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Introduction

Lithium its traditionally thought to work only as an antipsychotic, whereby it suppresses excitatory neurotransmitters such as dopamine and glutamate whilst also increasing the inhibitory neurotransmitter GABA, however the reality is far more complex. Recent data has shone light onto a broad array of additional neuroprotective effects, such as enhancing brain derived neurotrophic factor and reducing oxidative stress. [1]

Whilst lithium is still tainted with the stigma of being a potent ‘zombifier’, suppressing cognition and mood – this couldn’t be further from the truth. A 2009 meta-analysis found that healthy subjects treated with lithium experienced no ill effects on any of the tested cognitive domains, and only minor effects on affective disorder patients. [2] At lower supplemental doses Lithium paints and even rosier picture with evidence for improved cognition at ‘sub-therapeutic doses’ (although these studies are typically performed on those with some mild cognitive impairment). [3]

Lithium increases Dopamine

It is true that at therapeutic doses lithium (>1000mg for humans) can decrease dopamine in some regions of the brain, but in other it can significantly enhance it. A study in rats found that 10meq/kg, lithium increased striatal dopamine by 56%. The striatum is a region of the brain that is critical for the reward system, co-ordinating motivation, decision making and reward perception. This effect was normalised 24h after the injection. [4] An additional study in rats found that a treatment of 74mg/kg of lithium carbonate for 12 days followed by a two day withdrawal period increased the dopamine in the striatum by 99%, however this increase was accompanied by decreases in hypothalamus, hippocampus and pons-medulla. [5] In a model of Parkinson’s low dose lithium helped to increase the number of dopaminergic neurons in the substantia nigra compared to controls.

Lithium has an opposing effect on many of the pro-apoptotic proteins that are increased during Accutane treatment such as Bcl-2 and p53. Lithium treatment of cerebellar brain cells stimulated a 5 fold reduction in the ratio of p53 target Bcl-2 mRNA. [6] A diet high in lithium was found to completely prevent the loss of striatal dopamine and tyrosine hydroxylase in a model of Parkinson’s, which was attributed to it’s anti-apoptotic effects via suppression of p53. [7] Lithium’s effects on the D2 dopamine receptor are particularly profound, with only 6 days of lithium feeding resulting in a 3-fold increase in D2 mRNA, with enhanced transcription rate. The researchers also found an increased sensitivity to stimulants following these 6 days. [8] D2 is one of the receptor regulated by retinoids and may be subject to aberrations following Accutane treatment.

Reversing the epigenetic effects of Accutane

The effect of Accutane on methylation is complex and occurs in two distinct stages. Initially Accutane causes dysregulation of enzymes that maintain a healthy methylation status, particularly DNTM1 and DNMT3. During the course of an Accutane suppression of DNMT1 leads to demethylation events of certain genes and are subsequently over-expressed.

A microarray analysis found that during an Accutane treatment 402 gene promoters became demethylated and 88 became hypermethylated. The process of de-methylation of certain gene promoters might in fact be the mechanism by which retinoids force differentiation, particularly in relation to NOS1. [9] Whilst some genes experience enhanced transcription, others are repressed through hypermethylation.

Poignantly, one of the genes subject to this transcriptional regulation was MYCN. This gene plays a pivotal role in the regulation of the WNT/beta-catenin pathway, which appears to be highly relevant in the aetiology of PAS. Once Accutane has been withdrawn, there is a very strong and sudden re-methylation. A study on mRNA expression patterns found that following a washout phase there remained no hypomethylated targets, but potentially 9156 repressed targets via hypermethylation. This analysis also found significant results pointing towards to WNT/beta-catenin pathway [10] Following this burst of intense of re-methylation, it’s possible that many of the gene targets marked for repression could continue to be aberrantly repressed. Given the role the Wnt/beta-catenin pathway plays in acne pathogenesis, [11] it’s possible that this explains how Accutane is so effective in permanently remediating severe cystic acne.

Lithium reverses accutane epigenetic effects

Lithium occupies a special place in pharmacology because as well as being a mood stabiliser, it also has hypomethylating effects. This appears to be a feature that’s common to mood stabilisers, as Valproic acid also enhances gene expression through similar mechanisms. Lithium not only enhances gene expression both by the removal of methyl marks at gene promotors (for example at the BDNF promotor), but also by promoting global acetylation of the H3 histone.[12] This mirrors the repressive action of retinoids on the H3 histone, which are known to place repressive methyl marks such on the lysine H3K9. [13] [14]

The effects of lithium on acetylation of the H3 histone can be rapid, after just 30mins there is an increase in the global H3 acetylation level in the amygdala, allowing for enhanced gene transcription through open chromatin structure. The diverging epigenetic effects of Lithium and retinoids centres on their opposing action on the beta-catenin. Whilst retinoids suppress beta-catenin, Lithium enhances it. When beta-catenin is suppressed, TCF/LEF binds to HDAC1 and HDAC2 subsequently reducing the acetylation at the promoters of Wnt-dependent genes, repressing gene transcription. [15] [16][17] Adding to this picture is the fact that acne is a commonly reported side effect of Lithium treatment, possibly owing to its beta-catenin boosting effects. [18] This evidence would indicate that Lithium could be effective in reversing the lasting epigenetic effects of Accutane treatment.

Lithium can also influence methylation by potentially enhancing the absorption of B-vitamins. One of the notable possible side effects of Accutane treatment is an increase in elevation on Homocysteine, which can have disastrous impacts on cardiovascular health even in young people. Typically Homocysteine is broken down by b-vitamins such as B12 and folate, however Accutane appears to disrupt this process by disrupting the enzyme cystathionine-β-synthase. This not only has implications for cardiovascular health, but also hairloss and bone degradation. To learn more about the link between Lithium and B12, read here.

Lithium reverses accutane epigenetic effects

Lithium occupies a special place in pharmacology because as well as being a mood stabiliser, it also has hypomethylating effects. This appears to be a feature that’s common to mood stabilisers, as Valproic acid also enhances gene expression through similar mechanisms. Lithium not only enhances gene expression both by the removal of methyl marks at gene promotors (for example at the BDNF promotor), but also by promoting global acetylation of the H3 histone.[12] This mirrors the repressive action of retinoids on the H3 histone, which are known to place repressive methyl marks such on the lysine H3K9. [13] [14]

The effects of lithium on acetylation of the H3 histone can be rapid, after just 30 mins there is an increase in the global H3 acetylation level in the amygdala, allowing for enhanced gene transcription through open chromatin structure. The diverging epigenetic effects of Lithium and retinoids centres on their opposing action on the beta-catenin. Whilst retinoids suppress beta-catenin, Lithium enhances it. When beta-catenin is suppressed, TCF/LEF binds to HDAC1 and HDAC2 subsequently reducing the acetylation at the promoters of Wnt-dependent genes, repressing gene transcription. [15] [16][17] Adding to this picture is the fact that acne is a commonly reported side effect of Lithium treatment, possibly owing to its beta-catenin boosting effects. [18] This evidence would indicate that Lithium could be effective in reversing the lasting epigenetic effects of Accutane treatment.

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