Vitamin B12 Deficiency and Insomnia

There are over 200 enzymes in the body involved in methylation
A critical methylation reaction is the formation of Melatonin.
Melatonin is critical for sleep
Functional B12 deficiency results in sleep disorders

Vitamin B12 and Melatonin

Synthesis of Melatonin through methylation of N-ActylSerotonin by the enzyme Hydroxyindole-O-methyl Transferase (HIOMT). N-AcetylSerotonin-[HIOMT] + SAM => Melatonin=[HIOMT] + SAH (Gallardo and Tamezzani 1975; Klein and Lines, 1969; Urry etal, 1972; Quay 1965;Kuwano and Takahashi, 1980; Yokim and Wallen 1975; ). Deficiency in methyl B12, results in reduced levels of SAM, which in turn leads to conditions such as poor sleep, poor maturation of the gut wall, and developmental delay due to lack of activation of neuronal stem cells and subsequent differentiation into myelin-producing oligodendrocytes in the brain.

Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer’s disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders.

It is known that melatonin receptors are expressed in the fetal brain. During pregnancy melatonin levels rise in the mother, and is transferred transplacentally to the fetus. In disorders of pregnancy, melatonin levels are decreased in both the mother and fetus. Further it has also been found that alterations in the levels of maternal melatonin have been associated with disrupted brain programming and long-term sequelae (Sagrillo-Fagundes etal, 2016). The newborn also does not produce its own melatonin and is thus dependent upon melatonin supplied to the baby via milk. The neonate has not developed the pineal gland and maturation of pineal function is required before rhythmic melatonin production is achieved in the new-born (roughly 9-12 weeks after birth). The diurnal production of melatonin by the mother will therefore dictate the melatonin levels in milk. Late in fetal development the fetuses’ sleep patterns develop through the regulation of melatonin.

Reduced levels of B12 in pregnant mothers would lead to lower methylation and hence lower production of melatonin, both in the mothers, and then in the foetus/new-born. Reduced methylation has been shown to occur in ASD kids (James etal, 2014).

Reduced levels of melatonin in the brain of ASD would also affect sleeping patterns in these children, and sleep disorders are a common feature of ASD, with around 80% of children “suffering” from the condition( Blackmer and Feinstein 2016; Kotagal and Broomall, 2012).

Vitamin B12 Deficiency, Adrenalin and Melatonin Deficiency

In Methyl B12 deficiency, there is a greatly reduced production of SAM, and in an attempt to overcome the deficiency the cell tries to accommodate by producing more and more precursors for the production of melatonin and adrenalin. However in severe deficiency this then leads to a significant increase in the breakdown products of dopamine and nor-adrenalin (HVA and VMA) and breakdown products of tryptophan metabolis, Kynurenic acid (KA) and Quinolinic acid (QA), As well there is an increase in the breakdown product of Serotonin, 5-Hydroxyindoleacetic acid (5HIAA) start to accumulate and can be detected as elevated levels in urine.

Methylation, melatonin and Sleep Disorders

Melatonin Deficiency and Sleep Disorders A deficiency in functional Methyl B12 leads to reduced production of melatonin, thereby increasing the incidence of sleep disorders. Sleep disorders are very common in those with functional B12 deficiency and are particularly prevalent in conditions associated with functional vitamin B12 deficiency, such as dementia (Benca and Teodorescu., 2019; Cipriani etal, 2015; Shenker and Sing, 2017), autism and CFS. Despite the obvious role of methylation in the formation of melatonin, and its role in promotion of sleep, few researchers seem to understand this. Insomnia, or difficulty sleeping is common in neurological development disorders such as Autism 53-80%, Ballester etal, 2020; Kohyama 2016; Blackmer and Feinstein, 2016; Robinson-Shelton and Malow, 2016; Geier etal, 2012; Gringras et al 2017; Maras et al, 2018; Devnani and Hedge, 2015; Cagnon and Godbout, 2018; Gobi and Comai, 2019; Esposito etal, 2019). A new diagnostic Pediatric Sleep Clinical Global Impressions Scale has recently been developed as an aid to diagnosis (Malow et al, 2016). Sleep disorders occur in only 1-2% of children with normal development but in 80% of kids with developmental disorders such as Autism. Often such disorders continue through to early childhood and can lead to behavioural problems at school Hirata etal, 2016). Problems are encountered with sleep duration, night wakenings and bedtime resistance. Difficulty in sleeping is likely to be due to the lower levels of melatonin produced in ASD kids. Many doctors though, treat sleep disorders with melatonin, or delayed release forms of melatonin, rather than fixing the functional B12 deficiency (Quera-Salva and Claustrat, 2018; Esposito etal, 2019; Huysmans etal, 2019)

Identification of vitamin B12 deficiency related sleep disorders

A recent study looking at markers of methyl vitamin B12 in 10 randomly selected children under 2 years old, who had continued sleep deprivation revealed an anomalously high markers of functional vitamin B12 deficiency (Russell-Jones, 2022). Representative data is presented below. These individuals also had metabolic signs of functional vitamin B2 deficiency, suggesting that the observed functional B12 deficiency was linked to reduced levels of functional vitamin B2. Hence, there were increased levels of glutaric acid, adipic acid and suberic acid.

As can be seen there are highly elevated levels of HVA/VMA/QA/KA/Adipic Acid, Ethylmalonate, Succinate and Suberic Acid, in the 10 individuals with sleep disorder, in comparison to the Normal situation. The data strongly supports the concept that functional B2 deficiency results in functional B12 deficiency. The functional B12 deficiency, then results in decreased melatonin production and an extreme elevation of the neurotransmiiter metabolites, HVA/VMA/QA/KA. Resolution of the sleep disorder has been found to require establishment of functional B2 sufficiency and treatment with repeated high dose Adenosyl/Methyl B12.

Resolution of vitamin B12 deficiency related sleep disorders

Restoration of brain vitamin B12 is quite complicated. There is no evidence that this can be done orally, and there are many studies that have been unsuccessful at low doses. Hence, daily oral administration of 2 ug Cyanocobalamin, was ineffective in restoring sleep patterns ( Hysing etal 2022). High dose oral B12 given ()1.5 mg 2 x bd was effective for restoration of sleep patterns during duration of treatment (Okawa, 1990), and 3 mg Methyl B12 per os per day (Ohta etal, 1991; Takahashi, etal, 1999). In paradoxical B12 deficiency, administration of cyanocobalamin is totally ineffective,, as FAD is required for reduction of the cyanide group, whilst adminstration of methyl B12 is only effective once the functional B2 deficiency is resolved (Okawa etal, 1999).

Successful treatment of sleep disorders in children has been achieved with the RnB protocol, in which functional vitamin B2 deficiency is resolved and is combined with topical sdministration of the B12 oils Adenosyl/Methyl B12 oils

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Methylating Enzymes

From Wikipeida N-methyltransferase - Wikipedia

N-methyltransferase may refer to: