Re: broken gradient concentration theory cAMP ( for PSSD )
u/drwillpowers
r/DrWillPowers2026-05-17T18:55:08Z
Dr Will Powers’ own statements and theorizing
Mentions treatments or doses — not guidance
Summary (paraphrased)
On a proposed cAMP/concentration-gradient theory for PSSD, Powers reports having tried cyproheptadine: it can create temporary windows but doesn't solve the problem — much as bicalutamide doesn't cure PFS — because, in his view, it's not about the receptor but the ligand: a concentration-gradient issue. Antagonizing or agonizing the receptor can be overridden by strong stimuli, but that doesn't restore default signaling; he suspects intracellular accumulation of an unidentified molecule, as in PFS. He notes the asymmetry that all androgens can be removed from a man safely, while removing all serotonin would be fatal, and asks what feedback loop maintains the bad mechanism — his answer being the microphone-next-to-speaker loop where metabolite accumulation weakens androgenic signaling, driving more androgen production and more crowding. He argues evolution had no selective pressure against SSRIs, so the system can't calibrate around them. His confidence in the model, he says, will hinge on the initial PFS castration-trial participants' outcomes — if their systems reboot to normal, it supports the same metabolite-accumulation mechanism for PSSD — and he expects much better treatment options within a year.
Key points (paraphrased)
- "Not the receptor, the ligand": cyproheptadine and bicalutamide analogized as windowing without restoring gradients.
- Suspected intracellular accumulation of an unidentified molecule in PSSD, parallel to PFS.
- Self-amplifying feedback loop (microphone/speaker analogy); no evolutionary calibration for SSRIs.
- Castration-trial outcomes framed as the decisive test of the shared-mechanism hypothesis.
Why it’s in the corpus
Powers' receptor-vs-ligand framing and his explicit statement that the castration trials are the make-or-break test of the shared PFS/PSSD mechanism — important for the corpus's account of how he validates his own theories.
Context — the post Powers was replying toVerbatim third-party text, shown for context only — not Powers’ statement. Usernames removed.ShowHide
Powers' comment replies to the original post "broken gradient concentration theory cAMP ( for PSSD )" by [username removed]:
firstly, let me say thank you DrPowers for all the work you are doing for PFS and PSSD community. As a PSSD sufferer i appreciate it. This thing has ruined my life, but i am fighting.
I've spent recent few days studying your posts on PFS and PSSD mechanisms you are proposing or thinking of.
my background is mathematics, not biology/medicine so maybe im connecting the dots, maybe not but please hear me out everyone.
here is a wild guess :
SSRI use - > cellurar transporter ABCC5 is blocked -> gradient is damaged ( but we dont know how, maybe cAMP lvl is flatlined, maybe cell is oversaturated with metabolic waste ) -> no signal -> system stuck in bad equilibirum -> numbness, anhedonia, genital anasthesia
so i read that you have some initial success with roflumilast ( pde4 inhibitor ) but you are unsure if thats a window or permanent improvement
so what do you think about this strategy ?
perhaps this signalling mechanism is stuck in a scenario optimized for high stimulus, which is no longer there, after stopping SSRI use, or just from adaptation
instead of shocking a system with surge ( like giving PDE4 ) , lets starve it with use of sertonin and dopamine receptor antagonists , we block signals, we trick cells to thinking there is sensory deprivation, mechanism has to upregulate
how to do it ? 5ht1a receptor antagonist. i think it worked with rats, but assumed mechanism of action was different. https://pubmed.ncbi.nlm.nih.gov/19435548/
kind regards and all the best […]
(Parent context recovered from the r.genit.al mirror on 2026-10-07; Powers' comment text itself is from John's user-provided export.)
Some fields on this page come from the release’s Markdown edition, which carries text the JSON edition omits.
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