Substances worth further exploring/researching

[Meso]

There are research chemicals and other substances out there that look promising but they are poorly researched thus requiring further exploring/researching.

1- CBD and/or CBG: CBD is a weak CB1 antagonist. This might be enough to upregulate CB1 without inducing dysphoric symptoms. Problem with CBD is that it's also a 5HT1A receptor agonist and will eventually raise serotonin by desensitizing the 5HT1A autoreceptors. That's when CBG enters the picture. CBG is a 5HT1A antagonist so it would counteract that. It's also an adenosine receptor agonist (opposite to caffeine). Adenosine agonism is relaxing and increases dopamine receptors sensitivity.

2- Fenclonine: Acute tryptophan depletion (ATD) is a method of lowering brain serotonin through depleting tryptophan. Fenclonine should only be used as a probe for a week maximum. It's a FAR better probe than BCAA + depletion diet since it doesn't take into consideration the diet's effect on brain chemistry as well as BCAA's on tyrosine.

3- Berberine and Evodiamine: Upregulation of SERT. Berberine looks good on paper aside from its 5-alpha reductase inhibition. I don't know much about Evodiamine.

4- Chaihu-jia-Longgu-Muli decoction (CLM): Works through boosting BDNF and normalizing NMDA/AMPA ratio in the PFC. It's rapid antidepressant effect akin to Ketamine. I think it's weaker though.

"Chaihu-jia-Longgu-Muli-tang (a single dose of 2.1 g/kg) has also been shown to produce a rapid antidepressant-like activity in olfactory bulbectomization mice through activation of Akt-mTOR signaling and normalization of AMPA receptor/NMDA receptor ratio in PFC "

5- Levothyroxine (L-T4): This is an accidental discovery, but when I was on TRT it caused increased libido and shortened refractory period despite raising serotonin. Effects were short-lived, though. Might be interesting in a regimen.

6- Serotonergic Psychedelics: Psilocybin, LSD, DMT, etc. are interesting due to the fact that they act rapidly to raise BDNF and promote rapid synaptogenesis and LTP. They can reduce anhedonic and depressive symptoms of PSSD. Some people like Ghost report some increased sexual functions after tripping.

In very severe PSSD, people lose reaction to serotonergic psychedelics altogether. So, this is only useful for people still reacting to psychedelics.

7- Ketamine and its derivatives: This can also raise BDNF and induce rapid synpatogenesis. It can improve depressive and anhedonic symptoms of PSSD in theory.

8- TRT + HDACi: One of the most potent intervention I tried. I did a ton of research on estradiol, HDACi, and T which I shared with the forum before. Estrogen, through ER-alpha, increases serotonin synthesis but also raises SERT expression. Estrogen increases SERT expression in male and female rats' dorsal raphe:
https://pubmed.ncbi.nlm.nih.gov/9878762/

9- Trenbolone: Although risky, 2 people who tried it say that it's more effective than traditional T. I'm still unsure why Trenbolone is more effective for PSSD than Testosterone. Maybe in PSSD, conversion to DHT is limited or maybe it's indeed Tren's progesterone activity. taarn didn't react to testosterone much, but he did to Trenbolone. If that's the case, then adding progesterone to traditional T might be worth researching.

10- Lecozotan: This is a selective 5HT1A antagonist currently in phase III for Alzheimer's disease. This is because 5HT1A antagonism increases glutamate and acetylcholine within the hippocampus.

11- WAY-100135 & WAY-100635: Slightly less selective than Lecozotan (D4 & 5HT1B), but should be equally interesting nonetheless.

12- Yueju pill: A still-popular traditional Chinese medicinal (TCM) herbs mixture which rapidly attenuates depressive-like behaviors, increases hippocampal BDNF expression, activates prefrontal Akt-mTOR signaling, and downregulates NR1 expression within days. Effects are comparable to Ketamine.

https://portlandpress.com/bioscirep/art ... ssant-like

13- High-impact (type II) AMPA positive allosteric modulator: Mibampator, Tulrampator, and IDRA-21 (? not so sure about last one).

AMPA receptor activation is very neurotrophic and has rapid anti-anhedonic and anti-depressant effect.

14- Melanocortin receptor agonists: Melanotan II and Bremelanotide.

Very promising for sexual dysfunction overall. However, there's this ancedote on Melanotan II:

"Melanotan II has been featured in the news in the UK because some people use it illegally for tanning their skin. I've seen several reports that have mentioned that it can cause sexual dysfunction and various other serious health problems. I know that there are risks associated with some chemicals that also might cause an improvement, but thought I'd better point out the possible dangers of that one."

15- Alprostadil: Useful for erectile/shrinkage problems if PDE5 inhibitors fail to help.

16- Pitolisant: H3 receptor inverse agonist. This increases monoamine transmission by quite a bit.

17- Etifoxine: Multi-acting as a GABA-A positive allosteric modulator + increases natural production of neurosteroids + possible translocator protein (TSPO) agonist (helpful for chronic fatigue syndrome).

Bottom-line:
These are substances that look cool on paper but they need further exploring because they are under-researched and/or have insufficient trial data.

[cdraham]

I tried idra-21. It helped 10%. How to reverse root cause?

[Meso]

I tried idra-21. It helped 10%. How to reverse root cause?

The root cause is currently unknown; we have nothing but hypotheses which can be wrong. I hope PSSD gets more research opportunities in the future.

[cdraham]

I tried idra-21. It helped 10%. How to reverse root cause?

The root cause is currently unknown; we have nothing but hypotheses which can be wrong. I hope PSSD gets more research opportunities in the future.

Ok. How was your last regime going? I think you tried to reverse it?

[Meso]

I tried idra-21. It helped 10%. How to reverse root cause?

The root cause is currently unknown; we have nothing but hypotheses which can be wrong. I hope PSSD gets more research opportunities in the future.

Ok. How was your last regime going? I think you tried to reverse it?

So far, I only managed to reverse the sexual symptoms with risky regimens. I've failed to reverse anhedonia and blunted affect, though. That said, temporary relief from anhedonia is possible.

[fellow1]

Can confirm t4 restored brain---> penis connection instantly to about 70% . This only worked while I was taking aromasin. Tried to replicate few times again later, and it was making me very tired and sleepy and worse in general.

[ErgogenicHealth]

I tried CBG Extract, and made a thread about it here.

My current theories are as follows:
2. 5-HT1A receptor modulation/upregulation from hardcore antagonism?

Other compounds that have “given me windows” of cure are:

St John’s Wort (You can read my post here - St. John's Wort: PSSD Eliminated, Anhedonia Gone, Emotions Online!)

Zeolite.

ALCAR (Only lasts a day or two, then WORSENING of symptoms).

Homeopathic Phosphorus (Don’t even fkn ask me how this works, and also, don’t call it a placebo, because I have gotten my brother to BLIND FOLD me and test it out on me).

So now we enter CBG Extract:

The reason why I decided to try CBG extract was based on ONE finding:

“Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist”
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823359/)

This caught my attention because as you know, Cyproheptadine is ALSO a 5-HT1A antagonist!!

Now here’s where it gets super interesting:

When I acutely dose CBG orally (Between 10-40mg), I remember the first day I tried it, feeling heightened energy and stimulation. I was generally in a good mood.

But that’s NOT what I was looking for.

Remember, the whole goal here is to alleviate my messed up 5-HT1A signalling that causes PSSD-like symptoms.

That night after dosing, I slept very average, and for the first time in years I woke up at like 3-4am HUNGY!!!

I rarely wake up hungry like that.

This effect has continued.

So after continuous dosing, I quickly noticed something rather spectacular.

My PSSD symptoms disappear about 10-12 hours after dosing CBG… As in, when it “wears off” I feel my orgasm return full strength and penis to brain connection return again.

So now I am trying to dertermine whether or not I can use CBG as a form of “re-set” instead of Cyproheptadine to help my condition.

So far so good, and only time will tell how long this rebound lasts.

Some other effects about CBG:
CBG can activate alpha α2 adrenergic receptors and block CB1 receptors (Cascio et al., 2010), suggesting CBG does have therapeutic potential in the treatment of depression.

[ErgogenicHealth]

10- Lecozotan: This is a selective 5HT1A antagonist currently in phase III for Alzheimer's disease. This is because 5HT1A antagonism increases glutamate and acetylcholine within the hippocampus.
-I do NOT know a single person with PSSD that has tried this compound?!

[Tree]

We need a drug developed that specifically targets and upregulates sert. Does such a drug exist or being developed?

[cdraham]

We need a drug developed that specifically targets and upregulates sert. Does such a drug exist or being developed?

Why do you think thats the issue? Can it explain all symptoms including severe ones like brain fog and such?