I have some ideas about potential ways to treat PAS that I thought I would share. I think they might be useful in helping us to more accurately model the etiology of PAS so that we’re at least not shooting in the dark about this
First of all, accutane is very very similar to retinoic acid. While it does not directly activate the same pathways its metabolites may be able to. In case you werent aware, retinoic acid is basically a derivative of vitamin A. Unsurprisingly PAS symptoms closely resemble the symptoms of hypervitaminosis A, which is congruent with the idea that accutane is basically a very potent form of vitamin A. Why is this important? The reason why its important is because it helps narrow down the potential ways that accutane may have damaged people. In order to further narrow this down lets consider one of the most common side effects related to accutane which is depression.
The fact that accutane commonly causes depression suggests that accutane strongly affects the neurotransmitters/the brain in some way. In what way does accutane affect the neurotransmitters/the brain though? Well, depression (along with anhedonia which is another common accutane side effect) is commonly due to dopamine dysregulation. Therefore keeping this in mind, we can assume that accutane’s primary mechanism of leaving nasty side effects might be its effect on the dopamine system. From this we can infer that retinoic acid (which accutane is a form of) can have negative effects on dopamine functioning
Upon searching for connections between retinoic acid and dopamine receptors I found the following:
Dopamine is a neuromodulator involved in the control of key physiological functions. Dopamine-dependent signal transduction is activated through the interaction with membrane receptors of the seven-transmembrane domain G protein-coupled family. Among them, dopamine D2 receptor is highly expressed in the striatum and the pituitary gland as well as by mesencephalic dopaminergic neurons. Lack of D2 receptors in mice leads to a locomotor parkinsonian-like phenotype and to pituitary tumors. The D2 receptor promoter has characteristics of a housekeeping gene. However, the restricted expression of this gene to particular neurons and cells points to a strict regulation of its expression by cell-specific transcription factors. We demonstrate here that the D2 receptor promoter contains a functional retinoic acid response element. Furthermore, analysis of retinoic acid receptor-null mice supports our finding and shows that in these animals D2 receptor expression is reduced. This finding assigns to retinoids an important role in the control of gene expression in the central nervous system.
Retinoids are known to bind to retinoid receptors in the brain and to exert effects on gene transcription. Retinoid receptors are concentrated in limbic areas that have been associated with depression, including the amygdala, prefrontal cortex, and hippocampus. Retinoids also influence neurochemical systems that have been implicated in depression, in particular dopamine but to some extent serotonin and norepinephrine.
Its apparent that the connection between retinoic acid and dopamine is real, and it has been established; although I dont think that many PAS sufferers are fully aware of this. My overall impression is that the PAS community is not yet very well organized, as such the PAS community doesnt have the same resources that the PFS community has in terms of researching and clearly delineating the exact nature of their problem. As a result of this there seems to be lacking a clear consensus about what PAS is even caused by and because of this its difficult to model any potential treatments for it. With that being said, I feel pretty confident in stating that the most likely cause of PAS is probably dysregulation of the dopamine system due to the usage of potent, synthetic forms of retinoic acid (accutane). More specifically though, the root cause of the dopamine system dysregulation itself might be due to the retinoic acid receptors themselves malfunctioning, this is what in turn is causing the dopamine receptors to malfunction. Its important to realize this because it gives us a more specific target to focus on than just clumsily focusing on the dopamine receptors themselves. This was mentioned in one of the above quotes that I mentioned, although it was really easy to miss:
We demonstrate here that the D2 receptor promoter contains a functional retinoic acid response element. Furthermore, analysis of retinoic acid receptor-null mice supports our finding and shows that in these animals D2 receptor expression is reduced. This finding assigns to retinoids an important role in the control of gene expression in the central nervous system.
We now have a more clearly defined target to focus on when it comes to treating PAS. Before I go any farther I want to clarify what I think has happened to the retinoic acid receptors; IMO I think that they basically got burned out/overstimulated by accutane. Its basically analogous to how PFS guys got their androgen receptors silenced by a flood of DHT, except for PAS guys their retinoic acid receptors got continually exposed to accutane metabolites (which is a highly potent synthetic for of retinoic acid) which is what ended up silencing/burning out their retinoic acid receptors which in turn screwed up their dopamine system.
Keeping that in mind, lets focus on things that can help us to modulate the retinoic acid receptor in some way. So far I have thought of two different approaches for this:
1.the direct usage of retinoic acid receptor antagonists to help resensitize the retinoic acid receptors.
-the only problem I have with this approach is that the only retinoic acid receptor antagonists Ive found are research chemicals which im a little bit leery about. Preferably I would prefer to find some natural retinoic acid receptor antagonist (if it even exists), but barring that I suppose any form of retinoic acid receptor antagonist (synthetic or not) would have some theoretical utility in helping to resensitize the retinoic acid receptors which in turn would reregulate and normalize dopamine functioning in PAS guys
2.lowering vitamin A (retinoic acid) and inducing a state of hypovitaminosis A which in theory should help resensitize the retinoic acid receptors
-It was difficult for me to think of an easy way to induce a vitamin A deficiency. It can be easily done, but it involves months (?) of following a highly restricted diet. While this is still doable, I think its not really preferable. In lieu of following a highly restricted diet to induce a vitamin A deficiency it occurred to me that maybe there might be some workaround which could be used instead. While I was thinking about this I remembered that iron deficiencies are commonly related to vitamin A deficiencies in some way:
https://academic.oup.com/jn/article/132/12/3607/4712131
Although marginal VA deficiency did not exacerbate indices of poor iron status during iron deficiency, iron deficiency was associated with lower plasma retinol and elevated liver VA concentrations. These results are consistent with an impaired mobilization of liver retinol during iron deficiency as well as multiple alterations in iron metabolism.
So, as it turns out if you have an iron deficiency then your body has a hard time mobilizing retinol (the prohormone of retinoic acid) and as a result it just sits in your liver instead of going systemic. Thus for all intents and purposes, an iron deficiency can induce a condition that is very similar to a vitamin A deficiency. So, now we have to figure out how to induce an iron deficiency; fortunately this is a little bit easier than figuring out how to induce a vitamin A deficiency. There are two methods of doing this:
1.give blood frequently
- How much iron do I lose when donating blood or platelets? Each time you donate blood , you lose between 220-250 mg of iron . If you donate a Power Red, you lose twice that amount, about 470 mg of iron . It may take up to 24-30 weeks for your body to replace the iron lost through a blood donation.
2.take high doses of turmeric for an extended period of time (a few months?)
A 66-year-old physician treated himself for an osteoarthritis flare after steroids with six turmeric extract capsules (538 mg) daily, to help with inflammation. During this time, his hemoglobin never rose above 12 and his iron and ferritin levels were consistent with iron deficiency. Upper and lower endoscopy and Hemoccult™ studies were negative. Two weeks after stopping the turmeric and continuing his usual iron supplement, his hemoglobin had returned to normal, with normalizing iron studies. Turmeric was associated with significant iron deficiency anemia, consistent with the binding of available iron in the gut and the prevention of absorption. This resolved after the turmeric was stopped, consistent with animal studies.
In theory, if you induce an iron deficiency then it should lower the amounts of circulating retinol in the body which in turn would be less able to convert into retinoic acid thus preventing the stimulation of the retinoic acid receptors and subsequently helping to resensitize them. That being said, im not sure how safe a prolonged iron deficiency would be, for this reason I would prefer to find a more direct way of reducing vitamin A levels in the body
Alternately you could try a different approach by trying to prevent the retinol from converting into retinoic acid, but I havent done as much research into figuring out ways to do this. Im sure its probably pretty easy though, maybe easier and faster than giving blood/taking turmeric for a few months.
Lastly I want to add that maybe its not simply about resensitizing the retinoic acid receptors, the reason I say this is because apparently the retinoic acid receptors also play an important role in the control of gene expression in the central nervous system. This can be seen in the quote I posted earlier:
We demonstrate here that the D2 receptor promoter contains a functional retinoic acid response element. Furthermore, analysis of retinoic acid receptor-null mice supports our finding and shows that in these animals D2 receptor expression is reduced. This finding assigns to retinoids an important role in the control of gene expression in the central nervous system.
If this is the case then maybe modifying the levels of retinoic acid in the body or manipulating the retinoic acid receptors themselves can possibly help flip back on certain genes in the central nervous system which in turn could help reactivate normal dopamine functioning the body. In my opinion this might be an equally important aspect along with the retinoic acid receptors interfacing with the dopamine receptors.
Either way, I think this is an interesting angle to consider treating PAS from; while I dont know how effective these hypothetical treatments would be, at the very least we now have a more concrete idea of where to start when it comes to treating PAS. Perhaps we can think of other ways to treat PAS too given this clearer understanding of what might cause PAS