When it comes to SSRI-induced sexual dysfunction, the 5-HT1A serotonin receptor appears to be the most important modulator of sexual function.

Not everyone suffers from sexual dysfunction on anti-depressants and not everyone develops PSSD after quitting.

One of the main reasons is because of the variety of anti-depressant drugs out there.

Here is an example of different drugs and their effect on sexual function (top of the list is the least inhibitory and they get more inhibitory down the list).

SSRI drugs induce an increase in serotonin. Serotonin acts on its receptors, one being 5-HT1A.

5-HT1A is expressed presynaptically and post-synaptically. Pre-synaptically, it inhibits the release of serotonin, as it acts as the brake. Post-synaptic activation of 5-HT1A (heteroreceptors) modulates glutamate, GABA, oxytocin, dopamine, noradrenaline, etc., neurotransmission.

Some SSRI drugs desensitize the autoreceptor, whereas others inhibit both the autoreceptor and the post-synaptic receptors, whereas others desensitizes the autoreceptors and sensitizes the post-synaptic receptors.

This might make your head spin a little, but studies actually found that both activation of the pre and postsynaptic 5-HT1A receptor enhances sexual function.

When SSRI drugs desensitize both pre and postsynaptic 5-HT1A receptors, then you’re much more likely to suffer from sexual dysfunction.

Just some examples from the list above, the drugs (citalopram, venlafaxine (suppresses oxytocin release) (R), fluoxetine (R), paroxetine (R)) that were most likely to inhibit sexual function are those that desensitize the 5-HT1A receptor.

Those at the top of the list are either 5-HT1A agonists or doesn’t even affect 5-HT1A levels.

So here are a few tips to improve sexual function.

#1 Switch meds

If you’re having sexual dysfunction from the drug you’re on, then try to convince your doctor to switch you to one of the lesser problematic ones, such as mirtazapine, mianserin, bupropion or agomelatine.

Studies show that adding in or switch to an anti-serotonergic and dopaminergic drug, such as mianserin and bupropion improves PSSD (R).

This study found that: “low dose mianserin (7.5-15 mg/day) improved PSSD. Fifteen of the 17 patients (88%) included in this study reported improvement in sexual dysfunction following this intervention. Ten (59%) reported that sexual function achieved pretreatment level. Five (29%) reported “significant improvement,” and two (12%) did not respond to this intervention.”

Bupropion and adamantane derivatives, such as amantadine are also a good options.

Bupropion is the most widely used AD due to its positive performance in numerous trials in the United States [100]. It leads to the release of dopamine and noradrenaline without affecting serotonin. The incidence of TESD [treatment emergent sexual dysfunction] in patients treated with bupropion is similar to placebo, and in certain cases bupropion can even improve sexual functioning compared to previous levels, improving sexual desire.

Reference

This study found that both bupropion and amantadine are effective at relieving PSSD symptoms. Bupropion was more effective when both drugs were compared at 200mg doses daily (R).

#2 Resensitize the 5-HT1A receptor

If switching meds helps, but not completely, then focus on resensitizing the 5-HT1A receptor.

It can be done with:

• Yokukansan 
• Lithium (R)
• Shuyu (R)
• Rhodiola Rosea (R)
• Butyrate (R)
• Ginkgo Biloba (R)
• Cannabigerol (CBG) (R).
• It’s a 5-HT1A antagonist and can theoretically upregulate 5-HT1A sensitivity.
• St Johns Wort (R).

A word on the extract of St John’s Wort

The researchers used the LI 160 extract, which contains 7.0 mg hyperforin (2.3%), 0.45 mg total hypericin (0.15%), 16.16 mg total flavonoids (5.4%) per cap.

The standard extracts contain 0.3% hypericin with unknown, but still high hyperforin.

 The ZE117 extract contains up to 0.3% hypericin and low amounts of hyperforin (≤ 0.2%).

Effects of hyperforin

• Inhibits synaptosomal uptake of glutamate and GABA. Glutamate firing is elevated in sexual dysfunction and GABA agonists, such as allopregnanolone might be elevated in PSSD.
• The ZE117 extract inhibits the reuptake of both noradrenaline and serotonin, which is due to the oligomeric procyanidines (OPC) content and not hyperforin. Hyperforin appears to have a much stronger inhibitory effect than OPC (R).
• Effect on 5-HT2A.
  • This study found that hyperforin doesn’t upregulate 5-HT2 receptors and can even downregulate it. A recent study showed that the xanthones in the extract induce the upregulation of 5-HT2 receptors. However, this study found that the LI 160 extract (high in hyperforin) significantly up-regulated the 5-HT2 receptors in the frontal cortex (R).
  • Hyperforin may contribute to the facilitatory effect of LI 160 on dopamine function, but hypericin does not (R). This is either through the 5-HT1A or 2A receptor since both are linked to the dopamine D2 receptor, but it’s most likely the 5-HT2A.
  • LI 160, hypericin and hyperforin significantly and equivalently increased plasma corticosterone. This effect was blocked by ketanserin (5-HT2A and 2C antagonist) but not WAY-100635 (5-HT1A antagonist), suggesting mediation via 5-HT2 receptors (R).
  • So in conclusion, hyperforin most likely upregulates 5-HT2A or at least signal through it.
• Hyperforin has a half-life of 9 hours.

Effects of hypericin

• Hypericin has a modest affinity for sigma receptors.
• Antagonizes the NMDA receptors (anti-glutaminergic effect) which is the opposite to hyperforin.
• Hypericum (500mg/kg) and hypericin (0.2mg/kg) given daily by food for 8 weeks significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 16-22% in the hypothalamic paraventricular nucleus (PVN) and serotonin 5-HT1A receptor mRNA by 11-17% in the hippocampus. The stress-induced decrease in 5-HT1A was not prevented by Hypericum or hypericin (R).
•  The ZE117 extract, low in hyperforin, inhibits the uptake of noradrenaline, dopamine and serotonin at potencies of 30, 7 and 1, respectively (R).
• Hypericin has an approximate half-life of 25 hours.

It might be that neither hyperforin nor hypericin is able to increase 5-HT1A, but rather the OPC, xanthones, or flavonoids in St Johns Wort. When the extracts contain a higher concentration of flavonoids the effects are more widespread and involve brain regions such as diencephalon and brainstem that are implicated in depression (R).

#3 Optimize dopamine

Dopaminegic drugs are known to enhance libido (in some cases make people hypersexual) and cause spontaneous erections and even priapism (long (>4h) and painful boners without stimulation).

Cabergoline, a known D2/D3 agonist and also lesser known 5-HT1A, 5-HT2A, 2B and alpha 2 adrenergic receptor agonist and alpha 1 adrenoreceptor antagonism, can induce hypersexuality.

Bromocriptine, a D2/D3, 5-HT1A, 2A and alpha-adrenergic receptor agonist induce spontaneous erections and also improves sexual function.

Rotigotine, another potent dopamine agonist, also with 5-HT1A and alpha 2 adrenergic receptor agonistic and alpha 1 adrenoreceptor antagonistic properties, can also induce priapism and hypersexuality.

Although the D2 receptor family seems to be responsible for most of the behavioral effects of dopamine (libido), D1 receptors also may play a role in sexual response (erections).

Apomorphine, another dopamine D1/D2/D3 agonist and 5-HT2A, 2B, 2C and alpha 2 adrenergic receptor antagonist, induces spontaneous erections.

So in order to get fantastic erections:

• Increase D1 and D2 receptor expression
  • Read here on how to increase dopamine receptors
• Increase dopamine synthesis and levels
  • Read here on how to increase dopamine levels

#4 Try cyproheptadine

It’s been hypothesized that stimulation of 5-HT2A receptors has negative effects on sexual function. Drugs that stimulate 5-HT2 and 3 impairs sexual function in rodents. Furthermore, in humans, antidepressant drugs that increase serotonin signaling (e.g. SSRIs) in the absence of 5-HT2A antagonism are commonly associated with sexual side effects while agents which possess 5-HT2A antagonist activity (e.g. mirtazapine and nefazodone) have a relatively low likelihood of inducing sexual side effects (R).

Interestingly, St John’s Wort that increases 5-HT2A density doesn’t seem to negatively affect libido and erections (depending on the extract ofc) and this could be that St John’s Wort stimulates D2 activity through 5-HT2A signaling.

There are a few reports of people who started experiencing mania from St John’s Wort, where they experience lots of energy, little need for sleep, irritation, agitation, talking confusion, being delusional (e.g. need to drive around the city after midnight to buy a cat), hypersexual, anxiety, etc (R, R).

Stopping the St John’s Wort and starting lithium helped to reverse these incidents. Feeling anxious, jittery, afraid, fearful, jumpy, etc., are not good and are most likely because of an excess in serotonin and 5-HT2A signaling.

But back to cyproheptadine. Cyproheptadine is a broad anti-serotonergic drug (an antagonist to 5-HT1A, 2A, 2B, 2C, 3, 6 and 7). There are a few reports where people improved their sexual function with cypro while on antidepressants or after quitting antidepressants. Typical doses are between 4 to 12 mg before sexual intercourse (R).

However, cyproheptadine is also somewhat of a decent dopaminergic antagonist, which could theoretically upregulate dopamine receptors. So it doesn’t make a lot of sense to take cypro before intercourse but rather a few days before, so that you get more 5-HT1A and D1, D2 and D3 density in the rebound.

#5 Increase liver detoxification enzymes

Individuals with reduced CYP2D6 and CYP2C19 activity in the liver are considered “poor metabolizers” and therefore more likely to experience sexual side effects from SSRIs (R).

The Chinese herb mix called Buchang NaoXinTong, are able to increase CYP3A4, CYP2D6 and CYP2C19 through activation of the pregnane X receptor (R).

BuChang NaoXinTong is composed of powder from 16 medicinal herbs or animal powders.

St John’s Wort and Artemisinin are also able to increase CYP2C19 (R).

#6 Rosa Damascena oil

Rosa damascena oil, in 2ml doses daily, has been shown to reduce PSSD symptoms after 8 weeks (R). No mechanism is known atm.

#7 Saffron

Saffron has been shown to help against PSSD (R).

Saffron, specifically the aqueous extract, dose-dependently increases dopamine in the brain without affecting brain serotonin or norepinephrine concentration. It also appears to affect the opioid system, modulate glutamate neurotransmission and reduce the stress-induced increase in cortisol (R). Much more research on this chemical and its effect on neurotransmitters is required, but it does look very promising and beneficial.

The water extract has been shown to improve libido and erectile function (R, R).

#8 Chai Hu Long Gu Mu Li Wan

7.5g of Chai Hu Long Gu Mu Li Wan (a.k.a. Saikokaryukotsuboreito) has been shown to reverse antipsychotic-induced sexual dysfunction (R). Not the same as PSSD, but it still involves the serotonergic and dopaminergic system, so it might be helpful nonetheless.

This herbal combination has been shown to:

• Increase dopamine
• Inhibit excess glutamate release in the hippocampus
• Normalize the HPA axis
• Normalize the glutamate system (R)
• Increase hippocampal BDNF (R)

#9 EDOVIS

According to this case study, a guy with PSSD used the product EDOVIS, (a dietary supplement containing L-Citrulline, Tribulus Terrestris, Peruvian maca, turnera diffusa (damiana), Muira Pauma, and folic acid) and cured his PSSD (R).

#10 Learn more deeply about sexual function

If you’re struggling to recover, then looking at all avenues that might be hindering your progress is a good idea.

Previous articles I wrote that covers similar topics include:

• PSSD: the why and the how to fix it
• Erectile dysfunction part 1: your neurotransmitters
• Erectile dysfunction part 2: your hormones
• Erectile dysfunction part 3: nitric oxide, oxidative stress and insulin resistance
• Erectile dysfunction part 4: effective supplements
• Erectile dysfunction part 5: porn and masturbation
• Top 5 libido-boosting fundamentals