1. Introduction
2. Aldehyde Dehydrogenase
3. Stem Cells and ALDH
4. ALDH: Alcohol & Dopamine
5. Disulfiram
6. Restoring Dopamine with ALCAR
7. Conclusion
8. ALCAR
9. Article Summary
10. D2R: Autoreceptor vs heteroreceptor
11. References
12. Related Articles

Introduction

A meta-analysis involving 25 randomized controlled trials found that neurological complaints were among the most frequent side effects of Accutane treatment. In particular, 24% of subjects experienced severe fatigue, and 10% reported substantial changes in mood and personality. [1]

In addition to numerous case studies, there is a strong neuroanatomical basis for the involvement of retinoids in cognition and mood. Specifically, the enzymes responsible for synthesizing retinoic acid are highly expressed in dopamine-rich areas of the brain, such as the mesolimbic system. [2]

Dopamine is a neurotransmitter linked to feelings of reward, excitement, and pleasure. However, dysregulation of dopamine can lead to mania and psychosis. In this post, I will present compelling evidence that these enzymes facilitate dopamine transmission by neutralizing harmful metabolites such as DOPAL. Additionally, I will demonstrate that Accutane treatment suppresses these enzymes, which may explain anecdotal reports of persistent anhedonia following therapy.

Aldehyde Dehydrogenase

In previous articles I’ve highlighted the significance of Accutane in down regulating key enzymes involved in the body’s detoxification processes, namely the Aldehyde Dehydrogenase (ALDH). Whilst ALDH enzymes are thought primarily to breakdown reactive aldehydes, they’re also involved in a variety of other processes throughout the body including the production of neurosteroids, and importantly the synthesis of retinoic acid from dietary sources of vitamin A.

Retinoic Acid is typically produced in the body in a two-stage process. First retinol is converted to retinal with enzymes called Alcohol/retinol dehydrogenases (ADH/RDH), and then retinal is oxidised to retinoic acid with the different ALDH isoforms expressed in different tissues.  

Unlike dietary retinol, which must first be metabolised, Accutane is directly converted into Retinoic Acid within the cells. In fact, Accutane even avoids triggering the enzymes (P450) that would otherwise breakdown excessive retinoic acid, leading to even greater concentrations within the cell nucleus. [3]

Stem Cells and ALDH

The way Accutane influences ALDH is complex and is linked to the primary function of Retinoic Acid in the body, which is to regulate stem cell proliferation and differentiation. Stem cells are the unique cells in the body in that they can self-renew in a process called proliferation. Stem cells can transform (differentiate) into specialised tissue cells which supports the growth and repair of organs. These cells are particularly relevant during embryonic development and early life when the body grows most rapidly, however they’re also relevant during adulthood where they support certain organs that undergo continual growth and renewal such as the skin and brain. [4]

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

Within these organs, a delicate balance must be maintained to ensure that stem cells appropriately differentiate into the necessary tissue cells, while also preserving a healthy population of stem and progenitor cells to sustain the tissue’s long-term capacity for repair and regeneration. Retinoids, like Accutane, dramatically shift the balance of this process in favour of differentiation to accelerate cellular turnover, such as in the epidermis. Whilst this can give the appearance of more youthful skin, it can also leave stem cell pools depleted – essentially borrowing future capacity for repair in favour of immediate appearance of the skin.

The way Accutane influence the processes of differentiation and proliferation is by suppressing a key growth signalling pathway called Wnt/β-catenin. β-catenin is a protein that signals for stem cell proliferation and tissue growth. Accutane, through its active metabolite, Retinoic acid, inhibits β-catenin signalling which results a depletion of stem and progenitor cells (read more). [5] This growth signalling pathway is also intimately interconnected with the enzymes that synthesise retinoic acid, including a wide range of ALDH isoforms. [6][7]

By inhibiting β-catenin, Retinoic Acid also downregulates ALDH through a negative feedback mechanism. This can wreak havoc on the body’s detoxification processes and leads to an increase in Reactive Oxygen Species (ROS), which can result in increased DNA damage and cell death (apoptosis). One of the tissues where this is perhaps most consequential is in the brain, and in particular during dopamine transmission, since the toxic by-products of dopamine are broken down by ALDH isoforms.

ALDH: Alcohol & Dopamine

There is abundant evidence pointing to Accutane treatment causing lasting repression of ALDH in various contexts. One of the most frequently observed effects is night blindness. The specific isoform of ALDH responsible for maintaining photoreceptors in the retina is 11cRDH (11-cis-retinol Dehydrogenase). By repressing this enzyme through the mechanism outlined above, Accutane can cause lasting changes in vision under low-light conditions. [8][9]

However, given the diverse roles of ALDH enzymes, the range of possible consequences is extensive. The detoxifying function of ALDH is particularly relevant, as it breaks down reactive aldehydes in response to various drugs and pollutants. For example, ALDH2 is responsible for oxidizing acetaldehyde into the much less harmful acetic acid. Mutations on the gene for ALDH2 common among East Asians (colloquially called ‘Asian Flush’), can give rise to a particularly harmful response to Alcohol consumption. [10]

Another, perhaps less appreciated role of ALDH, is detoxifying harmful byproducts of dopamine transmission in the brain. The metabolites of dopamine, such as DOPAL, are neurotoxic, and excessive dopamine can result in the death of dopaminergic neurons. However, another member of the ALDH family, RALDH1, metabolizes these destructive aldehydes, thereby protecting dopaminergic neurons. [11]

Given the involvement of ALDH in neurodegenerative diseases, it should be concerning that administering retinoic acid causes the repression of these enzymes. [12] ‘Asian Flush’ may seem like a minor issue, but underactivity of ALDH2 is negatively associated with the progression of Alzheimer’s and Parkinson’s diseases. Parkinson’s disease is characterized by the progressive loss of dopaminergic neurons, driven by dopamine metabolites such as DOPAL. [13][14]

Disulfiram

A useful analogy in understanding the neurological effects of ALDH repression is Disulfiram, a medication used to treat alcoholism by inhibiting ALDH2. It was long believed that Disulfiram made alcohol consumption less rewarding by triggering the accumulation of toxic aldehydes, similar to the mechanism behind ‘Asian Flush.’ However, research has since shown that it curbs addictive behaviour by directly impacting dopamine transmission.

By preventing the clearance of toxic dopamine metabolites, Disulfiram treatment results in lower levels of extracellular dopamine. [15] This makes Disulfiram effective in treating addiction to other substances unrelated to Alcohol, such as amphetamine. [16] It is therefore unsurprising that patients treated with Disulfiram often report muted feelings of reward. Given the evidence suggesting that retinoic acid has a similar effect on ALDH in certain contexts, Disulfiram could provide insight into some of the side effects of Accutane treatment.

Restoring Dopamine with ALCAR

The dopaminergic system is deeply complex, and few interventions are considered free from side effects. While dopamine is crucial for mediating feelings of pleasure and reward, improper dopamine signalling is implicated in psychosis. [17] Despite the widespread use of amphetamines in the treatment of ADHD, even prescription medications can cause oxidative stress and inflammation. [18][19]

Any direct intervention in dopamine signalling is best avoided. However, ALDH can be effectively targeted with certain medications and over-the-counter supplements. One such supplement that shows promise in this regard is Acetyl-L-Carnitine (ALCAR).

ALCAR is simply the acetylated form of the naturally occurring L-carnitine. Studies indicate that ALCAR can reduce Parkinson’s symptoms and protect the brain against the neurotoxic effects of amphetamines. There are several mechanisms underlying ALCAR’s antioxidant properties, including free radical scavenging. [20] One significant finding is that ALCAR, along with another antioxidant, CoQ10, appears to potently upregulate ALDH activity in the brain. [21]

ALCAR with CoQ10 lowered the levels of malondialdehyde (MDA) and pro-inflammatory cytokines in the cerebellum of rats treated with propionic acid. Propionic acid significantly downregulated ALDH1A1, and treatment with ALCAR (alone and with CoQ10) effectively restored its activity compared to controls. The dosage used in this study was relatively high compared to most over-the-counter supplements, equivalent to approximately 1.2g for a 70kg human.

Another study on ALCAR in reversing Parkinson’s in rats found similar dosing to be effective in protecting dopaminergic neurons. This study induced Parkinson’s via injections of a toxic dopamine metabolite, 6-hydroxydopamine (6-OHDA). The researchers even attributed ALCAR’s neuroprotective effects to the activation of the Wnt/β-catenin pathway.

Inhibiting GSK3-β had the opposite effect on β-catenin compared to retinoic acid. [22] Even higher doses of 3g daily in humans have been found to be well-tolerated and effective in peripheral nerve regeneration. [23] Other studies have pointed to the tolerability of higher ALCAR doses (>2g daily), particularly in the context of neurodegenerative disorders. [24]

Conclusion

In conclusion, Accutane exerts significant effects on aldehyde dehydrogenase (ALDH) enzymes. One of the most well-known consequences is night blindness due to the repression of 11cRDH, an ALDH isoform crucial for photoreceptor function in low-light conditions (read more). Concerningly, this enzyme suppression can result in lasting visual impairments.

The role of ALDH enzymes extends to detoxifying harmful aldehydes, including neurotoxic dopamine metabolites like DOPAL. Repression of ALDH by Accutane raises concerns about neurodegenerative risks, as impaired detoxification can lead to the death of dopaminergic neurons—a hallmark of conditions such as Parkinson’s disease.

The analogy with Disulfiram, an ALDH2 inhibitor used in treating alcoholism, illustrates how inhibiting ALDH can affect dopamine transmission and reduce feelings of reward, paralleling some of the mood alterations reported with Accutane use.

Research into protective measures like Acetyl-L-Carnitine (ALCAR) shows promise in upregulating ALDH activity and offering neuroprotective effects, particularly in the context of dopamine and excitotoxicity.

Article Summary

• Accutane Causes ALDH Repression: Accutane represses the ALDH enzymes which are involved in the natural synthesis of retinoic acid. These enzymes are also involved in a variety of other processes such 11cRDH in the retina. Repression of 11cRDH is the cause of enduring night blindness documented following Isotretinoin treatment by impairing the maintenance of photoreceptors under low-light conditions.
• Impaired Detoxification of Aldehydes: Accutane’s repression of various ALDH enzymes disrupts the detoxification of reactive aldehydes and dopamine metabolites like DOPAL, increasing neurotoxicity and the risk of dopaminergic neuron death.
• Increased Risk of Neurodegenerative Diseases: Reduced activity of ALDH2 from Accutane treatment is associated with the progression of Alzheimer’s and Parkinson’s diseases, as impaired ALDH function hinders the clearance of toxic substances in the brain.
• Similarity to Disulfiram’s Effects on Dopamine: Like Disulfiram, which inhibits ALDH2 and affects dopamine transmission to curb addictive behaviours, Accutane’s repression of ALDH may lead to altered dopamine levels and muted feelings of reward, contributing to some of its neurological side effects.
• ALCAR Combined with CoQ10 Enhances Neuroprotection: Studies indicate that ALCAR, especially when combined with Coenzyme Q10 (CoQ10), lowers levels of malondialdehyde (MDA) and pro-inflammatory cytokines in the brain. This combination effectively restores ALDH1A1 activity in animal models, suggesting a potent neuroprotective effect.
• Effective Dosing and Activation of Wnt/β-catenin Pathway: Higher doses of ALCAR are well-tolerated. The neuroprotective benefits include the activation of the Wnt/β-catenin pathway, offering potential therapeutic effects for neurodegenerative disorders.

Related Articles

How Accutane Changes Your Brain

Accutane and Serotonin: Revealing Its Effects on Mood, Libido, and Cognitive Function