The Holy Grail © Nina Otulakowski June 2022
You need to click on the image to get the full effects.
Post-SSRI Sexual Dysfunction (PSSD) is a debilitating consequence of taking serotonin reuptake inhibiting drugs (SSRIs, SNRIs, some antihistamines, some antibiotics, some analgesics and other medicines) that can leave people of all ages, and from all countries on earth, but increasingly young people, unable to make love for years and possibly for the rest of their life.
It is closely related to a mirror image condition, Persistent Genital Arousal Disorder (PGAD), where there is genital hyperarousal. This is also a consequence of serotonin reuptake inhibitors and some other drugs.
PSSD and PGAD have links to two very similar conditions – post-finasteride syndrome (PFS), which stems primarily from finasteride, a drug used to reverse hair loss in young men. Finasteride is a 5-Alpha Reductase Inhibitor (5-ARI) and other 5-ARIs, like dutasteride and minoxidil can also trigger it.
The other syndrome is triggered by tetinoids of which isotretinoin (Accutane) is the best-known trigger a Post Retinoid Sexual Dysfunction (PRSD), also called Post-Accutane Syndrome (PAS), which again is very similar to PSSD. Retinoids are used primarily by young people for acne.
SSRI and related drugs, along with finasteride and isotretinoin, also cause suicidality, emotional blunting, depersonalization, anhedonia, birth defects, dependence and withdrawal.
These problems likely stem from a similar source to the sexual problems PSSD, PFS and PRSD. The genital numbing of these conditions seems closely related to emotional numbing. The restlessness that leads to suicide closely related to the restless genital syndrome that is PGAD.
Finding an answer to the enduring sexual dysfunctions will hopefully help these other problems as well as help clarify what causes dependence on and withdrawal from antidepressants and related drugs.
With several different drugs causing closely related problems and with these problems being very clearcut, research in this area should be easier than most.
Solving the problem of enduring sexual dysfunction would be a major step forward in pharmacology – perhaps allowing us to design drugs that could deliver permanent good effects after a short course.
Unravelling the intimate links between brain, genital, and emotional sex, seen in these conditions, will likely dramatically impact on the way we understand ourselves.
A Research Fund
With this in mind and linked to recent research on thalidomide and on locating where the clitoris is represented in the brain, we have set up a PSSD Research Fund to enable research on these related conditions to happen rapidly.
The normal research process takes two years or more to write grant applications and get funding approved for just a single project and then the researchers have to stick inflexibly to pre-stated goals rather than follow promising leads.
The RxISK Prize that offers $100,000 to anyone who comes up with an answer for this condition – what causes it and what might treat it – remains in place.
The PSSD Research Fund aims at supporting new research.
This fund will come with a transparent log showing a running total of the amount of money given, the researchers to which it has been given and for what projects, and indicators of what the preliminary results look like, as soon as we have them.
Our expectation is that the researchers will be very interested in the insights of RxISK readers and research donors, on what they are doing and what the next steps might be. Those of you who are affected are the greatest research resource any researchers could have.
Thalidomide is history’s most famous drug. The birth defects it caused led to the 1962 Food and Drugs Act in the United States, which shapes the way we view every drug we now take.
To this day, no one has established exactly how thalidomide causes birth defects. Recent research in Japan, the UK and Italy points to thalidomide’s effects on a set of regulatory proteins and enzymes – Cereblon, p53, p63 and p73. These are not the full story, but they are the most promising lead in 60 years.
How does this link to PSSD, PFS and PRSD?
Thalidomide, and its derivative lenalidomide, cause
- birth defects,
- sexual dysfunction,
- agitation and suicidality,
- treat cancer
- treat Covid
SSRIs, Finasteride, Isotretinoin cause
- birth defects,
- sexual dysfunction,
- agitation and suicidality
SSRIs and Retinoids also
- treat cancer
- treat Covid
There have been persistent indications from epidemiological studies that SSRIs like Prozac have anti-cancer effects. Retinoids, like isotretinoin and finretinide, were initially developed as cancer therapies.
There has also been a lot of media press about a range of studies showing fluoxetine (Prozac) and fluvoxamine have anti-Covid benefits. Isotretinoin and finretinide are certainly anti-viral agents, although whether specifically anti-Covid remains to be established.
The Spike protein of the Covid virus binds to and gets into cells through ACE-2 receptors. Among the commonest antibodies produced by people who have been vaccinated for Covid are antibodies to the ACE-2 receptor
A number of antiviral drugs, and other drugs proposed as helpful for Covid, like the SSRIs, also directly bind to or indirectly act on ACE-2 receptors through the p63 system.
Thalidomide and lenalidomide destabilize p63 which has knock-out effects on ACE-2 receptors.
All of these details come Professor Luisa Guerrini in Milan, whose work was brought to our attention by one of the people affected by PSSD who has contributed a lot of break through ideas.
Extraordinarily Professor Guerrini had looked at the effects of sertraline on p63 over a decade ago and found that it has effects on p63 and has knock-out effects on ACE-2 levels similar to those seen with thalidomide – both thalidomide and sertraline lead to p63 degradation.
She has repeated these experiments recently and as she explains:
- transcription factors p63 and p53 regulate gene expression, and the p63 degradation we have seen with sertraline could lead to p63 target gene deregulation.
- p63 is also a stem cell factor expressed in the stem cells of our organs. Depletions of p63 from stem cells by SSRIs can likely cause loss of stem cells.
- SSRIs therefore cause epigenetic modifications remaining after SSRI withdrawal, some of which may form the basis of post-withdrawal problems.
It has been known for some years that differences in our individual ACE-2 genetic profiles have been linked to sexual dysfunction.
And recently there are reports of both Covid and its vaccines producing clinical pictures that are quite similar to PSSD in some people – see Welcome to Mondor, Frodo.
After initial unsuccessful efforts to treat PSSD with drugs that act on the serotonin or dopamine systems in the opposite way to SSRIs, in 2009 Antonei Csoka and colleagues put forward one of the earliest ‘other’ hypotheses about what might be wrong in PSSD proposing that PSSD stems from epigenetic changes. The problem is a drug can trigger several thousand changes in gene expression and we need to work out which count.
This is like hunting for a needle in a haystack. A factor like p63, or p53, or p73 which has more links to the nervous system, might offer a magnet to fish out the important changes associated with PSSD, PFS, PRSD and PGAD.
Thanks to research supported by the PFS Foundation, we also know there are thousands of epigenetic changes following finasteride.
We need to see if there are common effects of SSRIs, Finasteride and Isotretinoin on some of these regulatory factors, what epigenetic changes they might share in common and whether these are shared with thalidomide and lenalidomide.
We still don’t know the full thalidomide story and it is clear it produces more severe birth defects than SSRIs, so these drugs are not all identical. This is helpful in that SSRIs and isotretinoin may make a contribution to establishing the bigger picture we still don’t have even for thalidomide.
This research cannot fail. It seems bound to shed light on some of the most enduring mysteries in pharmacology.
This research also offers incentives for pharmaceutical company support – as it is not just looking at harms but at possible treatments for cancer as well as for viral illnesses.
All of the above was written two months ago, when we were initially setting up the bank account for this research. Some of you emailed me about this fund and I responded it should be ready any day but we have had awful difficulties and embarrassingly it hasn’t been ready.
During this delay another person who has done a lot to point us in useful directions drew our attention to work and a paper by Professor Liu and colleagues in Science looking at the molecular basis of pleasant touch.
Liu’s group make a compelling case that this protein found in the spinal cord might be key to our moods, eroticism and emotions and in particular mediate the social effects of touch rather than just the sense that my skin was touched by a pin several inches from my kneecap.
Prokineticin acts on PROK and PROK2 receptors. There is a compelling case to establish if SSRIs, finasteride, or isotretinoin have effects on this system either directly or as a consequence of their effects on p53 or p63 or maybe p73.
So, the fund will support work on these developments also.
In addition to crowdsourcing funding we will be depending on you to crowdsource research leads or information linked to any of the above.
Find out if there are any drugs known to affect prokineticin in the opposite direction to SSRIs. Or to see whether there are any epigenetic effects that link to p63 or prokineticin.
It might be useful to set up p63 and prokineticin work-groups. The one thing that I have learned from a decade chasing PSSD is that all the good leads have come from people like the readers of this post.
You can view and donate to the Research Fund here.
The initial funding need is for p63 and prokineticin research in Professor Guerrini’s laboratory.
But we are also looking at something else where prokineticin might play a part.
A recent fMRI study done by Christine Heim and colleagues at Berlin’s Charité Hospital claiming to have located the brain site that corresponds to the Clitoris not surprisingly got widespread attention. The study opens up fascinating perspectives.
The researchers had to devise a way to stimulate volunteers without ‘disturbing’ them. They created a device that stimulated touch receptors only using puffs of air. This led to a location for the clitoris in a different place to where majority opinion had thought it was. Perhaps the other place registers ‘disturbances’.
This device brings Quantitative Sensory Threshold (DST) Testing back into the PSSD frame. QST so far has been the test most likely to detect abnormalities in PSSD. It tests touch, temperature and vibration rather than the erotic touch sufferers from these syndromes say has vanished
Some years ago, there were proposals that within our c-fibre nervous system, which mediates pain, touch, vibration, temperature and other intimate sensations, there are also caress fibres. There may be caress fibres but an alternative is that arousal eroticizes c-fibre sensations into caresses.
It may be that the brain does not create the erotic but interprets what is happening in the erotic body.
Previous work by the Charité researchers had shown that the cortex of the brain where they locate the clitoris appears to be thinner in women who have been sexually abused. But is this because of abuse? If some women were on SSRIs at one point, what effect would these have? What might we find in PSSD?
And what would it mean? A brain that is less active can be a brain fault or a fault in genitals that are not providing stimuli to disturb the brain.
Is it possible perhaps in animals to reproduce this research and see what happens if prokineticin is knocked out or interrupted?
In PSSD, the genitals go numb and orgasms mute first with libido vanishing later. The process may be driven by our bodies rather than our brains. If true, this echoes the philosophy and psychology of William James and Carl Lange from 125 years ago and would have far-reaching effects on the ways we view ourselves and who we are.
These days, we want our brains to be us but maybe there is more of us in our bodies than we think.
This line of thinking can be taken a lot further. More extensive sensory mapping might open up new fields of research calling on people to map themselves and try to make sense of what fluctuations in their map might mean – what might be going on if a ‘hole’ opens in some place. Perhaps these holes open and close when we get emotional or open and remain open if there is an abnormality at that site.
Discussions with Berlin and Maastricht are ongoing on how best to move these ideas forward.
You can view and donate to the Research Fund here.