills can cause PSSD.
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Meso
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Meso »

Jaxx wrote:This was posted on the PSSD facebook page
His theory is at fault because Flibanserin is selective to postsynaptic 5HT1A receptors, not presynaptic ones.



In the rat's brain:
Therefore, flibanserin presented a marked selectivity for postsynaptic 5-HT1A receptors when applied locally, but not when administered intravenously. It remains to be determined if flibanserin preferentially activates postsynaptic 5-HT1A receptors upon sustained systemic administration.
In the human brain:
Flibanserin significantly reduced the activity of AC post-synaptically, i.e. in the prefrontal cortex [EC50 (mean +/- S.E.M.), 28 +/- 10.2 nM; Emax, 18 +/- 2.3%] and in the hippocampus (EC50, 3.5 +/- 3.1 nM; Emax, 20 +/- 4.0%), but had no effect in the raphe nuclei, i.e. at pre-synaptic level.
https://www.ncbi.nlm.nih.gov/pubmed/12135537
https://www.ncbi.nlm.nih.gov/pubmed/9661257
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Blueturtle
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Blueturtle »

Jaxx wrote:This was posted on the PSSD facebook page
As I promised at the first PSSD group, I am going to release some of the information that belongs to my scientific work. It would not have the scientific structure and would not be as near to be complete or anything like that. I would answer only questions that I’m allowed to answer and that would be done after a while.
In this post I’ll present the medications and supplements I have used that brought me some relief in symptoms.

Until April 2018 every supplement or medications I have tried completely failed to help my PSSD symptoms. At April 2018 I started taking addy. I felt clear improvements with all aspects of my PSSD at the second night. The improvements disappeared the day after for another 5 days at my PSSD baseline. After another 5 days I had at least 7 days of dramatic improvements in all aspect (I have them all except of genital numbness). After those few days I came back to my baseline for several days and then a dramatic worsening appeared. It is clear to me that my 5ht1a auto receptor was desensitized after it was agonized by addyi. Once the 5ht1a autoreceptor is activated the serotonin released from the presynaptic neurons are reduced and thus the dopaminergic activity at the pleasure centers is disinhibited. I tapered addyi off for at least one month and I was in bad PSSD shape.
I tried CBD oil the day after completely stoping addyi (3-30 mg a day). It took me few days to notice a clear improvement after about 2.5 months of addyi which were terrible except of the early clear success from it. CBD oil is 5ht1a partial agonist so it let the autoreceptor to slowly up-regulate while still activating it. I had moderate improvement which was definitely above my PSSD baseline before addyi. That lasted for a month and a half.
I then moved to ropinirole (0.5 mg a day). That is a postsynaptic dopamine agonist. It had good results too while I wasn’t using CBD oil alongside it. CBD oil was actually destroying the ropinirole effects whenever I mixed them. Ropinirole bypasses the serotonin issues and directly activates the dopamine receptor. I only figured that CBD blocks the ropinirole effect after I mixed them at the second time. At that point I decided to stop using drugs as I saw the dangers of permanently messing my self up. There are many people who are trying to manage their PSSD symptoms but ending up with extreme worsening. I explain this issue in my hypothesis which I can’t reveal right now. Afterward I tried CBD again but it had no effect. It seems it has its effects only after using serotonergic drugs that wore the 5ht1a auto receptor out. I moved to NADH (5-20 mg a day) That is the antioxidant form of vitamin B3. It actually increases the biosynthesis of dopamine. I had great results with it. Actually on of my friend too. she had tremendous results with it too and much better then the results she had on CBD oil (she tried those supplements only) She suffers from mild form of PSSD. I have found out that demiana and avina sativa extracts helped me too for some extent.
I see that some supplements have an effect on me while others completely don’t (ginkgo, bacopa, Muira puama, mucuna, maca , fu ti, and many other supplements had completely no effect on me) . I may add that i tried Wellbutrin, amantadine, bremelanotide , testosterone, HCG, clomid, oxytocin and proviron with absolutely no benefits and the hormones were actually destroying my HPTA axis.
Overall I see PSSD as a result of extremely low dopaminergic activation at the pleasure centers that is caused mostly due to high levels of serotonin at the limbic system and hyperreactivity of all the receptors towards downregulation/de sensitization which prevents us to maintain the benefits from any supplements or drugs that can help. Cycling drugs is extremely risky so I prefer cycling the supplements.
In my research I am working on ways to heal this condition and not managing its symptoms. I cant reveal information about that yet as it would give you nothing at this point and would harm my research.
This is serious research with psychiatric, neurologist and urologist departments managers that are giving me there support. I can tell you that there is definitely hope and it would take several years till we get that thing solved !
I do not give advice in this post to anyone to try what I have tried as I’m not a doctor !!! So be very cautious about what you try on your own risk !!!

This was a good read. Yes it looks like so many of the PSSD symptoms have to do with dopamine, as well as general hormones.

Another person reporting benefit from CBD oil. I’m getting more curious about it.
PSSD from citalopram.
Took it Winter 2012-Summer 2016
Cut cold turkey. Symptoms include genital anesthesia, ejaculatory anhedonia, low libido, Burning/tingling genital pain.
My story: http://www.pssdforum.com/viewtopic.php?f=14&t=2536
ErgogenicHealth
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by ErgogenicHealth »

I am the guy who gets CURED from rebound of Cyproheptadine.

That is - I take a single 1mg of cyproheptadine on a wednesday night, I will be NUMBED completely for 3-4 days. But then say Saturday and Sunday, I feel INCREDIBLE, all emotions sexual feeling return. I feel so good.

But then if I have Yohimbine it makes me WORSE!

5-HT1A definitely playing a role here.
Spins
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Spins »

I also was very sensitive to 5ht1a agonist. My dick died when I went through a medication switch and dropped lexapro and added brintellix, a potent agonist of 5ht1a. When I switched, I felt that switch flip in my brain and my dick died and had not returned. Almost like the crash finasteride guys describe and then my hormones steadily declined over 3 years. Still no sex drive at all.
Tree
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Tree »

Crashed from Ginger, a partial 5ht1a agonist, it severely ruined my baseline. Severe cognitive and sexual dysfunction which hasn’t improved much and it’s been a year.
ErgogenicHealth
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by ErgogenicHealth »

Tree wrote: Thu Nov 28, 2019 1:48 am Crashed from Ginger, a partial 5ht1a agonist, it severely ruined my baseline. Severe cognitive and sexual dysfunction which hasn’t improved much and it’s been a year.


Exact same here... Any 1A agonist can worsen us. That means ALCAR would crash you too?
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