A 2016 RxISK post discussing how common post-ssri sexual dysfunction (PSSD) might be, highlighted Colpi et al., 1991, and Yilmaz et al., 1999 showing fluoxetine and clomipramine, both serotonin reuptake inhibitors, reduce genital sensation.
These studies feature in our 2018 paper: Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases.
In both studies, a small electric current was used as the stimulus, increased in intensity until subjects could feel it. This established their penile sensory threshold. This was Quantitative Sensory Threshold testing (QST). Not to be confused with nerve conduction testing.
Genital numbness can confuse. Some people figure they have PSSD but not genital numbness.
PSSD sufferers can be shown to have reduced genital touch, vibration, and temperature sensation. This may vary from not obvious for some, while others may feel like a local anesthetic – lidocaine – has been applied.
There is also reduced erogenous or sexual sensation. Sufferers can feel their genitals being physically touched, but it doesn’t feel sexual, or not as much. Similar to being touched on an arm.
Nobody knew how these two touches fit together when it comes to PSSD, but a recent PIEZO-2 paper – see below – suggests the same sensory receptors mediate both sensations, but in the genital area these receptors are much more sensitive than elsewhere – like the heightened sensitivity psychedelics give to vision and hearing and SSRIs obliterate.
We’ll only know if PSSD sufferers have reductions in both erogenous and ordinary touch if we can test them accurately. When creating the diagnostic criteria, we stated that a reduction in either type of sensation met the criteria.
Von Frey filaments
Several years ago, one of our team flagged up von Frey filaments as the best method of testing genital sensation in PSSD. These are a set of plastic monofilaments of different strengths. The filaments bend when pushed against skin with each one producing its own amount of pressure. The tip of each is pushed against the skin in turn until you can feel it – this marks your sensory threshold.
Von Frey filaments used to be part of QST tests. Von Freys are easily done by hand – no machines are needed. As we had some positive results with Von Freys, we wrote a post highly recommending getting QST tests done – Sex and Thresholds. People paid heed but the reports we had back was that QST showed no abnormality.
We now know why.
If we have sensory issues suggestive of Small Fibre Neuropathy now, clinics send us for QST testing. A probe is strapped to hands and feet which produces hot and cold temperatures and possibly vibrations. You are asked if you can feel it. Saying you can is regarded as evidence that you don’t have any sensory impairment.
But hands and feet do not have the exquisitely sensitive genital receptors. And machine tests aren’t good at capturing thresholds – the exact point at which you begin to feel a sensation.
Von Frey (photo of Max VF) filaments are better at finding a sensory threshold than QST machines and can be used genitally.
We tried to find somewhere that did old style Von Frey testing, even going to the person who invented QST Testing, but we found neurologists regard the idea of thresholds as too subjective. They prefer testing with machines and evidence of gross defects.
Several years ago we had a full-scale war with Impeto Medical, a Parisian company, who make a QST machine and even a genital adapter – which would likely have worked as the genital defects in PSSD are so gross. But they shockingly refused to engage. The company has since changed hands. See Device Wrecks and Business Opportunity.
Bear in mind the PSSD landscape was very different just a few years ago. There were no warnings in drug labels and the medical literature was limited. Using Von Frey filaments on genitals to look for PSSD seemed a step too far.
A new study in Science has shown genital sensation is almost missing in mice who lack PIEZO-2 receptors. PIEZO-2 is a mechanosensitive ion channel. RxISK has mentioned PIEZO-2 before but the Science article really brings it into focus.
The authors used Von Frey filaments to test the perineum in mice. They showed that the SSRI-like numbing that the local anaesthetic lidocaine produces has the same effect on Von Frey testing as missing PIEZO-2 receptors has.
They also tested several people born with PIEZO-2-deficiency. Table S1B on This Page suggests these people have a genital sensory loss and sexual impairment that overlaps with PSSD.
PIEZO-2 deficiency cases and PSSD are genital neuropathies. Even if the core genital and sexual issues in PSSD are linked to PIEZO-2, this is consistent with PSSD also being a peripheral neuropathy, or more precisely a sensory neuropathy.
Some folk with PSSD have almost exclusively genital abnormalities while others have features around their body and even in their visual and balance systems and emotional numbing more generally suggests a lot of abnormalities beyond the genital area. PIEZO proteins are plentiful in eyes, bladders and gut for instance.
The Science investigators could only use Von Frey filaments on one man whose:
Penile Von Frey detection threshold (3.1 ± 1.5 g) was far higher than values reported in the literature:0.3 to 0.6 g in a similar location (22).
He had difficulty detecting pressure below 1 kg/cm2 at the midshaft and was insensitive to strong vibration at 50 and100Hz, which is consistent with our findings in mice. By contrast, literature values for penile fine-touch pressure thresholds in a range of healthy men are far lower (23), and vibration is normally readily detected (23).
Ref 22 Morris et al is here.
Ref 23 Bleustein et al is here.
This gives us ways forward. RxISK has a group of PSSD volunteers getting tested on a peripheral neuropathy test battery – QST, CCM, biopsy etc. We will soon know whether there are some abnormalities on these standard tests.
The problem with peripheral neuropathies is that in the very best clinics patients with undoubted peripheral neuropathies may or may not be positive on biopsy, may or may not be positive on interview for standard signs and symptoms, and may or may not be positive on antibody testing, and if positive on one of these may be negative on the others. You’d expect this if there are several different neuropathies – some sensory, some not, for instance.
Research labs usually have to stick to research protocols and if the research protocol didn’t say you can also test genitals, they can’t do it.
So the plan is to get our current volunteers tested privately using Von Frey Filaments.
You can help.
Googling Von Frey Filaments will tell you a lot about mice and rats. Googling Von Frey Testing in Humans brings up machines that can cost up to $500 all the way down to build one at home for $5.
One. Check whether any neurology department near you still has Von Frey Filaments. Get a referral. Bring the attached articles for the staff there. Check your results against the reference range. We are compiling one and can make it available.
Consider bringing them a VFF set if they don’t already have one.
Two. Buy your own machine. Test yourself and some age and sex matched controls (friends), making sure you are all drug free, and its done at the same time of day and you control for underwear – See Penile Control Factors here. What you can’t control for is when you last made love.
Three. We need women to investigate Von Frey Testing of the genital and perineal area. It is easy to find articles testing men with premature ejaculation or who have been circumcised. There are fewer on women. The Science article suggests female mice have more sensitive PIEZO-2 systems than male mice.
The Clitoris is rich in PIEZO-2 protein and even before the Science article, a group of Spanish women linked PIEZO-2 to sexual sensation. (Must be something in the air in Spain these days).
Four. If you have post-finasteride or post-isotretinoin syndromes – it would be really compelling if it turns out there are the same abnormalities across all these conditions.
Five: If you have PGAD or related conditions, we will be liaising with researchers in these areas and will be happy to share anything we can find about testing – although in general it seems that women with PGAD do not meet the same indifference or hostility in Gyne or Pain clinics that both women and men with PSSD face.
If you have any theories about why these seemingly mirror image conditions get treated so differently, let us know.
If anyone gets any kind of test results – please let us know. If there are any hints of something useful, we will make our anonymised findings publicly available as they come in. There will be no waiting to write up an article and get it published. This will give others something to take to clinics and a reference range for test results.
If there is nothing useful, we will also make that clear to avoid people wasting their time.
The goal is to get a test that demonstrates a ‘real’ drug induced problem and not some mental problem stemming for instance from forgotten abuse in childhood.
If PIEZO-2 looks like it is involved, RxISK will repurpose the RxISK Prize money for Luisa Guerrini’s research on the effects of SSRIs on p 63 regulatory proteins. It is already known that SSRIs affect the p63 system and that p63 regulates PIEZO-1 receptors.
When we say repurpose Prize money to support Luisa’s research and other pertinent research, this will mean emailing everyone who has contributed to the RxISK Prize and asking them if they are willing to add the Prize Fund to the Research Fund given how close to The Holy Grail we now seem to be.
You can also help by donating to our PSSD Research Fund.
Finding what has broken is important. The way out of a problem is often not to retrace the way in and this is clearly true of PSSD. So the hunt for a nerve regeneration treatment needs to go on.
Research on p63 is important in this respect also as this is just the kind of mechanism that might be acting as a gateway to nerve regeneration. We need to find whether drugs like benztropine and bethanecol have effects on this or other regulatory proteins.
Like ACT-UP in the 1980s, this is Guerilla research with the ideas and the money coming from those affected and the resistance coming from the establishment – regulators, professional bodies and others.