L-methylfolate vs Deplin® for Depression: Are They the Same?

According to NCHS data, around 8.1% of American adults aged 20 and over suffer from depression in any given 2-week period. Between 10 to 35% of these people are affected by treatment-resistant depression (TRD), in which they are unable to find relief with antidepressant medications alone.

The solution for some people may be a specialized nutrient, methylfolate.

Deplin® is a prescription medication but is classified as a prescription ‘medical food’ rather than a drug. It is a synthetic form of folate that has already been converted to active L-methylfolate.

Folate plays a major role in the synthesis of key brain chemical messengers, including serotonin, norepinephrine, and dopamine. People with major depression or certain psychiatric disorders are often found to be low in these brain chemicals, which has led researchers to link folate deficiency with depression.

People with MTHFR genetic polymorphisms cannot metabolize folic acid to L-methylfolate. This polymorphism means that many people are unable to convert folic acid into the form called L-methylfolate, which is able to pass through the “blood-brain barrier” and enter the central nervous system. Taking ordinary folic acid is ineffective because it can’t be utilized for the creation of neurotransmitters in the brain.

Low MTHFR enzyme levels lead to low methylenetetrahydrofolate, which in turn leads to lower levels of monoamines (i.e. serotonin, dopamine, and norepinephrine). However, supplements that contain bioavailable folate have been shown to improve depressive symptoms and increase these mood-dependent neurotransmitters.

Deplin® provides this kind of folate so that it is readily available for making the brain’s “happy chemicals”. It is usually prescribed to people who are found to have low levels of L-methylfolate in the body.

Although Deplin® is not an antidepressant or antipsychotic, it is often used as an adjunctive treatment alongside antidepressant medication. Research has shown that Deplin® is particularly effective for those with low levels of L-methylfolate and major depressive disorder or schizophrenia..

Folate has many different names, depending on its chemical structure.

● Methylfolate

● L-Methylfolate calcium

● Metafolin® and Magnafolate®

● 5-MTHF and L-5-MTHF

● Levomefolic acid

● Deplin®

● 5-methyltetrahydrofolate

● (6S)-5-methyltetrahydrofolate and Quatrefolic

L- (also referred to as (6S)-) is the biologically active isomer version of Methylfolate (and the biochemically identical version that your body naturally uses in circulation).This form is immediately absorbed and available for use. It can cross the blood-brain barrier to play a part in the one-carbon cycle metabolic pathway required for the production of monoamines (or neurotransmitters).

D- (also referred to as (6R)-) is the inactive isomer version of Methylfolate, and it is not used naturally by the body. This includes the less bioactive diastereoisomer also known as (6S/R)-5-methyltetrahydrofolate (a generic racemic mixture) and is generally less recommended for restoring folate levels.

Deplin® is not an antidepressant in itself but a ‘medical food’ that provides the necessary nutrients to make your brain more responsive to an antidepressant. Medical foods are intended for those whose capacity to absorb or metabolize a certain nutrient is impaired.

Patients within sufficient folate levels are less likely to respond to treatment and more likely to experience a relapse. Nearly 1 out of 3 patients with depression do not experience complete resolution of symptoms from using standard antidepressants such as SSRIs(selective serotonin reuptake inhibitors) and SNRIs (serotonin-norepinephrine reuptake inhibitors). 

Studies show that patients taking L-Methylfolate alongside an existing antidepressants – such as Zoloft or Prozac – almost 50% of patients achieved remission after about 90days.. What’s more, the combination of Deplin® and the antidepressant can improve symptoms of depression by up to 59 percent based on PHQ-9 scores when compared with taking an antidepressant alone.

Deplin® is also found to cause no more side effects than a placebo.

Clinical studies have linked folate deficiency and low folate status to depression and poor response to antidepressants. These relationships have not been demonstrated in the general population.

Low folate levels have been detected in 15-38% of adults diagnosed with depression. Low folate levels have also been linked to reduced antidepressant response.

Most studies on patients with neuropsychiatric disorders have found that folate deficiency is associated with low levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). Patients with 5,10-methylenetetrahydrofolate reductase(MTHFR) deficiency have also been found to have decreased serotonin synthesis.

However, supplementation with folate has been found to restore CSF 5-HIAA levels to normal.

The link between depression and folate may also be related to S-adenosylmethionine (SAMe). SAMe is formed from methionine and plays a major role as a methyl donor. Folate is involved in the methionine-homocysteine cycle after SAMe is converted to S-adenosylhomocysteine, then to homocysteine. Animal studies have shown that folate deficiency decreases SAMe in the brain.

Some research suggests that up to 20% of patients with depression test positive for the MTHFR polymorphism.

One study showed that patients with depression who took L-methylfolate reported significant improvements in their symptoms and functioning. Over 12 weeks, 67.9% of patients responded to the l-methylfolate and 45.7% achieved remission. Patients were also more satisfied with their results of the L-methylfolate, and compliance was very high, with over 90% of patients reporting taking every dose or nearly every dose.

Allergic reactions to Deplin are rare. Medical help should be sought immediately if allergic symptoms develop, such as rash, itching/swelling of the face/tongue/throat, dizziness, or trouble breathing.

It is vital that you tell your doctor whether you have any allergies to the ingredients in Deplin® before taking it. Like all prescription medication, Deplin® may contain inactive ingredients (such as soy) which can cause allergic reactions or other health concerns. Talk to your pharmacist for more details.

Your doctor should also be aware of your medical history and whether you have a vitamin B-12 deficiency (pernicious anemia). You should also advise your doctor if you suffer from seizures or epilepsy or have a history of bipolar disorder (manic depression).

Tell your doctor if you are pregnant or breastfeeding.

It’s also important to note that L-methylfolate is not interchangeable with folic acid.

There are several known drug interactions with Deplin® (L-methylfolate). Talk with your doctor and pharmacist about interactions that might be relevant for you.

Dosing must be prescribed by a doctor. Users must not alter their prescribed dosage without first consulting with their doctor. It should not be taken in larger or smaller amounts or for longer than recommended. Brands or strengths should not be switched without a doctor's advice.

L-methylfolate may be taken with or without food.

The usual adult dose is one DEPLIN® 15capsule or one to two DEPLIN® 7.5 capsule(s), taken daily with or without food or as directed under medical supervision.

Each DEPLIN® 7.5 capsule contains 7.5 mg of L-methylfolate (from Metafolin®) and 90.314 mg Algae-S powder.

Each DEPLIN® 15 capsule contains 15.0 mg of L-methylfolate (from Metafolin®) and 90.314 mg Algae-S powder.

If you miss a dose, do not double your next dose. Take your normal dose when you remember. 

Store at controlled room temperature of 15˚C-30˚C (59˚F to 86˚F) (See USP). Store away from heat, light, and moisture.

Side effects that have been reported following the use of Deplin® include allergic reactions. Tell your doctor if you have symptoms like skin rash, itching, swelling of the face, or hives.

Other l-methylfolate supplement brands include:

● Denovo™: 15mg L-methylfolate (L-5-MTHF from L-5-methyltetrahydrofolate calcium salt).

● EnLyte™: L-methylfolate magnesium, folinic acid, folacin, cofactors of b1, b2, b3, b6, b12, betaine, zinc, magnesium, vitamin c, Omega 3s.

Many people who have suffered from treatment-resistant depression for years have found relief with Deplin®. However, as effective as this medication is, there are some drawbacks.

For a start, Deplin® requires a doctor’s prescription, which can make it unaffordable for those who don't have health insurance. Many insurance companies don’t cover this medication and it can be quite expensive.

Fortunately, there are some highly effective alternatives to Deplin® available over-the-counter. These supplements provide methylfolate labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF,and (6S)-5-Methylfolate (all using various labeling to denote the same bioactive version of methylfolate that Deplin® contains).

Some of the best-selling methylfolate supplements for depression are in the Methyl-Life® product range, including Methylfolate 7.5+,Methylfolate 10, Methylfolate 15,and Methylfolate 15+.Each product is designed to support the body’s requirements for energy production and neurotransmitter synthesis while restoring healthy levels of folate.

Methyl-Life’s® Methylfolate 15 product contains a high dose (15 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. This highly-regarded product is formulated specifically for people with an increased need for bioavailable folate due to genetic (MTHFR) defects. It is also suitable for those with dietary deficiencies or drug-induced needs (i.e. taking warfarin, coumadin, metformin, etc.)

This unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. It has been shown to have approximately three times the purity of any other competing L-Methylfolate brand, including Deplin®.

If you suffer from depression and haven’t experienced any benefits from taking standard antidepressant medication, you could find relief from Methyl-Life’s® products. Our team of experts can answer your questions regarding Methyl-life® products and whether they may be suitable for you.