Methylfolate & Insomnia

Folate is rarely a nutrient we associate with sleep, but emerging research suggests it may help with sleep duration.

A 2024 study identified a positive correlation between folate levels and sleep duration in adults, indicating that higher folate levels were associated with longer sleep. The researchers suggest folate supplementation could potentially improve sleep quality in people with low folate levels.¹

• Circadian rhythm
  Folate deficiency was found to result in weakened internal clocks and poor light responsiveness, which also occurs with aging. This suggests that poor folate status in elderly people might be a contributing factor to age-related sleep and circadian disorders, and that maintaining adequate folate levels could potentially help maintain healthy sleep-wake cycles as we get older. Researchers suggest that folate supplementation may improve sleep duration and quality.²

• Neurotransmitter synthesis
  Folate helps regenerate methionine from homocysteine, which is a precursor for S-adenosylmethionine (SAM-e). SAM-e is a methyl donor required for neurotransmitter synthesis, including serotonin. Folate deficiency can lead to lower SAMe levels, potentially affecting the production and activity of serotonin and melatonin.³
  Folate is also required for the synthesis of 5-hydroxytryptophan (5-HTP), a precursor of serotonin. Serotonin, in turn, is a precursor to melatonin. Serotonin is converted to melatonin, the primary sleep hormone.

• Homocysteine regulation
  Folate is essential for maintaining healthy homocysteine levels by assisting with the conversion of homocysteine to methionine. Folate deficiency can lead to elevated homocysteine, which has been linked to sleep disturbances and neurological problems. A recent study found that short sleep duration was associated with higher serum homocysteine levels in women.⁴

• GABA regulation
  GABA is a neurotransmitter that helps to ‘calm’ the mind and body, which makes it helpful with inducing sleep and relaxation. Some research has suggested that folate deficiency may affect GABA function. When folate is deficient, homocysteine levels rise and compete with GABA for binding to GABA receptors.⁵ This means that GABA can’t function effectively because homocysteine is "blocking" the receptors. However, folate supplementation was found to increase GABRB1 receptor expression, which could potentially compensate for any competitive inhibition by homocysteine and restore normal inhibitory signaling.⁶

L-methylfolate is the active bioidentical form of folate. It plays a vital role in the production of neurotransmitters involved in healthy sleep, particularly dopamine, serotonin, and norepinephrine. The MTHFR variant, which affects methylfolate production, is known to affect monoamine synthesis.

A 2024 study involving patients with MTHFR (both C677T and/or A1298C) and sleep problems examined the effects of 5mg methylfolate supplementation over eight weeks.

The patients’ sleep improved significantly after just two weeks, and by eight weeks, all patients reported better sleep patterns. The researchers concluded that L-methylfolate supplementation may help people with MTHFR variants sleep better.⁷

A genome-wide association study revealed that MTHFR is associated with several sleep issues, including sleep duration, insomnia symptoms, and sleep latency.⁸

A 2022 case study found that a patient with chronic insomnia, fragmented sleep, and short sleep duration had a homozygous MTHFR C677T variant, as well as mildly elevated homocysteine levels. She had failed to respond to multiple sedative-hypnotic medications, supplements, and cognitive behavioral therapy for insomnia, the current ‘gold standard’ for insomnia treatment.

The patient was supplemented with folate and vitamin B12 to compensate for reduced MTHFR enzymatic activity, along with melatonin. However, after her folate and B12 levels were restored, she was able to successfully discontinue the melatonin without any adverse effects on her sleep. The researchers stated that this was the first case of chronic insomnia being successfully diagnosed and treated by targeting a MTHFR variant associated with sleep disruption.⁹

The best time to take methylfolate depends on your own routine. Everyone is different, and some people may find that they prefer to take methylfolate in the morning, others at midday and some may even prefer evening. Clinicians find that in general, many prefer to take methylfolate in the morning or early afternoon as it can be too energizing for some and keep them awake at night. The most important thing is to take it every day, preferably at the same time each day.

Studies suggest that the most important nutrients for healthy sleep patterns include magnesium, vitamin B12, melatonin, methylfolate, and 5-HTP. Herbs such as ashwagandha, St John’s wort, chamomile and valerian may also help.