1. Introduction
2. How Does Accutane Work?
3. What’s The Evidence For Accutane’s Effects On The Brain?
   1. Neuronal Cell Death
   2. Disruption To Dopamine
   3. Serotonin And The 5-HT1A Receptor
   4. Altering Differentiation Pattern of GABA neurons
4. References

Introduction

Accutane, also known by its generic name isotretinoin, is a widely used medication primarily prescribed for the treatment of severe acne. Over the years, its effectiveness in treating severe acne has been well-documented, earning it a reputation as a potent solution when other treatments fail. However, despite its efficacy, it has also been associated with a range of potential side effects—particularly those affecting the brain.

The extent of its psychological impact gained prominence during a 2015 murder trial, where attorneys argued that a 15-year-old experienced homicidal psychosis as a result of his treatment with the acne medication. [1] Although this may seem far-fetched, it is not an isolated incident, and the connection between Vitamin A and neurological disorders has a long historical precedent.

The effects of overexposure to Vitamin A on the central nervous system were first documented in 1856 by Elisha Kane, an Arctic explorer who experienced dramatic changes in mood and temperament after ingesting polar bear liver.

The symptoms of Accutane treatment significantly overlap with those of Hypervitaminosis A, as Accutane exerts its therapeutic effects through retinoic acid, the primary metabolite of Vitamin A. However, unlike overexposure to Vitamin A, isotretinoin avoids xenobiotic responses that metabolise excessive retinoic acid, allowing for an even greater intracellular accumulation. [2]

A meta-analysis of 25 randomized controlled trials found that neurological symptoms were among the most common adverse effects associated with Accutane treatment—24% of patients reported extreme fatigue, and 10% reported significant changes in mood and personality. [3] Aside from the numerous case reports, there is strong neuroanatomical evidence suggesting that retinoids are fundamental to cognition and mood.

The enzymes that locally synthesize retinoic acid are highly expressed in the brain regions richest in dopamine, called the mesolimbic system. [4] Dopamine is the neurotransmitter associated with feelings of reward, excitement, and pleasure; however, dysregulation of the dopaminergic system can lead to mania and psychosis.

The exact role of retinoic acid in regulating dopamine is not yet fully understood, but evidence shows that the two systems are deeply intertwined [5][6] Accutane can more directly impact neurological function through the role of retinoic acid in regulating stem cell proliferation and differentiation, processes vital for neuroplasticity throughout both childhood and adulthood. In this article I’ll introduce the four key ways by which Accutane treatment can impact the brain.

How Does Accutane Work?

Before introducing some of the ways Accutane impacts the brain, I’ll give a brief introduction to the fundamental role of Retinoids in the body, for a full explanation read here. In essence, retinoids regulate the behaviour of stem cells. Stem cells are the unique cells in the body that can self-replenish, and can convert into specialised tissue cells through a process called differentiation. However high levels of retinoic acid can directly inhibit stem cell proliferation, interfering with growth and repair.

This is most relevant to foetal development, where cells are rapidly proliferating and differentiating. The mother needs healthy levels of vitamin A ensure that stem cells differentiate appropriately to form new limbs in a process called morphogenesis. [8] The absence of vitamin A leads to uncontrolled proliferation of stem cells that fail to differentiate. For this reason, there has been a strong interest in retinoids reducing cancer risk.

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

One of the key signalling pathways by which Retinoids influence differentiation is the Wnt/β-catenin pathway. The scope of this growth signalling pathway is broad and is key to understanding the effects of Retinoids more generally through the body. β-catenin is the growth-signalling protein central to the Wnt pathway, which is essential for cell adhesion, tissue growth, development, and homeostasis.

β-catenin signalling is regulated by a “destruction complex,” which continuously targets the protein for degradation. When β-catenin is released from this complex, it enters the cell nucleus and promotes stem cell proliferation within tissues. Conversely, when β-catenin activity is suppressed by the destruction complex, stem cells undergo irreversible differentiation into specialized cells. [7]

Retinoids act as differentiating agents by enhancing the destruction complex’s activity, thereby inhibiting β-catenin and reducing stem cell proliferation. This balance is crucial to prevent premature or excessive differentiation, ensuring the stem cell pool can replenish and maintain tissue repair capabilities. Many tissues rely on pools of progenitor stem cells for growth and repair throughout adulthood, and not least the brain, and so inhibiting β-catenin can have a spectrum of troubling neurological effects.

What’s The Evidence For Accutane’s Effects On The Brain?

There is a mountain of evidence within the scientific literature that points to the diverse and profound effects of Accutane treatment on the brain. The most striking of this evidence comes from brain imaging of patients being treated with Accutane, which indicated a 21% reduction in activity in the orbitofrontal cortex. [10]

The frontal cortex is the region of the brain most developed in humans as compared to other animals and is responsible for higher cognitive processing. The researchers also identified that this reduction in activity was accompanied by headaches, with the severity of the headaches correlating with the degree of inhibition.

Effects on Regional Brain Metabolism in a Representative Patient Receiving Isotretinoin Treatment for Acne (J. Douglas Bremner et al. Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin) [Fig 1.]

The findings of this study corroborate the evidence for Isotretinoin inhibiting new nerve growth in the brain, and even directly causing apoptosis (cell death) of neurons. [11] The prevailing theory for depression is that it is a consequence of reduced neurogenesis (neuronal cell growth), which can be mitigated by neurogenic compounds. [12] It is therefore reasonable to connect the evidence of Accutane induced depression to these neurogenic effects.

β-catenin signalling is crucial for maintaining stem cell populations in tissues that require continuous growth and repair throughout adulthood, including the brain. In the hippocampus, progenitor cells are particularly important for memory formation, as this region is essential for generating episodic and spatial memory. Most first-line treatments for depression aim to increase neuroplasticity in the hippocampus.

Research shows that when β-catenin is removed from hippocampal cell cultures, synaptic strength declines. Neurons without β-catenin become thin and spindly, with reduced spontaneous glutamatergic currents. [13] In contrast, enhancing β-catenin signalling in transgenic mice promotes neuronal growth and even increases brain size due to an expanded neural stem cell population. [14] This evidence suggests that Accutane may inhibit new cell growth in the hippocampus by affecting β-catenin signalling. [15]

Neuronal Cell Death

Notably, the neurological role of β-catenin extends beyond the hippocampus; it also significantly influences synaptic activity in two other regions: the hypothalamus and the amygdala. The hypothalamus is a component of the limbic system that regulates hormone release, which is involved in various processes such as sexual responses, hunger, and circadian rhythms. Hypothalamic cells are subject to growth and regulation by β-catenin, which can be specifically guided by oestradiol, a hormone that activates the PI3K/Akt signalling pathway.

Interestingly, this action of oestradiol contrasts with the mechanism by which Accutane (isotretinoin) suppresses β-catenin activity. The role of oestradiol is particularly important for women, as it relates to the menstrual cycle (oestrous cycle in non-human animals) and the periodic changes it induces in synaptic structures. [16] Given this evidence, it is perhaps unsurprising that hypothalamic cells, along with hippocampal cells, are among the neuronal cells most susceptible to apoptosis (cell death) following exposure to retinoic acid. [17]

Another structure within the limbic system is the amygdala, which comprises two clusters of nuclei located centrally in the brain and plays a pivotal role in regulating memory, emotional responses, and feelings of reward and pleasure. Similar to the hypothalamus, the amygdala also appears to be significantly influenced by β-catenin.

There’s evidence that β-catenin is needed for the transfer of newly formed memory into long term memory, and specific deletion of β-catenin prevented this memory consolidation. [18] Furthermore, researchers have been able to trigger dysregulation of the amygdala of rats by applying retinoic acid, resulting in heightened fear and anxiety responses.

Disruption To Dopamine

Retinoic acid is typically produced in the body through a two-stage process. First, retinol is converted to retinal by enzymes called alcohol/retinol dehydrogenases (ADH/RDH), and then retinal is oxidized to retinoic acid by various ALDH (aldehyde dehydrogenase) enzymes.

The Aldehyde Dehydrogenase (ALDH) family of enzymes plays a pivotal role in the metabolism of aldehydes, which are a type of reactive molecule within biological systems. It’s a diverse family of enzymes consisting of many isoforms with wide ranging targets contributing to a variety of physiological processes. In particular, ALDH enzymes are known for their critical detoxifying function in oxidizing aldehydes to their corresponding carboxylic acids.

Given that ALDH enzymes have been implicated in cellular protection against oxidative stress, they subsequently play a role in the development of a number of diseases, in particular neurodegenerative disorders.  They have a particular relevance to the metabolism of retinoids, as they catalyse the conversion of retinol to retinoic acid locally within tissues. [26] As discussed previously, ALDH activity is regulated by β-catenin in a negative feedback loop (read more).

The administration of Isotretinoin marks these enzymes for downregulation by interrupting this feedback loop and suppressing ALDH activity. [27] Long term application of retinoic acid downregulates these enzymes through post-translational modifications, potentially giving an epigenetic basis for the lasting nature of Post Accutane Syndrome. [28]

The adverse effects of suppressed ALDH activity are potentially very broad given the diversity of roles they play outside of metabolising retinoids. One of the best attested lasting adverse effects of Isotretinoin treatment is permanent night blindness. Researchers concluded that this is a consequence of the suppression a particular member of the ALDH family, RDH11, which serves to recycle rhodopsins in the retina (read more). [29]

A possible Link To Parkinsons?

It’s hard to overstate both the importance and diversity of ALDH activity in the body, from the production of neurosteroids (read more), to metabolism of alcohol to detoxification, but the particular focus of this article is their role in neurological functioning and how it relates to the adverse effects of Isotretinoin treatment. The first indication that play an important neurological role that ALDH isoforms are expressed in regions of the brain rich in dopamine. [30]

For example the enzyme retinaldehyde dehydrogenase 1 (RALDH1) is present in the dopaminergic terminals that innervate the striatum from the ventral tegmental area is necessary for the synthesis of RA in these areas. [31] The previously cited neuroimaging study found that the regions of the brain most rich in dopaminergic activity, such as the midbrain and mesolimbic, experience the greatest reduction in activity during Isotretinoin treatment.

This could potentially be explained by the detoxifying role played by ALDH isoforms such as RALDH1 during dopamine transmission, which is likely inhibited by Isotretinoin treatment. The metabolites of dopamine such as DOPAL (3, 4-dihydroxyphenylacetaldehyde) are neurotoxic, but can be metabolised by RALDH1 to protect dopaminergic neurons. If RALDH1 is inhibited these dopaminergic neurons within the mesolimbic are more susceptible to cell death. [32]

Metabolisation of DOPAL into the less neurotoxic DOPAC using nicotinamide adenine dinucleotide

This effect is so profound that ALDH inhibitors are even able to induce Parkinsonian like symptoms, which is a type of Alzheimer’s characterised by the rapid loss of dopaminergic neurons. [33] Additionally, the overaccumulation of toxic dopamine metabolites results in negative feedback to acutely inhibit dopamine neurotransmission.

This is why ALDH inhibitors such as Disulfiram can cause a blunted response to stimulants such as amphetamine. [34] Given that dopamine is needed to facilitate feelings of pleasure and, reduced libido is one of the most common complaints of people being treated with Disulfiram, which is a medication used in combatting alcohol addiction.

In fact, it is now believed that Disulfiram is effective in treating addiction by blunting feelings of pleasure that drive addictions, through the negative feedback of toxic dopamine metabolites.  [35] The evidence for Isotretinoin inhibiting ALDH expression indicates that Disulfiram could potentially serve as an effective analogue for some of the effects of Isotretinoin treatment. To read more about the effect of Accutane on dopamine transmission and how it could be remediated, (read more).

Serotonin And The 5-HT1A Receptor

Serotonin has long been tied to theories of depression, with treatments often attempting to boost this ‘happy’ neurotransmitter with reuptake inhibitors. Despite the medical paradigm shifting in favour of neurogenesis-based models of depression, the role of serotonin continues to be paramount. This is because of the accumulating data that suggests that serotonin is able to mediate the therapeutic effects of antidepressants by increasing neurogenesis.

In particular the serotonin 5-HT1A receptor is frequently implicated across a variety of antidepressant treatments. Studies in mice have found that Isotretinoin treatment reduced serotonin transporters and in particular serotonin transmission across to certain 5-HT1A receptor sites. [36]

The effect of Accutane at the 5-HT1A receptor might be fundamental in explaining the common neurological symptoms of ‘Post-Accutane Syndrome’ such as anhedonia and loss of libido. However, the behaviour of this receptor is very complex and will require its own dedicated post to fully explore.

In short, the 5-HT1A receptor is subdivided into two categories, distributed within different regions of the brain and with vastly different effects. The presynaptic autoreceptors exert an inhibitory effect on serotonin transmission, preventing the transmission of serotonin to the postsynaptic heteroreceptors expressed within cortical structures. The frontal cortex is the region of the brain that governs higher cognitive faculties, as well as feeling of reward and motivation. [37]

Activation of the 5-HT1A hetero receptor increases dopamine release in the prefrontal cortex and hippocampus and is an effective treatment for depression by medications such as buspirone. In contrast to less targeted serotonin therapies, binding of the 5-HT1A receptor appears to facilitate sexual functioning.

[Fig 1.] J. Douglas Bremner, M.D., Negar Fani, M.S., Ali Ashraf, M.D., John R. Votaw, Ph.D., Marijn E. Brummer, Ph.D., Thomas Cummins, M.D., Viola Vaccarino, M.D., Ph.D., Mark M. Goodman, Ph.D., Lai Reed, M.B.A., Sajid Siddiq, M.D., and Charles B. Nemeroff, M.D., Ph.D. Functional Brain Imaging Alterations in Acne Patients Treated With Isotretinoin, American Journal of Psychiatry https://doi.org/10.1176/appi.ajp.162.5.983