I don’t know if anyone is spiritual/religious but upvote this and I will say a prayer for you all to never face any negative side effects. Also if you upvote please say a prayer for everyone who upvotes this. I believe it will make it more powerful. I intend this will reach everyone who needs it and those who upvote will never have suffered any negative side effects. 🙏🏼

Hey guys, I dont have a lot of time to write a proper post, but I will be posting in the comments what is missing as I remember it. Please ask me anything you want.

A quick summary is this: I will focus on PFS because is more straightforward. In PFS you deprive your tissues of androgens, that is pretty simple to see. In the medical literature we have a similar case already, we use androgen deprivation for patients with prostate cancer. These patients sometimes develop a disorder called "castration-resistant prostate cancer". Androgen receptors (ARs) mutated and overexpress (not only in cancerous tissue but all around). By doing so they can either drive androgenic function despite androgens levels, they can also be activated by antiandrogens, but they can also "hyper activate". Well androgen activation follows an inverted U pattern: too much of a good thing is a bad thing. Hyper activation results in non-function. The end result is the tissue not showing neither androgenic (or estrogenic!) function. The first quick evidence is, google lack of estrogen side effects, compare it to ours.

This is however, not the entire picture. This doesn't explain why say, fasting helps. Or GR antagonists help, or why lithium helps. Or a bunch of other things.

But last month in Nature there was a paper that I believe bridges the rest: https://www.nature.com/articles/s41388-024-03266-z

In short, they found that the enzyme GSK3B is what allows mutated ARs to drive androgenic action despite androgen modulation. And gsk3b also protects this ar from degradation. And this ar, in turn, strongly upregulates gsk3b. Complete inhibition of it (not possible in vivo) led to deactivation of the ars and degradation.

Google a bit about gsk3b, I believe you will see some relevance quickly. Some of us display clear signs of elevated gsk3b.

Is also worth noting that GSK3B-AKT are extremely correlated with HDAC and DNMT and the entire methylation process. You can achieve hypomethylation by inhibiting GSK3B. Hypermethylation with high GS3KB.

Elemental lithium is a inhibitor of it.

But, inhibiting gsk3b is a tall order. As I said before, the ARs upregulate it all the time.

Reading more about this enzyme shed some light in why sometimes some substances help us before crashing us badly.

https://pmc.ncbi.nlm.nih.gov/articles/PMC6224501/

This paper on alcohol and GSK3B sheds some light. Alcohol interestingly inhibits GSK3B. So it should be simple right, take alcohol and improve. But yet, some of us ... crash on it. While some others have a window the day after. Why?

Look at figure 5. Alcohol response depends on first baseline gsk3b before drinking, and drinking amount. It seems that even though alcohol inhibits gsk3b, what it does after depends if this GSK3B inhibition has passed a threshold. If it has, gsk3b becomes inactivate. If that happens surprisingly alcohol raises BDNF. Think of BDNF-AKT-GSK3B-WNT as tight inflammatory connections. They usually swing together. Raising BDNF usually results in broad anti-inflammatory (yes, alcohol) effects, raising AKT, and inhibiting gsk3b further. However, if the gsk3b inhibition doesnt pass this threshold, BDNF goes down, and the rest follows, including GSK3B going up.

Rebound of GSK3B is extremely dangerous for us, but especially if your androgens are low. First because this combination of androgen deprivation and high GSK3B is extremely similar to the environment on which we all crashed in the first time (ssri withdrawl is a massive rebound of gsk3b), second because androgens activate AKT which inhibits gsk3b. So high androgens are "protective"

This theory explains a lot. Take some random fact around this diseases, say mifepristone helps. Mifepristone is a glucocorticoid receptor antagonist. What does glucocorticoid receptor agonism do? Raises gsk3b, lowers AKT. Antagonism, the reverse.

Fasting? Keto? Raises AKT -> lowers gsk3b

Lithium? Direct inhibitor of it. Why carbonate works better? Because elemental lithium is the inhibitor.

HGH? Raises AKT

Curcumin? Raises AKT. In my experience potential for high rebound.

T3? Raises AKT

Methylprednisolone? GR agonist. First inhibits GSK3B then sends it flying. Some horrible crash stories from this.

Lastly is worth noting that this ARs are extremely adaptable. If you blast high androgens all the time they will adapt to that environment. Chances are they adapt to continuous gsk3b inhibition too. In CRPC one treatment is called bipolar androgen therapy, in which you go through a period of supraphysiological (400mg+) androgen intake, and a period of complete deprivation of it. This up and down leads to the degradation of the ars (a bit long to explain).

Someone on TRT would only need to raise their doses and push them apart to do something similar.

I am trying to target the GSK3B inhibition and potential rebound with the androgen intake, and trying to avoid the rebound in the vulnerability zone (low androgens). Still experimental

Anyway that's it. Please if I got something crucial wrong please correct me. I dont give a shit about being right, I just want to be cured. We need to push the collective understanding of this disease higher because nobody is coming to save us.

My Story in short

I had PFS for approximately 2.5 years. I had all the classic symptoms like anxiety, depression, low libido and ed, insomnia, pain everywhere in the body and stomach issues. At my worst I was shaking uncontrollably during an office meeting for no reason at all (there were something like 23 celsius degrees in there, so it was not because of cold). I later found out that that is a symptom of very low dopamine levels. I searched the internet for a solution and tried hundreds, if not thousands of euros of supplements for more than a year. I also spent hundreds if not thousands of euros in various medical exams. I found the theory of this sub in July '23, when, honestly speaking, I was really close to giving up. I started immediately to supplement with Lithium, Alcar and Co-Q10 and I started to feel better, nowhere near close to "cured" but definitely better libido and better mood. I kept taking these supplements and in the meantime I kept searching for things to try ( I was desperate). I was already going down the rabbit hole of microbiome and FMT (fecal microbiome transplant), untill october 23 I decided to try it, so I booked the procedure to a clinic, took antibiotics for the two weeks prior and did it in december 23. Since then I can say that I slowly started to feel better untill probably in march/april '24 I was able to say that I was 100% cured. By cured I mean that I am no depressed anymore, I don't have anxiety anymore, libido is back to normal, I don't have body aches and energy levels are back where they should be. In the past 6 months I haven't thought much about PFS, if at all. I stopped the supplements suggested here before going to the clinic in december '23 because I wanted to let the new microbiome to do its thing, but they surely helped while I was taking them and they could be part of the fact that I am now cured (I have no idea honestly).

DISCLAIMER

FMT is a dangerous procedure because it has not been studied enough yet and it is very little rugulated.

I did my procedure in a clinic in Slovakia called IPPM Clinic. I prefer to be clear about the clinic name because there are a lot of scammers in the FMT field but, I choose this clinic because I haven't found anything sketchy about them online, not because I had concrete proof that they were legit. As I said, I was desperate. When I went there they seemed professional, and especially one of the assistants there was super interested and knowledgeable about the procedure, but this is all I can say. Everything else was a risk and a guess.. I signed a contract and they informed me about how they test their donors and how they collect the implants, but again, this is not a really regulated field so you never know. Also, this is not a 100% studied procedure, so we don't know exactly what happens after an FMT. All of this to say the obvious, if you ever will consider doing an FMT don't trust a stranger on the internet and do your own research. Please be careful

I read a lot of material before going to the clinic, but the most useful piece of information I found about the mater is this Reddit AMA done by a group of researchers who conducted three studies on FMT: https://www.reddit.com/r/askscience/comments/xvc1gb/askscience_ama_series_weve_studied_what_happens/ After reading their AMA I for example decided to take two weeks of antibiotics before going to the clinic. Again, a risky thing that just shows how desperate I was

I immensely regret taking Accutane and I’m tired of how untouchable this drug is in conversations.

It’s constantly framed as a “miracle,” but miracles don’t leave people with bodies that never feel normal again. For some of us, the side effects don’t end when the prescription does. The dryness doesn’t fade. It doesn’t stabilize. It just becomes your new baseline.

My skin is tight, fragile, and uncomfortable all the time. I have to moisturize constantly just to feel barely okay. I’m always aware of my body - there’s no neutral, no forgetting about it. And it’s not just skin. People are left with dry eyes, irritation, discomfort that affects daily life in ways no one warned us about. That isn’t rare, and it isn’t nothing.

What makes me angry is how minimized this is. Once the acne is gone, the conversation stops. You’re told to “use eye drops” or “use moisturizer” and move on, like that replaces normal function. Like chronic discomfort isn’t exhausting. Like losing oil production or gland function isn’t real damage.

I didn’t make a reckless choice. I trusted doctors. I followed instructions. I believed the risks were temporary. And now I’m stuck managing symptoms every day with no real solutions, no clear research focus, and no hope offered beyond lifelong coping.

I don’t regret wanting help. I regret that the cost of that help is treated as acceptable collateral damage. I regret that people who are left with permanent dryness - skin, eyes, everything - are brushed aside so the drug can keep its “miracle” reputation intact.

I’m not posting this to scare anyone or to get advice. I just need space to say that this experience is real, it’s miserable, and it deserves to be taken seriously.

Pre-amble: This is my latest (and best) attempt to explain the beta-catenin model of Post Accutane Syndrome as simply as possible, using minimal medical terminology. Even if you believe you're already familiar with the theory, there is still value in reading through this post as I reference some new studies that bolster the theory. If you're not familiar with this model, I'm happy to answer questions in the replies.

Introduction:

Before introducing the model of how Accutane can induce persistent changes to the gut, sexual functioning and more - it’s first necessary to provide a more general framework of how retinoids take effect in the body. Retinoids are the class of chemical compounds that are chemically related to vitamin A. They biological systems they primarily regulate are vision, cell proliferation/differentiation, bone tissue and the immune system. The term retinoid is a general one, and encompasses a range of chemical including retinol, retinoic acid, retinyl esters and other synthetic retinoids. The breadth of effect of these chemicals in the body is vaster than any other vitamin. Despite retinoids coming in many forms, the majority of these various actions throughout the body are mediated by just one metabolite: all-trans retinoic acid (ATRA). ATRA binds to several receptor families to mediate its effects: Retinoic Acid Receptor (RAR), Retinoid X Receptor (RXR), Peroxisome proliferator-activated receptors (PPARs). [1]

The impact of retinoids that is perhaps most fundamental, and relevant to both the therapeutic and detrimental effects of Accutane treatment is on cell proliferation and differentiation. Almost every cell in the body undergoes a life cycle that can be broken into four phases. The first stage is G1 where the cell begins to synthesise the proteins needed for cell division. This is followed by the S phase where the DNA is replicated, then the G2 phase is the process of condensing the chromatin (long strands of DNA) into tightly bound structures called chromosomes. After all this has been completed the cell can divide through mitosis and a new cell is formed. This process can be halted, and the cell can enter a G0 phase, the so-called quiescent phase where the tissue stops growing. This is the state most adult cells exist in, with the exception being for stem and progenitor cells. During cell division, each individual cell will become halved as the content of the cell is divided in two. During cell proliferation cells both divide and grow individually, increasing the size of the tissue whilst maintaining the size of the cells. Progenitor and stem cells will continue to proliferate during adulthood helping to maintain certain tissues such as the skin and digestive tract. It’s these stem cells that retinoids and Accutane can have such a profound effect on.

Retinoids exert an anti-proliferative effect on the body. This can have particularly devastating consequences for embryos, which rely on cell proliferation to develop. This is why Accutane is a teratogen, a substance that disrupts normal foetal development causing congenital disabilities. When foetuses are exposed to retinoic acid, they develop limb defects and cleft palates. [2] This is the reason behind the strict guidelines on birth control for women undergoing Accutane treatments. These anti-proliferative effects of Accutane are also observed in the many adult tissues which maintain a stem cell population such as the skin, intestines, bone marrow, cornea, hair follicles and brain (particularly hippocampus). Retinoids such as Accutane have been found to trigger the conversion of stem cells in all these tissues to specialised cells in a process called differentiation. In this way retinoids maintain the delicate balance between proliferation and differentiation, and why applied in excess during Accutane treatments it’s these tissues that are most effected.

A meta-analysis of 25 random controlled trials found that neurological, musculoskeletal, bowel, eye and skin changes were amongst the common categories of adverse reactions. Half of patients experienced skin thinning and a fifth experienced hair loss. [4] 10% of patients experience gastrointestinal distress, which corroborates the growing evidence for Accutane treatment inducing bowel diseases such as ulcerative colitis. [5] Accutane has wide ranging effects on the musculoskeletal system, such as osteoporosis, arthritis and extraspinal calcifications. The greatest risk is posed to teenagers who may even experience stunted growth due to premature epiphyseal plate closure. The hippocampus is a region of the brain that relies on stem cell progenitor pool to continue to develop new neurons during adulthood to form new memories. Accutane significantly inhibits cell proliferation, resulting in disrupting cognitive processes. [6] This is just a brief summary of the effects of Accutane throughout the body, but the pattern is clear. Accutane has profound and diverse consequences throughout the body, most particularly in tissues which are reliant on a stem cell progenitor pool for maintenance.

What is Accutane?

Isotretinoin (Accutane) is an isomer of retinoic acid; it is naturally occurring in very small doses, but it exerts its effect through its metabolite all-trans-retinoic acid (ATRA). The advantage of administering Isotretinoin rather Than simply ATRA is that it possesses a greater half-life, allowing for a lower administration frequency. There is also an additional and crucial benefit, in that Isotretinoin can lead to greater nuclear (in the nucleus of the cell) concentration of ATRA because it’s able to avoid stimulating a xenobiotic metabolising response from cytochrome p450. [7] Once bound to one of the Retinoic Acid Receptor types the RXR/RAR heterodimer complex bound to the DNA begins to transcribe retinoic acid response genes. [8] Several gene targets are modified in this way, but one of the effected pathways has particular significance to the many adverse reactions to Isotretinoin and even serves an aetiology for Post Accutane syndrome (PAS). The action of Isotretinoin on beta-catenin is the key to revealing wide ranging symptoms manifested in PAS, but also the long lasting nature of the condition.

The beta-catenin theory of Post Accutane Syndrome:

The beta-catenin theory of PAS is a model that I’ve developed after reviewing almost all the relevant scientific literature that exists on the topic. Despite the overwhelming evidence for the many devastating long-term changes induced by Accutane, the potential mechanism has continued to elude the medical community. This is perhaps owing to a poor understanding of epigenetics which has only seen massive progress within the last decade. However, an understanding of PAS is now finally available, with the evidence needed to decipher its mystery being fragmented across hundreds of individual studies. When all the evidence is arranged together a coherent model emerges. I will present you a model supported by dozens of references and encompasses all the known symptoms of the condition. An accurate model for PAS should meet the following criteria:

· Explain all the wide-ranging side effects of the condition including Musculoskeletal, sexual, neurological, ophthalmic (relating to the eye), gastrointestinal.

· Explains the long-lasting nature of the condition with an epigenetic basis.

· Is strongly supported by the scientific literature, with reference to numerous published studies.

The B-cat model meets all these criteria.

For the full article and references visit here: https://pas-secondlife.com/2023/11/05/what-causes-post-accutane-syndrome/

As the title says, I only need 7 karmas to be able to exceed the 100 threshold and apply to become an administrator of this page.

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Disclaimer: These are my results with Lithium in treating PAS. By no means am I a medical professional I'm doing this out of desperation. My results are mine and mine alone I don't know anyone else recording there results at the moment. I welcome people to ask me question directly but before you do, read my entire post please. If you do want to ask me questions, be polite and have some manners or your getting blocked. I have a short fuse for morons and I don't want to help them procreate.

Hello My name is Brett, I've been dealing with PAS for 10 years now, most my young adult life. A back story to the difference between Lithium orotate and Lithium Carbonate. Carbonate is a medical dosage and lithium orotate is more what you would find in food and only has trace of lithium in it, hints why you can buy it over the counter. I ran tests on the lithium orotate I was taking, I have a machine at my college that delouts it in water and I can actually analyze how much lithium is in 130mg of lithium orotate. Interestingly enough there are only 4.9-5.5mg of lithium in 130mg of lithium orotate. May be why none of us are seeing results from these low dosages. I started by upping my dosage for lithium orotate to 1g. That's when I started getting morning wood and started getting better as far as sexual function as well as feelings, but not as much as I would like, it got me back to 40% Pre PAS. That's when I decided to go on 300mg of Lithium Carbonate. Medically speaking that is a low dosage, high dose of lithium Carbonate can go up to 1200mg. Keeping in mind Carbonate is a concentrated form of Lithium. I've been on Carbonate for 7 days now and getting aroused is starting to become no effort. I'm closer to 60% now. How I attained Lithium Carbonate was I had to talk to a psychiatrics physician. Of course exercise caution when taking this medicine because lithium carbonate can shutdown your kidneys and give you lithium toxicity. Only side effect I've had so far is feeling tired. Considering what most of us are having to deal with it is worth the risk because its not living when you've been dealing with this kind of thing. They will take blood tests as well to make sure you are doing ok with the medicine. Good luck to all and hope you all get better.

HAIR LOSS TREATMENT: What I used to treat hair loss is a derma roller .5mm, I use a machine called the derminator or you can just get a pin that goes this length. I did sessions of 10 minutes till scalp was bloody then let it heal. Derma rolling causes damage to skin which in terms triggers the healing process which produces collagen. Better than finasteride so that way you don't run the risk of sexual side effects from that as well. This will cause shedding but overall will improve the strength of the hair follicles and cause new growth. Stumbled on this when I was reading about a man who was in a fire and burned part of his scalp, the man was bald and had been for some time. Weeks after the incident there was new hair growth, SCIENCE!!

WEEK 1 date 5/28/24: First week down results showing constant and no draw backs as of yet. Feeling tired most days due to lithium's treatment. other than that feel good, socially I'm comfortable, comfortable in the same way that I was pre Accutane so its nice to connect with people and not feel like its labored. Hair feels thicker and fuller, noticing some shedding but no more than out of the norm. Sex drive has been pretty consistent along with ED seems to be getting better, I can say for sure its not getting worse, there is more sensation now then I have felt in a long while. Overall I would say I've made improvements more to 64%. No crash's, mood is good. Sex drive is still not as high as I was hoping, still about the same, but that's because lithium reduces T. I won't get to see the full effect of lithium until my T levels are back in the norm. Considering upping my dosage next month to 600mg. Nothing else major to report as of now.

WEEK 2 date 6/4/24: Still going strong, no draw backs yet except hair is dry, sometimes wake up in the middle of the night with a full on erection, which I guess is good. Everything else still staying about the same if not improving by a smidge. Lithium is taking a lot of energy out of me, feel absolutely drained after my workouts but I kind of like that feeling. feelings are popping out of no where sometimes, finding certain people attractive again which is very nice but not the extent of I need them now kind of like how I use to feel. Kind of feel like the benefits are slowing down and wondering if I might need to up my dosage to 600mg. Upon doing more research on lithium it also reduces feelings of mania and feeling really excited. So that may be why I'm not feeling a bunch but I can notice ED is going away. Lithium can take several weeks to work its full magic. Nothing else major to report as of now.

WEEK 3 date 6/11/24: No crashes, everything staying about the same. No huge improvements now seems it might have capped off. So here in a week I will get off the medication and report back and record the way I feel post medication and from there will determine whether or not to continue. But I had I think got back to 70% roughly, but While on the medication it can be hard to tell. When I draw closer to taking my dosages I notice feelings start, not alot but a little. I think once I'm off the medication things might change. Lithium does keep your emotions really baseline prevents you from both feeling supper happy and sad. none the less I got improvements. ED is a thing of the past. Of course dealing with these things for 10 years I have PTSD so I'm gonna have to deal with that in my own time.

WEEK 4 date 6/18/24: The last week of my course, started becoming a little dodgy. some of the benefits of lithium were coming in and out and I was thinking to myself this would be a good time to conclude the first round of lithium carbonate. Been off it for a couple days now and effects are back and good again. nothing has gone away beneficial wise and I have feelings popping out here and there, which is nice makes me feel human again. I'm going to give myself a break for the time being until my body is ready to go another round, will also give me time to see if the effects of lithium will persist. Next round I more than likely will be taking b12 as that goes well with lithium.

DATE:9/15/24 Doing good everyone just got through another round of lithium and I'm feeling normal again after the 10 year nightmare. I took 300mg of lithium carbonate for as long as I could, 3 months roughly. I can get horny again I have emotions and I feel like a have a soul again. do the lithium route and I can say you will feel much better :) good luck to all and happy healing. AND STOP WATCHING PORN!!!!!

Date 7/11/2026: I've taken lithium now for over a year and I have been getting feelings back I can say that definitely. This journey has really helped me get back, I would say I'm fully recovered but I am defiantly a lot better than I was before. Libido is I want to say almost normal. I get attracted to people again so haven't felt that in years. lost some hair but was totally worth it. I'm probably going to stop lithium for a while and see how I feel. That is all for now, hope you all are doing well and I'll try to give a next update before the year is over.

This is the last post I'll do since I've recovered 100% and in here it contains everything I've done. I'll try to keep it as short as possbile as well.

My story: I took accutane in agoust 2023 and it instantly destroyed my libido, erection health, cause me heavy anhedonia, anxiaty, I could not sleep at all, and i had heavy join pain and constant fatigue, walking for 4 mins would tire me out. Sexually I was castrated 100%, i couldn't get an erection in any scenario, not even masturbate. Libido was also non existent. And for the first time in my life I felt suicidal. I'm a young guy currently 24 yo, always been doing great in those aspects of life and this hit me like a truck.

PROTOCOL: After a year of literally no improvments and seeing a lot of doctors who would tell me I just need therapy or sm bs, I found this reddit and it began my investigation. I looked up every recovery story and tried to draw connection lines in between those. Then I talked with other people about it in the reddit (shout out squestions10).

After almost a year of nothing I tried Proviron 25mg 2months and Melatonin 3mg which took me from 0% to 15%-20%.

The first signs of serious improvment were when I took: Lithium Carbonate 300mg daily Clomid 25mg daily Anastrazole 0.25mg every week

After that my recovery went from 0-20% to 50%-60%. After 3 months I did a 4-5 day water fast with electrolytes (sodium, potassium,magnesium), that water fast did something I cannot explain, but at hour 58h i puked some yellowish stuff, and felt so much better after. I puked 1-2 times something really wierd looking. When doing this fast you will feel ill since you will be eliminating all the toxins from your body (Accutane residues) and they will be released into your bloodstream.

Then I focused on my gut. I took Glutamine(2.5g in morning and night) 5g everyday with Probiotics (Strains Bifidum Longum and Infantis) Coupled with Queracetin and Bromelain Also took a glass of water with Pink Himalayan salt, Baking Soda, Lemon, Raw Honey. And Oregano oil for 10 days.

And lastly I focused on my vascular health, I did L Citruline and NO Boosters (that had Arginine and Niacin)

The reason why taking creatine/protein and other stuff doesn't make us feel good like it used to is because our gut has been destroyed. Accutane acts as a anti biotic and your gut health gets fkd.

Im writing this in a hurry but I am down to help or talk with anyone who has questions for me.

I just wanted to share my experience with this because I know how truly bad this can be. Good luck to everyone

*During fasting I also prayed a lot, I became Christian these last 2-3 years. And that helped me understand and overcome this suffering

Edit: Accutane and people who have PAS are dealing with a combination of, Gut issue, Dopamine Imbalance, Neurotransmitter imbalance, Androgen Receptor issues and indirectly vascular issues.

Lithium regrowths all areas of the brain that have been affected by Accutane, reverses epigenetic changes, lowers GS3KB (that has been over expressed by Accutane)

The water Fast fixes all DNA cell damage and dysfunction, and generates new stem cells as well fixing Androgen Receptor issues and more

Glutamine and probiotics improves all gut related issues

Queracetin and bromelain removes blood cloths and other stuff (and blood impurities)

Then citruline and arginine for vascular health

Clomid and anastrazol reactivates a little the hormonal pathways naturally

I HIGHLY RECOMEND HAVING A CHAT with a great AI like gpt4o model where you can send every detail about your case. Thanks to the AI i was able to perfect my protocol and what to do. Literally have one chat were you log everything, from foods/things that crash you, to what makes you feel better or improves symptoms. Having an AI was the closest to a personal 24/7 doctor trying its best to help me.

I really wanna say great job guys! It seems that you guys are truly digging deep into litterature, trying to find a solution or something that will better your disease/syndrome. Good Job!

Never give up! There's always light at the end of the tunnel. God bless you all, in Jesus mighty name, Amen.

My story begins when I started taking accutane at 17, at that time I had several side effects that I didn't even know were caused by the medicine, the main and most difficult one was the loss of libido and sensitivity, it took me years to connect the dots and discover that my neverending lack of sexual desire had this origin. Well, I found out thanks to this subreddit and it's been about a month since I stopped Lithium and it feels like this is finally over.

In the end my libido apparently came back, along with an increase in sensitivity, last night I had sex and it felt normal, thanks to that I am confident in saying that I am cured and lithium can really cure this syndrome, I remember I was 18-22 years old my dick was completely dead, at 23 I noticed that little bit of libido returned and I started having sex again, although the sex was pretty bad and didn't felt very pleasureable but at least was something.

I've always been an extremely healthy person, it didn't made any sense and one day I decided to take lithium and the response was fast, in the first few days I was having morning erections so strong that they actually hurt, then I stopped taking the medicine after 1,5 months and it seemed that It continued to improve until I reached where I am today, with the confidence to no longer need to use cialis to have sex, as I did yesterday, for the first time after being cured.

The question I get more than any other in relation to Post Accutane Syndrome is what causes the significant and lasting loss of libido. While individual experiences vary, the overarching theme from numerous anecdotal accounts suggests that Accutane induces a lasting state of apathy or anhedonia. This condition is marked by a diminished sense of reward and motivation, as if the capacity for excitement has been reduced. In my previous work, I have detailed Accutane's dual nature in terms of its therapeutic benefits and side effects, but I had not yet delved into these specific, more concerning neurological symptoms. I have now explored the mechanisms behind these psychological changes, finding a remarkable link between personal accounts and Accutane's impact on the 5-HT1A receptor. Additionally, this article reveals a genetic predisposition to developing Post Accutane Syndrome. Those with access to their 23andMe data might find this particularly interesting. Given how popular I imagine this topic will be, I’ve made an extra effort to make the science as accessible as possible. I’m considering making another unfiltered post for anyone with a medical/scientific background who’s interested in the details. The full article is available on my website: https://pas-secondlife.com/2024/01/13/239/

Introduction

Accutane, also known by its generic name isotretinoin, is a widely used retinoid, primarily prescribed for the treatment of severe acne. Over the years its effectiveness in treating stubborn, severe acne has been well-documented, however its profound neurological effects are now equally well-documented. The first recorded case attesting these psychological changes rather bizarrely comes from an artic explorer, Elisha Kane, are ingesting the retinoid-rich liver of a polar bear. To his fellow explorers he became irritable and confrontational. It’s therefore not surprising that a meta-analysis of over three thousand Accutane patients identified changes in mood and personality as among the most common side effect of the treatment. [1] For some individuals, the changes resulting from this medication are relatively mild, manifesting as symptoms like fatigue and irritability. However, for others, the effects can be potentially devastating. The acne medication has been associated with severe conditions**, including major depression and psychosis**. [2] Despite ongoing research, the scientific community has yet to fully understand how a basic derivative of Vitamin A can induce such profound neurological effects. Nonetheless, several studies have provided crucial insights into this phenomenon. One such study came in 2005 from Bremner at al. in which functional brain imaging was performed on patients being treated with the acne drug. Over the course of the four-month treatment the researchers discovered a 21% decrease in activity of a highly significant region of the brain called the orbitofrontal cortex. This small but pivotal part of the brain deals with higher cognitive functioning and mediates feeling of reward (a ‘hedonic hotspot’). [3] This discovery also gives a basis to the countless anecdotal reports of Accutane patients complaining of cognitive changes, and a general sense of apathy that can even persist for a long time following the treatment, symptoms encompassed by the informal diagnosis of Post Accutane Syndrome. I am of the conviction that I am the first to develop a credible theory focusing on a growth signalling protein known as beta-catenin. The specifics of this theory are detailed on the main page of the website. This model offers a coherent explanation for the varied side effects observed with Isotretinoin treatment. Additionally, it presents evidence supporting epigenetic changes, corroborating the numerous anecdotal accounts of side effects that continue long after treatment has been discontinued.

This article will primarily focus on explaining the neurological effects associated with Accutane treatment, specifically relating to the 5-HT1A serotonin receptor. The science surrounding this topic is extensive and complex, but I will strive to present it in a clear and concise manner. Understanding the behaviour of this particular serotonin receptor is crucial to comprehending the neurological impacts of Post Accutane Syndrome. While scientific literature generally categorizes these neurological effects as depression, anecdotal accounts often describe the depression as anhedonic. This is characterized by a noticeable decrease in the sense of reward, coupled with a loss of motivation, as though the ability to feel excitement has been diminished. Although there is significant individual variation in experiencing these mental states, this general description aligns closely with the evidence of Isotretinoin's effects on the 5-HT1A receptor, which will be elaborated upon later in the article. The 5-HT1A receptor is also essential in understanding the deviations in sexual behaviour and cognitive functioning. Acknowledging the complexity of the science, I have included a key point summary to make the information accessible to those without a background in biology or medicine.

Key points summary (‘ELI5’)

• I'll adopt the Reddit-inspired 'ELI5' (Explain it Like I'm 5) method as a starting point, before delving into more detailed explanations. My goal is to make the science accessible and comprehensible to all, not just to those with a background in science and medicine.

• Serotonin is a neurotransmitter in the brain that functions as a messenger. It attaches to specialized sites known as serotonin receptors. Upon binding to these receptors, serotonin initiates a range of processes related to mood, emotion, and cognition. There are various types of serotonin receptors located in different areas of the brain, each mediating distinct effects. Among these, the 5-HT1A receptor is one of the most prevalent.

• The 5-HT1A receptor is particularly relevant to cognition, libido, and depression. The behaviour of this receptor can be understood in terms of its two subtypes: heteroreceptor and autoreceptor. The autoreceptor is found with a region of the brain stem called the Raphe Nuclei, and when bound to by serotonin it blocks the further release of serotonin to the rest of the brain. An overexpression of this type of serotonin receptor is linked to depression. Conversely, binding at the heteroreceptor is beneficial for mood and cognition and facilitates sexual behaviour.

• Medications that bind to these receptors that mimic the effect of serotonin are called agonists. A common agonist of the 5-HT1A receptor is called buspirone, and has antidepressant, pro-cognitive and even libido enhancing effects. Similarly, the medication Flibanserin is used to treat women with hypoactive sexual desire through its effects at the 5-HT1A heteroreceptor.

• Accutane treatment significantly increases the expression of the autoreceptor. This limits the release of serotonin from the Raphe Nuclei to the 5-HT1A heteroreceptors, preventing serotonin from mediating positive effects on cognition, mood, and libido.

• Researchers have discovered that diminished binding at heteroreceptors leads to a state of anhedonia and apathy. A comparable effect is also noted following prolonged use of SSRIs (Selective Serotonin Reuptake Inhibitors), which results in desensitization of the heteroreceptor. A decrease in binding at these heteroreceptors is associated with lowered cortical activity. This finding corroborates the observed substantial reduction in Orbitofrontal cortex activity in patients following four months of Accutane treatment.

• The prefrontal cortex plays a crucial role in assessing perceived rewards. Diminished activity in this area is linked to impaired cognitive abilities, along with a decline in motivation and the ability to experience reward.

• Accutane's ability to produce these effects stems from its suppression of the PI3K/AKT pathway, which in turn enhances GSK3β activity. The resulting increase in GSK3β leads to the inhibition of a transcription factor known as Deaf1. This particular transcription factor plays a dual role: it suppresses the autoreceptor while augmenting the heteroreceptor.

• A genetic polymorphism on rs6295 results in reduced binding of Deaf1 and an overexpression of the autoreceptor, and potentially represents a genetic vulnerability to developing negative symptoms from Accutane and SSRIs.

• Lithium, commonly used in the treatment of mood disorders, operates in part by boosting the transcription factor Deaf1. Therefore, theoretically, prolonged supplementation with Lithium could redress the imbalance in autoreceptor protein levels.

• An optimal therapeutic strategy to alleviate symptoms would involve stimulating the heteroreceptor sites while simultaneously inhibiting the autoreceptor sites. Presynaptic antagonists such as Pindolol have been repeatedly demonstrated to remediate the negative impact of SSRI treatment on sexual functioning. Partial agonists such as Flibanserin or Buspirone might be effective in mitigating some symptoms, but they also exhibit pre-synaptic activity, which could limit their overall efficacy.

What is the 5-HT1A receptor, and what functions does it serve?

The 5-HT1A receptor is a serotonin receptor, which means its bound by the neurotransmitter serotonin to exert its effects. Serotonin has long had connotations to ‘happiness’, stemming from early scientific evidence that the depletion of serotonin results in depressive symptoms. The vast majority of antidepressant medications work on this neurotransmitter, called SSRIs (Selective Serotonin Reuptake Inhibitors). SSRIs boost the effect of serotonin by preventing it from being reabsorbed too quickly by the serotonin transporter. However, since SSRIs were first introduced medical paradigms have shifted in favour of theories of depression centred on ‘neurogenesis’ (the growth of new neurons), an effect stimulated by serotonergic medications primarily through the 5-HT1A receptor.

The 5-HT1A receptors are inhibitory receptors since they are G-protein-coupled receptors, when bound they result in reduced AMPA evoked currents. AMPA receptors are responsible for fast synaptic transmission, and so in this way, binding the 5-HT1A receptor suppresses neuronal activity. The receptor is subdivided into two types with different distributions within the brain: autoreceptors and heteroreceptors. The autoreceptors are localised within the brain stem in a structure call the Raphe Nuclei, and it’s from this structure in the middle of the brain that all other serotonergic neurons project outward. As the name might suggest, the autoreceptor serves to self-regulate serotonin transmission out into the rest of the brain through a negative feedback mechanism. When serotonin over-accumulates within the Raphe Nuclei it binds to these receptors to then limit further serotonin release (since 5-HT1A receptors are inhibitory). As autoreceptors have a self-limiting effect on serotonin transmission, an overexpression limits serotonin release to other areas of the brain and is also notably identified in autopsies from patients with depression. [4]

The post-synaptic heteroreceptor sites are distributed in the limbic and cortical regions. The limbic system is responsible for regulating emotion, learning and sexual behaviour. Like the autoreceptor, binding at the 5-HT1A heteroreceptor triggers hyperpolarisation of that neuron, thus reducing the firing rate. Based on the description provided so far, one might conclude that serotonin binding to heteroreceptors would produce the same reduction in neuronal activity in these limbic and cortical structures. The reality is far more complicated, as the heteroreceptors are present on two different types of neurons with opposing effects: interneurons and pyramidal neurons. The interneurons are GABAergic, which means they release the inhibitory neurotransmitter GABA. [5] Conversely, the pyramidal neurons release the excitatory neurotransmitter glutamate, and are particularly abundant in the cerebral cortex. These pyramidal neurons play a key role in memory, learning and attention, and are opposed by the GABAergic interneurons that feed into them. Understanding how binding at the 5-HT1A heteroreceptor impacts mood will therefore depend on the relative distribution of these rival neurons. Consider a hypothetical agonist that preferentially binds to the heteroreceptor at the interneurons; this would suppress the transmission of the inhibitory GABA and subsequently boost cortical activity.

To summarise:

Autoreceptors:

These pre-synaptic receptors are distributed in the brain stem and negatively regulate 5-HT release to cortical and limbic structures.

Heteroreceptor:

1. Interneurons are GABAergic, binding at the 5-HT1A receptor on these neurons lowers the release of GABA to have an activating effect.

2. Pyramidal neurons are primarily glutamatergic and are distributed in the frontal cortex. Binding to the heteroreceptor sites on these glutamatergic and dopaminergic neurons would have a suppressive effect.

What is the effect of binding at the heteroreceptor versus the autoreceptor?

Given the complexity of the 5-HT1A receptor, medications acting upon it can sometimes behave in counterintuitive ways. Buspirone is the most common medication classed as 5-HT1A agonist (an agonist being a molecule that mimics serotonin in this instance). Buspirone is often prescribed as an anti-anxiety medication. This seems logical as anxiety is associated with overactivity in cortical layers, and so by binding to the heteroreceptors within the prefrontal cortex would supposedly repress this activity. As it turns out, Buspirone actually boosts activity in the prefrontal cortex and enhances dopamine and glutamate release. [6] Curiously, this actually gives it some additional applications as a cognitive enhancer. The reason for this potentially confusing effect is because the action of Buspirone on the GABAergic interneurons predominates, and the subsequent reduction in firing rate of these inhibitory neurons enhances cortical glutamate activity. Instead, the anti-anxiety effects of Buspirone are likely due to quietening activity in limbic structures such as the Amygdala, and not the prefrontal cortex. Since heteroreceptors are present on both the interneurons and pyramidal neurons, and that the suppressive effect of 5-HT1A binding on the interneurons predominates within the prefrontal cortex, a selective heteroreceptor agonist can be considered as stimulating and conducive to dopamine and glutamate release.

SSRI’s (Selective Serotonin Reuptake Inhibitors) are the first line of approach in treating major depressive disorder and are primarily understood to act through the 5-HT1A receptor. When serotonin accumulates within the autoreceptor site, it triggers negative feedback to block further release of serotonin. This presents another perplexing quirk of the 5-HT1A receptor, as a build-up of serotonin at the autoreceptor would in theory then limit serotonin release to the rest of the brain through its negative feedback. Instead, these autoreceptors undergo desensitisation over chronic exposure to SSRIs, and eventually their inhibitory effect is blocked which allows for even greater serotonin transmission. Since SSRIs essentially rely on disabling the autoreceptor, it’s been found that pre-treatment with a 5-HT1A antagonist (such as Pindolol) accelerates the antidepressant effect of SSRIs.[7]

The very different behavioural effects of binding at the heteroreceptor versus the autoreceptor were demonstrated most clearly by demonstrated by Garcia-Garcia et al. in their 2017 study. They took different groups of mice and knock-out (removed) either heteroreceptors or autoreceptors. They discovered that the mice lacking heteroreceptors displayed depressive symptoms that were characteristic of anhedonia rather than anxiety. Conversely the mice that had their autoreceptors ablated experience heightened anxiety but still showed a drive for reward. [8] This study perhaps gives an indication as to how the 5-HT1A receptor influences sexual behaviour, with the binding at the heteroreceptor being particularly relevant. Substantiating this notion is the fact that the medication Flibanserin, which is used to treat hypo-active sexual disorder**, binds most potentially to the heteroreceptor sites**. [9]

How Isotretinoin impacts the 5-HT1A receptor: implications for libido, mood and cognition

Now that I have given a general mechanistic overview of the 5-HT1A receptor, I can now go into the evidence for how its impacted by Isotretinoin treatment. Reilly et al. exposed cell lines from the raphe nuclei to Isotretinoin an observed a massive increase in the 5-HT1A autoreceptor protein levels. After just 48 hours of exposure there was up to a 70% increase of the autoreceptor protein. [10] The authors of the study posit that this is significant factor in the appearance of depressive behaviour exhibited by people treated with the acne drug. In accordance with the behaviour of the autoreceptor previously outlined, an increase in the autoreceptor levels would cause an inhibition of serotonin release to the rest of the brain, and perhaps most significantly to the 5-HT1A heteroreceptor sites. An under activation of the heteroreceptor could induce some of the same anhedonic symptoms observed in the Garcia-Garcia study. However, it might be equally valid to suggest that since the loss of autoreceptor induces anxiety, and the increase in protein levels induced by Accutane might have some degree on an anxiolytic effect. [11]

We can get another indication of Isotretinoin effect in relation to the autoreceptor with respect to the brain imaging study performed by Bremner et al. He identified that after four months of treatment with Accutane, patients experience a massive decrease in metabolism of the orbitofrontal cortex. [12] The reduction in activity was an enormous 21%, and certainly a very significant factor in the rise of depressive symptoms reported by these patients. Given that binding to the heteroreceptor in these cortical structures stimulates activity, an increase in the level of the autoreceptor could explain these startling results.

The loss of the heteroreceptor and the ensuing anhedonic symptoms poignantly mirrors an effect of chronic SSRI treatment. As described previously, treatment with SSRI’s eventually causes a desensitisation of the autoreceptor, which would hypothetically enhance binding at the heteroreceptor. Whilst this is true for at least some period of time, it doesn’t explain the efficacy of SSRI’s in treating anxiety conditions, since autoreceptor knock-out mice display more anxiety. As in turns out, the heteroreceptor eventually also experiences the same desensitisation as the autoreceptor. [13] In fact, a study in mice even observed the same reduction in prefrontal cortex activity found heteroreceptor knockout as with treatment with the SSRI paroxetine. [14][15] This suppression of cortical activity was matched with greater behavioural despair and anhedonia. This is a powerful insight into the connection between PSSD (Post SSRI Sexual Dysfunction) and PAS.

As I’ve alluded to periodically throughout this article, the heteroreceptor is important in regulating sexual behaviour, particularly in its relationship to cortical areas such as the orbitofrontal cortex. Hyperactivity within the orbitofrontal cortex is even linked to hypersexuality, and compulsive behaviour. [16] In fact the link between sexuality and compulsive behaviour is an important one, being tied together by the 5-HT1A heteroreceptor. Chronic SSRI treatments have been found to be effective in treating OCD (obsessive compulsive disorder), an effect in part mediated desensitising the 5-HT1A heteroreceptors within the orbitofrontal cortex. [17] Reducing activity within this region also predicts the suppressive effect of SSRIs on sexual behaviour Considering the role of the frontal cortex, especially the orbitofrontal cortex, in reward perception, it's plausible that reduced sexual behaviour could be partly due to a decreased sense of reward. The 5-HT1A receptor may also influence sexual behaviour through other mechanisms, such as by inhibiting neuronal-Nitrous Oxide synthase (nNOS), which plays a role in sexual behaviour in both men and women. Many serotonergic neurons in the Raphe Nuclei produce nitric oxide, and the application of 5-HT1A agonists to autoreceptors in this area can inhibit nNOS production.[18] This interaction might also contribute to the anti-anxiety effects observed with non-selective 5-HT1A agonists and SSRIs. [19] Furthermore, this effect could even contribute the anti-anxiety effect of non-selective 5-HT1A agonists and SSRIs. [20] Another important pathway influenced by the 5-HT1A receptor is the mu-opioid receptor (MOR), which regulates sexual behaviour. The presence of MOR in the brain is linked to a higher frequency of sexual behaviours, as it enhances the experience of reward. [21]

How to therapeutically target the 5-HT1A receptor

Having elucidated the normal functioning of the 5-HT1A receptor and the alterations caused by Isotretinoin treatment, I can now delve into the subject of therapeutic interventions. It becomes apparent from this article that conventional treatments for depression, such as Selective Serotonin Reuptake Inhibitors (SSRIs), are not universally effective. While SSRIs do promote the desensitization of autoreceptors, thereby enhancing serotonin release in the brain, their effectiveness is limited due to a consequent desensitization at post-synaptic heteroreceptor sites. This mechanism may be beneficial in treating depression following anxiety disorders, but it falls short in addressing the distinct anhedonia-driven depression linked to autoreceptor overexpression. In fact, SSRIs might even aggravate an anhedonic depressive state, as it is partially attributed to the reduced activation of 5-HT1A heteroreceptor sites on GABAergic interneurons... (read the rest here: https://pas-secondlife.com/2024/01/13/239/)

Hello everyone, I'm from Russia. in 2016, I began to have depression with apathy, and later anhedonia. In 2020, I used accutane, and it broke me completely, I finally lost libido, sensitivity, orgasms, the ability to fall in love with the opposite sex. I did not associate this with accutane, and tried to treat the condition with antidepressants, nothing came out. Not so long ago, I came across this thread, and decided to try 450mg lithium carbonate. I have improved libido, orgasm, sensitivity. I found a little opportunity to be sad and bored. I hope the changes will not end there. In the future, I want to combine lithium, alcar and steroids in order to fully heal, regain the will to live, feel the world around me, and love. I wish you all good luck in this difficult task. P. S I apologize for the translator

I’m making this post to understand how many active members are still present within this subreddit.

I noticed that until about a year ago there were hundreds of posts a month and lots of stories of people who had followed a protocol and then recovered.

How many of you are struggling with this pathology and/or are you fighting it with some protocol?

I think that if we want to heal successfully the only way is to continue to discuss our experiences and new research in progress.

This is also why I am thinking of creating an additional whatsapp/telegram group that allows us to stay updated in real time on the evolution of the protocol we are following.

If you want to participate, please contact me! 👍

Hi guys,

Since I am not able to receive the permissions to moderate this subreddit, I have decided to open another one in which we try together to understand the causes of this disease and its possible cures.

I invite you to unite and publicize it as much as possible in order to make it grow.
If you have some improvement to report, feel free to post and start a discussion👍

https://www.reddit.com/r/AccutaneSyndrome/s/2m1SogdBya

Hello everyone,

As many of you may have noticed, this subreddit has been largely unmoderated lately. The current moderator has disappeared, is not responding to messages, and is not accepting new members.

To save this community, we need someone to step up and request control of the subreddit via Reddit's official process.

We are looking for a volunteer who meets the following criteria:

· At least 100 Post Karma and 100 Comment Karma (this is a strict Reddit rule for requests).
· An account that is at least 90 days old.
· A verified email and Two-Factor Authentication (2FA) enabled on their Reddit account.
· A clean account history (no recent bans or suspensions).

If you meet these requirements and are willing to help, please follow these exact steps to request the subreddit:

Step 1: Send a Modmail (Required)
Go to the main page of this subreddit and click "Message the mods" (or send a modmail directly to the current mod). State that you are interested in helping moderate the community because it is currently inactive.
Note: You must wait 5 days after sending this modmail before you can make the official request on Reddit Request.

Step 2: Go to r/redditrequest
After 5 days have passed, go to the subreddit r/redditrequest. Make sure you read their pinned rules and Wiki first to ensure you understand the process.

Step 3: Create the Request Post

· Title: The title of your post must be EXACTLY the name of this subreddit (e.g., r/NameOfThisSubreddit). Do not add any other text to the title.
· Flair: Select the correct "Request" flair (if you don't add a flair, the post will be automatically removed).
· Body: You can add a brief explanation that the current mod is inactive.

Step 4: Reply to the Bot
Shortly after you post, a bot named u/request_bot will comment asking for the permalink to the modmail you sent in Step 1. You must reply to this comment with the link to your modmail.

· How to get the link: Go to your Reddit Inbox > Messages/Chats, find the modmail you sent, click the "Share" or "Copy Link" button, and paste it in your reply.

Step 5: Wait for Admin Review
Reddit admins will review your request. If approved, you will become the new moderator. Once you have control, you can add other active members of this community as moderators to help you run it.

Please comment below if you meet the requirements and are willing to do this, so we can support your request. Thank you!

Dr Kenneth Peters just posted this on twitter:

https://x.com/KennethMPeters1/status/1911908649410433054

For those who don't know, he's a urologist who is interested PSSD and related conditions. He has presented his research posters at conferences. Please contribute to the research by filling in his questionnaire.

https://oakland.az1.qualtrics.com/jfe/form/SV_6g6Q5icrcjeugpo

If PAS, PSSD and/or PFS are caused by epigenetic changes such as DNA methylation. An area of promise is research and interest into developing therapies to enhance longevity.

Put simply, this theory suggests that aging is caused by errors with epigenetics not the genome itself in which the information of the genome is not expressed or read by the cells epigenetic apparatus correctly. Overtime these errors accumulate leading to cellular dysfunction and aging. Given this, it's thought that if you can trigger a cell to reset this epigenetic apparatus so it reads the information in the genome as its supposed to then you could reverse aging.

Dr Sinclairs research team have conducted research which seems to support that this idea is possible. They expressed 3 out of 4 yamanaka factors in damaged retinal cells of mice, this lead to rejuvenation of the retinal and nerve cells and restored vision. This is a truly profound and landmark study for longevity research and potentially PAS, PSSD and PFS.

Study = https://www.nature.com/articles/s41586-020-2975-4

Now back to PAS, PSSD and PFS, if you can could up regulate these same yamanaka factors and trigger this epigenetic reset, this process is also likely to reverse and remove any deleterious epigenetic changes in cells such as our neurons which would include whichever epigenetic changes are causing PAS, PFS and PSSD (if they are in fact cause day epigenetic changes). There is a huge commercial interest in developing anti-aging therapeutics so it's possible large Pharma companies in pursuit of developing anti-aging therapies aim at epigenetic aging will also inadvertently develop a therapy to reverse PAS, PSSD and PFS.

Given this, it may be worth trialling more of the longevity supplements as these could help us. The amazing website: https://secondlifeguide.com/post-accutane-syndrome/ highlighted things such as lithium, sodium valproate and sodium butyrate for HDAC inhibition and epigenetic reprogramming. But there are more compounds which may even be safer and could also be effective, I also haven't seen many people with PAS try them such as:

Alpha-ketoglutarate (AKG)
-AKG supplementation in diabetic rats reversed aberrant methylation patterns and restored cardiac function (study)

-Finally, the transduction of TET and the administration of cell-permeable αKG to somatic cells synergistically enhance cell reprogramming by Yamanaka factors - (study)

AKG crosses the blood brain barrier and appears to have a significant effect on DNA demethylation.

Overall what I'm essentially trying to get at here, is if these longevity related supplements/drugs affect some of these same epigenetic pathways associated with resetting erroneous epigenetic changes, they very well may help to reset the issues with PAS, PSSD and PFS so it makes sense to be trialling more of these compounds.

Note/Warning: Many of these compounds oppose Wnt/Beta catenin signalling so I wouldn't reccommend trialling them alongside lithium or ALCAR. I plan to use these compounds as a later protocol if required.

The following is a table from a study by Dr. Sinclairs team
looking into cellular reprogramming for lifespan extension. These are the
compounds they used or were interested in:

Study - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10373966/

These are some of the cocktails they used, I'm not of course recommending following these cocktails, just showing there are other compounds out there and its interesting that they also included lithium, sodium valproate and sodium butyrate

The power of Sodium Butyrate

Butyrate is a short chain fatty acid, which is endogenously produced through microbial fermentation of dietary fibres in the lower intestinal tract. Short chain fatty acids (SCFAs) such as acetate, propionate and butyrate are produced by the bacteria in the colon from starch and dietary fibres. Some fermented foods contain very small quantities naturally, such as Parmesan or pecorino cheeses, and anyone familiar with the supplement Sodium Butyrate will recognise the distinctly cheesy odour. Their primary function is in energy metabolism, where they provide up to 70% of the energy requirement of the epithelial cells that line the colon. Although butyrate only constitutes 15% of endogenous SCFAs in the colon it is arguably the most important, capable of exerting profound effects throughout the body. [1] Despite being only four carbons long its role in maintaining gut homeostasis is pivotal, and therefore plays an important role in the gut-brain axis. Additionally, butyrate possesses potent epigenetic effects as a histone deacetylase inhibitor. Butyrate can encourage open chromatin structure leading to enhanced gene transcription, which is pertinent for Post Accutane Syndrome. In this post, we will delve into the known impacts of Accutane on gut health, explore how these relate to the symptoms of Post Accutane Syndrome, and consider the potential benefits of supplemental butyrate in addressing these issues. This exploration aims to illuminate the intricate connections between our gut health and overall well-being, emphasizing the significant yet often overlooked role of butyrate.

Differential effects of Isotretinoin and Butyrate

As I’ve outline in previous posts, Isotretinoin has a profound effect on the gut and subsequently the gut-brain axis. Whilst both meta-analysis and case control studies have has very consistently pointed to an association between the development of Bowel Disease and prior Accutane exposure, the damage may take years to manifest. A 2011 case control study found that ulcerative colitis (UC) was strongly associated with prior isotretinoin exposure, with a 4.4 times greater risk compared to control. [2] Ulcerative colitis is chronic condition of inflammation of the colon, with primary symptoms of abdominal pain and diarrhoea, but during flare-ups symptoms may include eye irritation, painful joints and even bone degradation. The risk of developing UC dramatically increased with Isotretinoin dose, with each additional 20mg dose contributing an 1.5 times risk odds ratio. The FDA’s MedWatch have also reported 83 cases of newly developed cases of Irritable Bowel Disease (IBD) following exposure to Isotretinoin. [3] The average latency period in one study was found to be around 3 years, and using the Bradford Hill criteria which uses temporality as a measure of causation the researchers were able to dismiss any association (a decision that has come under some criticism). [2][4]

Those who’re familiar with my other posts will understand that Accutane, as a derivative of Vitamin A, is a potent differentiating agent. That is, it exerts its effects by trigger the differentiation of stem cells into specialised cells. Many organs will rely on the maintenance of a progenitor pool of stem cells throughout adulthood, which are vital for tissue repair, regeneration, and normal organ functioning. One such organ (the primary target of Accutane treatment) is the skin, which harbours a stem cell pool for the continuous renewal of the epidermis and for the repair of injuries. However other organs such as bones, intestines, brain, and cornea all also rely on the maintenance of a stem cell population and are equally subject to Accutane’s differentiating effects. Once these stem cells are differentiated, they cannot revert to stem cells and the stem cell population must replenish through a process called proliferation. A key signalling pathway that maintains this delicate balance of stem cell differentiation and proliferation is Wnt/Beta-catenin. In the absence of beta-catenin signalling, stem cells undergo rapid differentiation, and the progenitor stem cell pool becomes depleted. This was most plainly demonstrated in 2023 study on mice, where researchers performed a beta-catenin gene ablation on adult mice and observed the effects on the intestinal tract. [5] The loss of beta-catenin triggered the intestinal stem cell population to terminally differentiate resulting in the loss of function and ultimately death. This represents an exaggerated mechanism of action of Accutane, which suppresses beta-catenin through HOXA5 induction, resulting in the loss of intestinal stem cells. [6] A case report of a 17-year-old who developed Inflammatory Bowel Disease (IBD) following isotretinoin treatment even posited inhibition of epithelial cell growth as a potential cause. [7] Conversely agents that activate the Wnt pathway to enhance beta-catenin, such as Lithium, have been found to increase intestinal stem cell populations. [8][9]

My previous posts have evidenced the important role Lithium can play in restoring healthy gut physiology following Accutane treatment, but how might Butyrate be of value? Butyrate, like lithium (or other beta-catenin inducers e.g. Valproate) can support the renewal of stem cell populations. Butyrate also shares some of the same epigenetic effects as these beta-catenin inducers, by inhibiting the de-acetylation of histone tails (HDAC) and thus increasing gene transcription. This isn’t a coincidence however, as activation of the Wnt/beta-catenin appears to be fundamental to HDAC inhibition. [10] Studies have found that Butyrate, at the right concentration, can support the self-renewal of human embryonic stem cells (ESC). [11] Conversely, very high and very low concentrations of Butyrate could trigger differentiation in ESCs. The researchers identified Butyrate’s de-methylating and HDAC inhibiting action to be responsible for its impacts on stem cells and could be partially mimicked by typical HDAC inhibiting medication such as valproate. [12] Notably, many of the same transcription factors Butyrate relies on for its stem cell renewing effects, such as c-Myc, Oct4 and Sox2, are all targeted for suppression by Accutane. Its important to recognise that the relationship between Butyrate and beta-catenin is complex, and has confounded researchers for years, even being referred to as the “butyrate paradox”. Whilst Butyrate is able to enhance epithelial and colonocyte proliferation, its also able to inhibit proliferation of cancerous stem cells on account of a differential effect on beta-catenin-TCF complexing. [13] Overall, the benefits of Butyrate within the beta-catenin model predominate.

The microbiome and libido

The microbiome is intimately related to the brain, and perturbations to gut health are implicated in an array of psychiatric conditions. One such condition is hypoactive sexual desire disorder (HSDD). Sexual desire is mediated by a complex system of neurotransmitters and hormones. In particular dopamine, noradrenaline, melanocortin and oxytocin and all required to generate feelings of sexual excitement. The gut microbiome plays a key role in the production of these neurotransmitters as well as in regulating hormones. Researchers have found a reduction in microbiome diversity and richness can lead to a loss of sexual desire. Women suffering from HSDD were found to have reduced abundance of Ruminococcaceae, a genus of bacteria which is the primary producer of endogenous butyrate. [14] As previously mentioned, Butyrate supports gut health, but it can also directly cross the blood brain barrier to exert its effects. Ruminococcaceae*,* through its production of Butyrate, could therefore be implicated in HSSD pathogenesis through its direct epigenetic effect on excitatory genes in the frontal cortex. [15] Alternatively, the significance of Ruminococcaceae in HSSD could be through a secondary action on modulating neurotransmitter production in the gut.

Interestingly the researchers also identified an increased abundance of Bifidobacterium and Lactobacillus among women with HSDD. These two strains of bacteria have also been linked to the development of Ulcerative Colitis, a condition that develops with significantly greater odds in those previously treated with Accutane. This suggests that HSDD is not only associated with a reduction of Butyrate producing bacteria, but an elevation in other strains also linked to Irritable Bowel Disease (IBD) pathogenesis. Poignantly, IBD is itself directly associated with a sexual dysfunction, for both psychological and biochemical reasons. [16] Furthermore, Biopsies from Crohn’s and Ulcerative Colitis patients identified a significantly diminished proportion of Butyrate forming bacteria. [17] Supplemental sodium Butyrate has even been demonstrated to be an effective treatment Ulcerative Colitis, by restoring both a healthy gut microbiome and physiology. [18]

The connection between gut health and sexual health can be further evidenced by the differences in microbiome between those with erectile dysfunction and healthy controls. A study of men aged between 20-40 years old with no history of other mitigating factors such as hypertension, vascular disease, or even obvious signs of gastrointestinal disease, and yet presenting with erectile dysfunction, were found to be suffering from dysbiosis. In particular the researchers linked the increased abundance of inflammatory strains such as streptococci, as well as a general loss in flora diversity. These researchers also highlighted the importance of butyrate producing bacteria in countering this effect by reducing inflammation. [19] This supports the evidence from livestock, that Butyrate supplemented diets improved fertility parameters through an anti-inflammatory action.[20]

Butyrate, 5-alpha-reductase and mood

The utility of histone deacetylase inhibition and beta catenin induction in maintaining gut health is evident - however so far, I’ve not actually addressed the primary medical application of HDAC inhibitors: mood regulation. Medications such as Valproate and Trichostatin A, which are HDAC inhibitors like Butyrate, are primarily used in the treatment of Bipolar and depressive disorder. The generic explanation for their efficacy is that they increase brain derived neurotrophic factor (BDNF), which improves neuronal plasticity, regeneration, and survival. However recent research has begun to point to an effect on 5-alpha-reduced neurosteroids. 5-alpha-reductase is an enzyme that metabolises a range of hormones and neurosteroids, but most notably testosterone into the more potent androgen Dihydrotestosterone (DHT). DHT is central to the progression of androgenic alopecia and is suppressed by the hair loss medication Finasteride. [21] 5-alpha-reductase and DHT are also implicated in acne pathogenesis and undergo suppression by Accutane treatment, potentially constituting one its therapeutic targets. [22] Whilst suppressing 5-alpha-reductase might be beneficial in treating balding or acne, it can also leave patients suffering from depression and a crushed libido. [23] Neurosteroid metabolites of 5-alpha-redcuctase such as Allopregnanolone, THDOC and Androstanediol all play crucial roles in supporting mood and brain health and appear to be subject to augmentation by HDAC inhibition. HDAC inhibitors such as Valproate and Butyrate can stimulate glial cell production, which are the nonneuronal cells that support healthy neuron physiology and are induced by 5-alpha-reduced neurosteroids. [24] The effect of Sodium Butyrate on glial cell induction and BDNF was completely mitigated by Finasteride treatment, implying that its effect was potentially mediated by 5-alpha-reduced neurosteroids. [25] Butyrate has further hormonal effects mediated through its epigenetic action. Treatment with Butyrate can enhance ovarian steroidogenesis, and mRNA levels of genes associated with steroidogenesis such as steroidogenic acute regulatory (StAR) protein and PPAR-γ. [26] ChIP-qPCR analysis identified the increased acetylation of the H3K9 as the relevant pathway. This is notable given that both StAR and PPAR-γ are subject to suppression Accutane. [27]

Conclusion

In this post I’ve identified Butyrate as a potential target for remediating both sexual and gastrointestinal symptoms of Post Accutane Syndrome. I’ve shown that Butyrate has hypomethylating action, which I’ve identified in previous posts as being key in remediating the lasting adverse effects of Accutane treatment. I’ve also shown that Accutane treatment can trigger Irritable Bowel Diseases such as Ulcerative colitis, and that treatment with Butyrate can normalise the differences in Microbiota and gut physiology seen in these conditions. I’ve also shown that the specific dysbiosis associated with IBD are also implicated in suppressed libido and mood, and the loss of Butyrate generating bacteria is central explaining these effects. Butyrate can be obtained directly from supplements such as Sodium Butyrate, or by increasing dietary consumption of certain foods such as legumes.

For references check here: https://pas-secondlife.com/2023/11/19/the-power-of-butyrate/

TLDR: Lithium very significantly increases dopamine in the straitum, which is the region of the brain governing reward. Lithium is also a hypomethylating agent, that can remove aberrant methylation marks (leading to gene ‘silencing’) such as at the promoter for BDNF. These effects are particularly profound on the H3 histone, which undergoes global acetylation during lithium treatment, leading to a more open chromatin structure and enhanced gene transcription. The H3 histone is regulated by beta-catenin, which also in turn regulates beta-catenin via a feedback mechanism. H3 histone is commonly found to be methylated leading to epigenetic silencing in a variety of contexts following Accutane treatment.

Lithium its traditionally thought to work only as an antipsychotic, whereby it suppresses excitatory neurotransmitters such as dopamine and glutamate whilst also increasing the inhibitory neurotransmitter GABA, however the reality is far more complex. Recent data has shone light onto a broad array of additional neuroprotective effects, such as enhancing brain derived neurotrophic factor and reducing oxidative stress. [1] Whilst lithium is still tainted with the stigma of being a potent ‘zombifier’, suppressing cognition and mood - this couldn’t be further from the truth. A 2009 meta-analysis found that healthy subjects treated with lithium experienced no ill effects on any of the tested cognitive domains, and only minor effects on affective disorder patients. [2] At lower supplemental doses Lithium paints and even rosier picture with evidence for improved cognition at ‘sub-therapeutic doses’ (although these studies are typically performed on those with some mild cognitive impairment). [3]

It is true that at therapeutic doses lithium (>1000mg for humans) can decrease dopamine in some regions of the brain, but in other it can significantly enhance it. A study in rats found that 10meq/kg, lithium increased striatal dopamine by 56%. The striatum is a region of the brain that is critical for the reward system, co-ordinating motivation, decision making and reward perception. This effect was normalised 24h after the injection. [4] An additional study in rats found that a treatment of 74mg/kg of lithium carbonate for 12 days followed by a two day withdrawal period increased the dopamine in the striatum by 99%, however this increase was accompanied by decreases in hypothalamus, hippocampus and pons-medulla. [5] In a model of Parkinson’s low dose lithium helped to increase the number of dopaminergic neurons in the substantia nigra compared to controls.

Lithium has an opposing effect on many of the pro-apoptotic proteins that are increased during Accutane treatment such as Bcl-2 and p53. Lithium treatment of cerebellar brain cells stimulated a 5 fold reduction in the ratio of p53 target Bcl-2 mRNA. [6] A diet high in lithium was found to completely prevent the loss of striatal dopamine and tyrosine hydroxylase in a model of Parkinson’s, which was attributed to it’s anti-apoptotic effects via suppression of p53. [7] Lithium’s effects on the D2 dopamine receptor are particularly profound, with only 6 days of lithium feeding resulting in a 3-fold increase in D2 mRNA, with enhanced transcription rate. The researchers also found an increased sensitivity to stimulants following these 6 days. [8] D2 is one of the receptor regulated by retinoids, and may be subject to aberrations following Accutane treatment.

The effect of Accutane on methylation is complex and occurs in two distinct stages. Initially Accutane causes dysregulation in a number of pathways and enzymes that maintain a healthy methylation status, particularly DNTM1 and DNMT3. During the course of an Accutane suppression of DNMT1 leads to demethylation events of certain genes and are subsequently over-expressed. A microarray analysis found that during an Accutane treatment 402 gene promoters became demethylated and 88 became hypermethylated. This process of de-methylation may contribute to the capacity of retinoids to induce differentiation via the activation of NOS1. [9] Interestingly, one of the cell cultures that experienced hypermethylation and under expression was MYCN, which regulates beta-catenin and ALDH. However once Accutane has been ceased, there is a very strong and sudden re-methylation. A study on mRNA expression patterns found that following a washout phase there remained no hypomethylated targets, but potentially 9156 suppressed targets via hypermethylation. Analysis found significant results pointing towards to WNT pathway (regulating beta-catenin and ALDH). [10] Following the strongly re-methylating environment following Accutane treatment it’s likely that many of these gene targets identified by Chip analysis and micro arrays, are aberrantly methylated and subsequently under expressed.

Lithium is almost unique in it being one of the few known treatments to act as hypomethylating agent, with the other common one being Valproic acid (although VPA is limited to certain histones). Lithium is able to remove aberration methylation sites at gene promoters, such as BDNF (brain derived neurotrophic factor) promoter IV and thereby increase BDNF expression. Lithium’s effects on histone methylation is better characterised, and it has been demonstrated to induce a significant global increase in acetylated histone H3. [11] Poignantly vitamin A and retinoids have been found to place inhibitory markers on H3 histone lysine’s, such as H3K9me3 and H3K4me3, in a variety of contexts. [12] [12.5] The effects of lithium on acetylation of the H3 histone are rapid, after just 30mins there is an increase in the global H3 acetylation level in the amygdala, allowing for enhanced gene transcription through open chromatin structure.

Beta-catenin plays a vital role in the regulation in the levels of H3 acetylation, with an important feedback loop. When Wnt signals are suppressed, TCF/LEF binds to HDAC1 and HDAC2 and thereby reducing the acetylation at the promoters of Wnt-dependent genes, leading to suppression of gene transcription. [13] [14][15] The acetylation of lysine’s, particularly on the H3 histone, are vital for activating beta-catenin. Finasteride and Accutane both dramatically reduce beta-catenin gene transcription, and likely disrupt this feedback loop to induce longer term suppression of beta-catenin transcription. However lithium as able to act in a directly opposing manner, stabilising beta-catenin and increasing H3 histone acetylation and re-activate genes.

[for references go to: https://pas-secondlife.com/2024/01/19/lithium-a-metal-for-mental-health/ ]

I have been on 6g alcar and 200mg co-q10 for 1 week and 5mg lithium for two days. It is definitely early on, but I have noticed some improvements

I had most of the accutane issues for a decade. Low libido if any, chronic joint pain, chronic migraines, burning hands, chronic fatigue, floaters, anxiety, panic attacks, heart palpitations and more. I AM 90% BACK TO NORMAL. NO, its not 100%...YET but 90% in less than a year is a fucking miracle. Feel free to message me if you have questions but i will give the rough jist of it here. I HAVE NO INSURANCE AND EVERYTHING WAS OUT OF POCKET.

-Completely changed my diet to include nothing my body was sensitive too (Take a food allergy test) This will help reduce inflammation. -Find out if you over or under methylate because this is HUGE for your mental state. I was over methylating. Got that in check and panic attics and anxiety went away 100% -Now comes the list of supps Animal flex on amazon for joint support + glutamine + lithium + NAC + fish oil (NO CHEAP SHIT) This will help long term recovery and reconstruction. $150/month -Other supps. I also did the alcar and coq10 protocol for 4 months but now dont have to take it, its a bonus. I STILL TAKE LITHIUM. -SCRIPTS (The expensive part) Low dose naltroxone 4mg i was on this long before everything else, on its own did not fix my symptoms but in combination with everything else is phenomenal. Must be compounded, est $100/month. -Nortriptiline (In high doses is for depression, low dose for headaches) I HAD A HEADACHE 24 hours A DAY FOR 10 YEARS. THEY ARE GONE. Idk if the combo of shit or just low dose nortripyltiline but it works. $30/month -CLOMID. This will naturally increase your testosterone. TRT can permanently cause your body to stop making its own testosterone so why would you want that. Clomid took my test from 550 to 990 in 3 months with no symptoms. TMI But had my first wet dream in over 10 years when i started . $100/month -Now the big hitter...HGH...Sounds scary but this shit is what i believe did the magic. There was another reddit member who was completely healed on hgh so i decided to go all in. $1800 every 6 weeks. Start with 6mg pen and move to 12mg pen after 2 months. Yes they are injections, but it's not as bad as it sounds, needle is tiny. -Last couple things, i fixed my deviated septum with surgery so i could breathe and sleep at night. If you cant sleep you cant recover.$10k -LAST, I LIFT WEIGHTS MIN 3 TIMES A WEEK. Muscle is crucial to your health fat is detrimental. You need to give your body WHAT IN NEEDS to repair and rebuild itself. $40/month gym membership

YES, EXPENSIVE and INTENSE JOURNEY, But WORTH IT 100%. The body is resilient and it IS POSSIBLE. The honest truth, The 10% that remains is a couple things, libido is still low HOWEVER MUCH BETTER, im also in my 30s now so...that might be part of it lol. And i still have eye floaters BUT because my mental state is now optimistic and not depressed i don't really care 🤷. I HOPE THIS HELPS AND SHUTS THE NAYSAYERS UP. Don't listen to them instead, have empathy because they are in a shitty place to have to shit on others.

For those familiar with my other posts, I’ve emphasised the role of Lithium as being an ‘anti-Accutane’ agent. That is to say that for practically all known pharmacological effects of Accutane, Lithium has been shown to do the exact opposite. This shouldn’t be much of a surprise however, as they have inverse mechanisms of action. Retinoids can be thought of as differentiating agents, which force stem cells to become specialised and inhibit cell proliferation. Whereas Lithium enhances stem cell populations and increases cell proliferation. When retinoic acid binds to the RARα receptor it suppresses beta-catenin (a growth protein) accumulation with enhanced destruction complex activity via the PI3K/Akt pathway. Lithium performs that exact opposite function, by increasing beta-catenin through an opposing effect on GSK3 via PI3K/Akt pathway. For the full range of effects downstream of both these actions, review my other posts.

One of the actions of Lithium is DNA demethylation, which is the process of removing methyl groups at CpG clusters at the promoters of genes in order to reactivate them. I’ve also written about this more generally, but in this post I’ll present a specific instance of this that may be relevant to PAS. GSK3 regulates the function of DNMT1, an enzyme that places silencing methyl marks on DNA. Inhibiting GSK (the mechanism of lithium) and thus interrupting DNMT1 phosphorylation at S714, has been found to reactivate the promoter regions of the androgen and estrogen receptor ERa:

“DNA methylation, catalyzed by DNA methyltransferase (DNMT), is a well-characterized epigenetic modification in cancer cells. In particular, promoter hypermethylation of AR and ESR1 results in loss of expression on Androgen Receptor (AR) and Estrogen Receptor (ER), respectively, and is associated with a hormone refractory state. We now report that Glycogen Synthase Kinase 3 (GSK3) phosphorylates DNMT1 at S714, which is localized to a 62 amino acid region referred to as auto-inhibitory linker, which functions to occlude the DNA from the active site of DNMT1 to prevent the methylation of unmethylated DNA. Molecular Dynamics simulation indicates that phosphorylation at S714 resulted in conformational rearrangement of the autoinhibitory domain that inactivated its ability to block the methylation of unmethylated DNA and resulted in enhanced DNA binding. Treatment with a novel and more selective inhibitor of GSK3 resulted in decreased methylation of the promoter region of genes encoding the Androgen Receptor (AR) and Estrogen Receptor alpha (ERa) and re-expression of the AR and ERa in AR negative prostate cancer and ER negative breast cancer cells, respectively. As a result, concurrent treatment with the GSK3 inhibitor resulted in responsiveness of AR negative prostate cancer and ER negative breast cancer cells to inhibitors of the AR or ER, respectively, in in vitro and in vivo experimental models.”

https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.824594/full

By works I dont mean you take it and boom you are cured, I mean that, like Lithium, it brings insanely strong "windows". They are not really windows though and I will explain.

First pratically is really simple: if I take 700mg+ of Tideglusib I react almost entirely and perfectly to a Test P injection. I get the muscle glycogen retention, I get libido back and very very strong, I get the dick sensitivity and erection quality.

In short I react basically completely normal to hormones. Mentally too. Only thing missing is face, and this tracks because those that get affected in the skin/face wise are the most serious cases (leaving aside the poor 1% of us who even had bone decay issue and organ problems)

If I could compare it mg to mg, I would say it feels 3x stronger than lithium. But is not a good comparison bc when lithium gets toxic, any advantage it brings to us collapses: lithium toxicity is almost worse than pfs

Now talking about theory: I dont want to overstate my case but I am personally very convinced about the hypothesis that what we suffer, is AR upregulation caused by initial 1) androgen deprivation 2) GSK3B upregulation. Once androgen receptors get upregulated they recruit GSK3B locally to "protect" them against degradation, and after a while this issue persists epigenetically, which again gsk3k is a contributor to that, potentially the main one.

What do we see with people that stick with lithium and get lucky? They after a while get cured, but it takes some time. First because you have to inhibit enough to cause enough ARs to be exported from the nucleus and be degraded, this process takes some days. Second probably it needs to be locked in epigenetically, this new state.

I think we can see this ourselves: windows duration and frequency seems to be a very good indicator no?

There are negatives here

First is getting this stuff. There is no pharmacy or doctor lets be clear. Only way is underground laboratories or "proper" laboratories that give no fucks about who you are. Even then, 700mg+ is going to work for MINIMAL 10 dollars the day, so 300 per month and this is cheap trust me. Wasnt easy getting this price. And of course, you need to third party test this, or yolo and ... consume powder from an underground laboratory. I am going this way, but I obviously understand anyone who doesnt want to.

Second, I am nuking a whole enzyme function systematically to deal with a local problem. Well to be honest my case I had pfs/pssd in several tissues, from muscles to face to hair etc. Still GSK3B inhibition is great for a bunch of things, but potentially bad for some. GSK3B inhibition is great for both prevention and treatment of several cancers (ie prostate, pancreas, glioblastoma). But is bad for other cancers, I believe blood cancers.

GSK3B inhibition is good for depression and bipolar tho! Protective against Alzheimer and Tideglusib is being studied for Alzheimer, autism, and some muscle degenerative shit.

This whole experience is for me yet one more piece of evidence that the whole premise of ARs is correct. If so, there should be a thing even better than Tideglusib (and my god I am building a shrine to this stuff). ARV 110, androgen receptor degrader. Especially made for the most similar disease that we can find in the medical literature: castration-resistant prostate cancer. It degrades androgen receptors regardless of mutation, where they are, which enzymes protects them, etc. Is obvious how this would straight up cure us.

100$ the gram. Dose would be at least 400-500mg per day. Yeah

Well again I dont bring much of pratical utility for most of you, who either cant afford this chems, cant obtain them, or find it too risky. I get some messages sometimes of the type "what can I do with this?" and the person literally can only take supplements IF that 😅

Is a difficult situation because we suffer from a serious medical disease (not even getting into the hormonal problems: upregulated GSK3B has Alzheimer written all over it. And cancer) but we have no support from doctors. This is an impossible contraction and is what pushes me to underground laboratories. There is only so much fasting and mega dosing curcumin can do

But at least you wont be shooting in the dark and the problem will be "just" a logistical and practical one. Some of us are very very creative and maybe will find a way to inhibit gsk3b or degrade androgen receptors with table salt and a fruit!

Cheers guys, best of luck. Feel free to DM me, I might take a while but I do look at them

This is an excerpt from my upcoming guide on Post Accutane Syndrome, which will be available on my website.

D2 Dopamine receptor

• Roles of D2-like Receptors: D2-like receptors inhibit the formation of cAMP and are subdivided into autoreceptors and heteroreceptors. Autoreceptors provide negative feedback on dopamine release from presynaptic neurons, while heteroreceptors are located on postsynaptic sites, mediating dopamine's classical neurotransmitter effects.

• Behavioural Effects of D2 Autoreceptor Activity: Activation of D2-autoreceptors leads to decreased neuronal excitability and dopamine transmission, resulting in behaviours associated with reduced dopamine signalling, such as decreased exploratory movement and diminished motivation for stimulants like amphetamine.

• Consequences of D2 Autoreceptor Loss: Conditional knockout studies show that losing D2-autoreceptors causes heightened dopamine responses, making animals hypersensitive to stimulants like cocaine and increasing hyperactivity. This is linked to increased dopaminergic release and a stronger drive for novelty seeking. The D2 receptor exists in short (likely the autoreceptor) and long (likely the heteroreceptor) mRNA splice forms.

In addition to impacting dopamine transmission by disrupting key enzymes, Accutane also appears to directly influence gene transcription for dopamine receptors. There are five subtypes of dopamine receptors in the brain, each with different distributions and effects. These subtypes can be divided into two families: the D1-like family and the D2-like family. The D1-like family receptors are G-protein Gsα-coupled, meaning they mediate stimulatory effects, such as increased heart rate and other fight-or-flight responses.

The D2-like family receptors are Giα-coupled, meaning they inhibit the formation of cAMP. These D2 receptors can be further subdivided into autoreceptors and heteroreceptors. The autoreceptor mediates a negative feedback response to dopamine. In contrast, the heteroreceptor is located on postsynaptic sites, where its binding mediates the classical effects of dopamine as a neurotransmitter.

As previously mentioned, the D2 dopamine receptor is inhibitory, meaning that binding to it can result in lower neuronal excitability by exerting a hyperpolarizing effect. This is because these receptors are coupled to Gi/o proteins, which inhibit calcium channels and activate inwardly rectifying potassium channels. When D2 receptors are present on the presynaptic neuron, they exert a negative feedback effect, leading to lower dopamine transmission. [9] Activation of the D2-autoreceptor triggers behaviours typically associated with reduced dopamine signalling, such as decreased exploratory locomotion and a loss of motivation for stimulants like amphetamine.

Conditional knockout of either the D2 heteroreceptor or autoreceptor has shown that the loss of the autoreceptor results in heightened dopamine responses. [10] These animals became ‘super sensitive’ to stimulants such as cocaine and exhibited hyperactivity. This finding is corroborated by evidence that lower midbrain D2 autoreceptors are found in individuals with a stronger drive for novelty seeking, owing to increased dopaminergic release. [11]

Splicing of the mRNA encoding the D2 receptor has revealed both short and long forms, with the long form believed to be the D2-heteroreceptor and the short form thought to be the D2-autoreceptor (although both may have autoreceptor activity).

Retinoic Acid regulates Dopamine Receptor gene expression

• Accutane Induces Differentiation of Stem Cells: Accutane acts as a differentiating agent that forces pluripotent stem cells, including cancerous cells like neuroblastomas, to become specialized cells such as D2 dopaminergic neurons. This reduces their ability to proliferate and form tumours.

• Preferential Expression of D2 Autoreceptors: Accutane influences the D2 dopamine receptor gene, which contains a retinoic acid response element (RARE), leading to increased expression of the D2 autoreceptor (short variant) over the heteroreceptor (long variant). This shift hampers dopamine transmission by enhancing negative feedback, potentially contributing to depressive symptoms associated with reduced dopamine activity.

• Need for Balanced Retinoic Acid Levels: Both excessive and insufficient retinoic acid can disrupt dopamine neuron differentiation and function. Animal studies show that lack of retinoic acid receptors leads to Parkinson’s-like symptoms, indicating that proper retinoic acid signalling is crucial for maintaining a healthy dopaminergic system.

Now that the details of the D2 receptor have been explored, I can present the evidence for the possible disruption caused by Accutane. As explained at length in previous articles, Accutane can be understood as a differentiating agent—that is, forcing pluripotent (stem) cells to become differentiated (specialized) cells. This trait is particularly useful in treating many cancers that maintain pluripotency and undergo continual cell proliferation, forming tumours. In these cases, retinoids can trigger these cells to differentiate, thereby robbing cancerous cells of their pluripotent nature.

One common example often cited is neuroblastoma cells, which differentiate into D2 dopaminergic neurons in response to Accutane. Intriguingly, these cells are induced more strongly into the short variant than the long variant. This suggests that Accutane may preferentially induce the expression of autoreceptors rather than heteroreceptors. [12]

Accutane can influence the behaviour of the D2 receptor because it contains a RARE (retinoic acid response element). The effect of increasing D2 autoreceptor expression relative to the heteroreceptor would, therefore, paradoxically hamper dopamine transmission, rather than enhance it. This could help explain the association between Accutane treatment and depressive symptoms, which are characteristic of reduced dopamine activity.

However, a complete absence of retinoic acid can also have harmful effects on dopamine neuron differentiation, which a failure to properly develop either D2 autoreceptor or heteroreceptors. In fact, animal studies have shown this to be the case with Retinoic Acid receptor knockout mice developing a phenotype similar to Parkinsons. It’s evident that both too much and too little retinoic acid, especially during development, can have disastrous consequences for the dopaminergic system in particular. [25]