PSSD has been considered an incurable disorder, however, that’s about to change.
For over 50 years, serotonin-boosting drugs have been used to “treat” depression and other mental disorders.
Despite poor results, the “low serotonin hypothesis of depression” keeps on being pursued, fortunately, not as hard as before though (now they’re looking into serotonin antagonists).
If using somewhat ineffective serotonin modulating drugs with lots of side effects isn’t bad enough, quitting them doesn’t even make it better for a significant amount of the people.
There is an ever increasing problem called PSSD (post SSRI sexual dysfunction).
Common PSSD symptoms include:
- Penile numbness
- Low enjoyment
- Weak, unsatisfying orgasm, basically anhedonic ejaculations
- Decreased sex drive
- Erectile dysfunction
- Delayed or premature ejaculation
And these are just some of the common sexual side effects. The other side effects include feeling depressed, which reduces your mood even more, anxiety, which can also contribute to erectile dysfunction and premature ejaculation, etc.
So all in all, this is a horrible disorder to suffer from and there is currently no “cure” for it. Ofc there isn’t because everyone is still a little different and if one thing works for someone, it might only work partially for someone else.
Regardless, let’s get into what’s going on so that we can become aware of possible solutions.
The mechanisms behind PSSD
There are many different SSRI drugs all with different effects. Some are serotonin re-uptake inhibitors, others are serotonin releasing promoters, others are serotonin receptor agonists, norepinephrine re-uptake inhibitors, or even serotonin receptor antagonists.
All of that can make your mind feel like dog vomit in a washing machine, lol.
Some of the most common changes, often permanent, include:
- Increased serotonin, even after SSRI drugs have been stopped.
- Serotonin regulates proopiomelanocortin (POMC) neuron output and inhibits melanocortin MC4 receptors through 5-HT2A and 5-HT2C action. Melanocortin signaling is essential for sexual function. So blocking 5-HT2A and 5-HT2C can be very helpful.
- Serotonin-enhancing agents that do not stimulate 5-HT2 and 5-HT3 receptors apparently do not cause significant sexual dysfunction (R).
- Reduced 5-HT1A sensitivity, due to chronically elevated serotonin and 5-HT1A agonism.
- This study shows that antagonizing 5-HT1A during SSRI treatment prevents the induction of SSRI induced sexual dysfunction. More on that in a bit.
- Increased prolactin
- Prolactin and serotonin correlate very well and prolactin is a major inhibitor of sexual function. Serotonin primarily increases prolactin through 5-H2C, however, that receptor can be downregulated and you can still have high serotonin and low/normal prolactin.
- Decreased dopamine
- Serotonin and prolactin are inhibitors of dopamine release. When dopamine levels drop, prolactin and serotonin get out of hand even more.
- Decreased testosterone
- Serotonin and prolactin are well-known inhibitors of testosterone synthesis.
- Decreased oxytocin
- 5-HT1A activation releases oxytocin, so desensitized 5-HT1A can lead to reduced oxytocin levels as well, and this can also reduce sexual pleasure.
- Lowered nitric oxide synthase
- Low nitric oxide production, possibly due to enhanced oxidative stress, could also contribute to ED. However, excess NO can contribute to vascular leakage.
- Blockage of cholinergic receptors
- Cholinergic fibers help in filling the corpus cavernosum, a requisite for erection (R).
So a very important receptor that I want to talk about is the 5-HT1A receptor.
Reduced 5-HT1A sensitivity in PSSD
The 5-HT1A receptor has a plethora of benefits that we want. SSRI drugs, by boosting serotonin very high, desensitize this receptor, thus lowering most of 5-HT1A’s actions.
A few of 5-HT1A’s beneficial actions include:
- Promoting vasodilation. This can cause someone to cool off as well as help get an erection.
- Inhibiting glutamate release.
- If 5-HT1A is desensitized, glutamate will be elevated, which contributes to anxiety, depression, ADHD, rumination, etc.
- Improving cognitive functions, possibly via inducing prefrontal cortex dopamine and acetylcholine release.
- Stimulating the adequate release of cortisol during rest, while reducing the secretion of ACTH and cortisol induced by an array of stressors.
- Overactivation of the adrenal axis is common amongst people with depression, low stress intolerance, social defeat, etc.
- Releasing oxytocin
- Releasing β-endorphins
- β-endorphins and adrenocorticotropin (ACTH) are derived from the same precursor, proopiomelanocortin (POMC), and are co-synthesized and co-secreted (R).
- Releasing dopamine
- Inhibiting nNOS
- Elevated nNOS promotes anxiety, so lowering it has anti-anxiety effects.
- Inhibiting the μ-opioid receptor (R)
- Excess opioid signaling is also anti-libido, anti-erection, etc.
In summary, 5-HT1A is a very important receptor we want full sensitivity to. If it’s desensitized, agonists, such as zinc, don’t give the mood uplifting benefits unless used at very high doses.
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Restoring 5-HT1A sensitivity
So how do we sensitize 5-HT1A? First off, excess serotonin suppresses 5-HT1A, so lowering serotonin can be helpful.
Secondly, blocking 5-HT1A has been shown to increase its levels.
There aren’t a lot of natural 5-HT1A antagonists that I know of, but one good synthetic one is cyproheptadine. So if you dose it once or for a few days, you should be able to increase 5-HT1A expression as a rebound effect. While you’re using it, you might not feel better, but then you might get this rebound effect where you feel awesome when you stop the drug. However, if excess serotonin isn’t being lowered, then 5-HT1A will be desensitized again.
Additionally, a few things that can increase 5-HT1A include:
- Curcumin significantly prevents the stress-induced decrease in 5-HT1A mRNA and BDNF protein levels in the hippocampal subfields; two molecules involved in hippocampal neurogenesis. Moreover, curcumin, via up-regulation of 5-HT1A receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin (R).
- My only beef with curcumin is that it inhibits 5-alpha reductase (5-AR) and DHT production, since DHT is essential for sexual function (R).
- Estrogen desensitizes 5-HT1A (R), which will increase serotonin.
- Estrogen is also a potent inducer of serotonin synthesis by upregulating tryptophan hydroxylase (TPH) in the brain.
- Testosterone lowers serotonin (R).
- Chronic stress downregulates 5-HT1A, whereas testosterone can restore 5-HT1A in certain brain areas under stress (R). As a side note, 5-HT1A activation reduces aggression, whereas estrogen prevents this reduction in aggression. DHT, since it doesn’t increase estrogen (but actually lowers it), doesn’t increase aggression, but actually decreases it (R).
- Alcohol can also possibly be an antagonist since 5-HT1A agonists prevent alcohol-induced aggression (R).
- Yokukansan (R)
- It increases 5-HT1A and decreases 5-HT2A (R).
- Avoid Ashwagandha
- Ashwagandha reduces the sensitivity of 5-HT1A, but increases the sensitivity of the 5-HT2 receptors (R). Blocking the 5-HT2 receptors are recommended for PSSD.
- Low dose acts agonistically whereas high doses can act antagonistically. However, we don’t know how high high doses are (R).
- T3 appears to desensitize 5-HT1A (R).
- This could be why some people feel worse when taking thyroid.
- Lithium (R)
- Shuyu (R)
- Exercise (R)
- Tiansi Liquid (Morinda ofﬁcinalis and Cuscuta chinensis) (R).
- Rhodiola Rosea (R)
- Butyrate (R)
- Ginkgo Biloba (R)
- St Johns Wort, containing high hypericin, not hyperforin (R).
- It increases both 5-HT1A and 5-HT2A density.
- St. John’s Wort also inhibits cytochrome 3A4 acutely and then induces this enzyme with repeated administration (R). This is a good thing as it’s been hypothesized that cytochrome 3A4 is downregulated in PFS.
- Cannabigerol (CBG) (R)
- It’s a modest 5-HT1A competitive antagonist, so it should increase 5-HT1A over time.
5-HT1A and the endocannabinoid connection
Another very important thing I should mention is the 5-HT1A-endocannabinoid connection. Endocannabinoids are involved in making us feel good and activation of the CB1 cannabinoid receptor activates the 5-HT1A receptor.
CB1 activation can lower serotonin through the 5-HT1A receptor, however, chronic stimulation of the CB1 receptor with THC, CBD, oleamide, etc., can actually desensitize the 5-HT1A receptor and increase serotonin.
We don’t want too much or too little cannabinoid signaling. The way we can tweak this is to inhibit the enzyme that breaks down one of the endocannabinoids, namely anandamide. This enzyme is known as fatty acid amide hydrolase (FAAH).
Contrary to stimulating CB1 with agonists, inhibiting FAAH doesn’t cause downregulation of 5-HT1A or have any of the side effects of CB1 agonists (R).
In fact, the CB1 receptor is so important to 5-HT1A function, that CB1 knock out mice (mice without the CB1 receptor) have profoundly reduced functional coupling of 5-HT1A. The reduction in the function of the 5-HT1A receptor doesn’t appear to be associated with any significant changes in its expression levels (R).
How to increase endocannabinoids
Like I mentioned, using a CB1 agonist can downregulate 5-HT1A, whereas inhibiting FAAH or inhibiting endocannabinoid uptake can actually increase 5-HT1A function.
Here are a few ways to increase endocannabinoids:
- Palmitoylethanolamide (PEA) – inhibit FAAH (R)
- Kaempferol (R)
- Pterostilbene (R)
- Maca powder (R)
- Guineensine – a dietary N-isobutylamide widely present in black and long pepper (Piper nigrum and Piper longum) inhibit cellular endocannabinoid uptake (R).
Glutamate overactivation in PSSD
There is this hypothesis that SSRI drugs only start to work after 2-3 weeks of use since it’s needed to desensitize 5-HT1A. So intially, there is actually a decrease in serotonin, followed by a normilization or increase in serotonin.
This is coined the 5-HT1A desensitization hypothesis. However, this study shows that it’s not that simple. There is still some inhibition going on even though the 5-HT1A receptor has been desensitized.
The reason for the increase in serotonin might actually be due to an increase in glutamate firing.
The most plausible explanation is the disinhibition of glutamatergic neurons via mPFC GABA interneurons expressing 5-HT1A heteroreceptors.58,74Reference
And we definitely do not want elevated glutamate.
Prefrontal cortex (PFC) circuits utilizing glutamate may be overly active when sexual desire is low (R, R).
Plan of action against PSSD
So our goal to restore proper sexual function, is to restore 5-HT1A function and this can include optimizing the endocannabinoid system and lowering excess glutamate.
#1 Sensitize the 5-HT1A receptor with cycling an antagonist, such as cyproheptadine, or use something that can increase 5-HT1A levels, such as curcumin, Rhodiola Rosea, etc.
#2 Antagonize serotonin receptors
- 5-HT2A with feverfew, cyproheptadine, metergoline, Ginkgo Biloba, Bacopa monneiri:
- 5-HT2C with ginseng (if you get anxiety from ginseng, combine it with a pro-GABA supplement) or Silk tree
- 5-HT3 with ginger
#3 Increase SERT, which transports serotonin out of the synaptic cleft. Salt and zinc can effectively help.
Endotoxins in the gut can potently inhibit SERT when they bind to the TLR4 receptor (R). So anything that might be irritating your gut, such as raw foods, starches, crispy food, partially digested food, etc., might dramatically worsen your symptoms by increasing serotonin.
Also, if you have an excess of pathalogical endotoxin producing bacteria, you’re going to have a bad time…a high serotonin time. Check out my article on the high serotonin personality.
#4 Increase dopamine. A few good compounds include Bromantane, uridine, huperzine A, taurine, phenylalanine, phenylpiracetam, etc.
- Dopamine receptors: 14 Best supplements and practices and to increase it
- What foods to eat to increase dopamine
- The ultimate guide on boosting dopamine levels
- The high dopamine personality
#5 Increase endocannabinoids by inhibiting FAAH, with maca, PEA, blueberry extract (it contains Pterostilbene), etc.
#6 Use aphrodisiac supplements, such as yohimbine, Muira puama, etc., or sythetic melanocortins such as melanotan.
Solving PSSD can rarely be done from only one angle. It has to be addressed from multiple angles.
Lastly, I want to mention that there is a case report of a man that used EDOVIS, (a dietary supplement containing L-Citrulline, Tribulus Terrestris, Peruvian maca, turnera diffusa (damiana), Muira puama, and folic acid) and cured his PSSD (R).
A good stack would look something like this:
- Rhodiola Rosea – (iHerb)(NeuroActive (10% off code))
- Ginkgo Biloba – (iHerb)(NeuroActive (10% off code))
- Bromantane – (NeuroActive (10% off code))
- Blueberry extract – (NeuroActive (10% off code))
- Muira puama (iHerb) / yohimbine – (iHerb)
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34 thoughts on “PSSD: The why and the how to get it fixed”
Would Black Seed oil work for this as well? Or would it contribute to worsening the symptoms?
It might be helpful, since it positively modulate the gut bacteria and is also pro-thyroid and neuroprotective. Although one study showed that it increased serotonin in rats, the rats showed greater resilience, which is actually an anti-serotonin trait.
Hello Hans, I’ve tried Ginkgo, Ginseng, Maca and Tribulus , all cycled through months. They all seem to worsen my numbness. Any ideas ? Thanks . Andy
Ginkgo and ginseng antagonize the 5-HT2A receptor, which might play a role. Maca increases dopamine, noradrenaline and endocannabinoids and it lower cortisol. Tribulus also lowers cortisol, so I wonder if the drop in cortisol/adrenal activity might play a role. Not exactly sure why maca or trib would do that.
Hey hans how about Piracetam for Pssd as you mentioned in one of your articles that it increases 5ht receptors and dopamine too?
I think it can be useful and is definitely someone can experiment with either on its own or in conjunction with other supplements. Have you used it before with good results?
Hans, am back again haha.. What do you think the effects of micro dosing ashwaghda would be? Would it up regulate that receptor?
Since chronic dosing of ashwagandha reduces the sensitivity of 5-HT1A, I don’t think lower dose should have the opposite effect.
If you’re getting benefits from ashwagandha, then perhaps you might have had supersensitivity of the 5-HT1A receptor.
Sometime small amount of down or up regulation will cascade into an opposite reaction though, that’s why I was asking.
It’s definitely something that you can experiment with.
Mr Amato, please help. I just left you a message..Thank you
I love the topics you cover on your website.
How much mg of Curcumin would Sensitize the 5-HT1A receptor?
I’m glad you’re enjoying the content.
1000mg once or twice daily is a good starting dose.
Not sure if I understood the point about t3:
“Additionally, a few things that can increase 5-HT1A include:
T3 appears to desensitize 5-HT1A”
So is it good that t3 desensitize 5-HT1A instead of blocking it?
I can’t say when I look at the bigger picture. Hypo and hyperthyroidism is usually an issue, but I’m sure normal levels of T3 would only be helpful.
Brilliant, Hans. Spot on. I’m tossing out my Prozac as we speak. Your site is the most informative on a variety of subjects. I’m getting off all my Big Pharma bs pronto. Respect, fam.
Thanks so much for the kind words. Much appreciated. Let me know if I can be of assistance.
Thank you for the well written article.
I wondered if it might be of benefit to distinguish between ht51a receptors in your analysis.
As I understand it there are two sets of ht51a receptors, the autoreceptor and the heteroreceptor. I think I’m right in saying that it is the pre-synaptic autoreceptor that is downregulated, whilst the postsynaptic heteroreceptor remains upregulated in a lot of pssd cases. It would be interesting to know your thoughts on how to upregulate one but not the other and distinguish between the two types.
My thinking is that if you can lower serotonin then that may go some way to stimulating a recovery of sert and a recovery of these receptors. I couldn’t find any references to your advice in improving sert function with zinc and salt. References to that would be most useful. Also zinc supplement presents a slight paradox as it is a partial ht51a agonist, and I’m assuming you’d need an antagonist to see any possibility of upregulating 5ht1a sites.
I also have read that serotonin produced in the gut is unable to pass the blood/brain barrier, so presumably the brain makes its own serotonin independently of the gut. That said, the precursor to serotonin is L-tryptophan, which is only obtainable by food. So by reducing L-tryptophan consumption, you might be able to reduce serotonin production in the brain. My thought is you could do this with a Keto diet, or high protein/low carb intake. As glucose is needed to transport L-tryptophan through the blood/brain barrier, a diet low in glucose could reduce the brains ability to produce its own serotonin, thus helping to reduce serotonin in the synapses and potentially assisting in 5ht1a recovery.
So I guess this was more of a ramble than a set of questions but I’d be interested to know your take in the above thoughts.
There isn’t much research on upregulating 5-HT1A unfortunately. I linked all of the research I could find.
I don’t think PSSD is only due to serotonin or more specifically 5-HT1A. The opioid, endocannabinoid and dopamine system also plays a big role. Potentially the glutamate and adrenergic system as well.
is this protocol have a time limit? or is the expectation to take it forever? or can one stop once symptoms change?
There is no time limit since everyone responds differently. Some make progress quickly, whereas others don’t.
What are your thoughts on this.. the only window I have had was with wellbutrin similarly to how you mentioned the cyproheptadine effect. I felt worse on days I took it but when tapering on days I didn’t take it I had a rebound effect and was better. This lasted about a month after stopping then I returned back to pssd. I think wellbutrin desensitizes 5ht1a though doesn’t it? Hoping you can shed some light on it
It might upregulate the dopamine receptor long term.
Hi hans, Will microdosing with an ssri like prozac reverse this condition?
That’s a good question that I don’t know. Worth a try.
Hey Hans, beautiful Article.
Thanks so much for you help. I have ashwa induced pssd anduse 4g maca about 800mg sjw and cbg. When I started cbg i finally got more libido and sexual arousment, but still ED. Ive heard tongkat ali and fadogia agrestis are good „cures“ as it boost testosteron.
But i will attack pssd with your takes now.
I can just say CBG brought back my arousal but im starting to cycle it due to your article.
I would like to thank you for your work. Really helps a lot of people.
Thanks for the feedback, much appreciated!
Hi Hans, another fantastic & informative article. Please keep them coming.
Should taurine supplementation also be avoided as it has 5-HT1A agonistic properties?
I’d say no, but it depends on what it is.