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
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,
They also
- 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.
New Perspectives
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.
Prokineticin
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.
See Liu et al 1 and Liu et al 2.
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.
Brain Sex
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.
See Heim et al 1 and Heim et al 2.
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.
Spruce says
My PSSD has been particularly bad the last two months.
Genital numbness, pleasure less orgasms, zero libido, emotional numbness, day in, day out.
I have been feeling suicidal again, and to be honest, I don’t know how much longer I can endure this existence.
I have suffered for almost 15 years now, and there is only so much more I can take.
I feel left behind, and all my peers, and family; have moved on to have relationships, marriages, children, and normal lives.
I have had nothing. I can’t even enjoy pleasuring myself.
I have been left to rot, by the mental health team that so badly betrayed me, and actively worked so hard to deny what has happened to me.
I am estranged from most of my family, and a big part of why, is because of PSSD.
In fact the only family I talk to is my mother, who is now quite elderly.
God knows how I am going to cope once she is gone, as she is the only person that really cares about me.
I have few friends, and most of the friends I do have, are fellow PSSD sufferers; as they are the only ones, who really understand what it is like to live with this hell.
I am struggling to see any light at the end of the tunnel.
Please find a cure for PSSD, as I can promise you, it truelly is a form of hell on earth!
Kianoosh Rabbani says
I developed severe small intestinal dismotility which is a really severe mortal disease after two month of SSRI.
Please stay away of this drugs. I am dying unless a cure could be developed for neurological problems due to ssri.
Wish you best
Kianoosh Rabbani
Atul says
PSSD from ashwagandha supplements.
I experienced PSSD symptoms from ashwagandha a year ago and still have loss of libido and penile numbness.
The brain fog and anhedonia symptoms went away with time and by fixing my gut by taking candibactin.
The vagus nerve controls the gut brain axis and DNPR may help with this just like it helps with CFS.
Please research more about the gut brain axis and how CFS and PSSD are related.
FMT has also cured multiple people.
Arjan says
What was the reason behind taking Candibactin?
All the improvements I got disappeared within days of diarrhea which hasn’t resolved after many months now.
The problem with FMT is that most people I’ve read and talked to say only a temporary improvement happened after it which disappeared after a while.
Low_waters says
If FMT works at peast for a while it’s a very good sign ; the process would have to be perfected (better donors, microbiota engineering etc) and repeated.
CFS gained tremendous attention with long COVID and the whole PFS/PSSD community and researchers shouldn’t shy away from reaching out to all the top institutions and researchers involved (polybio [dot] org).
The top world scientists, faculties and institutions are engaged in solving long COVID. There’s indeed links (at least causal) as suggested in the article between COVID or vaccine and the onset of PSSD.
Each one of us, researcher or sufferer from this condition should take the opportunity and try and reach out to these scientists.
Science doesn’t happen by chance, from single research centres, it happens with collaboration.
Juhana says
Dear Mr. Healy & Co.
The emotional problems, cognitive problems (memory), vision problems, skin problems (dry skin), partial loss of smell, dry eyes, GI problems, altered tacktile and thermo sensation in body, altered autonomic function (blood pressure, skin temperature, loss of sweating) should be considered. In my opinnion it is very harmful that our condition with as wide spectrum of severe symptoms as they have in PFS and PAS is still named as PSSD (…Sexual dysfunction). We people are really sick in every aspect. For many the sexual symptoms are not the most severe ones. Some of us can’t feel even our heart pumping, lungs when breathing, or a thing when urinating or defecating. Our nervous system is destroyed and we have also pains. We are living in a hell where it is not possible to even cry properly, no matter how hard you try. We should also remember that altered neurosteroids are linked to autism-like behaviour and flat feelings, anhedony and severe depression as well as many severe neurological conditions.
IS the theory of Small fiber neuropathy and autonomic dysfunction totally ruled out?
You are the biggest hope to us who rapidly lost everything to SSRI:s…
Dr. David Healy says
The SFN and autonomic dysfunction are not ruled out. They are very much alive. But we have to find which protein or enzyme within small fibres has been knocked out.
The reason to focus on sex and numb genitals is that this offers us a very clear target – explain this and we likely have the answer to everything else. Having some people look at eyes, some at hearts and some guts is a recipe for diluting our efforts.
D
Juhana says
Yes this is right and totally agree! As so many PSSD sufferer have clearly autonomic dysfunction / at least problems with it, so do we know if it is progressive and are these people in danger getting worse? Do we have cases of death due to autonomic dysfunction caused by SSRI?
I am sure Dr. Guerrini’s findings are extremely valuable for the future. This new research could be way to many new findings on medicine.
tim says
This really did demand reading and re-reading. Thank you.
The Holy Grail: Searching For A Cure for PSSD certainly did inspire hope.
‘- explain this and we likely have the answer to everything else’.
The ‘everything else’ is vast in terms of the enduring and evolving SSRI/SNRI/Atypical-ADs and other psychotropic drug injuries which affect so many different tissues, physiological functions, (hypothalamic functions??) and multiple organs. All of these in addition to PSSD and PGAD, endured by so many who comment here.
I have been distressed to watch a multiplicity of atypical symptom-complexes arise in our loved one over the last 9 years free of all medication. There is destruction of thermo-regulation (heat intolerance). Multi-site deep bone pain, limiting exercise. Low back/sacral pain limiting pronged sitting. Destruction of normal patterns of micturition. Destruction of Sleep/Wake Cycle. There have been thyroid changes. Atypical chest pain. Extreme vulnerability to atopic reactions – topical eczema – resulting from ‘gentle’ cosmetics and deodorants.
All of this adversity has been endured with a resilience which has been inspirational, yet heart breaking.
There are other symptoms, and none are likely to be understood by a primary care physician. A ‘diagnosis’ of functional neurological disorder and/or inappropriate presumption of ‘Underlying/Emerging/Revealed M. H. Disorder’ remains a constant threat; even an enduring terror. This alone is a lifelong disability in a person whose iatrogenic disability will never be acknowledged or compensated. Tragic. The cavalier and injudicious, enforced use of such widely toxic psychiatric drugs surely merits questioning from within my profession: But, like the decades of AKATHISIA DENIAL, few are prepared to question the status quo. Meanwhile, priceless years of youth, attractiveness and reproductive opportunity have passed by in lonely, enduring isolation and medical/societal rejection. Even more tragic? This takes a toll on the entire family, in addition to the injured loved-one.
A recent television program identified the courage of a medical whistleblower.
His words (as I recall them) were immensely moving:
‘I was appointed to care for my patients, not for my colleagues’. The context implied was apparently referring to alleged cover-up.
How much longer can these cascades of life-destroying ADRs to psychotropic drugs be denied, ignored or covered up?
When we are able (via RxISK) to explain everything, how might we then achieve prescriber awareness, prescriber understanding, and realise our need to end the rejection of such suffering?
annie says
Tim, this is for you –
This was the ‘Keynote Lecture’ as given at the International Congress of the Royal College of Psychiatrists, Monday 20 June 2022:
As far as I can see, this summary slide, from the keynote lecture of the RCPsych International Congress 2022, fails to mention AKATHISIA: a widely recognised potential consequence of all psychiatric drugs [particularly when starting , reducing, or changing dose].
Yet another opportunity to “improve safety” seems to have passed by.
https://holeousia.com/2022/06/23/elusive/
Who is wagging the dogs tail?
https://holeousia.com/2022/06/23/who-is-wagging-the-dogs-tail/
On Monday of this week [20 June 2022] I peacefully protested outside the 2022 International Congress of the Royal College of Psychiatrists:
Peter has put together a few thoughts on his visit to Edinburgh, his posts can be found after each composition.
I hope you will have a good pour over them, as I did.
tim says
Thank you Annie,
‘Yet another opportunity to “improve safety” seems to have passed by’.
Surely two fundamental tenets of ethical medical practice are:
The prevention of harm.
Ensuring that patients are told the truth.
It would appear that both of these principles have been compromised by some 40 years of AKATHISIA DENIAL. It must be hoped that the AKATHISIA AWARENESS advertisements placed on the London Underground in April may have afforded the opportunity for some families to recognise this common and devastating ADR. They may have been enabled to recognise what was happening to their loved ones and prevent the suffering described above.
Surely, the denial of akathisia, and the apparent prevention of prescriber awareness and understanding, demands formal investigation and urgent remediation.
Continued akathisia denial would appear analogous to allowing prescribers to believe that penicillin cannot cause anaphylaxis.
Cameron says
How close are we to figuring this out ? I think it may be some sort of autoimmune condition that the medications triggered. I developed an autoimmune condition right after getting PSSD and lots of people who have one autoimmune condition have another . Please let me know if there is any chance at any leads towards solving this. I already have one suicide attempt and the one person who speaks to me and understands is my mother . I’m seriously dying here
U. says
Dear doctor
I’ve read the blog posts that you mentioned and almost everything else on RXisk. Except for exercise intolerance, some of my symptoms point at autonomic neuropathy. I will try to get tested for this. If it helps, I can share my results with RXisk.
I feel utterly stupid and guilty for not once checking the internet during the years of my psychiatric treatment. There were warnings on RXisk dating back to 2013, just before my treatment started…
U
susanne says
Rxisk says ‘Those of you who are affected are the greatest research resource any researchers could have.’ This could be a chance of enlightning readers of thebmj by making more responses. No need for any kind of ;professional ;qualifications to make a response by the way.
Re above ‘Research’ Donations are made to Centre for Data Based Medicine, a registered charity in England and Wales. (See link in article )where J K Aronson works
His response says:-
Re: A system reset for the campaign against too much medicine Kamran Abbasi. 377:doi 10.1136/bmj.o1466
Dear Editor
The Editor of the BMJ is justified in calling for more scrutiny of harms [1], as did one of his predecessors: “Think harms always” [2]. The term “practices of no net benefit” has been suggested [3], stressing the need to consider the balance of benefits and harms, not merely one or the other [4].
However, there is ambiguity in the term “Too much medicine”. “Medicine” means “the science or practice of the diagnosis, treatment, and prevention of disease” (Oxford English Dictionary). However, in that sense the word is sometimes used to differentiate medicine and surgery. And “medicine” can also mean a medicinal product, a drug. In that case, the implication is that the harm from “too much medicine” is an adverse drug reaction, whereas all forms of medical practice are potentially harmful as well as potentially beneficial.
In fact, we could be said to have too much of [almost] everything:
Too many diagnostic tests (if used inappropriately)
Too much technology (enabling too many tests)
Too many guidelines (if used inappropriately)
Too many “diseases” (inappropriate labels)
Too many biomarkers (incomplete understanding of how to use them)
Too much monitoring (if used inappropriately)
Too much therapy (if used inappropriately)
Too much cost (too little money)
Too much enthusiastic hype (too little reproducibility)
Too much poor science (overreliance on observational studies, poor quality RCTs)
Too much licensing of medicinal products (too speedy licensing, too slow withdrawal, when indicated)
Competing interests: JKA has taught, lectured, and written articles about overdiagnosis and adverse reactions to drugs and devices, and has edited textbooks on adverse drug reactions.
21 June 2022
Jeffrey K Aronson
Consultant Physician and Clinical Pharmacologist
Centre for Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences, University of Oxford
Nuffield Dept of Primary Care Health Sciences, The Radcliffe Observatory Quarter Woodstock Road
@JKAronson
Respond to this article
Read all responses to this articleRe: A system reset for the campaign against too much medicine Kamran Abbasi. 377:doi 10.1136/bmj.o1466
ANON says
When I read how peoples lives have been impacted by these medicines, it makes me want to scream at the top of my lungs.
You are all worthy of life, irrespective of how/what/why/when!
Blood rushes to my head when I acknowledge and fully appreciate that:
1. Some people don’t give a damn about your circumstances
2. The system and some professionals don’t care
3. Some family members are judgmental and make a mockery of you
4. You feel all alone
5. Some people lie to ruin you. Stay away from people who do not genuinely/sincerely care about you
If I had my way, I would make those who do harm, pay for all the damages and more…………!
Changing the mindset is the biggest hurdle.
Forgiving is part of the process however, forgetting is the hardest part.
Try to find ‘the spark within’ that makes you happy.
Anything that puts a spring in your step.
susanne says
As campaigners know this drug is not only used for epilepsy, She is a regular writer in thebmj so should have known this and used the opportunity to alert those who take others including antipsycholtics.
It cannot be the only drug which will ‘potentially’ effect future generations. It’s still being prescribed to women …..
Valproate: UK regulator looks into possible transgenerational effects
BMJ 2022; 377 doi: https://doi.org/10.1136/bmj.o1531 (Published 22 June 2022)
Cite this as: BMJ 2022;377:o1531
The UK’s medicines regulator is examining animal data that show that the epilepsy drug sodium valproate could trigger genetic changes that are passed on to future generations.
The Medicines and Healthcare Products Regulatory Agency (MHRA) said that as part of its ongoing review of the safety of sodium valproate it has sought independent advice from the Commission on Human Medicines about animal data that show changes to the testes in juvenile male animals and transgenerational effects in mice.
In April new figures showed that valproate was still being prescribed to women of childbearing age.1
Will says
Why not use the prize fund to fully fund the study?
Dr. David Healy says
Because the Prize Fund is still acting as a stimulus to get people to do things.
There have been many proposals – all interesting but none that seem likely to be right.
A number of people though have come up with really good ideas, leading to our interest to fund these to make them happen. Hence the new Research Fund.
D
Jarrett says
The prize money has stopped growing for quite some time. If rxisk decided to change direction by transferring the prize money towards the new research fund in order to speed up the process, could it physically be accomplished?
Raising money in this pssd community will take a very long time to reach $50,000.
maryH says
I guess that the total will not have to be reached before the researchers begin to be supported by the Fund? It’s up to all of us to get cracking and make this work.
mary H says
Will, may I share with you the way that I see things. As so many others did also, I worked really hard to raise funds for the Prize Fund and to share the reason it was needed. Not only is it to be given for a cure for PSSD but, and this is where my interest lies, IT COULD PROVIDE ANSWERS FOR MANY OTHER REASONS FOR THE SUFFERING connected to these prescribed drugs. THAT is the Prize’s purpose and. as such, MUST remain there, awaiting a cure to be found.
The Research Fund, I perceive as being “a means to an end”, a support for those who feel that they’re really onto something extremely exciting and worthy of further investigation. Research is expensive. People cannot afford to do it for free. Hence the Fund – to provide a little support to ensure that the progressive work now established does not go to waste simply because of a lack of funds.
Those of us who supported the Prize Fund should now be wholeheartedly behind this new Fund to ensure progress is possible. The “Prize”, when eventually handed out , would not disappear into anyone’s personal pocket – it would be used to further the work already accomplished.
We need both trust and hope here. Trust in the knowledge that our monies in the Prize Fund are safe for its purpose and Hope that the support we provide through the Research Fund bears fruit as quickly as is absolutely possible. Many out there are crying out for an answer to this, and many other, problems.
Eric says
This is a fantastic post. I love how it keeps an open mind. That’s what research is all about.
The questions about weather the physiological drive the psychological or the other way around, so to speak, are interesting. I’m not sure the two are even different. Chemicals affect how we perceive things, i.e. our psychology, but the mind also affects the body.
On that note, I’ve had some success with meditation. It’s somewhat like the mind has forgotten to focus on certain things, but that it can, to some limited extent anyway, be taught to refocus.
jarrett says
I believe the prize money is not an incentive to find a cure. As you mentioned, “Research is expensive and people cannot do it for free”. To find a cure will cost way more money that what the prize fund has raised over a 10 year period? Where is the incentive for new researchers to look into pssd ?
The prize Money which is already in our possession could be working for us to find a cure. I strongly believe the prize funds will continue to sit there for years to come.
I would love to be given the opportunity to transfer my prize funds over to new research fund.
(1) THAT is the Prize’s purpose and. as such, MUST remain there, awaiting a cure to be found.
(2) Research is expensive. People cannot afford to do it for free. Hence the Fund – to provide a little support to ensure that the progressive work now established does not go to waste
ANON says
With all honesty, the research should be done before these medicines go out on the market.
What is the point in investing in something, that does not promise/yield results?
They have research for this; research for that however, they never really come up with substantial cures that eradicate health issues that some medicines/vaccines induce.
If this was the case, no one would be in research if they came up with cures.
I believe many of these medicines/vaccines induce health issues immediately or with time.
Before a medicine goes out on the market, it should go through vigorous research upon research so that people do not get harmed or death results.
The prize money should go to anyone who can make changes in the Laws regarding these medicines/vaccines.
All the negative clinical data trials should be out there for all to see before a pen is put to the script.
Perhaps, one day this will be reality.
Bill says
Some of us donated to the RxISK Prize fund under the assumption that it was a publicity stunt to gain more attention for PFS, PSSD, and PAS/PRS, and with the understanding that it would eventually be disbursed “to support the most innovative research proposal or donate it to the PFS Foundation who are already undertaking some elegant research.”
The “most innovative/elegant research proposal” is debatable. The fact that the above statement quoted was published by RxISK in regards to the RxISK Prize is not.
It’s been around 5 years since the RxISK Prize was launched and it would be great if RxISK/DBM could refund contributors or offer to dispense donations, by proxy, to university-level research the donors are supportive of as a show of good faith.
Dr. David Healy says
Bill
Your comment has crossed with a new post. Can you have a look at it
D
Arjan says
My pleasure senses and cognitive symptoms was recovering. My mind was sharp again. My blank mindedness was reversed to normal. Music was like usual again. My skin numbness was also gone in some parts of body.
Then had re-activation of stomach pain which caused me diarrhea for 3 weeks.
For the first 3 days of the diarrhea I was dizzy and my vision got cloudy. Then the feeling of pleasure was replaced with a tingling sense in the back of my brain. Now for the past months I’ve lost all the improvements I had gained.
I believe diarrhea somehow has reversed improvements but I’m not sure what to do to reverse what diarrhea has done. I’ve done all things I was doing right before my improvements with no help.
Johann says
Dear Mr. Healy & Co.
Has a link between the immune system and PFS/PSSD/PSI ever been considered ?I have an hypothesis to propose to you, I detail my reasoning below (while having some knowledge in biology, I have no expertise in the field so I ask my readers to be indulgent) :
INTRO : LINK BETWEEN DRUGS AND THE IMMUNE SYSTEM
First of all, many medication may elicit an immune response : streptomycin, aspirin, the sulfonamides, some anesthetics (e.g., succinyl choline), and some opiates … A known case study is penicillin which react to protein to create a penicilloyl-protein which behaves as a hapten-carrier conjugate eliciting an allergic reaction (mediated by IgE). In some patients, such drug-protein complexes induce formation of antibodies (mediated IgG, IgM), which then bind to the adsorbed drug on red blood cells, inducing complementmediated lysis and thus progressive anemia. Other drugs like hydralazine can also cause a syndrom, drug-induced lupus, which include clinical features of systemic lupus erythematosus . None of the processes above would explain all of the symptoms in people with PFS/PSSD/PIS, as the symptoms usually improve once the drug is withdrawn. I just wanted to emphasize that a link between the immune system and drugs is not necessarely far fetched.
AN AUTO-ANTIGEN AS AN EXPLANATION OF PFS/PSSD/PIS
It wouldn’t be impossible that the root cause of PSSD could be the immune system targeting a auto-antigen leading to the symptom set of PFS/PSSD/PIS. This is the case in some forms of Addison’s disease in which an enzyme is recognized as non-self. This has been proved in a “breakthrough” study which was the first to prove a link between some form of the Addison disease and a specific auto-antigen : 21-Hydroxylase, a major autoantigen in idiopathic Addison’s disease ( doi : 10.1016/0140-6736(92)91829-w ). The auto-antigen is a steroidogenic enzyme, 21-hydroxylase, which is needed to catalyze a set of reactions necessary for our body to supply us with two major hormones : aldosterone and cortisol. Lack of those hormones leads to a set of symptoms which caracterize the Addison disease : psychiatric symptoms (anxiety, depression …), sexual dysfunction (decreased libido), skin changes (darkening skin), adrenal crisis (which is life threatening). As everyone can see a “small” cause (enzyme being targeted by the immune system) can lead to a very wide range of symptoms (from psychiatric to sexual dysfunction). Other auto-immune diseases, such as the graves disease, involving receptors as an auto-antigen may induce debilitating symptoms (including decreased sexual drive) : anti-TSH receptor induce an overproduction of thyroid hormones. What is striking is that such auto-immune diseases are sometimes conflated with depression or anxiety because of the overlap with symptoms of depression. Why would PSSD/PFS/PIS not stem from an auto-antigen being targeted by our immune system ?
WHICH AUTO ANTIGEN WOULD BE INVOLVED ?
A cohort study, comparing the cerebrospinal fluid (https://doi.org/10.1016/j.jsbmb.2014.03.012) concentration of a set of neurosteroid among healthy volunteer with those having PFS, yielded some significant results. In fact despite the small cohorts size the differences were statistically significant for a wide range of neurosteroid. Whether this low level of neurosteroid explain the set of symptoms among PFS/PSSD/PIS patients or not cannot be concluded, but it seems like an interesting lead : what is the cause of such a low level of neurosteroid ? Assuming PSSD/PFS/PIS has an auto-immune explanation we can rephrase the question : What auto-antigen, if targeted by our immune system, can induce such an abnormal profile of neurosteroid that has been observed among PFS patient ? A process similar to that which occurs in Addison’s disease (auto-antigen is a a steroidogenic enzyme), but of course with a different auto-antigen, could be an explanation. it would be interesting to have an enlightened opinion.
WHAT KIND OF REASEARCH CAN BE CONDUCTED ?
The advantage of such a hypothesis is that it can be “easily” confirmed or invalidated. The protocol is almost the same as the one described in the Addison disease paper above. We perform a western blot analysis among PFS or PSSD or PIS patients : 1) we separate auto-antigen from a mixture of potential auto-antigen, using an electrophoresis, according to their masses 2) we probe each antigen with some PFS/PSSD/PIS sera (containing potential auto-antibodies) 3) by using radiolabeled or enzyme-linked anti-antibody we assess whether auto-antibodies have latched on a potential auto-antigen. We perform the same western blot analysis among a cohort of healthy patients. And we compare both cohorts. I have briefly described the different stages of such a protocol so that everyone can see that it does not require a lot of equipment or funds : it uses a well-known and widespread technique (western blot), in case of postive result it would provide an easy diagnostic tool.
PLAUSIBILITY OF SUCH AN HYPOTHESIS
Of course, a possible autoimmune cause is very speculative. Several symptoms of PFS/PSSD/PIS do not seem to match the usual symptoms of autoimmune diseases:
– Usually auto immune disease vary between remission phase and acute phase which does not seem the case with people with PFS/PSSD/PIS .
– inflammation are also pretty common with auto immune disease. I have not heard anyone reporting such symptoms having PFS/PSSD/PIS.
Although it seems unlikely that such an assumption will turn out to be true, there is a small chance that it will.
Sincerely
Dr. David Healy says
Johann
This is a good idea and the kind of thinking that is needed. Luisa Guerrini’s work heads in this direction in two ways. One is that any genetic effect like generating antibodies goes through a set of proteins like p53, p63, p73 so what is being proposed comes close to what you are thinking.
Second, it looks like the action of thalidomide and SSRIs on these proteins destabilizes what is called the ACE-2 receptor and this blocks the entry of Covid into cells – one of the things Covid appears to do is to produce antibodies to ACE-2 receptors which as I understand them would count as auto-antigens. Again this seems in the same ballpark.
I doubt if its a frank auto-immune disease though because we have had tardive dyskinesia for 60 years and PSSD for 30 years and I’d imagine someone would have stumbled over a link by now – perhaps finding someone showing huge improvement after a course of plasmapheresis. But that requires people to be curious and alert. If there is an auto-immune component you’d expect inflammatory markers to be raised and there is some evidence for this and changes in steroids in depression but these seem to happen in everyone not just in those with PSSD.
I have thought along the lines you outline and agree this would be worth doing – or at least checking out with someone who can advise us properly.
D
ANON says
Hello Susanne,
Medicine has turned into a conundrum, filled with so much ambiguity and uncertainty.
There are simple solutions out there to many diseases however, many are not inclined to think outside the box.
I love the way you compartmentalize systems/processes and say it the way it is.
Susanne eloquently stated:
Too many diagnostic tests (if used inappropriately)
Too much technology (enabling too many tests)
Too many guidelines (if used inappropriately)
Too many “diseases” (inappropriate labels)
Too many biomarkers (incomplete understanding of how to use them)
Too much monitoring (if used inappropriately)
Too much therapy (if used inappropriately)
Too much cost (too little money)
Too much enthusiastic hype (too little reproducibility)
Too much poor science (overreliance on observational studies, poor quality RCTs)
Too much licensing of medicinal products (too speedy licensing, too slow withdrawal, when indicated)
Please allow me to add another one to the list:
– Too much balderdash
My theory and experience tell me, that given time, some issues and damages incurred by medicines, will resolve themselves. You have to work hard at researching what benefits you. Hopefully, the damages done to nerves, myelin sheath, the barometer in the brain and multiple body systems will repair themselves eventually without drastic drug/medical interventions. It’s about trying to STOP the war (inflammation) within the body. Trying to undo what medicines have induced is a very tricky situation but I know it can be done. Nothing is impossible! Listening to many naysayers and not having any HOPE for the future is very detrimental to one’s faith. This is why I have chosen a path less travelled. It makes the journey worthwhile : )
ANON says
Hello David,
I am intrigued by what you have written:
– generating antibodies goes through a set of proteins like p53, p63, p7
– Second, it looks like the action of thalidomide and SSRIs on these proteins destabilizes what is called the ACE-2 receptor and this blocks the entry of Covid into cells – one of the things Covid appears to do is to produce antibodies to ACE-2 receptors which as I understand them would count as auto-antigens.
Please expand our knowledge. It is all science in a ‘petri dish’ for me.
Can you please elaborate.
As for you Johann, are you a scientist?
Sounds, very impressive.
I’m no expert in the field. A suggestion I could put forward is also finding a cure that re-generates nerve damage.
Keeping inflammation at bay within the body is also something that would be beneficial. When the body attacks itself there has to be a remedy that puts this to a halt. Lot of drugs out on the market tend to do this however, long term disadvantages is that they then go to weaken the immune system or burden other organs.
Input would be kindly appreciated.
Dr. David Healy says
Nobody has the answers to these things
D
Sandman says
Hello dr Healy
We have someone from Germany who showed significant improvement with immunotheresis and have another member heading to Germany for 2 sessions in februrary.
I will keep you updated.
Kind regards
Boost909
L says
Liu’s study
Molecular and neural basis of pleasant touch sensation
https://doi.org/10.1126/science.abn2479
they genetically modified mice by removing the function of PROK2 neuropeptides and saw that the mice lost the response to pleasant touch (but not to pain/itchiness). PROK2 neuropeptides through the spinal cord send the pleasurable (not specifically “sexual”) sensation from the skin to the brain.
Heim’s study
Sensory-Tactile Functional Mapping and Use-Associated Structural Variation of the Human Female Genital Representation Field
https://doi.org/10.1523/JNEUROSCI.1081-21.2021
using fMRI imaging and a particular method of clitoral stimulation (puffs of air not such as to arouse sexual arousal) they located the “representation” of the clitoris in the human female brain.
Georgiadis’s study
A psychophysical and neuroimaging analysis of genital hedonic sensation in men https://www.nature.com/articles/s41598-022-14020-4
Using neuroimaging, they identified which brain areas in the male brain are activated by the touch of penile skin (vs. forearm) focusing on the pleasant (not strictly sexual) sensation of participants.
pleasurable vs. sexual and rats vs. human
after locating the representation of the clitoris in the human brain and the specifically genital pleasurable touch of the penis in the human brain, if tactile stimulation is added that elicits an initial strictly sexual response, one would observe what more “turns on” (do the same districts intensify their activity, or will other districts predominate?), but a complexity of systems would be activated and one would lose sight of the skin as the source.
of specifically “sexual” in the genital skin there may be corpuscles that have not yet been well studied. however, hypoesthesia in PSSD involves sensation to light touch, sometimes not only at the genital level but of the skin of other parts of the body. it may also be useful to take into account whether in some genital anesthesia by ssri sensations of itching and pain are also lost.
since I don’t know about neuropeptides and proteins I don’t know if reversibly inhibiting their action (perhaps locally) on a human being with an inhibitor would mean impairing that human being. if it were harmless one could repeat the brain scan studies after deactivating PROK2 or the proteins and hear what the volunteers have to say and see the differences with previous scans.
complications in locating the pleasurable penile/clitoral touch in the rats’ brains (when they talk, they don’t make themselves understood well).
in this way we cannot then see whether ablating PROK2 or some protein would keep such brain areas inactive during light touch.
on the other hand, observing the mating behaviors of rats we would not understand whether their eventual compromission is really due to altered transmission from skin to brain or other systems.
one can observe whether rats subjected to ssri have an altered reaction to pleasurable touch and then check whether there is an altered presence of PROK2 or some protein. if so, this would not speak to the mechanism that makes symptoms persist but would be an important clue to possible treatments.
however, I’m not sure how true it is that ssri’s cause almost all people to experience some degree of skin/genital numbness from the first intake (the fact that they help with premature ejaculation is not evidence that the skin has become less sensitive). making it an evidence with a comparative study (before ssri/with ssri) would be relevant and not very complicated and even the media would then say “antidepressants make your genitals numb.”
I would add a personal observation that could have several interpretations and not necessarily have anything to do with skin function.
during the months of citalopram, in addition to no longer having genital erogenous sensations (without despairing about it and thinking “if I don’t want to touch myself anymore what’s the problem?”) perhaps it is true that the light touch of the skin on the body had less power, no longer aroused that emotion, thrill, but as if the skin was already satisfed and no longer needed it. it may also have been a consequence of a different psychological state of me.
there are women who after so many years on the contraceptive pill say things like “I’m off the pill, my libido is back and I’m feeling alive again, I feel every sensation, every touch again, I had forgotten.” several years ago on a women’s forum I used to read the heated complaints of a woman who after the contraceptive pill had never recovered her sexuality (from multi-orgasmic, to anorgasmic on the pill to only one difficult orgasm after discontinuation). there is also a paper that talks about this possible not full reversibility: https://doi.org/10.1111/j.1743-6109.2005.00198.x
Sarah Browne says
This is very interesting. I have long wondered whether being on the contraceptive pill and then switching straight over to sertraline (both were given for PMS) contributed to me getting PSSD. I guess that contraceptive-induced sexual dysfunction is yet another thing we aren’t warned about
L says
Both paroxetine and finasteride act on the epinephrine enzyme PNMT, newly identified by Melcangi’s team. Epinephrine may have something to do with ongoing (persistent who knows?) erectile dysfunction.
– Finasteride inhibits epinephrine synthesis in humans: implication for sexual dysfunction
https://www.endocrine-abstracts.org/ea/0081/ea0081p448
– Identification of a novel off-target of paroxetine: possible role in sexual dysfunction induced by this SSRI antidepressant drug
https://www.sciencedirect.com/science/article/abs/pii/S002228602201345X
Professors Guerrini and Melcangi both from Milan could collaborate to hunt for enzymes and proteins perhaps with the screening method used in these studies.
Lucy Thomas says
Dear Dr Healy
I have seen your name on various articles and papers when I’ve been looking for answer to my self-diagnosis of PRSD/PAS. The reason it is self-diagnosed is because in the UK, the prescribing dermatologists refute wholeheartedly that sexual dysfunction can be caused by that poison. Primary care/doctors are not diagnosticians, they clueless really, therefore the road to recovery is a dead end.
The overlap between PFS/PSSD/PRSD is alarming yet only PFS is a syndrome recognised in the medical community. I did read a post about the potential of gene editing using CRISPR. One of the theories which seems to be consistent is that Accuate is likely to have altered the expression of specific genes, resulting in a persistent downregulation after stopping the medication.
[https://www.pasforum.info/threads/plausible-cure-crispr-cas9-gene-editing.21/]
Please, visit this site. The creator is deeply impassioned and seems to have dedicated huge amounts of time to research. Does this sound plausible?
All I can attest to is how Isotretinoin has ruined my life and the thousands I have spent trying to regain what has been stolen from me. When a woman complains of sexual dysfunction the only root cause given credence is a psychiatric one. Nothing more. A quick prescription of SSRIs is offered and some counselling. The problem isn’t just the ignorance displayed by specialists – to the level of gross neglience – but there is a gender inequality at play as well. We are all suffering the same storm, there is no cure, but there isn’t one protocol for women. Men have a few different treatment options – obviously which doesn’t do a thing – but women?? Well, she might be stressed, or emotional or whatever the excuse IS that’s used to dismiss women – it only serves to perpetuate the very real truth: a woman’s fundamental human right to enjoy sex doesn’t even rank high enough to warrant a raised eyebrow, much less funding.
Please find a cure.
L says
– Established a comprehensive mice model of persistent genital arousal disorder and investigated the mechanism of VEGF-ERK signal pathing in vaginal microvascular injury
https://assets.researchsquare.com/files/rs-1773638/v1/882f8ad1-3728-456f-92c9-ad89fb02e8f3.pdf?c=1657047799
These researchers believe they have obtained a valid model of PGAD on rats.
“Microvascular injury can significantly appeared in the model, and the VEGF-ERK signaling pathway is a possible mechanism involved”
Maybe this VEGF (Vascular endothelial growth factor, a signalling protein that promotes the growth of new blood vessels) is one of those things that would have something to do with anything
– is expressed and released by endothelial cells (the tissue that lines the inner surface of blood vessels)
– treatment target in cases of erectile dysfunction with vascular causes
– potential target for therapeutic intervention in depression
– overexpression of VEGF has been associated with tumor progression
– critical player in the neurovascular stem cell niche of the hippocampus
– SSRIs and SNRIs increase VEGF expression in the hippocampus
– Finasteride inhibits angiogenesis and expression of VEGF in human
– Retinoids are potent inhibitors of VEGF/VPF production by normal human Keratinocytes
– Talidomide is a potent inhibitor of angiogenesis due to direct inhibitory action on VEGF secretion
– the two major isoforms of the p63 gene exert opposite effects on the VEGF gene expression
– Off-Target Effects of Antidepressants on Vascular Function and Structure. 2022
https://www.mdpi.com/2227-9059/10/1/56/htm
– Impairment of the Retinal Endothelial Cell Barrier Induced by Long-Term Treatment with VEGF-A165 No Longer Depends on the Growth Factor’s Presence. 2022
https://www.mdpi.com/2218-273X/12/5/734/htm
This seems to be a process to get to the bottom of what causes the persistence of an iatrogenic effect to the point of targeting a specific protein.
in cases of stable pssd without the so-called windows of improvement, with erectile dysfunction and the sensation of blood not reaching the genitals as it should despite libido (and this could be why erogenous sensation does not come and genital arousal is not felt) I would not rule out microvasculature damage either, alongside possible small fiber neuropathy with perhaps fibrotic tissue formation, which has been highlighted as a likely cause of persistent ED in PSSD: https://www.auajournals.org/doi/abs/10.1097/JU.0000000000000964.015
I found from surveys that almost no one who has pssd has had classical neurological exams such as electromyography or evoked potentials (to name a couple), perhaps because “in pssd they are not revealing”, perhaps because they have seen others who have done them unnecessarily… this kind of thinking may keep some people away from relevant findings about their case.
L says
A line from the insensitive nipples in the PSSD
The sensory innervation of the human nipple (2020)
https://pubmed.ncbi.nlm.nih.gov/31911160/
– Merkel cells, specialized cells in the skin that are important for proper neural encoding of light touch stimuli
– PIEZO2, mechanosensitive ion channel
Glans clitoris innervation: PIEZO2 and sexual mechanosensitivity (2021)
https://onlinelibrary.wiley.com/doi/10.1111/joa.13317
– PIEZO2 is also present in Merkel discs and isolated Merkel cells
– PIEZO2 participates in erotic and sexual mechanical sensing
Effects on tactile transmission by serotonin transporter inhibitors at Merkel discs of mouse whisker hair follicles (W Chang, 2020)
https://journals.sagepub.com/doi/pdf/10.1177/1744806920938237
– a Merkel disc is a main type of tactile end organ located in touch sensitive spots throughout the body but most abundant at the human fingertips and whisker hair follicles of all non-primate mammals
– serotonin transporters play a role in regulating tactile transmission at Merkel discs
– serotonin depletion from Merkel cells since methamphetamine can facilitate serotonin release and inhibit serotonin reuptake.
– serotonin in Merkel cells is released by methamphetamine initially and serotonin in Merkel cells is likely to be depleted following the prolonged methamphetamine treatment.
– the static phase relies on Merkel cells and the dynamic phase is due to a direct mechanotransduction at Ab-afferent terminals.
Piezo2 is required for Merkel-cell mechanotransduction (2014)
https://www.nature.com/articles/nature13251
Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors (2014)
https://www.nature.com/articles/nature13250
Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals (W Chang, 2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027443/
Role of microtubules in Piezo2 mechanotransduction of mouse Merkel cells (W Chang, 2020)
https://journals.physiology.org/doi/pdf/10.1152/jn.00502.2020
Cellular and Ion Channel Mechanisms Underlying the Sense of Light Touch in Mammal (ongoing)
https://grantome.com/grant/NIH/R01-DE023090-08
they want to understand how chemotherapy causes loss of tactile sensation and how it deals with PIEZO2 and serotonergic transmission, with also the prospect of treatments for hypoesthesia of the skin.
[No notable search results for finasteride/isotretinoin + PIEZO2 /Merkel cells]
Identification of touch neurons underlying dopaminergic pleasurable touch and sexual receptivity (2021)
https://www.researchgate.net/publication/354788325_Identification_of_touch_neurons_underlying_dopaminergic_pleasurable_touch_and_sexual_receptivity
– Mas-related G protein-coupled receptor B4 (MrgprB4): rare subpopulation of unmyelinated, nonpeptidergic sensory fibers that exclusively innervate hairy skin.
– Transdermal optogenetic activation of Mrgprb4-lineage neurons in the skin surrounding female genitalia is sufficient to induce dopamine release in the NAc (nucleus accumbens), representing the first demonstration of molecularly defined somatosensory neurons triggering activation of a brain reward center. Moreover, Mrgprb4-lineage neurons are required for this same dopamine release during male mounts.
– Mrgprb4-lineage neurons are the first neurons of a skin-to-brain circuit encoding the rewarding quality of social touch.
[however the genitals and nipples are not hairy skin..]
L says
On p53:
p53/p63/p73 in the epidermis in health and disease (2014)
http://perspectivesinmedicine.cshlp.org/content/4/8/a015248.full
– Although p53 has long been known as the “guardian of the genome” with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.
Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies (2021)
https://www.mdpi.com/2072-6694/13/15/3819/htm
– The genome is constantly harmed by spontaneous damage caused by endogenous factors produced by normal cellular physiological conditions such as bases alteration, aberrant DNA enzyme function or oxidation, and by a large variety of exogenous genotoxic factors [1]. Cells have evolved a complex network of hundreds of proteins, named the DNA damage response (DDR), to ensure genome integrity and the expression of dedicated proteins to each cell type.
– in the last decade as part of anti-cancer therapy have been designed inhibitors of proteins that play a role as DDRs: DNA damage response inhibitors
– among these proteins, P53 plays a central role in managing cell proliferation, inducing cells with damaged DNA to apoptosis (death) and autophagy (eating parts of itself)
The Role of the p53 Protein in Stem-Cell Biology and Epigenetic Regulation (2016)
http://perspectivesinmedicine.cshlp.org/content/6/9/a026153.full.pdf+html
– The p53 protein plays a passive and an active role in stem cells. The transcriptional activities of p53 for cell-cycle arrest and DNA repair are largely turned off in stem cells, but there is some indication that long-term stem-cell viabilitymay require other p53-regulated functions. When p53 is activated in stem cells, it stops cell division and promotes the commitment to a differentiation pathway and the formation of progenitor cells. In the absence of any p53 activity, stem-cell replication continues and mistakes in the normal epigenetic pathway occur at a higher probability. In the presence of a functionally active p53 protein, epigenetic stability is enforced and stem-cell replication is regulated by commitment to differentiation.
p53: key conductor of all anti-acne therapies (2017)
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1297-2
– This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin’s sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
– isotretinoin via increased p53 signalling apparently depletes the number and survival of p63-regulated sebocyte progenitor cells.
Isotretinoin treatment upregulates the expression of p53 in the skin and sebaceous glands of patients with acne vulgaris (2022)
https://assets.researchsquare.com/files/rs-1609874/v1/b766abc6-a1aa-4020-bf02-8d8e09c19ddb.pdf
– Biopsies from back skin of patients taken before and after isotretinoin treatment show that the treatment significantly increased the nuclear expression of p53 in sebaceous glands, the p53 protein and gene expression significantly increased in the skin after isotretinoin treatment
– isotretinoin induces both p53-mediated autophagy as well as p53-induced apoptosis, depending on the dose and duration of isotretinoin exposure and the resulting magnitude of p53 expression.
– isotretinoin-induced expression of p53 not only promotes sebocyte apoptosis in human sebaceous glands as the predominant sebum-suppressive effect bit is also responsible for isotretinoin´s adverse effects [such as..]
I see that there is now the possibility of stem cell treatments for erectile dysfunction in centers that offer them at a high price as if they were infallible, but few opinions from people who have done it and perhaps little scientific evidence as well…
Cameron says
Are there any legitimate new leads to how to cure this ? I will sell my house thats worth over 500k if someone can figure this out . I have literally every symptom and already one suicide attempt . How can I volunteer to be part of a CRISPR trial on how to rid of this . I already have one suicide attempt . What should I do/not do to help my chances of recovery
Dr. David Healy says
Cameron
Will be putting up a post about this in about 10 days
D
Harry says
Cameron. I feel your pain but I do believe that help is on the way. The recent media storm over the Julia Moncrieff’s rebuffal of the serotonin hypothesis suggests the media are less afraid to criticise the pharmaceutical model. This provides the opportunity to raise awareness of the terrible consequences that these drugs can have. I am writing to every media outlet who covered the story to alert them to this public health catastrophe. With public concern comes research funding.
This awful condition may be very simply reversible. We just can’t know without the research.
I’ve found it helpful to channel my grief and anger into raising awareness and donating to research funds.
Patricia says
I have just contacted Helen Fisher
She is a researcher and writter focused in the link between brain and LOVE
You can ASK her for getting involved in her webpage
Theanatomyoflove
samantha rivers says
Perhaps the prize fund should be used to secure a lawyer to sue these companies.
I was on Zoloft for 2 years – came off it October 2008. Nowhere in my literature did it say PSSD forever. After coming off, I had hyper arousal for several weeks, which started to disappear, I was so relieved. But then it went the other way, bit by bit, it was like the lights were going out, one by one. To now 2022, I feel numb everywhere, including genitals, fingers toes, arms legs. No sensation, outside or in. Orgasms are a joke. I have no desire and am single raising my son, who is leaving for Uni next year. Should be a me time, sort of time. But the fact is, would a new partner understand or want to even take it on? Every single Doc I have spoken too, has either not heard me, or suggested other issues. I am not heard, no-one understands and I still have 1/2 my life to live. It sucks. I was living in Canada when this started and now reside in the UK. All the chats with Docs have been with UK Docs to no avail.
Ricardo says
100.000 isn’t gonna get us anywhere in terms of a law suit against Pfizer.
Funds should be totally invested for scientific research, immediately, where it’s needed, and I’m thinking more about Melcangi than Guerrini. Or the pfsnetwork’s projects (continuing Khera’s breakthroughs). At least these ones know where they’re going.
It can’t be as simple as identifying a single gene, sorry but that makes no sense at all. The disease has to be fully described and researched at molecular level. By leading molecular biologists. That’s what is being done now. Needless to wander in such abstruse thoughts as one or another gene or quote William James’ philosophy. That thing is not a subject to fool around with. People are committing suicide. That problem needs a whole new scientific field to be set.
Finance the pfsnetwork and pfsfoundation NOW and stop fooling around. And thonk of adressing the US congress and the EU parliament. And create an international PSSD/PFS day.
andreas says
Dear Mr Healy,
first of all, thanks for your commitment to find a cure for PSSD (plus other side-effects, better: unwanted effects of SSRIs)!
We are a group of sufferers and you are a person who gives us hope and confidence.
I appreciate a lot.
I am no doctor or research worker but I am a sufferer of almost all persistent side-effects of the SSRI Escitalopram.
I have taken only one single pill of this poison and all the problems began immediately and lasting for three years now.
After a long personal research I actually came to the conclusion, a very simple conclusion, that all side-effects are only caused by too much serotonin in the synaptic gap.
Whereby this is the sense of all SSRI (selective serotonin reuptake inhibitors), that means you can call them unwanted effects.
So, the question is not about the side-effects per se but the persistence of them.
The SSRIs are switching off the gene SLC6a4 by gene silencing, so the SERT (serotonin transporter), a product of this gene, can not be encoded and this product/enzyme originally resumes the serotonin from the synaptic gap back into the presynapse.
(This should be ended after 24h to 36h after taking the pill and because of this you have to take the next one and so on).
So the serotonin reuptake remains inhibited and there is too much and long lasting action of serotonin in the synaptic gap, human body.
This is causing the persistent, long lasting side-effects like PSSD, insomnia, akathisia etc…
How does gene silencing work?
You have to put a methyl group (CH3-Group) on the gene you want to switch off.
In this case the SLC6a4 gene. (the gene which encodes the SERT)
Now look at the chemical structure of a SSRI, for example Escitalopram: there you can find CH3-groups.
For why?
To look good or to switch off a gene?
Understand what I mean?
Switch off SLC6a4 => no SERT (serotonin transporter) => no reuptake of serotonin from synaptic gap into presynapse => more and long lasting serotonin in the synaptic gap => PSSD and others!!
Maybe 95% (I do not know) of the people taking SSRI do not have persistent side effects but maybe 5% do have. Maybe these 5% can not break down methyl groups, maybe there is a loss of something in their body, maybe something like a poor metabolizer of a special enzyme.
Now I have read about CRISPRoff/CRISPRon.
This tool can remove methyl groups (CH3 groups) off genes in an easy, fast and cheap way.
If this actually works, then you can free the gene SLC6a4 off the methyl group (CH3-group) and it is working again, it is switched on, and the serotonin could be resumed from the synaptic gap into the presynapse and the persistence of the side effects like PSSD is over.
I would be a volunteer in testing this, there would be many sufferers who would volunteer.
Maybe the CRISPRoff/CRISPRon tool is also working for PFS and PAS sufferers.
(have a look on the chemical structure of these meds who lead to this)
To all PSSD/PFS/PAS sufferers: hold on, together we are strong.
MattKDH says
Part of what has always held the topic back is a kind of primitive obsession with the phallic side of a proper erection, and not enough talk or even precise localisation of numbness. Some even go so far to say, “I’m cured, I get a proper erection, even though I’m still numb – but I don’t care about that”. Although an erection is the most mechanical, treatment responsive, understood, and least “experiential” part. (Alternatively there has been a reasonable enough obsession with orgasm, although that is itself in a way just an extension of numbness, which some spinal research confirms.) Anyway.
More than that also various cult dogmas and structures have been regressive and oppressive.
Nonetheless, it seems too likely that in the most severe and persistent cases some kind of damage is at the root of it, unfortunately.
Ben says
Look into mycotoxins and fungus
Sam says
Dear Dr Healy,
I believe you can update this page for a clinical trial for 2023 by WinSanTor for the treatment of reduced penile sensation and/or orgasmic dysfunction. WinSanTor has been working on a cure for peripheral neuropathy. Their agent WST-057, is topical pirenzipine, an anti-muscarinic receptor agonist approved for use for the treatment of peptic ulcer, was found to promote axonal growth.
I for one was left solely with genital anaesthesia, and the cause of that can either lie in the CNS or the PNS. Most of the research projects you listed above ultimately are tied to systemic receptor up or down regulation, in the CNS, which is perplexing that such dysfunction will result in neuropathy of as specific an area as the genitals.
In my view, WinSanTor’s solution could be the most promising yet!
Dr. David Healy says
S
While some of the key features of PSSD are peripheral and topical pirenzepine might help – if it works in diabetic neuropathy and doesn’t cause problems, the disorder is also all pervasive and some of its features likely stem from an autonomic neuropathy – see a new post on kisspeptin and PSSD due next week for some insight on this. So we would need a pirenzepine pill – there is one but it stays in the stomach and gut rather than gets absorbed.
David