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:
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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.
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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
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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
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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:
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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