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

People all around the world are constantly looking for a way to prevent, manage, and control their depression. It has been reported that over 264 million people suffer from depression across the globe and that number only continues to increase. Each year, nearly 40 million people above the age of 18 in the United States alone struggle with this condition, and the trend is increasing among children and teenagers. Depression and Anxiety can coexist because they affect your brain's neurochemistry, biological processes, and hormonal balance.

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®, a prescription product that has been helping patients regain their quality of life by providing your body some of the fundamental nutrition it needs along the methylation pathway. Deplin® contains a very powerful form of Vitamin B9 - L-methylfolate - which is essential to mood management, DNA production, and so much more. In fact, it contains the highest amount of this studied nutrient at 15 mg of “free methylfolate” via the patented brand form of L-methylfolate, Metafolin®.

One of the many functions of methylfolate in the body is the production of neurotransmitters in the brain. More specifically, methylfolate helps produce serotonin, dopamine, and norepinephrine through SAMe. These neurotransmitters play an important role in mood management and when they aren’t firing on all cylinders, it’ll make us feel depressed or disconnected from our surroundings.

When people experience depression, they will likely be directed to take an antidepressant. These prescription drugs can help the availability of neurotransmitters in the brain and can help reduce the symptoms in many people. Unfortunately, this won’t work if those people aren’t producing enough neurotransmitters, to begin with. 

This is where high doses of L-methylfolate or the product Deplin® can step in because it’s an active nutrient that can be combined with your antidepressant, making it more effective. Deplin® is technically classified as a ‘medical food’ (a fancy way to refer to a vitamin in the prescription world). 

It’s also considered an ‘adjunct’ prescription (doctors are recommended to prescribe it in conjunction with an antidepressant drug). The idea is that the two will work hand in hand as the L-methylfolate produces neurotransmitters and the antidepressant makes them more available in the neural pathways.

Vitamin B9 is an essential vitamin needed to produce neurotransmitters (chemical substances produced in the brain) known as serotonin, dopamine, and norepinephrine. These neurotransmitters are essential for healthy brain function and mood balance

Folate plays a major role in the synthesis of key brain chemical messengers[12], including SAMe, BH4 (tetrahydrobiopterin), serotonin, norepinephrine, and dopamine. People with major depression or certain psychiatric disorders are often found to be low in these brain chemicals[13], 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[14] (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.

Certain factors, such as poor diet, gut inflammation, genetics, certain medications, malabsorption and more can deplete vitamin B9 (or folate) levels. This also reduces its conversion into the active bioidentical form, methylfolate, increasing the risk of folate & neurotransmitter deficiencies.

Taking L-methylfolate, the active and bioidentical form of folate, allows the body to create the necessary neurotransmitters that can help increase serotonin levels in the body more naturally.

Research shows that over 40% of the planet’s population, as well as a majority of patients with depression, have what is called an MTHFR gene variant, often called a gene mutation. This means they cannot properly metabolize folic acid into methylfolate for effective absorption and use.

Folic acid requires a multistep conversion before it can be used. L-methylfolate, on the other hand, is the bioactive form that is easily absorbed into the bloodstream from the gut. It is then quickly transported as 5-methylfolate (5MTHF) to cross the blood-brain barrier and be used by all of the body's cells and tissues.

Deplin® is a registered L-methylfolate medical food with two dosage options, 7.5mg and 15mg of L-methylfolate.

Methyl-Life® L-methylfolate 7.5mg, 10mg, and 15mg products are therapeutic nutraceutical supplements which do not require a prescription to purchase.

Studies with Deplin® and therapeutic doses of L-methylfolate indicate that they can successfully restore folate levels in the body to reduce the symptoms of depression, and improve mood.

SAMe controls our neurotransmitter regulation, including serotonin and those who do not have enough methylfolate can’t promote enough SAMe to keep producing the levels of serotonin needed for optimal mental health. Since our body turns Vitamin B9 into methylfolate, there are several reasons why someone might be deficient.

They’ll either:

1. struggle to consume enough folate (the active form of Vitamin B9) throughout the day
2. consume too much folic acid (the synthetic form of Vitamin B9 which actually blocks up the receptors)
3. have a mutation in the process that makes the conversion or
4. be ingesting medication or chemicals that reduce methylfolate amounts in our bodies

L-methylfolate is a special nutrient that allows the body to bypass this required folate conversion process in order to directly get the necessary amount of methylfolate into our bodies at the cellular level.

These products provide the kind of folate that is readily available for making the brain’s “happy chemicals”. It is usually prescribed by medical professionals 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[15] for those with low levels of L-methylfolate and major depressive disorder or schizophrenia.

Studies with antidepressants and L-methylfolate include:

Hunter TS showed that bioactive forms of folate, especially L-methylfolate, have been shown to help antidepressants work better in people with major depressive disorder who do not respond well to standard treatments.[1]

Fava et al. discussed how adding l-methylfolate at doses of 7.5 mg/d and 15 mg/d can enhance the efficacy and safety of antidepressants compared with other treatments.[4]

Zajecka et al. discovered that giving people with major depressive disorder L-methylfolate calcium (15 mg) along with SSRIs showed promising results and better rates of remission.[5]

Dartois et al. found that adding L-methylfolate to antidepressant treatment may be a safe and effective way to help children with depression who do  not respond to other treatments. In 80% of the cases, depression, anxiety, and irritability got better.[2]

Papakostas et al. showed that adding 15 mg of L-methylfolate 15mg to the treatment of depressed people who did not respond well to SSRIs led to much bigger drops in their depression scores. This was especially true for people who had certain biological and genetic markers linked to inflammation or folate metabolism.[3]

Studies with L-methylfolate as a standalone treatment include:

Martone G. showed the use of L-methylfolate as a standalone therapy for depression, recommending its inclusion as part of standard treatment regimens in clinical practice to enhance antidepressant effects.[6]

Reynolds et al. compared 5-methyltetrahydrofolate (5MTHF) monotherapy to amitriptyline in patients with mild to moderate depression. The study suggested that 5MTHF could be an effective monotherapy, warranting further large-scale studies.[7]

Di Palma et al. tested the effectiveness of very high methylfolate levels as an antidepressant in chronic alcoholics with major depression, noting beneficial effects and recommending further investigation.[8]

Freeman et al. investigated how a prenatal supplement with methylfolate could help women planning or already pregnant avoid relapses in depression and treat MDD. The results showed positive benefits.[10]

Both products are formulated with the same ingredient, L-methylfolate calcium, the bioactive form that is easily absorbed into the bloodstream and quickly transported as 5-methylfolate (5MTHF) to be readily used by the brain and all of the body's cells and tissues.

Deplin® is registered and requires a doctor's prescription. The doses prescribed are either 7.5mg or 15 mg. Doctors typically prescribe Deplin® with antidepressants to help them work better, it’s not usually prescribed as a standalone treatment.

Doctors and integrated health professionals recommend Methyl-Life's® therapeutic L-methyfolate supplements. Thelp support various health outcomes and are available without a prescription.

• Doses for general health and restoring folate deficiencies are 2.5 mg and 5 mg.
• Doses of 7.5 mg, 10 mg, and 15 mg restore folate deficiencies associated with mood disorders, including depression

Folate has many different names. These can refer to brands or chemical structure.

• Methylfolate (short name for methylenetetrahydrofolate)
• L-methylfolate calcium (specific type of methylenetetrahydrofolate, tied to a calcium salt molecule, taken as a nutrient)
• Metafolin® and Cerebrofolate™ and Magnafolate® (stable brand name calcium-salt based methylfolates taken as nutrients)
• 5-MTHF and L-5-MTHF (short chemical notation for methylfolate)
• Levomefolic acid (another name for methylfolate - what’s found in the body’s circulation)
• Deplin® (high dose L-methylfolate as Metafolin® in 7.5mg & 15mg doses)
• 5-methyltetrahydrofolate (the longer way to notate 5-MTHF)
• (6S)-5-methyltetrahydrofolate (the longer way to notate L-methylfolate)
• Quatrefolic® (brand name glucosamine salt based methylfolate)

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® 15 capsule 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. Talk to your medical professional to determine if Deplin® would be a good addition for your health needs.

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+ (7.5 mg of L-methylfolate + 2 active B12 forms)
  
• Methylfolate 10 (10 mg of L-methylfolate)
• Methylfolate 15 (15 mg of L-methylfolate)
• Methylfolate 15+ (15 mg of L-methylfolate + active B12 + inositol)