When to Choose Methylfolate Versus SAM-e | Methyl-Life®

Those affected by depression may be curious about the benefits of using methylfolate and/or SAM-e (S-adenosylmethionine) to assist in treating their symptoms.

L-Methylfolate has been shown in numerous studies to enhance the response to antidepressants. SAM-e has been on the US market for only two decades but is now a prescription drug in several European countries, primarily for major depression.

This article will explain what SAM-e is, how it works, and how it compares with methylfolate to treat depression. We will compare each supplement and their efficacy in improving depressive symptoms and whether patients can choose between the two.

We will then suggest how best to supplement with methylfolate and/or SAM-e. 

S-Adenosylmethionine (SAMe) is an essential compound that plays a major role in the central nervous system function through the body’s transmethylation pathways, including the methylation of DNA, histones, and several neurotransmitters and hormones. SAM-e is almost as valuable as adenosine triphosphate¹ when serving as a cofactor in biochemical methylation reactions.

SAMe is found throughout the body, but its highest concentrations are in the liver, brain, adrenal glands, and pineal gland. It functions as the major donor of methyl groups² required to create neurotransmitters and phospholipids, DNA, ribonucleic acid, and proteins.

SAM-e is produced in the body from two other compounds: methionine, a sulfur-containing amino acid, and adenosine triphosphate, an energy-carrying molecule found in the cells of all living things.

The process of generating SAMe involves both the folate and methionine cycles, which both belong to the one-carbon cycle. Folate or folic acid is converted into SAMe via L-methylfolate.

SAM-e then functions in the transmethylation pathway as it produces the neurotransmitters serotonin, dopamine, and norepinephrine. For this reason, numerous studies have demonstrated that SAMe may be useful in treating depression³ or major depressive disorder.

Both L-methylfolate and SAMe are shown to be effective and well-tolerated⁴ in treating depression and may be especially useful as a means of improving the response to antidepressants.

The pathway to neurotransmitter synthesis requires enzymes and cofactors, including both SAMe and folate. Impairment in the functioning of these enzymes or cofactors will impair neurotransmitter generation, which is crucial for healthy mood and cognitive function. Learn more here about how MTHFR and low methylfolate are linked to anxiety/depression.

Folate deficiency has been causatively linked to depression⁵ because folate is required in the synthesis of neurotransmitters in the central nervous system. Depressed people with low folate are significantly less likely to respond to antidepressants and more likely to relapse during treatment.

Folate deficiency can also lead to elevated homocysteine levels, which in turn cause oxidative stress, resulting in cerebral, vascular, and neurological damage as well as neurotransmitter deficiency⁶.

SAMe deficiency has been reported in patients with folate and methionine metabolism defects and depression. Deficiencies of folate and vitamin B12⁷ may account for decreased SAMe levels as they are necessary co-factors in the synthesis of SAMe.

Researchers suggest that the correlation between low folate levels and low SAMe levels may result in decreased monoamine synthesis⁸, increasing the risk of depression or treatment resistance.

Preliminary studies suggest that taking SAMe may help treat chronic liver disease caused by medications or alcoholism.

A 2013 study⁹ in which 33 depressed patients supplemented with SAMe for 8 weeks found that 60% of those patients showed improvement in their symptoms. The researchers concluded that SAMe might improve depression by enhancing the methylation of catecholamines and increasing serotonin turnover. It also appeared to enhance dopamine activity and the reuptake inhibition of norepinephrine and increase the conversion of phosphatidylcholine.

Folate acts as a coenzyme required¹⁰ to convert homocysteine to methionine, and methionine is required for the synthesis of SAM-e.

Folic acid and dihydrofolate undergo enzymatic transformation to become L-methylfolate, the only form that can be used by cells and can cross the blood–brain barrier for use in the central nervous system. L-methylfolate supplement then joins with homocysteine to form methionine, which is then metabolized by methionine adenosyltransferase and vitamin B12 to form SAMe. SAM-e can then be used for methylation reactions¹¹ and neurotransmitter synthesis, among many other functions.

SAMe and folate are needed as cofactors and methyl donors in the one-carbon metabolism cycle to generate neurotransmitters.

In clinical trials, supplementation of SAMe and folate¹² has been shown to improve symptoms of depression. The mechanism of action of both of these compounds is to provide donor methyl groups to support the one-carbon cycle and the production of monoamine neurotransmitters.

L-methylfolate supplementation is preferable¹³ over other folates as it has greater bioavailability in patients with a genetic polymorphism, and none of the side effects associated with folic acid supplements.

One study involving 554 patients¹⁴ with depression showed that taking L-methylfolate significantly improved symptoms and functioning. Over 12 weeks, 67.9% of patients responded to the L-methylfolate, and 45.7% achieved remission.

Although studies on SAMe are limited, it is also found to be an effective and well-tolerated form of adjunctive treatment¹⁵ for depressed patients who have not responded to SSRIs (Selective serotonin reuptake inhibitors).

As every patient’s needs are different, consulting with a medical professional regarding supplementation with L-methylfolate, SAM-e, or both, is strongly recommended.

Both L-methylfolate and SAM-e are available as OTC supplements in-store and online. As mentioned above, it is important to first discuss with your doctor before starting any new supplement regime, especially if you are already taking other medication.

When choosing an L-methylfolate supplement, be sure to look for a product that contains the highly bioavailable Calcium salt form of (6S)-5-methyltetrahydrofolic acid. It has been shown to increase plasma folate more effectively than folic acid, irrespective of whether a patient has genetic defects that affect uptake.

Methyl-Life’s® Methylfolate range is made with the internationally-patented Magnafolate® PRO, the most active folate form in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body. This can help provide the folate required for the one-carbon metabolic cycle and the subsequent synthesis of SAM-e.