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Gene silencing

Over a decade ago, Antonei Csoka put forward an epigenetic theory of post-SSRI sexual dysfunction (PSSD). His work is referenced in the template letter to epigeneticists.

David Stofkooper, a young man from Holland with PSSD, put great hope in this and went to senior researchers working on gene related problems hoping that something like the proposal below might help him. His questions led him to the conclusion there would be no ‘epigenetic’ cure soon and several years ago he took his own life.

His family have been generous supporters of the RxISK Prize and Research Fund.

Another person with PSSD has recently offered a similar thought – which is a good question to take to epigeneticists, primarily to find out how plausible and safe an approach like this might be.

SSRIs switch off the gene SLC6a4 so the serotonin transporter cannot be encoded. This inhibits serotonin reuptake in long term not just the immediate term and could cause persistent, long lasting side-effects like PSSD, insomnia, akathisia …

To silence a gene you have to put a methyl group (CH3-Group) on the gene you want to switch off. The chemical structure of SSRIs has lots of CH3-groups.

Perhaps up to 5% of people taking an SSRI have persistent side effects maybe because they cannot break down methyl groups perhaps owing to a loss of something in their body.

CRISPRoff/CRISPRon is a tool that can remove methyl groups (CH3 groups) from genes in an easy, fast and cheap way. This might be able to remove the methyl from the SLC6a4 gene and switch it back on.

Maybe this CRISPRoff/CRISPRon tool would also work for PFS and PAS sufferers. I would be a volunteer in testing this – if it’s possible.

It is definitely worth asking an epigeneticist:

  • if this option is remotely possible?
  • if possible would it be safe?
  • if not possible at present, might it ever be possible?
  • are there other ways to achieve this effect?

One of the researchers active on the forum took the question of expression of KISS genes to the team in Baylor who ran an epigenetic study in subjects with PFS, and there seems to be no difference in the expression of the genes for kisspeptin in the scrotal skin of subjects with PFS compared to controls. This is exactly the kind of input that helps move a research forum forward.


  1. Hello Dr. Antonei Csoka,

    I am Andreas, I am the one behind this thought written here.
    Maybe you can read the whole article of mine on this website.
    You can find this on “RxISK Blog”: “The holy grail: Searching for a cure for PSSD”.
    Blog Date is: June 21, 2022.
    It is comment number 41 of 43: andreas says: august 20, 2022 at 4:16 pm.

    I am very happy that you read this article because for me (only my opinion, I am no researcher) gene silencing is the only plausible reason for ALL these long lasting terrible side-effects, there must be only one single reason and that must be gene silencing of the serotonin transporter gene SLC6a4 which causes no SERT production, no serotonin reuptake into presynaptic neuron (it is persistently stopped) and too much and long lasting effect of serotonin in the synaptic cleft and in the post-synapses (various parts of the body).

    These side-effects, in my case, began immediately after only one single pill (Escitalopram) and that one was really the only one, no second one. Truly!!!!!!

    These side-effects are getting immediately much worse when there is a situation where more serotonin is produced or poured out. For example after I have done sports or I ate something which contains tryptophan like tomatoes, cheese, potatoes.
    So only too much serotonin and the non-reuptake are causing these side-effects.
    (this is the sense of SSRI by the way, it is easy)

    In a normal way serotonin poured out and maybe 20 percent had an effect, 80 percent were resumed.
    Taking an SSRI maybe 100 percent of serotonin has an effect and nothing more will be resumed.
    When you are a person who produces, because of personal constitution, very much serotonin in normal status, the effects of SSRI must be worse.
    So maybe not every person has such big problems because of SSRI.

    I have read the following:

    Gene silencing: methylation with CH3-groups and methyltransferase.
    Gene enhancing: demethylation (remove CH3-groups) with ??????. (TET enzymes?)
    Maybe these TET-enzymes are missing in PSSD sufferers and you only have to add them from the outside?
    Maybe you should look after the methylation of the gene SLC6a4, the amount of serotonin transporter (SERT) and the amount of TET enzymes.

    I think it is important to differentiate between ALL these side-effects per se and their persistence (after taking only one pill like me).
    If SSRI would directly act on the enzyme SERT there could not be a persistance. So SSRI must act on the gene SLC6a4.
    This persistence you can only “achieve” when you switch off the serotonin transporter gene SLC6a4 with methyl groups (=> no further SERT) and no removal of them.

    My opinion:
    The fundamentals to find a cure for ALL these awful side-effects are my main problems caused by this poison:
    my insomnia (extraordinary sleep like sleeping 1h, abruptly get awake, then sleeping 1h, abruptly get awake and so on for 5 to 6 times every night, strange nightmare and heart racing), my abnormal restlessness, my unnatural aggressiveness, my genital numbness, all effects caused by the non-reuptake of serotonin into the presynaptic neuron and too much and long lasting serotonin in the synaptic cleft and the post-synapses.
    These side-effects began immediately after only one single pill and that one was really the only one, no second one. Truly!!!!!!

    There are furthermore side-effects by the way which are all obviously caused only by too much serotonin also.

    If you have any question about my life with ALL these long lasting side-effects and how it all began, because this is the reason for my theory, please let me know.

    If my theory is right it would be quite simple to help so many people in such an easy way, isn’t it???
    (topic: Crispron/Crisproff, remove CH3-groups of SLC6a4)

    And it would be the same to help sufferers of PFS and PAS.
    (also Inhibitors with CH3-groups)

    Best regards, Andreas.

    • Dear Andreas,

      We can not say that it’s just the gene SLC6a4, but surely it’s an interesting idea.

      SSRIs have extreme antiandrogenic effect in the brain just like Finasteride. PFS people found so many genes altered, but Dr. Melcangi had recently found genes most likely in charge of PFS from the hypothalamus etc. Surely we have a major neuropathy as Dr. Melcangi has been thinking for a while, and now we are getting more and more evidence of SFN amoung PSSD patients. It’s just like after chemotherapy: You can have a severe chemo brain with cognitive declain, emotional / personality changes – and severe Sexual problems; loss of libido, erection / lubrication problems, problems getting arroused and anorgasmia / ejaculation problems. These processes are mediated via pheriferal and autonomic nervous system. Chemo brain has been linked to mitochondrial dysfunction and recent evidence supports that it could be reversed by intranasal suply of stem cells.

      Many people crash from some supplements/meds while the others can get little benefit of them. Interestingly mitochondrial function could be why this happen. No one can really now if they are getting worse or better when trying something. Also AR Gene should be investigated as any change in this might lead to significant androgen toxicity while having normal levels of plasma androgens. Persistently altered neurosteroids could be due to AR dysfunction, mitochondrial dysfunction or something else.

  2. Dear Juhana,

    Thanks for your input and interest in my theory.
    In this forum you could discuss and exchange opinions and that with engaged people, that’s great.

    In my opinion it is a very easy way to check the gene SLC6a4 in SSRI sufferers, to look after its methylation and remove the “SSRI caused” CH3-groups.
    Because the persistent non-reuptake of serotonin and the following persistent act of too much serotonin as a result is/must be the reason for all these big terrible problems of SSRIs.
    (that is the sense of all SSRIs and therefore called: selective serotonin reuptake inhibitor, whereby not persistantly, only as long as you take the drug)
    SSRIs do not have any direct effect on a disease (like most drugs), they have an indirect effect: they only increase the level and extend the duration of serotonin in the synaptic gap and that should stop diseases like depression, anxiety, etc., the prescribers tell you.

    If the pharma industry wants to develop a (new) drug, first of all there must be a target where the active substance should have an effect.
    In the case of SSRIs it obviously has to be the gene SLC6a4 (serotonin transporter gene) as a target.

    My persistent side-effects and all the others you can read in different forums, especially these side-effects written down by the pharma companies in the leaflet (serotonin syndrome for example), are all caused by the persistent non-reuptake and the consequent long-lasting effect of serotonin on various serotonin receptors in the body.
    Actually you can call them unwanted effects because the drug does want to stop the reuptake and to increase the level of serotonin in the synaptic gap, it is the sense of it, but not persistently, only as long as you take the drug.
    That permanence must underlie a “fault” in the human body, I think.

    That permanence is the key. That permanence must be the attackpoint to find a cure.
    Not the side-effects per se are the problems. They are only important to find the target and the acting of the drug. (silencing the gene SLC6a4)
    As I took this SSRI (only one pill),I got these side-effects independently of the permanence. These side-effects should stop when I discontinue taking this drug. And that was/is NOT the case.
    That is the problem: the permanence.

    It would be a first, very easy and cheap step to remove these methyl groups (by CRISPRon) from that gene.
    Then you can regain the normal level/acting of serotonin back again and the side-effects hopefully disappear.
    I am convinced that there would be a fast improvement of this terrible suffering.

    The research has not to be over then.
    I think Dr. Melcangi is doing a great and important research and he should be supported.
    We have to use different approaches, go different ways and ask different researchers.
    The more the better.

    Regards Andreas.

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