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Psychopharmacology book

L-methylfolate (DEPLIN)

Folate (Vitamin B9), also known as folic acid, is necessary for synthesis of neurotransmitters including dopamine, norepinephrine, and serotonin. L-methylfolate is the active form of folate that crosses the blood-brain barrier with no need for enzymatic conversion.  


About 1 in 3 individuals have difficulty converting folate to methylfolate due to a deficiency of the MTHFR enzyme (methylene tetrahydrofolate reductase). Among individuals with depression, about 60% have MTHFR mutations (Mischoulon et al, 2012). The 10% of individuals with 2 copies of the C677T MTHFR allele—“poor M*TH**F***Rs"—should be taking L-methylfolate.


Deplin is the brand of L-methylfolate marketed to physicians as a prescription-only “medical food” for depression. Other brands of L-methylfolate are now available without a prescription, though they are not FDA-regulated. There is no reason to believe Deplin is of higher quality than MethylPro, a reputable OTC version of L-methylfolate. Insurance rarely covers either brand, so the expense is borne out-of-pocket. Deplin costs 5x more than MethylPro and 50x more than generic folic acid. 

L-methylfolate DEPLIN MethylPro mnemonics MTHFR by Dr Jason Cafer MD

L-methylfolate is intended to be an augmenting agent (add-on) to an antidepressant) in individuals who are not necessarily folate deficient. Refer to the “steps” advertisement below. As an augmenting agent, the number needed to treat with L-methylfolate was 6 (Papakostas et al, 2012).

L-methylfolate DEPLIN MethylPro interactions and indications by Dr Jason Cafer MD

Now that affordable brands are available, L-methylfolate is recommended over folic acid because it is more likely to be effective. There are no head-to-head trials of L-methylfolate vs folic acid, but results of L-methylfolate trials were more impressive.


Obese patients are more likely to respond to L-methylfolate, possibly because obesity causes inflammation, which impedes serotonin production (Shelton et al, 2015; The Carlat Psychiatry Report, Aug 2019). Generic folic acid may be adequate for non-obese individuals with normal MTHFR genes.


Supplementation of an antidepressant (fluoxetine specifically) with generic folic acid 0.5 mg/day demonstrated modest benefit at 10 weeks of treatment (Coppen & Bailey, 2000). The effect size was small, and some studies have not shown benefit from folate augmentation of antidepressants. Regardless, adding folate (vitamin B9) is a benign intervention—folate is “Vitamin Be-nign”.


Some studies combined folate (vitamin B9) with vitamins B6 and B12, Count by 3’s—B6, B9, B12 = pyridoxine, folate, and cobalamin, respectively.  Folic acid (B9) supplements can mask megaloblastic anemia that would otherwise lead to a diagnosis of vitamin B12 (cobalamin) deficiency. If untreated, B12 deficiency leads to peripheral neuropathy.


EnLyte is another prescription-only medical food containing 7 mg of L-methylfolate 7 mg and other “brain-ready, pre-metabolized coenzymes and cofactors”. It costs about $170 monthly. 


Folate is present in fresh green vegetables and other sources listed below. Garbanzo beans (chickpeas) contains an abundance of folate. Cooking reduces folate content by as much as 90%. 


Now let’s talk about actual folate deficiency. About 20% of depressed patients have low folate levels. Individuals with low folate do not respond as well to antidepressants. Patients with normal serum folic acid levels may still respond to treatment with folate because levels in the CNS may be low. 


Folate deficiency leads to an elevation of homocysteine, a nonessential amino acid. Homocysteine is an NMDA receptor agonist and oxidant, i.e., something damaging to human cells An elevated homocysteine level is associated with cardiovascular disease. 


Folic acid deficiency during pregnancy leads to neural tube defects.


Dosing: For Deplin (expensive, prescription) or MethylPro (affordable, OTC) start 7.5 mg QD and increase to 15 mg, which is the target and maximum dose. MethylPro is available in 2.5, 5, 7.5, 10, 15 mg capsules. For generic folic acid (cheap) to augment an antidepressant you would give 0.5–5 mg QD. To treat folic acid deficiency, use 1 mg daily of generic folic acid plus a multivitamin.  For a patient who responds to L-methylfolate for depression, consider changing to folic acid 3 mg (cheaper) at 6 months and see if recovery is maintained (Chris Aiken, MD, The Carlat Psychiatry Report, Aug 2019).

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