A possible Hormetic/Biphasic effect of Accutane on neurosteroid production

Several studies have shown that Accutane/Isotretinoin/13-cis Retinoic Acid, and one of its key active metabolites ATRA(All-Trans Retinoic Acid)/tretinoin/ or simply RA (retinoic acid) significantly reduce hippocampal neurogenesis and functional interactions between the hipppocampus and serotonergic neurons.

This is a proposed explanation for depressive symptoms associated with the drug:

K. C. O’Reilly, J. Shumake, S. J. Bailey, F. Gonzalez-Lima, and M. A. Lane,Chronic 13-cis-retinoic acid administration disrupts network interactions between the raphe nuclei and the hippocampal system in young adult mice,European Journal of Pharmacology , vol. 605, no. 1–3, pp. 68–77, Mar. 2009.


P. Hu et al. , “Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis, in close correlation with depressive‐like behavior,Hippocampus , Mar. 2016.

These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA-induced impairments in hippocampal neurogenesis correlate with depression-like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA-associated mood disorders


Y. Liu et al. , “Effects of retinoic acids on the dendritic morphology of cultured hippocampal neurons,” J. Neurochem. , vol. 106, no. 3, pp. 1104–1116, Aug. 2008.

These results suggest that RAs at high concentrations cause a negative effect on the dendritic morphology of cultured hippocampal neurons through RA receptors, while RAs at low concentrations exert a positive influence on cultured hippocampal neurons.

^note that a biphasic effect is described above

It’s probably common knowledge among those reading this that there is a correlation between neurosteroid levels and hippocampal neurogenesis, so it stands to reason that Accutane (and ATRA) might have such an effect by decreasing neurosteroidogenesis.

But the only investigations performed indicate that retinoids (including Accutane and ATRA) induce production of neurosteroids:

E. Munetsuna et al. , “Retinoic acid stimulates 17beta-estradiol and testosterone synthesis in rat hippocampal slice cultures,” Endocrinology , vol. 150, no. 9, pp. 4260–4269, Sep. 2009.

A. Kushida and H. Tamura, “Retinoic acids induce neurosteroid biosynthesis in human glial GI-1 Cells via the induction of steroidogenic genes,” J. Biochem. , vol. 146, no. 6, pp. 917–923, Dec. 2009.

P. R. Manna, A. T. Slominski, S. R. King, C. L. Stetson, and D. M. Stocco, “Synergistic Activation of Steroidogenic Acute Regulatory Protein Expression and Steroid Biosynthesis by Retinoids: Involvement of cAMP/PKA Signaling,” Endocrinology , vol. 155, no. 2, pp. 576–591, Feb. 2014.

E. Bonnet, K. Touyarot, S. Alfos, V. Pallet, P. Higueret, and D. N. Abrous, “Retinoic Acid Restores Adult Hippocampal Neurogenesis and Reverses Spatial Memory Deficit in Vitamin A Deprived Rats,” PLOS ONE , vol. 3, no. 10, p. e3487, Oct. 2008.

.^and this last one describes an effect contrary to the other studies (at what appears to be a relatively small replacement dose)

There are also studies on the prostate, steroidogenic tissues, fertility parameters, and androgenic tissues showing contradictory effects.

If the retinoids generally elicit a biphasic dose-response curve across their range of observed concentrations, from supplemental, to toxic/therapeutic (typical Accutane therapy is considered equivalent to a “controlled” vit-A toxicity), to extremely high experimental, it could explain the contradictory observations.

And it appears Accutane, at least through conversion to RA, absolutely does have such an effect, and on GnRH receptors in the female reproductive cells that produce estrogen and progesterone. They are roughly equivalent to the T producing steroidogenic cells of the testes.

P. Bagavandoss and A. R. Midgley, “Biphasic action of retinoids on gonadotropin receptor induction in rat granulosa cells in vitro,” Life Sci. , vol. 43, no. 20, pp. 1607–1614, 1988.

T. Minegishi, T. Hirakawa, H. Kishi, K. Abe, Y. Ibuki, and K. Miyamoto, “Retinoic acid (RA) represses follicle stimulating hormone (FSH)-induced luteinizing hormone (LH) receptor in rat granulosa cells,” Arch. Biochem. Biophys. , vol. 373, no. 1, pp. 203–210, Jan. 2000.

S. Cho et al. , “A functional retinoic acid response element (RARE) is present within the distal promoter of the rat gonadotropin-releasing hormone (GnRH) gene,” Brain Res. Mol. Brain Res. , vol. 87, no. 2, pp. 204–213, Mar. 2001.

Thanks to @guitarman01 for reminding me of this “paradox”, in his words.

There was a study showing a higher level of a small concentration of endogenous 13-cis Reinoic Acid is associated with healthy male fertility, so the poison truly is in the massive dose provided by Accutane.

This paradoxical benefit from low-level exposure to a toxin or stressor that follows a biphasic dose-response curve is known as a hormetic effect


Some additional evidence of a concentration-dependent biphasic effect of Accutane and other retinoids:

C. C. Zouboulis, B. P. Korge, D. Mischke, and C. E. Orfanos, “Altered proliferation, synthetic activity, and differentiation of cultured human sebocytes in the absence of vitamin A and their modulation by synthetic retinoids,” J. Invest. Dermatol. , vol. 101, no. 4, pp. 628–633, Oct. 1993.

Addition of isotretinoin and acitretin exerted a biphasic effect. At concentrations < or = 10(-7) M, both compounds enhanced sebocyte proliferation and synthesis of total lipids, especially triglycerides and cholesterol, and decreased lanosterol, keratin 16, and the keratin 16:keratin 4 ratio. In contrast, retinoid concentrations > 10(-7) M inhibited sebocyte proliferation in a dose-dependent manner.

I do wonder if this might explain the flare effect many experience when they begin treatment, often followed by remission of acne.

Interesting that an opposite effect at extremely high doses of testosterone was described in a publication briefly discussing PFS

What are the ways to restore hippocampal neurogenesis ? Is it linked only with depression ? Or somehow it affects sexual sides ?

Just to be clear, it is accepted that much of the pharmacological action of Accutane results from its intracellular isomerization to ATRA/RA (Retinoic Acid).

This shows a biphasic effect of retinoic acid on prostate cancer cells and provides a reasonable explanation for the many contradictory studies of the effects of retinoids on the prostate and prostate cancer cells:

@slick1, decreased hippocampal neurogensis is certainly linked with depression, possibly with sexual symptoms. Increasing BDNF and increasing neurosteroids through different means have been suggested as ways to achieve this.

Exercise (for those of us who can tolerate it) is attributed with increasing BDNF and the allopregnanolone analogue SAGE-217 (Zuranolone), that should be on the market in the next couple years is basically a synthetic neurosteroid replacement therapy.

While on the topic, allopregnanolone also exhibits a biphasic effect on anxiety.

It is a surprisingly common theme in biology.

Interesting for sure. It begs the question why persistent adverse symptoms are so rare in Accutane and Finasteride users, and why something so dramatic can happen after a single dose with some users. Others go for years without any noticeable side effect profiles.

It seems like in these studies large doses were used and the outcomes were relatively homogeneous.

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Don’t SSRIs increase hippocampus neurogenisis?

It’s hard to tell without seeing the data sets. They are homogenous as far as the higher doses, on average, having an inhibitory or toxic effect. The thing is, there is a huge variation among patients for serum levels of Accutane/Isotretinoin and ATRA during treatment. There is a study I will need to dig up that shows something like a 4x higher than average blood level of Accutane for some outliers. I guess those are the poor metabolizers/excreters of the drug.

It’s worth noting that the hormetic effect often occurs over a logarithmic scale for concentration, so even 4x higher than average wouldn’t necessarily be that much going by this effect. Serum levels of Isotretinoin at baseline (it occurs naturally in small concentrations) are 5.2510^(-9)M but at end of treatment at 40-60mg/day the average serum Isotretinoin concentration is 5.9310^(-7)M. This is more than a 100-fold increase in concentration and could easily elicit a hormetic/biphasic dose response. And the hypothetical poor metabolizers could have as high as a 450-fold increase compared to endogenous levels!

I will also need to dig up the studies of ISO and ATRA levels when I find the time and compare them to the concentrations noted in my first post in this topic.

@Mcbbould, yes, SSRIs have been found to increase hippocampal neurogenesis, but you risk the adverse effects of decreasing 5-ar metabolites for the sake of increasing the neurosteroids that influence neurogenesis. Hell, DHT and DHP have their own benefits as neurosteroids, so this is a huge sacrifice and a risk for worsening this condition under the assumption that PSSD = a form PFS.

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Would this suggest that possibly a “low” dose supplementation of vitamin A / ATRA would be beneficial for those who had taken Accutane?

Also, to build off of this, I clearly remember within the first week of me starting Accutane my oil production was through the roof. I recall having to remove oil off of my face at least once every hour. It was after this period when all the side effects I have now developed (I never experienced the “crash” that everyone talks about).

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Nope. Is vitamin A or retinoid resistance really the problem when we with PAS developed symptoms indicative of a resistance to androgens, probably due to it’s potent anti-androgenic effects at high doses?

Also, even viewing PAS as a modulation of the normal reaction to retinoids, rather than modulation of normal reaction to androgens, do we now experience an adaptation of resistance/tolerance, where we need more to attain the same effect, or an adaptation of resistance/intolerance where the same amount has a toxic effect? There’s no way to tell and PAS patients have reported everything from retinoid intake being irrelevant to their symptoms, to an adverse reaction to both increased and decreased consumption.


Yep. There is a lot of variation among us. @Axolotl and I just had a conversation where he seemed surprised to hear me say that not many PAS patient crashed after stopping and I was equally surprised to hear him say that he was under the assumption that we usually crashed post-drug, going by his past conversations with PAS patients.

I personally crashed around 6 weeks post-drug with an insane oil production, sebum plugs pushing out of my skin, erections lasting for hours, and moments of intense libido. This lasted for 2 weeks, followed by apparent cease in oil/sebum production and total remission of acne that occurred alongside a severe crash. To me, this was a sign of normal androgen production returning post-drug, while the concentration threshold of maximum effect of androgens had been drastically lowered. This type of stuff will need to be answered by more research.

What you experienced would hypothetically be the flare effect of an increasing level of Isotretinoin and ATRA having a positive effect on the normal function of retinoids, followed by an increasingly negative effect as the level of Isotretinoin and ATRA continued to increase beyond the threshold of the maximum positive effect.

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This makes sense; however, the fact that I didn’t ever experience a crash or any type of temporary remission of symptoms worries me that the condition that I’m experiencing is different that of others. I guess there’s no gravity behind that worry since there’s no way of knowing at this point for sure.

On top of that though, I have a hard time understanding how the current prominent theory of silenced androgen receptors could apply to a case like mine. Since all of my symptoms developed while on the drug, it makes me think a more permanent form of damage occurred rather than a disruption in some endocrine cycle.

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Same with me. One pill did some damage, and ED was almost immediate after a pill.

A few points to consider, with nothing written in stone:

  • It makes more sense that we’re all suffering from the same condition (IMHO) due to the general overlap in symptoms, persistency, and outcome of therapeutic attemps. The destination matters more than the road we took to get here. Not all post-Finasteride patients crashed, not all post-Accutane or PSSD patients developed the severest of symptoms while taking the drug. Some PSSD and Finasteride patients took the drugs for years without much trouble, then either got hit while still on the drug or had the brief recovery + hard crash. Some from all patient groups mentioned have been persistently affected after only a few (one in some cases) standard doses.
    This is what makes gathering data about this so important, and hopefully anyone reading this who wants to get better has filled out the symptomatic profile survey. Many thanks to those who have.

  • The odds of the existence of 2 or more different rare conditions with the same general symptom profile, that are practically untreatable, undiagnosable, all caused by drugs with an anti-androgenic effect on some level, and are beyond explanation by conventional medical and scientific knowledge, are slim to none. I mean, this is already unbelievable enough to us that we’re living in a state of existence that isn’t supposed to be medically possible. Go ask one of the gods of knowledge of human physiology why this happened and %90 of them will, almost reflexively, send you home with an antidepressant and referral to a psych because they believe this condition is so impossible that you must be delusional or a liar.

  • A “crash” isn’t ubiquitous either across the different patient groups, or within them. I’ve spoken with several PAS and PFS victims who took less than 10 pills and developed nearly identical symptoms as me; including magnitude of severity. Several of them were on the drug(s) for less than a week. PSSD and post-Lupron/GnRHa patients say the same.

  • If the threshold for a paradoxical dose response is lowered to a lesser concentration, a crash may only be indicative of rapidly attaining and exceeding that concentration in the absence of the drug’s effects. i.e.: perhaps I crashed because my androgen levels rose rapidly when the influence of Accutane wore off, others may have not experienced a crash due to a less rapid restoration of normal levels. If all it takes is one dose to elicit an effect significant enough to lower this threshold, then it is what it is. This is outside of the context of this discussion, but Accutane does have one such rapid anti-androgenic effect that might be achievable after only one dose in vivo. Finasteride is known to have such an effect, as it has a near flat dose-response curve, with a 0.2 mg dose decreasing DHT by %62 and 5 mg by %70. SSRI studies have shown such a profound and rapid effect on DHT in brain tissue via modulating steroidogenic enzymes that convert DHT -> Adiol, Adiol -> DHT, and Androstenedione -> DHT.

  • A little off-topic, but there must be some confounding variable to explain varying responses to these in the same individual across different periods of usage. Why did I only crash after a brief 2nd course and not the longer 1st course, why did @slick1 develop persistent ED after 1 pill, why do some post-finasteride patients only develop persistent symptoms during or after their 2, 3, sometimes 4th period of usage. PSSD patients have been on one SSRI for years, switch to another, and BAM! What is causing this?, Time of year?, Diet?, stage of lunar cycle?, wind direction? Just kidding a little, but there must be some explanation for this that has been missed or is an inherent part of the problem.

@BearOf17, this is far more than simply a disruption of the endocrine cycle. If that’s all it was, we would know what hormone to take to fix this after years and years of testing and hormonal therapies. Granted, a hormonal disruption is the apparent triggering mechanism, then something much deeper goes awry for us. It’s not like we can go to any doctor and ask them to order obscure gene expression assays like we do with blood tests.


After looking further into it, the term “hormesis” was born from the concept of something typically ascribed as being a toxin or stressor exhibiting beneficial effects at very low doses and there doesn’t seem to be a consensus on a strict definition.

Technically, it can be used interchangeably to describe any biphasic dose-response, but in essence, I think it’s incorrect to apply it to something that is harmless at naturally occurring levels and under normal circumstances.

Let’s hope whatever that is can be ‘fixed’, or at the very least treated.

A great post by the way. Made some good points.

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youre the man ! great post !