21+ Fixes For Post-SSRIs Sexual Dysfunction (PSSD) - With Mechanisms And Genetics

21+ Fixes For Post-SSRIs Sexual Dysfunction (PSSD) - With Mechanisms And Genetics

In this post, we will discuss Post-Selective Serotonin Reuptake Inhibitors (SSRIs) Sexual Dysfunction (PSSD), its mechanisms, and possible fixes to help PSSD sufferers.

pssd post ssri sexual dysfunction.jpg

Basics of PSSD

In the last two decades, much progress has been made in the neurobiological, pharmacological and neuroimaging research of sexual dysfunctions. R

Post-SSRI-Sexual-Dysfunction (PSSD) is a fairly new, unexplored and underdiagnosed iatrogenic condition, that arises for individuals following the use of antidepressant medication. R

The symptoms of PSSD can start days or weeks after beginning SSRIs and can persist after discontinuing SSRIs. R

In fact, PSSD also can present after a single dose of an antidepressant. R

PSSD can affect both men and women. R

SSRIs can cause long‐term effects on all aspects of the sexual response cycle that may persist after they are discontinued. R


Symptoms of PSSD

Common PSSD symptoms include: R R

  • Decreased sex drive

  • Erectile dysfunction

  • Genital anaesthesia (decrease in sensation and numbness in the genital area)

  • Pleasure-less or weak orgasm

  • Premature ejaculation

  • Vaginal dryness/pain (n = 9), and reduced nipple sensitivity

Neurotransmitter Signalling & PSSD Pathology

Different theories have been proposed to explain the pathophysiology of PSSD: R

  • Cytochrome actions

  • Dopamine-serotonin interactions

  • Downregulation of 5HT1A

  • Epigenetic gene expression

  • Hormonal changes in the central and peripheral nervous systems

  • Proopiomelanocortin (POMC) and Melanocortin effects

  • Serotonin neurotoxicity

Sexual behavior is impaired by many 5-HT agonists and agents that increase 5-HT. R

Serotonin (5-HT) is primarily inhibitory, although stimulation of 5- HT2C receptors increases erections and inhibits ejaculation, whereas stimulation of 5-HT1A receptors has the opposite effects like facilitation of ejaculation and, in some circumstances, inhibition of erection. R

Post-Synaptic 5-HT1A activation may cause sexual dysfunction. R

Stimulation of other 5-HT2 receptors hypothetically mediates several of the side effects of the SSRIs sexual dysfunction. R

Excessive release of serotonin (which has a mixed but essentially inhibitory role on sexual functions) by the serotonergic neurons (concentrated in the raphe nuclei of the midbrain) causes "desensitization" of 5-HT1A autoreceptors (that act as sentinels that regulate the release of a substance according on how much there is already in circulation). R

The "down-regulation" of the 5-HT1A autoreceptors is instead caused by chronic and excessive activation by its natural "agonist" (serotonin) that is made available in abnormal quantities by the use of SSRIs. R

It is therefore natural to think to the autoreceptors as something that is "damaged" by excessive competition and that can be cured using an antagonist that lead the person to be again "sensitive." R

For example, when rodents were administered an SSRI medication, they noted a sustained desensitisation of 5-HT1A receptors after removal of the drug. R

In another study, a 5-HT1A antagonist was shown to reverse and prevent sexual dysfunction in rodents that were being administered with fluoxetine. R

However, PSSD sufferers through online support forums have tried and reported on the effects of all combinations of medicines acting on serotonin and dopamine systems, and medicines known to enhance functionality (ie sildenafil), are without benefit. R

It is also hypothesized that SSRI treatment induces disturbances of Transient Receptor Potential (TRP) ion channels of mechano-, thermo- and chemosensitive nerve endings and receptors resulting in the penile anesthesia in PSSD. R

Downsides of PSSD

Some downsides of PSSD are:

  • Impacts relationships R

  • Reduced enjoyment of sexual activity R

  • Severe reduction of quality of life R

User Experiences

“I first took citalopram in November 2007, at the age of 22. I had quite bad OCD and because there was a long wait to try CBT, I was persuaded to try citalopram to treat my OCD.

Initially it made me feel a bit sick, but the most noticeable thing was it completely abolished my sex drive. I simply stopped thinking about, desiring, or fantasising about sex in any way. When I had an orgasm, it was nearly pleasure-less, and my penis felt anaesthetised.

I thought this was odd, but when I asked my then GP he told me that sexual dysfunction was a common side effect of taking SSRI antidepressants, and I assumed it would return to normal when I stopped taking the drug.” R

PSSD Fixes



  • Cognitive Behavioral Therapy (CBT) R




  • Bupropion/Wellbutrin R

  • Buspirone R

  • Cyproheptadine R

  • Donepezil R

  • Ketamine R

  • Loratadine R

  • Metformin R

  • Mirtazapine R

  • Nefazodone R

  • Sildenafil R

  • Trazodone R

Things To Avoid

  • Antidepressant medications that possess SSRI, SNRI properties R

  • Ashwagandha R

  • Berberine can worsen symptoms via acting on the 5-HT1A receptor R

  • Ginseng may worsen symptoms for PSSD users, since it may act as a mild SNRI R

  • Herbal 5-HT1a partial agonists such as Ginger R

Testing and Biomarkers

Some labs will be posted in future post.

Labs and tests can be ordered here.



  • 12.12-repeat 5-HTT VNTR and GG of HTR1A+272G>A showed the highest HAMD-17 Scale percentage reduction during the study period and a better treatment response status after 4 weeks. R

  • "Our data suggest that an enhanced capacity of HTR1B or HTR1A transcriptional activity may impair desensitization of the autoreceptors during SSRI treatment." R

Other Genes

  • SLC6A4, HTR1A and MAO-A seem to be involved in the response to fluoxetine, while the genes COMT, CRHR1, PDEA1, PDEA11 GSK3B and serpin-1 also seem to play a role. R

More Research

  • If PSSD is hypothesized to be a result of decreased 5HT1A Autoreceptor Density in the Raphe Nuclei, it may be fair to assume that this is a result of altered gene expression. Alterations in Methylation of receptor sites of 5HT1A cells may be a be leading pathogenic role. R

  • “Chronic mild stress and antidepressant treatment alter 5-HT1A receptor expression by modifying DNA methylation of a conserved Sp4 site.” R

  • “Epigenetic modifications such as histone modification or DNA methylation can induce long lasting changes in gene expression that could explain the persistent and relapsing nature of depression and the need for chronic drug treatment.” R

  • It also told us what we already know: “Similarly, an increase in raphe 5-HT1A autoreceptor levels is expected to decrease serotonergic activity throughout the brain

  • “DNA methylation is a dynamic and tissue-specific event that could play an important role in the persistent and relapsing nature of depression.” R

  • “Although stress and imipramine both increase 5-HT1A expression, they may up-regulate different 5-HT1A populations.” R

  • “Epigenetic modifications can induce long-lasting changes in gene expression and mediate the emergence of persistent behavioral phenotypes.” R