1. Introduction
2. Retinoids:
3. Accutane Inhibits cell growth
4. How is Accutane different to vitamin A?
5. Wnt/β-catenin
6. Retinoid Synthesis: The Link to Parkinsons and ‘asian flush’
7. ALDH feedback loop
8. Changes to Neurosteroids
9. Androgens
10. Suppression of dopamine signalling
11. Musculoskeletal pain and cartilage degradation
12. Ocular and vision changes
13. Gastrointestinal changes and IBS
14. Epigenetic changes:
15. Related Articles
16. References

Introduction

Isotretinoin, more commonly known by its brand name Accutane, is a retinoid commonly used to treat severe cystic acne. However, just as it is renowned for permanently treating even the most severe cases of acne, so too does it have the reputation for having a number of nasty side effects. Just as the roles of Vitamin A are broad and diverse, so too as the possible side effects of Accutane, including changes to vision, joint health, hair, the gut, and most notably – the brain.

The impact of Accutane on the brain is most striking, with an accumulating body of ‘in vitro’ evidence to show that it could be responsible for directly killing neurons in the hippocampus and hypothalamus (read more). One of the most dramatic finding came from a 2005 brain imaging study by Bremner et al. which found a 21% reduction in brain activity in the prefrontal cortex after four months of treatment with the acne drug.

Many of the side effects of Accutane, including neurological symptoms, have been reported to be enduring. [53] The neurological changes could manifest in alterations in mood and personality, and even sexual functioning. In fact, practitioners have even begun to formulate diagnostic criteria for so-called ‘post-retinoid sexual dysfunction (PRSD)‘. [54] Whilst so much of Accutane’s diverse effects throughout the body remain unknown, much can be gleaned from research on ‘all-trans retinoic acid’ (ATRA) – which is the primary active metabolite of Vitamin A as well as Accutane.

In this article I’ll communicate the evidence for how Isotretinoin impacts the body more broadly, as well as offer my hypothesis regarding some of the specific side effects of Accutane treatment. Specifically, I’ll show how Accutane disrupts the activity of a family enzymes called ‘Aldehydes Dehydrogenases’ (ALDH) which perhaps explains a broad range of side effects including disturbances to vision, increased oxidative stress, dopamine dysregulation, joint damage and more.

Retinoids:

Retinoids are the class of chemical compounds that are chemically related to vitamin A. They play a role in regulating a wide range of biological systems including vision, cell proliferation/differentiation, bone tissue, and the immune system. Retinoid is a general term and encompasses a range of molecules including retinol, retinoic acid, retinyl esters as well as synthetic retinoids.

The breadth of effect of retinoids in the body perhaps is vaster than any other vitamin. Despite retinoids coming in many forms, the majority of retinoid signalling comes from the primary metabolite all-trans retinoic acid (ATRA). ATRA binds to several types of nuclear receptor including Retinoic Acid Receptor (RAR), Retinoid X Receptor (RXR), Peroxisome proliferator-activated receptors (PPARs). [1]

The most fundamental role of retinoids, key to both the therapeutic and adverse effects of Accutane, is regulating cell growth and differentiation. Cells undergo a four-phase life cycle: in G1, they synthesize proteins for division; in the S phase, they replicate DNA; in G2, chromatin condenses into chromosomes. Finally, in the ‘M’ phase the cell divides through mitosis, forming a new cell. 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 of progenitor/stem progenitor cells.

Stem cells are the unique cells that have the ability to self-renew as well as transform in speciliased tissue cells to support the growth and repair of organs, including neurons, skin cells, hair and more.

The populations of these stem cells rely on a delicate balance between proliferation and differentiation, to ensure both the replenishment of tissue-specific cells and the preservation of a stem cell pool. This balance is crucial for maintaining long term tissue health and future capacity for repair and regeneration.

The variety of cells that a stem cell can differentiate into. Haileyfournier, CC BY-SA 4.0 https://creativecommons.org/licenses/by-sa/4.0, via Wikimedia Commons

During cell proliferation, stem 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, digestive tract, brain and many of the other organs most vulnerable to side effects from Accutane treatment.

Accutane Inhibits cell growth

Retinoids exert an anti-proliferative effect on the body. The evidence for this effect is most strikingly observed in embryos overexposed to vitman A. If these embryos reach full term, they offer suffer from underdeveloped limbs and cleft palates. [2] This is why Accutane is a teratogen (a substance that disrupts normal foetal development causing congenital disabilities). This is the reason behind the strict guidelines on birth control for women undergoing Accutane treatments.

However the anti-proliferative effects of Accutane can also be observed in the many adult tissues which also rely on pools of stem cells for continual renewal and growth such as the skin, intestines, bone marrow, cornea, hair follicles and brain (particularly hippocampus). Retinoids such as Accutane trigger the conversion of these stem cells in to specialised cells through a process called differentiation. In this way retinoids maintain the delicate balance between proliferation and differentiation, and why certain tissues are particularly effected by Accutane treatment.

A meta-analysis of 25 random controlled trials found that neurological, musculoskeletal, bowel, eye and skin changes were amongst the common categories of adverse symptoms. Epidermal tissues are one such tissue which rely on stem cell pools for continual renewal, which is why half of patients treated with the acne drug experienced skin thinning. [4] The gut, another epithelial tissue, is also effected – with 10% of patients experience gastrointestinal distress. There is also 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 and even arthritis.

The greatest risk is posed to younger teenagers who may even experience stunted growth due to premature epiphyseal plate closure. Perhaps most disturbing is the possible anti-proliferative effect of Accutane in the brain. The hippocampus is a region of the brain that relies on stem cells to continue to develop new neurons during adulthood to form new memories.

Accutane significantly inhibits hippocampal neurogenesis, disrupting hippocampal dependent learning. [6] This is just a brief summary of the effects of Accutane throughout the body, but the pattern is clear. Accutane has both profound and diverse consequences throughout the body – most significantly in tissues which are reliant on a stem cell progenitor pool for maintenance.

How is Accutane different to vitamin A?

Isotretinoin (Accutane) is an isomer of retinoic acid; it is naturally occurring in very small doses, but primarily exerts its effect through the 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 even greater nuclear (in the nucleus of the cell) concentration of ATRA than applying ATRA directly.

This is because Isotretinoin is able to avoid stimulating a xenobiotic metabolising response from cytochrome p450. [7] Once bound to the Retinoic Acid Receptor (RAR), the RXR/RAR heterodimer complex binds to the DNA to transcribe retinoic acid response genes. [8] There’s one pathway in particular that has significant interplay with retinoid signalling, that’s key to understanding the adverse effects of Accutane treatment: Wnt/β-catenin.

All trans retinoic acid (ATRA) vs. cis-13 retinoic acid. (Vaccinationist, Public domain, via Wikimedia Commons)

Wnt/β-catenin

β-catenin is a growth signalling protein that’s central to the Wnt pathway. This pathway 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 the ‘canonical’ Wnt/β-catenin pathway to activate β-catenin target gene transcription. In the absence of any Wnt ligands (binding molecules), β-catenin is continually marked for degradation within a ‘destruction complex’.

This destruction complex entraps β-catenin and consists of Axin, APC, GSK-3β (glycogen synthase kinase 3 beta), and CK1. When Wnt proteins bind to receptors (Frizzled and LRP5/6) on the surface of cells, the destruction complex is inhibited and β-catenin is stabilised and accumulates in the cytoplasm. β-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 relate to cell proliferation and differentiation. [9]

ATRA (the main functional metabolite of Accutane) can block the action of β-catenin by further enhancing the action of the destruction complex. ATRA does this inhibiting PI3K-AKT, which upregulates GSK-3β degradation of β-catenin. [10] One of the many roles played by β-catenin is the maintenance of stem cell populations. When β-catenin action is blocked, 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 β-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).

Retinoid Synthesis: The Link to Parkinsons and ‘asian flush’

Aldehyde dehydrogenases (ALDHs) represent large family of enzymes that catalyse the oxidation of aldehydes. 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. 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 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]

ALDH feedback loop

It’s clear that ALDH activity is essential for good health, however it also has an additional property of being 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 β-catenin. As previously discussed, β-catenin supports the growth and proliferation of stem cells- including cancerous stem cells.

The reason ALDH is elevated in cancerous tissue is precisely because of their capacity to synthesise retinoids. Under normal conditions, elevated ALDH (and related enzymes) would result in increased retinoid synthesis, and thus trigger growth arrest and reduced stem cell expression. [18] It’s only within the last few years that scientists have been able to comprehend this complex feedback loop regulating β-catenin signalling. The increase in retinoid synthesis inhibits β-catenin signalling resulting in 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 β-catenin maintains a higher ALDH expression. This overexpression of ALDH can also hamper cancer treatment by nullifying the toxic effects of chemo drugs. This is why exogenous retinoids, like Accutane, have been found useful in cancer treatment – by triggering differentiation in these cancer stem cells by suppressing β-catenin. [20] Since β-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, improving cancer treatments. [22]

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 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 β-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 3β-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.

Androgens

Accutane alters androgenic signalling in several important ways. The most direct way is by disrupting hormonal secretion by disrupting the vital regulatory feedback mechanism called the Hypothalamic-Pituitary-Testicular Axis (HPTA). This complex set of hormonal feedback loops between the brain and gonads governs the production of testosterone, and by extension other androgen metabolites. In fact, I’ve presented convincing evidence to suggest the drop in testosterone levels that occurs during Accutane treatment is a direct effect of the increase in oxidative stress in the testes caused by the inhibition of ALDH enzymes via the mechanism outlined above (read more).

Accutane treatment further interferes with androgenic signalling by suppressing key enzymes needed to synthesise important androgen metabolites like DHT, which contribute significantly to androgenic processes throughout the body. The importance of DHT is laid out in my article on Finasteride, which similarly blocks DHT production (albeit more strongly) by inhibiting the 5-alpha-reductase enzyme (read more).

There is a third and crucial mechanism by which Accutane could also contribute to changes in androgenic activity, and that’s by influencing the androgen target itself – the androgen receptor. You can consider hormones like keys, by carried through the circulatory system to be delivered to tissues. The androgen receptor is like the lock the key must bind to in order to unlock the effects of testosterone on gene expression and protein synthesis. Without these receptor sites, hormones like testosterone can simply have no impact on the body. As it turns out, Accutane dramatically reduces the number and binding affinity of these sites (read more).

Interestingly, it’s possible that this finding could also be explained in the context of Isotretinoin’s impact on β-catenin. The activity of the androgen receptor is highly regualted by co-activators and co-repressors that determine how strongly a ligand like testosterone can influence gene transcription. β-catenin has been found to complex with the androgen receptor to potently boost androgen 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. Even more striking is the ability of β-catenin to reactivate the androgen receptor in androgen deprivation 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]

Musculoskeletal pain and cartilage degradation:

In the context of cartilage development, β-catenin activity 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 profoundly alter the differentiation 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 β-catenin signalling on chondrocytes, suggesting that this may be the relevant mechanism of action. Inhibition of β-catenin in chondrocytes resulted in increased cell apoptosis (cell death) and “articular cartilage destruction”. [37]

Ocular and vision changes:

One of the enduring adverse effects of Accutane treatment that is well attested to in the scientific literature is night blindness. [38] It’s this symptom in particular which gives a vital insight into enduring effect of Accutane throughout the body more generally, and substantiates a mechanism involving ALDH/β-catenin. Retinal is a derivative of Vitamin A and is a vital for vision, being a light absorbing molecule called a chromophore.

Isotretinoin has been found to slow down rhodopsin regeneration and chromophore recycling, by inhibiting the 11-cis retinol dehydrogenase (RoDH-11) enzyme which is necessary for the synthesis of 11-cis retinal. [39] Other retinoid synthesising enzymes such as ALDH3A1 and ALDH1A1 contribute to the protection of the inner ocular tissues from ultraviolet radiation and reactive oxygen-induced damage. 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]

Like other tissues which rely on continual renewal from a stem cell population, the gut is highly reliant on β-catenin signalling. Blocking β-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). Further highlighting its significance, a 2023 study found deletion of the β-catenin gene triggered the complete differentiation of stem cell populations – resulting in loss of intestinal homeostasis which was ultimately fatal. [43] Conversely enhancing β-catenin, by suppressing GSK3 with Lithium, has been found to improve gut structure and health. The action of Lithium on β-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 β-catenin signalling. [47] The suppression of this gene and subsequently β-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 β-catenin gene transcription. [48]

modified from original byAnnabelle L. Rodd, Katherine Ververis, and Tom C. Karagiannis, CC BY-SA 4.0, via Wikimedia Commons

There’s some evidence that the epigenetic status of the Wnt/β-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 β-catenin pathway is the mechanism of action histone deacetylase inhibitors (HDACis). Structurally distinct HDACis all share a common target of the Wnt/β-catenin pathway. [51]

Related Articles

What Does Accutane Actually Do?

How Accutane Changes Your Brain

References