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.
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Stem cells can specialise (differentiate) into different tissues
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 RXRAR 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.

Beta-catenin:

I’ll begin by introducing protein central to the Beta-catenin model: beta-catenin. Beta-catenin is a multifunctional protein that plays the central role in the Wnt signalling pathway, which is essential for cell adhesion, tissue growth, development, and homeostasis. Wnt (short for ‘wingless’ on account of their shape) is the name of the proteins that can activate so-called ‘canonical’ Wnt/beta-catenin pathway to activate beta-catenin target gene transcription. In the absence of any Wnt ligands (binding molecules), beta-catenin is continually marked for degradation within a ‘destruction complex’. This destruction complex entraps beta-catenin and consists of Axin, APC (adenomatous polyposis coli), GSK-3β (glycogen synthase kinase 3 beta), and CK1 (casein kinase 1). When Wnt proteins bind to receptors (Frizzled and LRP5/6) on the cell surface, the destruction complex is inhibited and beta-catenin is stabilised and accumulates in the cytoplasm of the cell. Beta-catenin then translocates into the nucleus where it interacts with TCF/LEF transcription factors to regulate the expression of its target genes. These target genes are all to do with cell proliferation and differentiation. [9]
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Destruction complex degrades Beta-catenin
^{https://www.sciencedirect.com/science/article/pii/S0092867412005302}
ATRA (the main functional metabolite of Accutane) can block the action of beta-catenin by further enhancing the action of the destruction complex. ATRA can do this by inhibiting PI3K-AKT and thus increasing the GSK-3β degradation of beta-catenin. [10] One of the many roles played by beta-catenin’s action on cell proliferation and differentiation is the maintenance of stem cell populations. When beta-catenin action is inhibited stem cells undergo differentiation, losing their pluripotent self-renewing properties. [11] One of the medical applications of Accutane is in treating cancers, where tumours maintain their self-renewal stem cell properties to rapidly proliferate. ATRA can interrupt tumorigenesis by blocking beta-catenin, and thus triggering differentiation. [12] Whilst Accutane exerts this differentiating effect on cancer stem cells, it is also able to induce differentiation other healthy tissues throughout the body that rely on a stem cell population for maintenance (bones, skin, gut, and brain).

ALDH beta-catenin feedback loop:

Aldehyde dehydrogenases (ALDHs) represent large family of enzymes that catalyse the oxidation of aldehydes to their corresponding acids. The family is diverse with 19 different isoforms coming under its umbrella, playing vital roles in metabolism, production of neurosteroids and pertinently to PAS – the endogenous production of retinoic acid. They convert retinol to retinal with enzymes called Alcohol/retinol dehydrogenases (ADH/RDH), and they then oxidise retinal to retinoic acid with different isoforms being expressed in different tissues (ALDH1A1, ALDH1A2 etc.) One isoform, ALDH2, has been implicated in the phenomenon of “Asian Flush”, which is the red facial flushing caused by poor alcohol metabolism prevalent in some East Asian populations. [13] Though this may seem fairly benign, poor ALDH2 function has been negatively associated with the progression and severity of Alzheimer’s Disease given its additional role in the clearance of toxic dopamine metabolites. [14] Parkinsons is a disease characterised by the progressive loss of dopaminergic neurons. Dopamine is a neurotransmitter that governs feelings of satisfaction, pleasure, and excitement – but its primary metabolite DOPAL (3,4-dihydroxyphenylacetaldehyde) is toxic and kill dopaminergic cells. This metabolite can be broken down into a less toxic form through ALDH enzymes. When this action is impaired, it can accelerate the loss of dopaminergic cells driving Parkinsons disease pathogenesis. [15]
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https://www.teawithmd.com/2014/12/the-truth-about-alcohol-flushing-or-asian-glow/
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Retinoids regulate ALDH, with evidence from Cancer studies:

Whilst it’s clear that ALDH is essential to healthy functioning, it has an additional role as a cancer stem cell marker. ALDH is found elevated in cancerous tissues, where ALDH is not typically displayed. [16] Not only does elevated ALDH point to the presence of cancer, but it can also result in poor response to chemotherapy as ALDH can protect the cancerous stem cells from the chemo drugs. [17] However, it should be clear that these are distinct mechanisms. The reason that ALDH can be sign of cancerous growth is all to do with beta-catenin. As previously discussed, beta-catenin support the growth and proliferation of stem cells- including cancerous stem cells. The reason ALDH is elevated, is precisely because of its capacity to synthesise retinoids which can in turn trigger growth arrest and reduced stem cell expression. [18] It’s only within the last few years that scientists have been able to elucidate the complex feedback loop that regulates beta-catenin expression. Under normal healthy conditions, elevated beta-catenin would upregulate ALDH, which would in turn induce greater retinoic acid synthesis, which would trigger differentiation and growth arrest – in turn mitigating the risk of cancerous stem cell development. [19] Under cancerous conditions, the tissue is not responsive to differentiation and the elevated beta-catenin maintains a higher ALDH expression. This overexpression of ALDH can have disastrous effects on disease progression by nullifying the toxic effects of chemo drugs. This is why exogenous retinoids, like Accutane, by triggering differentiation in these cancer stem cells and suppressing beta-catenin. [20] Since beta-catenin regulates ALDH expression, Accutane treatment leads to a downregulation of ALDH enzymes leading to better response to chemo drugs. [21] Accutane has been repeatedly shown to suppress ALDH action in this way, enhancing cancer treatments. [22]
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Beta-catenin ALDH feedback loop

Suppressed Beta-catenin/ALDH explains PAS:

Now that I’ve demonstrate the suppressive effect of Accutane on both ALDH and beta-catenin, we can begin to investigate how these effects manifest throughout the body and explain the spectrum of PAS symptoms.

Changes to Neurosteroids:

One of the ways of explaining the therapeutic effect of Accutane in treating acne is by modulating androgen signalling, which drives acne pathogenesis. I’ve detailed the role of ALDH in producing retinoids, but many members of the ALDH family more readily bind to androgen substrates than retinol and primarily serve in the production of neurosteroids. One such isoform is RoHD4, which is prevalent in the skin and liver and acts similarly to 3 alpha-HSD. It catalyses the oxidation of 3α-diol (5α-androstane-3α,17β-diol) to the much more potent androgen DHT (dihydrotestosterone). [23] The presence of this enzyme in the skin might contribute to the development of acne, and the suppression of RoDH4 (via the previously outlined beta-catenin/ALDH feedback loop) may constitute one of Accutane’s mechanisms of action. [24] Another product of RoHD4 is androstanedione, which undergoes conversion to DHT in peripheral genital tissue under the action of another enzyme: 17b-hydroxysteroid dehydrogenase. [25] The suppressive effect on a number of enzymes sharing both retinoid and steroid dehydrogenase activity has been observed in microarray analysis. 8 weeks of Accutane treatment resulted in a six-fold decrease in 3 beta-HSD expression, which is responsible for the conversion of DHEA into androstenedione. [26] This study also identified a 3-fold suppression 5 alpha-reductase, another key enzyme in the production of DHT.

Androgen receptor activity:

Whilst it’s evident that Accutane can mute androgen signalling by inhibiting enzymatic activity, the beta-catenin model also predicts an even more direct impact on Androgen receptor itself. Beta-catenin is found to complex with the androgen receptor to make the receptor dramatically enhance gene transcription. [27] This effect is so potent that relatively weak androgens such as DHEA can result in the same level of AR gene transcription as testosterone, when complexed with beta-catenin. Even more striking is the ability of beta-catenin to reactivate the androgen receptor in androgen depravation treatment of prostate cancer. It’s hypothesised that this was achieved by indirect activation of AR by modification of coactivators. [28]

Suppression of dopamine signalling:

As previously discussed, ALDH has a pivotal role in the progression of Parkinsons disease which is characterised by the progressive loss of dopaminergic neurons. ALDH has a protective effect against the toxic byproducts of dopamine metabolism such as DOPAL. [29] This could explain why retinoid dehydrogenase enzymes are abundant in the regions of the brain most rich in dopamine receptors, such as the striatum and nucleus accumbens. [30] A powerful ALDH inhibitor, Disulfiram, is used in the treatment of alcoholism. It was initially hypothesised to work by suppressing the degradation of toxic alcohol metabolites, therefore making drinking less pleasurable. However subsequent research has found that Disulfiram (and other ALDH inhibitors) can result in lower extracellular dopamine due a negative feedback mechanism triggered by the increased presence of toxic dopamine metabolites. [31] This mechanism also explains why a common side effect of this medication is reduced mood and libido. The prefrontal cortex is another region with high ALDH and dopamine expression is the prefrontal cortex, a region that is most evolved in humans and subserves our high order cognitive abilities. This was also the region that experienced the most significant suppression in activity over the course of Accutane treatment, with a 16% reduction in metabolism. [32]
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Decreased brain activity in the Frontal Cortex

Musculoskeletal pain and cartilage degradation:

In the context of cartilage development, the levels of beta-catenin determines both osteogenesis (formation of bone) and chondrogenesis (formation of cartilage). [33] Endochondral ossification is process of skeletal development that using the cartilage as a template. The chondrocytes transform during this process first by hypertrophy (enlargement), then dying and calcifying. Osteoblasts (bone generating cells) then migrate into this area and lay down a bone matrix. [34] Once cartilage has been damaged it is largely unable to repair itself, as chondrocytes are bound within lucanae (small pockets within the bone). Retinoic acid has been shown to reliably alter the differentiation pattern of chondrocytes, with the most profound effects being seen in the foetal development of mothers exposed to retinoic acid. Foetuses exposed to retinoic acid display craniofacial and limb malformation. There’s in vitro evidence that retinoic acid inhibits the formation of chondroblasts (the cells that form chondrocytes), resulting in the cessation of cartilage formation and ultimately the loss of pre-existing cartilage structures. [35] [36] Many of the observed effects of retinoic acid on chondrocytes match the known effects of suppressing beta-catenin signalling on chondrocytes, suggesting that this may be the relevant mechanism of action. Inhibition of beta-catenin in chondrocytes resulted in increased cell apoptosis (cell death) and “articular cartilage destruction”. [37]
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Permanent Skeletal changes induced by Accutane in 38 year old woman

Ocular and vision changes:

One of the side effects of Accutane most recognised in the medical literature to persist idenfinitely following treatment is the loss of night vision (nyctalopia). [38] The persistence of this symptom is actually one of the best pieces of evidence to support the Beta-catenin model of PAS. Retinal is a vital component in human vision, necessary for photo transduction. It is a chromophore (light absorbing molecule) that combines rod and cone opsins to for rhodopsin and activated cone opsins. Isotretinoin slows down rhodopsin regeneration and chromophore recycling by inhibiting retinoid isomerase (RoDH-11) and 11-cis retinol dehydrogenase enzymes that are necessary for the synthesis of 11-cis retinal. [39] ALDH3A1 and ALDH1A1 enzymes additionally protect inner ocular tissues from ultraviolet radiation and reactive oxygen-induced damage. Corneal crystallin’s contribute to cellular transparency in corneal stromal keratocytes, supporting a structural role of these ALDH proteins. A putative regulatory function of ALDH3A1 on corneal cell proliferation has also been proposed. [40]

Gastrointestinal changes and IBS:

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. [41] 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 a 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. [42] As you can guess from the emerging pattern over PAS symptoms, the gut relies on beta-catenin for stem cell maintenance. Blocking beta-catenin results in rapid loss of two important cell types within the gut, transient-amplifying cells (type of stem cell) and crypt structures (pocket of epithelial cells). A 2023 study found deletion of the beta-catenin gene triggered the complete differentiation of stem cell populations, resulting in loss of intestinal homeostasis which was ultimately fatal. [43] Conversely enhancing beta-catenin, by suppressing GSK3 with Lithium, has been found to improve gut structure and health. The action of Lithium on beta-catenin increased gut microbiome diversity and healthy and was even found to relieve colon inflammation. [44][45]

Epigenetic changes:

Epigenetics is the process by which genes can be switched on or switched off, and mediate the lasting changes induced by certain medications. Whilst its not possible to directly change your genome, it is possible for the epigenetic machinery that reads and transcribes your genome to be changed such that some genes are ignored (silenced) and other are activated. Accutane has a two-stage effect on the epigenome. During Accutane treatment there is a loss in epigenetic stability, through the downregulation of DNMT1 and DNMT3b, with both significant de-methylation and hypermethylation events. [46] Of the hypermethylated genes, around a dozen became significantly repressed. The most significantly downregulated gene was MYCN, which encodes the N-myc protein which is key regulator in beta-catenin signalling. [47] The suppression of this gene and subsequently beta-catenin was posited to be responsible for Accutane’s differentiative effects. An additional study on the epigenetic mechanisms of Accutane found that Accutane induced microRNAs that downregulate Wnt and Akt pathways, both needed for beta-catenin gene transcription. [48] There’s some evidence that the epigenetic status of the Wnt/Beta-catenin pathway is reliant on a feedback mechanism, [49] such that potential alterations induced by Accutane could persist. [50] All this is complementary to the fact that activation of the beta-catenin pathway is the mechanism of action histone deacetylase inhibitors (HDACis). Structurally distinct HDACis all share a common target of the Wnt/beta-catenin pathway. [51]
For references visit here: https://pas-secondlife.com/2023/11/05/what-causes-post-accutane-syndrome/