1. Accutane depletes B12 and causes Hyperhomocysteinemia.
2. B12, Folate & β-catenin
3. Folic Acid enhances Lithium treatment
4. B12 (methylcobalamin)
5. inositol and Valproate
6. Article Summary
7. References

Accutane depletes B12 and causes Hyperhomocysteinemia.

There’s a mountain of scientific literature pointing to the many adverse effects associated with Accutane treatment, but few are better attested and more repeatable than the suppression of B12 and folate. The suppression of B12 is accompanied by an excessive presence of homocysteine in the blood, resulting in a condition unimaginatively called Hyperhomocysteinemia. The reason being that folic acid and B12 serve as co factors in the recycling of homocysteine into methionine in a process called transmethylation.

Methionine is an essential amino acid used in a number of crucial processes in the body including methylation and protein synthesis. Given that methionine is so fundamental, it’s unsurprising that it’s depletion and associated elevation in Homocysteine wreaks havoc throughout the body. Symptoms of Hyperhomocysteinemia include cardiovascular damage, cerebrovascular diseases, atherosclerosis, and even depression. [1]

Why Accutane is able to suppress B12 and folate isn’t exactly known but its in part due to a suppression on the enzyme that metabolises Homocysteine: cystathionine-β-synthase. [2] What isn’t in doubt however are the many disastrous consequences for the patient if this issue is left unaddressed. Given the centrality of B12 and folate in the production of neurotransmitters, some researchers are even included to attribute the psychiatric effects of Accutane to this alone. [3]

I’ve presented a more robust explanation for the lasting neurological effects of Accutane in prior posts, but this at least gives an indication of the significance of B12. Interestingly the reduction in B12 might even constitute one of Accutane therapeutic pathways in the treatment of acne. B12 supplementation can actually exacerbate acne development by altering gene transcription of the microbiota on the surface of the skin. [4]

B12, Folate & β-catenin

One of the organs in which symptoms of Hyperhomocysteinemia manifests is in the musculoskeletal system. Excessive homocysteine increases osteoclast (cells that break down bone) activity, and results in an increased risk for bone fracture and osteoporosis.

There’s even been six recorded case reports of Accutane patients suffering from musculoskeletal discomfort being treated with B12 and folate, and then recovering from their symptoms. [5] These patients received shots of B12 every two weeks with 1mg of Folic acid daily and after 6 weeks of treatment symptoms “completely disappeared”, although the treatment was continued for another five months.

In previous posts I’ve highlighted the significance of β-catenin in explaining the many diverse and lasting symptoms of Accutane treatment, including skeletal aberrations (read more). Incredibly it appears that B12 is able to support the canonical Wnt/β-catenin pathway by acting as a Wnt surrogate. [6]

This appears to be a very significant, and yet previously unreported link. Researchers found that B12 binds to the Wnt frizzled receptor FZD8. This finding is bolstered by the evidence for B12 activating the β-catenin pathway in hair follicles by suppressing GSK3, the same mechanism by which Lithium exerts its effects. [7]

The impact of B12 on hair shaft elongation was significant and dose dependent, with higher doses inducing a stronger effect, and was proportionate the degree of GSK3 suppression. Although the literature on the relationship between B12 and β-catenin is sparse, it might be reasonable to conclude that the suppressive effect of Accutane on β-catenin is exacerbated by the concomitant reduction in serum B12. It could also be reasoned that the apparent effectiveness of B12 treatments in remediating the adverse effects associated with Accutane treatment might be in part due to enhance β-catenin signalling, rather than through increased homocysteine metabolism.

Folic Acid enhances Lithium treatment

Folic acid has repeatedly been identified as a tool in offsetting the psychiatric effects of Isotretinoin, on account of its normalising effect on homocysteine and neurotransmitters. [8] However there’s been increasing evidence that folate instead mediates its anti-depressant effect through GSK3-beta inhibition. [9] In a forced-to-swim test in mice, the treatment of a PI3K inhibitor or PPAR-gamma antagonist prevented the antidepressant effect on folic acid supplementation.

Additionally, folic acid significantly amplified the anti-depressant effect of Lithium. This perhaps explains the evidence found in the mid-eighties that folic acid supplementation significantly enhanced Lithium’s efficacy in treating bipolar and depressive patients. [10] The mutual potentiation of Lithium and B12/folate can be further demonstrated with the evidence that Lithium may also improve the cellular absorption of B12. [11] Researchers used hair samples to show that Lithium supplementation was positively correlated with the B12 marker Cobalt. This bolsters the in vitro studies support the finding that Lithium improved B12 absorption into cells.

inositol and Valproate

One of the more common complaints by those undergoing clinical dosing of Lithium is a feeling of reduced energy and general somnolence. For those being treated for mania, a bit less energy might actually be beneficial – but in treating PAS it makes higher doses undesirable. It isn’t exactly known how Lithium causes this effect, but the leading theory is that it reduces the concentration of a particular sugar called Inositol (also known as vitamin B8) in some regions of the brain. [12] By depleting inositol in some regions of the brain, Lithium can attenuate intracellular signalling. [13]

Interestingly inositol depletion is also a feature of Valproate treatment, a medication that has a lot of overlap with Lithium in terms of both β-catenin signalling and HDAC inhibition. Similarly, Valproate also induces a somnolescent effect, making it useful in treating mania.