PSSD: the microbiome-brain-genital connection

Antidepressants have significant antibacterial activity and they can affect the microbiome negatively as well as cause the gut walls to become leaky, leading to toxin build up in the blood, subsequent activation of the microglia in the brain and leading to prostate and sexual symptoms. I'll discuss this in-depth in this article so without further ado.

It all begins in the gut

Antidepressants have shown time and again in scientific studies that they possess significant antibacterial effects [1,2,3,4]. This has dire consequences for gut microbiome as a significant reduction in bacterial viability was observed [4].

The gut microbiome is home to an enormous and complex community of commensal bacteria and these microbes' communities influence all systems of the body directly or indirectly including, but not limited to, the brain [5], the prostate [6], the sexual pathways [7], and emotional pathways [8].

Not only that, but it was found that those treated with SSRI's exhibited an increased permeability in the ileum, a condition called leaky gut [9].

Let's talk about gut junctions

The gut wall is held together by adjacent intestinal cells through tight junctions that are essential to the function of the physical intestinal barrier, regulating the paracellular movement of various substances including ions, solutes, and water across the intestinal epithelium [10]. When those tight junctions malfunction, the gut start leaking its contents to the surrounding blood vascularity, leading to build up of toxins (lipopolysaccharide - LPS) from gram-negative bacteria [11].

Leaky gut is very problematic and causes a plethora of symptoms. This is because the toxin build up leads to systemic low-grade inflammation affecting the whole body. Symptoms include major depressive disorder, chronic fatigue, bodily aches, joint pain, chronic prostatitis, autoimmune diseases, and many, many more [11, 12].

PSSD: the microbiome-brain connection

Perhaps the gut microbiome and leaky gut can explain some symptoms of post-SSRI sexual dysfunction (PSSD). When the gut microbiome is altered in favor of gram-negative bacteria as with seen with many antibiotics [13], combined with a leaky gut, this leads to elevation of toxin level in the blood. Antidepressants can single-handedly lead to this outcome as previously described [4,9].

The most dire consequence of this is perhaps the consequent activation of the microglia [14]. The microglia are the representative of immune cells in the relatively immune-privileged central nervous system (CNS) and account for 10% of the total glial cell population in the brain. The microglia has two phenotypes it can exist in: the resting state and the activated or reactive state [15].

When toxins in form of lipopolysaccharide/LPS become elevated within the brain, the microglia switch to its reactive state which is detrimental and pro-inflammatory. This leads to elevation of cytokines and excessive release of glutamate within the CNS [16, 17].

Here's the problem: certain cytokines, which are elevated, act as potent dopamine antagonists [18,19,20], and they raise glutamate even more [19]. This leads to symptoms such as brain fog, memory loss, blunted affect, anhedonia, depression, derealization, depersonalization, brain zaps, loss of libido, erectile dysfunction, genital numbness, and blunted orgasms -- sounds familiar?

Not only this, but the blockade of dopamine receptors and the heightened tonic glutamate firing cannot be corrected by simple supplements or drugs as long as the LPS toxins are elevated in the brain. Anti-inflammatory drugs or gut repairing interventions are needed [21].

PSSD: the microbiome-genital connection

I have discussed how cytokines act as potent dopamine antagonists. This effect includes the hypothalamus so it naturally affects sexual functions. However, there is a more direct way the microbiome affects sexual functions which is through acting directly on the prostate gland.

Intimately involved indeed

One thing that bothers me greatly is how people often overlook the role of the prostate gland in sexual health and in these post-drug syndromes. The prostate gland is a sexual organ.

The prostate gland plays a direct role in erectile function. One only needs to read research studies on patients undergoing prostatectomy (surgical removal of the prostate) to know how intimately involved the prostate gland is in sexual functions.

Patients who have undergone prostatectomy experience the following: erectile dysfunction, loss of libido, weak orgasms and genital numbness [22,23,24] - does that sound familiar?

Here's the problem: when there is leaky gut and microbiome dysbiosis after antidepressant intake, elevated LPS/toxins in the blood lead to chronic prostatitis which can lead to the aforementioned symptoms as well as premature ejaculation [25].

Finally, PSSD: the microbiome-neurotrophy-neuroplasticity connection

Those of you following me on my server know how highly I think neurotrophy plays a role in PSSD. The gut-brain axis also involves BDNF, NMDA receptors as these are believed to be involved in synaptic plasticity and cognitive function. Let me quote the study directly this time [26]:

In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain.

It is very important to realize the importance of this quote. Low NMDA receptor count can lead to symptoms similar to the negative symptoms of schizophrenia, which is exactly what this study is alluding to. Negative symptoms of schizophrenia include blunted affect, anhedonia, apathy, brain fog, and lack of concentration [27].

How to fix this mess?

Let me tell you this right away: if you have a leaky gut, then I don't think even a fecal microbiome transplant (FMT) would help you. You must focus on repairing your gut wall and tight junctions first. This is done by increasing intestinal alkaline phosphatase (IAP).

Intestinal alkaline phosphatase (IAP) plays many roles it would require another article to list them all but most importantly: it plays a pivotal role in maintaining the tight junctions holding the gut together [28] and directly influencing the gut microbiome in a positive direction [29].


I'm learning every day of new methods to increase or upregulate IAP. After coming to the conclusion that microbiome dysbiosis might be more involved in PSSD than we give it credit for, I've started including gut altering interventions during patients' consultations depending on symptoms and how far the patient wants to target this (i.e. water fasting, FMT, etc). It's extremely important for you as a PSSD sufferer to know how intimately your gut microbiome is involved in all of this and to take steps in the right direction in order to correct this malfunction.

Thanks for reading!