The right way: How to address PSSD comprehensively.

[Meso]

I'm writing this sort of guide on how to address PSSD comprehensively (symptomatic relief only, but without letting homeostasis reverse the benefits or cause tolerance) and also how to beat it permanently (actual "cure", or reversal). The reason for starting this thread is that I get so many PMs and I'm extremely busy in life, so I reply super-late, which I feel is bad since I want to help everyone get on the right track ASAP.

A little about me: many people have voiced concern on how I get my drugs. I'm a certified pharmacist, and I've provided proof to admins, and can provide further proof if need be. I didn't want to reveal my occupation because of fears that my posts would gain traction based on this alone, and being taken at face value without people double-checking the neurochemical and pharmacological information I provide. After all, I can merely offer educated guesses.

I've managed to achieve a 90% symptomatic relief (NOT a cure/reversal), but I will not post about my regimen until 1-2 months from now to make sure that the benefits are sustainable and there's no sign of tolerance. The worst thing a person can do to this community is over-hyping a treatment plan that would ultimately fail and giving false hope. I will avoid that.

This thread will be work-in-progress, and I will keep updating the OP as I have free time. I firmly believe that each person's PSSD is different and different pathways are affected, with some dysregulated pathways in-common, and a "general" guideline is needed to make you think how to address your own PSSD.

These are the main point that I will address here:
1. Fix gut dysbiosis and micro-organism overgrowth. Many people experience gut problems after PSSD. H2S and ammonia producing bacteria can cause neurological symptoms similar or more severe than PSSD. Candida should also be addressed.

2. Addressing the hormonal issues, at least to the best of our abilities.

3. Finding symptomatic relief long-term (without being counteracted by homeostasis). In this part, we shouldn't use directly acting agonists that would cause downregulation/tolerance, or hormonal replacement that would cause shutdown, without utilizing agents that upregulate said receptors, or depend on rebound phenomenon, or just use a partial agonist instead, etc.

4. Work on permanent cure through TrkB upregulation, BDNF, GDNF, and NGFs boosting, increasing LTP, epigenetic changes, etc.

5. Decreasing microglia activation and reducing neuroinflammation effectively. (i.e. LDN, TLR2 and TLR4 antagonism)

Important rule: Avoid polypharmacy as much as possible, and be minimalistic with dosing.

I will go in-depth on each point, once I have any free time. Stay tuned.

[Meso]

Step 1: Addressing gut microbiome dysbiosis
Many people report experiencing significant gut problems after getting PSSD. Many antidepressants are reported to have antimicrobial effect [1] and have a synergistic effect with antibiotics [2]. They seem to alter the gut microbiome, but the data is inconclusive on what changes they induce.

Certain bacteria can turn sulfur into the rotten egg smelly hydrogen sulfide gas (H2S), which is toxic to the nervous system and the mitochondria. If you start experiencing sulfur compounds/food intolerance, as such garlic and onion making you feel a ton worse, then you may have this dysbiosis. Rotten egg smelling flatulence is another tell-tale sign.

Another harmful bacterial overgrowth is the urease-producing bacteria which increase systemic ammonia. The liver is efficient in its ability to clear out the excess ammonia, but if there's liver impairment, expect severe neurological symptoms, which can also be mistaken for PSSD.

To make things worse, microbiome dysbiosis is associated with autoimmune conditions and neurodegeneration. Those bacteria release endotoxins leading to the activation of immune response and systemic inflammation. Changes in intestinal tight junctional proteins and increased gut permeability make sure that these toxin reach the systemic circulation. [3]

The body starts the synthesis of the proinflammatory cytokines TNF-α, IL-1β and IL-6. Activation of NF-κB and subsequent stimulation of toll-like receptors (TLR2 and 4) cause the brain microglia to switch on to their "active/reactive" state. [4] [5]

This is bad because the microglia switches on to "Kill and eat" state, producing neuroinflammatory cytokines and stimulating apoptosis. They can remain in this state semi-permanently under certain conditions [6]. This would cause neuroinflammation and degeneration due to dysregulated apoptotic mechanisms (c-Jun N-terminal kinase (JNK) pathway).

Ways to de-activate the microglia:
- Low dose Naltrexone (LDN): Happens to be TLR4 antagonist. [7]
- Minocycline/Doxycycline: Potently inhibit the production of proinflammatory cytokines and switches the microglia back to their anti-inflammatory state. [8]
- Sigma receptor agonism. [9] [10]
- Statins: Potently reduce production of proinflammatory cytokines. Switches microglia's phenotype back. [11] [12]. But if TLR are stimulated, statins do the opposite [13].
- Sartans: Angiotensin II AT1 receptor blockade ameliorates brain inflammation via modulation of microglial activation states [14] [15] and promotes hippocampal neurogenesis via activation of Wnt/β-Catenin signaling. [16]

What to do about gut microbiome dysbiosis?
Find a knowledgeable professional who would carry out SIBO tests for you, such as the hydrogen breath test (HBT). Make sure that this physician knows that H2S producing bacteria cannot be detected by oral lactulose test.

Work with your physician to change your diet, repair your gut with glutamine, prebiotics, probiotics, and sometimes a course of Rifaximin is also needed. The treatment plan depends on which dysbiosis you have and how bad it is.

Remember: Your PSSD symptoms may actually be symptoms of neurotoxicity caused by gut dysbiosis. Many of H2S or ammonia toxicity symptoms may be mistaken for PSSD symptoms due how similar they are [17] . Before attempting to target PSSD, make sure that you no longer have any gut-brain axis problem.
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Step 2: Addressing hormonal imbalance
Hormones are powerful chemicals and the logical next step to address because if your hormones are out of balance, no matter how much you alter neurotransmitters, the body will attempt to return to the new pathological baseline homeostasis. Hormones that are relative to PSSD are sex hormones (T:DHT:E2:Progesterone), prolactin, oxytocin, thyroid hormones and cortisol.

Antidepressants affect sex hormones both directly, and indirectly through elevating serotonin level. SSRIs act as weak SERMS with estrogenic/anti-estrogenic effects and decrease androgens [18] [19]. It's interesting to note that SSRIs and TCAs may also inhibit GnRH synthesis, with Clomipramine going as far as causing testicular damage in lab animals [20] [21]. This probably doesn't translate to humans, though.

Chronically elevated serotonin level desensitizes the presynaptic 5HT1A autoreceptor, leading to activation of postsynaptic 5HT1A heteroreceptors. This leads to cortisol, ACTH, prolactin, beta-endorphin, and oxytocin secretion [22][23][24][25]. These hormones have a negative effect on sexual function. Furthermore, activation of 5HT2, 5HT3, and 5HT4 receptors plays a facilitatory effect on prolactin secretion.

Beta-endorphin release, in itself, elevates prolactin significantly [26], and inhibits oxytocin neurons [27]. This is partly how antidepressants cause blunted affect as a side effect, along with the dopamine inhibition. Oxytocin sensitizes the brain to endorphin's effect [28], so increasing both beta-endorphin and oxytocin via postsynaptic 5HT1A heteroreceptors, in a chronic manner, would assure a negative feedback loop inhibition of oxytocin neurons.

Antidepressants induce ACTH and CRF release acutely, causing elevation of cortisol level [29]. However, certain studies have found no correlation, most likely because of the time of measurement (beginning of therapy vs end of therapy) [30], and because antidepressants are shown to modulate glucocorticoid receptors, causing an overall blunting of the HPA axis [31][32][33][34], which contributes to their antidepressant effect since cortisol is toxic to hippocampal neurons and mediates stress-induced hippocampal shrinkage [35].

The thyroid function is also blunted by SSRI and TCA antidepressants, with reduction of thyroid hormones reported and often correlated with the antidepressant effect [36][37][38][39] [40]. Subclinical hypothyroidism goes hand-in-hand with reduced sexual and emotional function as well as causing excessive daytime sleepiness and fatigue.

After some time, postsynaptic 5HT1A receptors would also become desensitized, causing a decrease in oxytocin, beta-endorphin, and ACTH/cortisol release. Since these hormones have a powerful suppressive effect on the immunity, a rebound immune activation and inflammation would occur. 5HT2C receptors upregulate in response to cytokines in the brain, this causes dopamine inhibition and illness syndrome. Also, glutamate function is heavily controlled by all serotonin receptor subtypes in many parts of the brain, and when those receptors become desensitized, glutamate function is inhibited, resulting in less hypothalamic function and more HPA axis blunting.

Bottom line:
If the SERT downregulation + 5HT1A desensitization and/or GIRK uncoupling theory of PSSD holds true, then we continue seeing these effects despite withdrawing from antidepressants. The HPA axis is significantly blunted, with a possible decrease in thyroid and sex hormones. This could explain the excessive fatigue and daytime sleepiness, malaise and illness symptoms, as well as blunted affect, anhedonia and sexual dysfunction.

Another PSSD theory that has come to my attention recently is CRF2-mediated serotonin release. Let me quote a member:

So a company is now trialing a new drug called Cortene. Their hypothesis is that a maladaptation within the limbic system, which shapes our response to stress, may underlie ME/CFS.  Specifically that a receptor called CRF2, which triggers neurons to release serotonin, has become unusually prevalent in parts of ME/CFS patients’ brains. Cortene believes that the elevated release of serotonin – in response to even small levels of stress – in turn causes ME/CFS. And this elevated serotonin level is due to 5ht1a receptor desensitization. I don’t believe it’s a coincidence that many people after SSRI exposure are diagnosed with this generally rare illness called cfs.

CRF is the key activator of the HPA axis. So, it would make sense that SRI antidepressants would alter its receptors activation, at least downstream. It does seem like many members experience windows of relief from things that alter or "nudge" the HPA axis, such as licorice and corticosteroids for example, but the effects are short-lived.

Either way, many of us have their hormones within normal range, but it's important to address any hormonal imbalance before we proceed. As a minimum, you should test:
- Testosterone (free and total).
- Estradiol (ultra-sensitive E2).
- FSH, LH
- Prolactin
- TSH, fT3, fT4.

With the help of an endocrinologist, restoring normal values should be possible until a way to reverse PSSD is worked out.
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Step 3: Finding symptomatic relief (WORK-IN-PROGRESS)
Since PSSD symptoms are diverse, with some being commonly found in PSSD patients whilst others are less commonly found, I've decided to write a part on each symptom, discussing the science behind what might be causing it, and how to address it with drugs for symptomatic relief. I'll start first with the most common symptoms.

1- Genital numbness and the link to pelvic floor dysfunction:
The pudendal nerve is what carries the sensory information from the penis/clitoris (via the dorsal branch) to the cortex of the brain. It also provides motor control of many pelvic muscles (via the inferior rectal nerve -> the perineal nerve). [41]

When this nerve is damaged or impaired, this may lead to sensory loss of the penis/clitoris and/or anal incontinence (inability to control pelvic floor muscles for defecation and urination). In short, this nerve is responsible for sensation in the penis/clitoris and erection, whilst also providing motor control of many pelvic floor muscles responsible for defecation and urination. Such, it functions as both sensory and motor nerve.

Acetylcholine (M2, M3, M4) is the main neurotransmitter of the somatomotor function, with further involvement of glutamate (NMDA), oxytocin, and serotonin (5HT1A).[42][43][44][45][46]

Also, spinal neurons are activated in response to pudendal or nerve stimulation, and carries the signal to the brain. Fast sodium channels are also important for spinal signaling [47]. When acetylcholine neurotransmission is altered, expect impairment of these functions. [48]

Antidepressants have recently been found to disrupt transient receptor potential (TRP) channels, inducing genital, and even nipples, numbness. TRPC are are major component of store-operated channels (SOCS). These channels are essential for calcium release in response to neurotransmitter activity. When you blunt these, you end up with impaired sensory nerve function in the periphery, and impaired astrocytes centrally.
https://www.ncbi.nlm.nih.gov/pubmed/25483212
https://www.ncbi.nlm.nih.gov/pubmed/22542657
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598437/

Furthermore, 5HT2B and TRPC4 colocalizes with HTR2B in dorsal root ganglion (or spinal ganglion). As such, reduced 5HT2B activity could potentially induce numbness through further calcium inhibition.
https://www.jacionline.org/article/S009 ... 8/fulltext

Furthermore, 5HT2B and TRPC4 colocalizes with HTR2B in dorsal root ganglion (or spinal ganglion). As such, reduced 5HT2B activity could potentially induce sensory numbness through further calcium inhibition.
https://www.jacionline.org/article/S009 ... 8/fulltext

Members here often report nipple numbness alongside genital numbness. Nipple oversensitivity is caused by over-expression of TRPV1 in skin nerve fibres and TRPV3 and TRPV4 in keratinocytes.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC554997/

Here's how elevated serotonin induce these symptoms:
- Many antidepressants inhibit both acetylcholinesterase and butyrylcholinesterase activities, this would lead to a compensatory upregulation of these enzymes and reduced central and peripheral cholinergic tone. [49][50]

NOTE: Same thing happens with acetylcholinesterase inhibitors (AChEI). The rapidly reversible actions of donepezil, tacrine and galantamine may lead to tolerance due to their ability to upregulate target enzyme activities; however upregulation is not seen with the slowly reversible (pseudo-irreversible) inhibitor rivastigmine. [51]

- 5-HT1A-mediated suppressing of NMDA receptors signalling via decreasing the number of surface NR2B subunits on dendrites (PFC).
[53][54]

- 5HT-mediated regulation of glutamate release, please refer to my other thread:
http://www.pssdforum.com/viewtopic.php?f=22&t=2754. Long-term elevation of serotonin would blunt glutamate release, and by extension NMDA receptor function.

- Serotonin inhibits voltage gated sodium currents (similar to lidocaine), affecting cortical and spinal nerve conduction. [55] [56] [57]

Treatment of genital numbness:
- Oral capsaicin supplementation. Although chronic activation of TRPV1 causes desensitization, it only happens with topical 8% patch (high concentration). Oral (systemic) intake can actually cause a paradoxical sensitization of TRPV1, and can cause central sensitization via many mechanisms.

- Rivastigmine: It's an acetylcholinesterase inhibitor that doesn't result in tolerance. I've been using Donepezil with success, but a study I have included says it induces tolerance. I will have to switch to Rivastigmine.

NOTE: I advice against Bethanechol since it interferes with spinal pottasium channels and could worsen genital numbness in some cases. [58]

- Cyproheptadine: Or any 5HT2 antagonist/inverse agonist. Since 5HT2 receptors downregulate in response to agonism or antagonism, tolerance should never be a problem. I've tried Cypro, and it had been the best med in combat of low libido and genital numbness, but side effects were intolerable. You may have more luck with a more selective one such as Ketanserin/Flibanserin, with less side effects.

- Drugs or herbs that lower serotonin level: Shilajit, feverfew, SERT activators, etc.

- NMDA potentiation: Sarcosine, D-aspartic acid, etc

2- Erectile dysfunction:
Although erectile function is also dependable on a healthy response of the pudendal nerve, there's also a vascular event and the reflex is mediated by the autonomic nervous system, so I choose to discuss erectile dysfunction on its own, including the hormonal aspect as well.

Let's briefly review the science of how penile/clitoral erections happen first.

Erections take place when both dilation of the penile arteries and relaxation of erectile tissues take place (corpus cavernosum and corpus spongiosum). This happens mainly due to an increase in intracellular cGMP and cAMP, which can be degraded by phosphodiesterases (PDEs). The autonomic nervous system is the main mediator for this reflex on the level of the spinal cord.

The sympathetic nervous response causes maintenance of the "flaccid/detumescence" or relaxed state, via noradrenergic (alpha-1 and alpha-2 activation) and serotonergic (5HT2C) activation [59][60]. The parasympathetic response causes relaxation of the smooth muscles of the penis and a resultant erection, this is mediated by NMDA glutamate and nitric oxide (NO) via increasing cGMP. [61]

Androgen hormones play a major role in erection physiology because they enhance all the pathways responsible for it. Here's the breakdown:
A sexual stimulus -> central nNOS-mediated NO release -> increased cGMP -> cavernous tissues dilation -> endothelial eNOS -> EDHFs -> engorgement and erections.

Not only this, but androgens also modulate the mesolimbic dopaminergic pathway, so a sexual stimulus triggers a greater response, appearing more appealing, and enhancing the reward system overall. [62]

And here's how SSRIs (or elevated serotonin) mess erections up:
1- Elevation of beta-endorphin: mainly postsynaptic 5HT1A. Beta-endorphin interferes with sex hormones drastically, blunting libido, as well as increasing prolactin. However, mu agonism is crucial for orgasmic intensity.

2- Nitric oxide inhibition: 5-HT1B/1D and 5HT2B receptors are involved in nitric oxide production. With chronic increase in 5HT, these autoreceptors (1B/1D) become desensitized and you end up with less nitric oxide production. [63]

3- Inhibition of the NMDA-NO-cGMP pathway by 5HT1A and 5HT2C receptors activation. [64]

4- Direct inhibitory effect of serotonin via the sympathetic nervous system, as mentioned earlier. This occurs via 5HT2 receptors.

5- Serotonin-mediated downregulation of AR receptor (thanks to iull1k for finding this), and SSRI-induced upregulation of 3α-Hydroxysteroid dehydrogenase (3α-HSD) blunting glutamate/NMDA even further. [65] [66]

So, this is how to reverse SSRI-induced (or elevated serotonin-induced) erectile dysfunction:
Generally, things that improve genital sensitivity would also improve libido through potentiation of the neural erectile response. But that's not always the case, so these are the options if it's not:
- PDE5 inhibitors: Straightforward, by preventing cGMP and cAMP degradation you get more bang for buck out of them. To counteract tolerance, makes sure to eat foods rich in nitrates and take breaks.

- 5HT2 antagonist + alpha-adrenergic blockers: This would prevent the sympathetic-mediated constriction of the erectile tissues by preventing the constrictive action of norepinephrine and serotonin. Examples of alpha blockers are Doxasocin/Prazosin (alpha-1), or yohimbine (alpha-2). Some 5HT2 antagonist also block alpha-2 receptors, examples of which are Mianserin and Mirtazapine, but their antihistamine effect would worsen genital sensitivity and anorgasmia, so make sure to take L-Histidine with them. AVOID beta-blockers as epinephrine/adrenalin is important for erections. Try finding a short-acting alpha blocker to prevent tolerance.

- Cholinergics: Acetylcholine is the main parasympathetic neurotransmitter through the muscarinic system, as such, boosting muscarinic activation could potentially boost erectile function. This is another reason why Rivastigmine could work.

- Boosting androgen levels: I haven't figured out a way to upregulate androgen receptors. TRT would suppress the receptors more and shut down the gonads, so I think Creatine is the best option for boosting DHT. Mesterolone at doses not higher than 50 mg wouldn't cause a shutdown while still activating AR.

If all of these fail, then nerve damage could be to blame. Boosting BDNF, NGF, and neurogenesis would potentially solve the issue. I won't go in details for this one since I plan to dedicate an entire step for this. Also, hypogonadism or AR receptor downregulation can trigger metabolic syndrome which is the main culprit for endothelial dysfunction and inability to repair endothelial tissues, so check if you are suffering from hyperlipidemia or prediabetes.

[Ghost]

I'm excited to hear what you have to say!

Thanks for posting!

[naiverat]

I'll be following this thread as well! I had been experiencing more and more good days and "windows," but I think the use of so many drugs (polypharmacy) in an attempt to further, or finalize, my progress has actually reversed it. Fuck.

[Meso]

I've added the first step "Step 1: Gut microbiome dysbiosis". This is a very important step to address before even thinking about managing PSSD.

[Psychedeliclove]

Everything written here MAKES A LOT OF SENSE! At least in my case! I have developed extreme intolerance to garlicky food since pssd, makes me bloated, tired,sick and makes my pssd symptoms a lot worse, even increases my anhedonia!

[RainebowGirl]

I've added the first step "Step 1: Gut microbiome dysbiosis". This is a very important step to address before even thinking about managing PSSD.

WOW, this explains a lot! I developed sulfur intolerance and candida overgrowth after taking anti-depressants and didn''t even connect the dots that it could be causing neurotoxicity.

I had been treating only a small part of the problem by killing off the candida without treating the imbalance of my gut bacteria.

[Ciprofloxacin]

The body starts the synthesis of the proinflammatory cytokines TNF-α, IL-1β and IL-6. Activation of NF-κB and subsequent stimulation of toll-like receptors (TLR2 and 4) cause the brain microglia to switch on to their "active/reactive" state. [4] [5]

This is bad because the microglia switches on to "Kill and eat" state, producing neuroinflammatory cytokines and stimulating apoptosis. They can remain in this state semi-permanently under certain conditions [6]. This would cause neuroinflammation and degeneration due to dysregulated apoptotic mechanisms (c-Jun N-terminal kinase (JNK) pathway).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608679/

Abstract

Neuroinflammation is closely associated with the pathogenesis of Parkinson’s disease (PD) and other neurological disorders. The hallmark of neuroinflammation is microglial activation. Increasing evidence suggests that inhibition of microglia-mediated neuroinflammation might represent a promising therapeutic potential for PD and related disorders. Fluoxetine, a selective serotonin reuptake inhibitor, is commonly used for the treatment of major depression due to its tolerability and safety profiles. Recent studies have shown that fluoxetine affords robust neuroprotection in a series of neurological disease models. However, the mechanism underlying fluoxetine-mediated neuroprotection remains unclear. Here, by using rat primary midbrain neuron-glia cultures, we report that both R and S isomers of fluoxetine attenuated chronic neurodegeneration induced by a commonly used inflammogen lipopolysaccharide (LPS). Reconstituted cell culture studies further revealed that microglia were required for fluoxetine-mediated neuroprotection. Fluoxetine significantly inhibited LPS-induced activation of microglia and subsequent release of multiple pro-inflammatory and cytotoxic factors including tumor necrosis factor-α, interleukin-1β, nitric oxide, and reactive oxygen species. Furthermore, inhibition of microglial NF-κB signaling pathway participated in fluoxetine-mediated neuroprotection. Collectively, fluoxetine exerted neuroprotection against microglia-mediated neurotoxicity. Thus, fluoxetine not only can relieve depression, a common nonmotor symptom of PD, but might also hold a potential to retard inflammation-mediated chronic neurodegenerative process of this disease.

It’s tragicomic. Fluoxetine made the exact opposite of this to me.

[Meso]

Sorry that I'm not around. I've been extremely busy at work and with moving out. I'll be back to the forum once I'm over this stressful period.

[Meso]

Added "Step 2: Addressing hormonal imbalance".

Blunting of the HPA axis could explain many of the symptoms, so I wonder if resetting its function would be a viable option.