The methylation cycle is a fundamental biochemical process that plays a critical role in mental health, influencing the synthesis and regulation of neurotransmitters, DNA expression, detoxification, hormone balance, and immune function. Methylation involves transferring methyl groups (–CH₃) to various molecules, which helps regulate gene activity and biochemical reactions throughout the body. One of the key pathways in methylation is the methionine cycle, which uses methionine (an essential amino acid) to produce SAMe (S-adenosylmethionine)—the body’s primary methyl donor. SAMe donates methyl groups in reactions that synthesize and regulate neurotransmitters like dopamine, serotonin, norepinephrine, melatonin, and even acetylcholine, which are crucial for mood, motivation, cognition, and sleep.

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Once SAMe donates its methyl group, it becomes SAH (S-adenosylhomocysteine), which is then broken down into homocysteine. Homocysteine must be recycled back into methionine via a reaction that requires vitamin B12 (methylcobalamin) and folate, specifically in its active form—L-methylfolate (5-MTHF). This distinction matters: folic acid is the synthetic form found in many lower-quality supplements and fortified foods, and it must be converted into L-methylfolate in the body. However, up to 40% of people (especially those with MTHFR gene variants) have a reduced ability to convert folic acid into its active form, which can impair methylation and reduce neurotransmitter production. This is why using L-methylfolate directly in supplementation is often preferred in mental healthcare, particularly for individuals with treatment-resistant depression or cognitive concerns.

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