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?
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.
PIEZO-2
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.
Guerilla research
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.
All:
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.
Mission
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.
Daniel says
To be honest i think that we have some reasons we might be skeptical,:first of all , if such a project fails to lead to a cure we may then have lost the hope of generating interest from people willing to claim the price. Secondly how do we know we really are close to a cure? Should not we wait until we have had some success with the drugs that seem to be much of the underlying cause for your enthusiasm , so that we have proof that we are on the right track? Thirdly:What if it is not merely enthusiasm but overenthusiasm : you have made statements roughly like (i could not find the exact qoute) “we may be close to a cure” and “looking into these biological systems could revolutionize medicine or lead to the next nobel prize ”
Your blog posts dont quite explain explicitly how knowledge on the role of p 63 regulatory proteins could lead to a cure!
Dr. David Healy says
These are all good points and you may well be right. A cure could appear out of the blue – something for some reason just happens to work. But we are better placed if we identify where the problem lies and at the moment PIEZO-2 looks like a good candidate.
In addition if Von Frey testing picks up an abnormality, it will stop doctors detained people for their crazy ideas, it will force FDA to put warnings on the drugs, it will stop psychotherapists telling people they are the way they are because they were abused in childhood but can’t remember it – it will stop primary care doctors laughing at people when they try to raise this problem. Stopping all this will reduce suicides – it will save lives.
Then the search to work out how SSRIs may damage the PIEZO system can get going – we know SSRIs affect p63 and p-63 helps regulate PIEZO proteins.
But we have to wait and see – we need to test people first and if nothing shows there will be no rush to move the Prize money
David
Chris says
It is totally worth doing, never thought I’d beat akathisia or migraine but I got there.
LL says
How did you beat akathisia and migraine? Did you have vertigo symptoms too? I have all of these.
zach says
Most of your points are ok but pls dont think that some 100K price will drive any researcher.. With 100K you get nothing done…
Dr. David Healy says
Zach
I agree but we are not talking about funding research. The idea was that there is a good chance that someone out there has the answer but doesn’t know there is a problem they have the answer to. So if they already have the answer 100 K might look very appealing.
Perhaps we should have introduced a finder’s fee also – something to incentivize you and Daniel to go hunting. There are thousands of people with PSSD who should have the motivation to look anyway – to approach researchers and dangle 100 K in front of them and say Hey guys… but it doesn’t seem to be working that way. How much of a finders fee would you or Daniel need to get motivatted and start tracking down people who might have an answer.
David
Daniel says
Is the idea behind trying to understand which biological systems are involved that you would find out receptors that could be affected by drugs? It sounds then superficially to me, that if testing of ones von frey filaments could be done as affordably as you have stated and at home, then it could be done repeatedly at home during various experimental treatments, to see if the measured values changes. 100 000 dollars does not grow on trees. The relevance of studying these various biological systems in animal models should be contingent on what we find from experimental treatments i figure, one should not throw such expense at an early stage of knowledge of the condition i think. Desperate people have given their money under the promise that it will attempt to make a cure a reality, it will not be fair to us to use it for work that is quite removed from bringing about a cure .In order to motivate research on these systems from a pssd-treatment point of view one has to resort to indirect and theoretical arguments about what it will say about which treatments might have effect, it will be far a more direct way to try medication regimens directly and measure the results i figure. Are there treatments that affect the piezo system that people could try? At any rate i belive that chances are that if you want to have the funds to study PIEZO-2 or whatever, then people might contribute to that separately if you make a new push to help fill up the research fund!
By the way, do you have any thoghts on systems involved in the brain fog or anhedonia often associated with pssd?
Dr. David Healy says
Again all good points that need to be taken into consideration. The Prize wasn’t just for a cure – it was for a substantial contribution. In the absence of evidence it is stimulating research or people who have done research to get in touch and show how what they have done has produced a cure or brought us to the edge of a cure – how long do you think it should just be let sit there.
We have had lots more people complain to us that we are just letting it sit there and not put it to a good use. One of the things that could make a difference is if you and others with PSSD do the reaching out to researchers doing work that might be relevant to draw their attention to the prize. There are thousands of people with PSSD – between you all you could do a lot to raise the profile of PSSD and the need to find a cure by dangling the Prize money in front of academics and the media – so what are you doing?
Re Brain Fog – there is a RxISK post dedicated to Brain Fog a few months back. Might be worth reading
D
Re Brain
zach says
Just out of curiosity, if the piezo channels are in cell membrane how does that relate to the actual density loss of fibers in SFN. More specifically, are the fibers basically axons not membranes?
All in all the piezo thing sounds possibly very relevant as it may be very fragile in some people (genetically) but the actual loss of fibers is even more “brutal” damage or loss of the cells.
So possibly these are two things present or stages of cell damage based on the severity?
Perhaps the ion channel damage leads to death of the cell or axon/fiber?
Evidently something equally fragile resides also in CNS/brain and they get harmed because of the same insult, because people have very radical mental and emotional symptoms too.
For autonomic system this seems very plausible and in my view clear. Numbness in genitals tells that something similar inside the body sensory and control system is damaged too..
Dr. David Healy says
If I knew the answer to these things I’d have collected the Prize long ago.
I don’t think we have to posit anything wrong with the brains of people with PSSD or protracted withdrawal. I know they experience brain fog and emotional numbness but looking at the campaign PSSDnetwork have launched, listening to their podcasts and seeing the thinking that folk with PSSD linked to RxISK have put in which is as good or better an assessment of the science than I have and better writing of posts than mine, I think their brains are working just fine.
David
John says
“I think their brains are working just fine.”
The reasoning for this statement is correct in all aspects. I really want to point at the traumatic aspect of PSSD and Protracted Withdrawal, and the agitation they bring – I DON’T SAY IT’S JUST MENTAL! – Besides the physiological changes that occur,
1. Being put in this situation against your will, without even being aware of what is going to happen to you
2. Being denied the situation you are in by professionals and being ridiculed
3. Absence of any treatment (hopelessness)
4. Reading about hundreds of hopeless people on the internet and RxISK
turn it into a drastic, traumatic experience. My symptoms get worse everytime I read the comments of victims on RxISK.
Now back to the concrete, physiological changes that occur: It is pure bullsh*t how some therapists or psychiatrists point at a potential forgotten trauma in childhood etc. A lot of abuse and rape victims have sexual dysfunction, it’s true. But these are also the people who have been put on SSRI/SNRI for a life time. On what scientific basis do they reject the idea that these pills cause the effect? If I’m not wrong, David talked about this somewhere.
I’ve known a woman and I’ve recently met one my age (I am a male). Both had narcissistic abuse in family. Both have no history of psychotropic use. Both have no sexual dysfunction. On the contrary, I’ve met a young woman and an older one via internet and one other woman in real life, who mentioned having sexual problems themselves after me sharing my story. They were ALL SSRI or SNRI users. They all linked their sexual dysfunction to their trauma and not to the medicines. Now the interesting bit: It didn’t bother them so much.
F*ck these topics. I am going back to my work. I don’t want to identify with this condition anymore.
JC says
Dr. Healy – I’m confused by this post. Dr. Irwin Goldstein diagnosed me with PSSD after doing QST on my genitals, inner thighs, buttocks, and hips. He used a wand that makes very small changes in heat, cold, and vibration, and asked me when I could detect the change. By comparing to reference values, he was able to determine that my whole pelvic area is significantly numb.
I thought this was the standard approach? Why doesn’t everyone just use this type of QST?
JC
Dr. David Healy says
Thanks for these details and great question. Irwin does sexual function. Very few others do. Neurologists don’t. They do peripheral neuropathy but do not test genitals and use a QST machine set to pick up gross defects rather than subtle changes. As far as I know it also needs a genital adapter.
Some Urologists might do QST and its certainly worth checking with them if they do genitals and whether they can monitor for subtle rather than just gross defects. Asking about Von Frey helps bring home the point as to what is needed
What you mention points strongly to the fact that this is the way to go.
D
Vogelweide says
I think it is very likely that PSSD, PFS, and PAS are closely related to Long Covid. I have spoken rather extensively to someone with an almost identical profile of symptoms to me (I’ve had what I’ve long held to be PSSD since stopping a starter dose of Prozac (I took it, very stupidly, to help me get off of Effexor. I didn’t have any idea what PSSD was at the time) in late July or early August 2022.
The thing is, this individual in question never took an SSRI before. These symptoms appeared shortly after he contracted Covid.
Long Covid also seems very similar in many ways to CFS/ME (as do the Post-Drug Syndromes). I believe some with Long Covid have developed PEM as a result of it.
Interestingly enough, apparently the FDA claims that the majority of people with FQAD (aka ‘Floxed’ people) recover from it in around 14 months. I believe that FQAD is likewise related to PSSD. Is it possible that many people recover naturally from PSSD? I think there is a strong argument to be had that perhaps even the majority of people with PSSD do not even know what PSSD is to begin with.
I’ve also noticed that many (most?) with PSSD seem to also have ASD (especially Asperger’s Syndrome) or ADHD. Do you think there is a correlation there? This could perhaps also be why the majority of those with PSSD seem to be male (ASD is apparently 4x more common in males than females). It could also be that PSSD is equally as common amongst both genders, but males are more aware of it.
Dr. David Healy says
These states may all share the fact they are toxic states but that no more makes them all the same than infections all share the fact they are infections but the treatments for a lot of these infections are pretty specific.
Second it simply isn’t the case that a lot of people with PSSD have ASD or ADHD. In the case of America especially and other places probably soon, the chances of having PSSD and ASD or ADHD are high because so many people get labelled with ASD and ADHD – without having a confirmed illness – and as a result get put on cocktails of meds that can cause the problem even if you are the most normal person on earth.
D
Vogelweide says
So basically, despite PFS and PSSD mirroring each other in terms of symptoms, you think they probably have a different cause? Therefore, a cure for PSSD may or may not also be a cure for PFS?
What do you think of this?
https://bornfree.life/understanding-the-model/6/updated-disease-model-wip/45/
This guy in question has researched, in particular, CFS/ME, but claims that syndromes like PSSD, PFS, Long Covid et al. have the same root cause as CFS/ME, but with different catalysts. He has researched this quite a bit, and has various diagrams of the deficiencies seen in these comditions. I’m not sure if you have heard of this person before. Apparently some with CFS/ME also experience sexual symptoms similar to PSSD as well (they appear to be in the minority though).
I’ve spoken to people who claim to experience similar conditions to PSSD or PFS, despite never having taken any SSRIs or Finasteride. This does sort of support the ‘same root cause, different catalyst’ narrative that the bloke I discussed above suggests.
Dr. David Healy says
There are general toxic effects that can produce a range of common symptoms across different conditions. This is why genital numbing is so important. Being able to rub a hard bristled brush up and down your genitals and feel nothing or rub chili paste into them is distinctive and not a feature of post Covid problems but it is a feature common to PSSD, PFS and PRSD – so finding what causes that and might reverse it is likely to offer a solution to all 3 conditions
D
Callum says
Dr Healey I understand you want more people with PSSD to contact researchers and tell them about the prize. I want to do this but I just don’t know where to start? Should I bring literature to a university near me and somehow try and speak to epigenetic researchers? Please let me know how I can do this and I will. I have tracked down some emails off of published articles that cover PSSD and sent them the mock template that you posted on here. We greatly appreciate all the work you’re doing and we all definitely need to push through to scientists that could perhaps provide some input.
Dr. David Healy says
Callum
There is an old phrase – necessity is the mother of invention. Doing something, anything, opens doors as to what else might be worth trying. Doing nothing is a recipte for nothing happening
David
MS says
Could other protracted withdrawal symptoms be related to the same nerve damage causing PSSD? I.e. tinnitus?
Dr. David Healy says
Yes – and hopefully an answer to one of them will help answer all of them – but you can’t just lump them all together when you’re trying work out what’s going on or what works
D
Daniel says
Callum, if you read this, a thought i have is to use the perplexity.ai website or chatgpt (preferably the latter) in order to ask questions about how to start and how to succeed at the task you stated. it becomes easier to get going i believe, if you can get fast answers/ideas from an entity that is trained on countless research papers. Though on the other hand it is probably better to ask a real academic on how to do it, but chatgpt might know alot about networking with researchers, raising awareness about medical conditions,and being able to give advice on how to motivate a person (ie a researcher) and the like.
NKOL says
Hi,
I have a referral for a neurologist. I’m going to bring up screening for Small Fiber Neuropathy since some of that rang familiar and I’ll look into asking about testing with Von Frey filaments (though no promises since it sounds like this is probably in the range of no insurance). Is there a writeup for wishlist of what people should ask for when you’re visiting the neurologist? Is there anything else that’s sex (female) specific you’re hoping people look into?
Dr. David Healy says
Neurologists are not good at sensory neuropathies. Mentioning Small Fibre Neuropathy can often lead them to investigate the motor system – where they have tests and these will tell you you’re nerves are fine when they aren’t. And if you insist things are wrong they may diagnose Functional Neurological Disorder (FND) which means they think you are hysterical or have health anxiety – there will hopefully be a post on FND soon. If they diagnose you as FND, let us know
So you are hoping for someone sensible, who has some knowledge of sensory neuropathies, who will confirm the diagnosis even if no tests prove positive, and who will get interested in you and your condition and perhaps even come up with some new ideas.
The idea that insurance might not pay for Von Frey Filament Tests is an extra twist to the story that hadn’t occurred to me. You can push for Quantitative Sensory Threshold Testing – this is done by machine – but here you have to insist they don’t do a routine screen for abnormal or not abnormal but that they try to establish the threshold at which you detect sensation and give you some sense as to whether your figures deviate from the norm rather than just a view that they aren’t plain outright abnormal and in that sense you are normal – and if you complain you have FND.
David