https://secondlifeguide.com/2024/01/07/accutane-effects-on-the-brain/

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 where other treatments fail. However, alongside its efficacy in treating acne, it has also been associated with a range of potential side effects – particularly in relation to the brain.
The extent of its psychological impact particularly came to prominence during a 2015 murder trial, where attorneys argued that a 15-year-old flew into a homicidal psychosis on account of his treatment by the acne drug. [1] Though this may seem farfetched it isn’t an isolated incident, and the connection between Vitamin A and neurological disorders is one with long historical precedent.
The effects of overexposure to Vitamin A on the central nervous system were first documented in 1856 by Elisha Kane, an Artic explorer who suffered dramatic changes in mood and temperament after ingesting polar bear liver. The many symptoms of Accutane treatment significantly overlap with those of Hypervitaminosis A, given that Accutane exerts its therapeutic effects through the primary metabolite of Vitamin A: Retinoic acid. However, unlike overexposure to Vitamin A, Isotretinoin is able to avoid xenobiotic responses that metabolise excessive retinoic acid, allowing for an even greater intracellular accumulation.[2]
A meta-analysis of 25 randomised controlled trials found that neurological symptoms were amongst the most common adverse effects associated with Accutane treatment – with 24% suffering extreme fatigue and 10% complaining of significant changes in mood and personality. [3] Aside from the many case reports, there’s a good neuroanatomical basis for believing that retinoids are fundamental to cognition and mood.
The enzymes that locally synthesise retinoic acid are highly expressed in regions of the brain that are rich in dopamine, such as the mesolimbic. [4] Dopamine is the neurotransmitter associated with feelings of reward, excitement and pleasure; however dysregulation of dopaminergic system can lead to mania and psychosis. The exact role retinoic acid plays in regulating dopamine is yet to be fully understood, but the evidence shows the two systems are deeply intertwined*.* [5][6]

STEM CELLS AND RETINOIDS:

Beta-catenin is a multifunctional protein that serves as a key regulator in many cellular processes, but most pertinently in stem cell proliferation. Many organs throughout the body rely on a pool of stem cells to draw upon for tissue repair and maintenance, such as the skin.
Beta-catenin signalling is regulated by a ‘destruction complex’, which continuously marks the protein for destruction. When it is unbound from the destruction complex it translocates into the nuclei of cells to signal for the proliferation (increase the number) of stem cells in these given tissues. When beta-catenin is repressed by enhancing the action of the destruction complex, the stem cells in these tissues undergo a process of specialisation called differentiation**.** [7]
https://preview.redd.it/efv0auyy860d1.png?width=1221&format=png&auto=webp&s=f980b81cced156a795193957fa3e6b04a788c21a
Final stem cell differentiation.svg), This file is licensed under the Creative Commons Attribution-Share Alike 4.0 International license.
This process can’t be reversed, and the stem cell pool must replenish in order to preserve future tissue reparative properties. Retinoids are differentiating agents, that repress beta-catenin by enhancing the action of the destruction complex and thus inhibiting stem cell proliferation.
A careful equilibrium must be maintained to ensure that stem cells don’t aberrantly differentiate. The consequences of disrupting this balance are most disturbingly evidence by the foetuses of mothers exposed to high levels of vitamin A, as foetal development is reliant on the proliferation of embryonic stem cells. These foetuses typically fail to develop normal limbs if they survive gestation at all. [8]
Whilst beta-catenin signalling is regulated by retinoids, retinoid signalling is in turn regulating by beta-catenin feedback through the ALDH (aldehyde dehydrogenase) enzymes. ALDH enzymes play a key role in synthesising retinoids, and a regulated by beta-catenin. High levels of beta-catenin trigger an enhance ALDH activity, which in turn leads to greater retinoid synthesis and therefore suppression of beta-catenin.
Alternatively high levels of retinoid signalling, as in during Accutane treatment, leads to suppression of beta-catenin and in turn ALDH activity. However, ALDH enzymes don’t exclusively serve to synthesise retinoids, they also play a vital detoxifying role in metabolising toxic acetaldehydes and lipid peroxides. [9]

ACCUTANE REDUCES CORTICAL BRAIN ACTIVITY

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.
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.
As previously established, beta-catenin signalling is needed to maintain stem cell populations in the many tissues that undergo continual growth and reparation throughout adulthood. The brain, and in particular the hippocampus, is one such region. The hippocampus is essential for the generation of episodic and spatial memory. Neuroplasticity in the hippocampus is needed to form new memories throughout adulthood.
It’s been found that when beta-catenin is ablated in hippocampal cell cultures, the synaptic strength is diminished. Neurons lacking beta-catenin became thin and spindly, with reduced amplitude of spontaneous glutamatergic currents. [13] Conversely, enhancing beta-catenin signalling in transgenic mice allowed for greater neuronal growth and even enlarged brains on account of the increase in neural stem cell populations. [14] Understanding the role of beta-catenin is key to explaining the evidence for Accutane inhibiting new cell growth in the hippocampus. [15]

BETA-CATENIN AND NEURONAL DEATH

Notably the neurological role of beta-catenin isn’t confined to the hippocampus, as it also greatly impacts synaptic activity in two other regions: the hypothalamus and the amygdala. The hypothalamus is a part of the limbic system that controls the release of hormones involved in diverse processes including facilitating sexual responses, hunger, and circadian rhythms. Hypothalamic cells are also subject to both growth and regulation by beta-catenin which can be guided in particular by oestradiol, which activates the PI3K/Akt pathway.
Poignantly, this action of oestradiol is the exact opposite of the mechanism of action by which Accutane suppresses beta-catenin. The importance of oestradiol is especially relevant for woman with respect to the oestrous cycle, and the periodic changes it induces on synaptic structures. [16] Given this evidence, it is perhaps unsurprising that hypothalamic cells (along with hippocampal cells) are amongst the neuronal cells most vulnerable to apoptosis (cell death) in response to retinoic acid exposure. [17]
Another structure within the limbic system is the amygdala, which consists of two clusters of nuclei in the centre of the brain and plays a pivotal role in regulating memory, emotional response and feelings of reward and pleasure. Like the hypothalamus, the amygdala also appears to significantly influenced by beta-catenin.
There’s evidence that beta-catenin is needed for the transfer of newly formed memory into long term memory, and specific deletion of beta-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.

ALDH: ‘DETOX’ AND DOPAMINE

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 beta-catenin in a negative feedback loop.
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. [29]

THE LINK TO PARKINSONS

It’s hard to overstate both the importance and diversity of ALDH activity in the body, from the production of neurosteroids, 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]
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.