L-methylfolate is not a stronger form of folic acid.  L-methylfolate is the active vitamin.  It crosses the blood brain barrier more easily than any other form of folate.   Folic acid is not found in nature.  The vitamin companies make it because it is cheap and easily absorbed.

It takes 5 steps to convert folic acid to L-methylfolate.   The limiting step is the last: MTHFR.  Over half of us have the MTHFR polymorphism

Giving higher doses of folic acid does not compensate.  In fact, folic acid binds tightly to the L-methylfolate transporter receptor, making it difficult for L-methylfolate to cross the BBB (blood brain barrier).  Doses of folic acid above 1mg/day can interfere with L-methylfolate entering the brain—particularly doses in the 3 to 5mg range.

Since folic acid is added to cereals, one almost never sees a low serum folate.  However, many people are low in L-methylfolate in the CSF and in the brain.

L-methylfolate significantly augments response to antidepressants in patients who are not full responders to the antidepressant, including those who do not have the MTHFR C677T polymorphism.

Pregnant women should be on L-methylfolate, not folic acid—especially if they have the MTHFR C677T polymorphism.Using L-methylfolate for depression

Certain patients are particularly good responders to L-methylfolate:

#1: the 2/3 of us who have the MTHFR C677T polymorphism

[heterozygous as well homozygous], which limits full conversion of folic acid to L-methylfolate

#2:  women

#3:  obese patients with BMI >30.  This is quite helpful, since obese patients have more severe depressions and are more treatment resistant.  Intra-abdominal fat increase pro-inflammatory cytokines.  Inflammation decreases  tetrahydrobiopterin (BH4), which is an essential cofactor in the production of serotonin, melatonin, dopamine, norepinephrine, and epinephrine.

Dihydrobiopeterin (BH2) is the degraded form of BH4,

#4:  patients with elevated inflammatory markers—e.g., hsCRP (highly sensitive CRP) above 1 mg/ml  [low hsCRP:  <1 mg/L;     moderate 1-3 mg/L;  high >3 mg/L]


The MTHFR C677T polymorphism is associated with an increased risk of depression. From a meta-analysis of 26 published studies:   4992 depression cases and 17,082 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR C677T polymorphism and depression susceptibility using random effect models. Heterozygous C677T:  T vs. C: OR = 1.19, 95%CI = 1.07–1.32; homozygous for C677T:  TT vs. CC: OR = 1.42, 95%CI = 1.16–1.75.

Wu, Y. – L., et al. Psychopharmacology & Biological Psychiatry. 2013; 46 : 78–85. A meta-analysis of 3 completed clinical trials, all double-blind, flexible-dose, active-controlled comparisons of antidepressants in the treatment of MDD was performed. Each study lasted a total of 8 weeks. 


People with increased body mass index (BMI) are less likely to have an adequate response to antidepressants when compared to people with lower BMIs.   

Body Mass Index and Response to Antidepressants in Depressed Research Subjects

Oskooilar N,  Wilcox, C Ton, My-Linh, Groxz, D J Clin Psychiatry. 2009 Nov;70(11):1609-10. 


Depression increases with BMI :  Prevalence of obesity increased from 25.4% among those with no depressive symptoms to 57.8% among those with moderate to severe depression.  This was cross-sectional study.     Gen Hosp Psychiatry. 2008 Jan-Feb;30(1):32-9. doi: 10.1016/j.genhosppsych.2007.09.001.   Association between obesity and depression in middle-aged women.  Simon GE, Ludman EJ, Linde JA, Operskalski BH, Ichikawa L, Rohde P, Finch EA, Jeffery RW.


Serum hsCRP is an independent risk marker for de novo major depressive disorder in women. This supports an aetiological role for inflammatory activity in the pathophysiology of depression.   A prospective study measured inflammation using plasma high sensitivity c-reactive protein (hsCRP) and measured depression at baseline in 1494 women followed for a decade. For the first 2 years, none of the women developed significant depression.  During 5827 person-years of follow-up, 48 cases of de novo major depressive disorder were identified. The hazard ratio (HR) for depression increased by 44% for each standard deviation increase in log-transformed hsCRP (ln-hsCRP) (HR = 1.44, 95% CI 1.04-1.99),

Br J Psychiatry. 2010 Nov;197(5):372-7. doi: 10.1192/bjp.bp.109.076430.

Association of high-sensitivity C-reactive protein with de novo major depression.

Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, Schneider HG, Leonard BE, Berk M.


Inflammatory markers predict significantly higher risk of MDD [hsCRP in particular]. 

Br J Psychiatry. 2010 Nov;197(5):372-7. doi: 10.1192/bjp.bp.109.076430.

Association of high-sensitivity C-reactive protein with de novo major depression.

Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, Schneider HG, Leonard BE, Berk M


Up to 70% of MDD Patients Have a Genetic Mutation Reducing Conversion Folic Acid
to L-methylfolate—i.e., being either homozygous or heterozygous for C677T. 
[A1298C  has no significant negative effect.]

Kelly CB et al. J Psychopharmacol. 2004;18(4):567-71.

Bottiglieri T et al. J Neurol Neurosurg Psychiatry. 2000;69:228-32.

Surtees R, Heales S, & Bowron. Clinical Science. 1994;86:697-702.


Response rate to adjunctive L-methylfolate over 30 days is about 32% vs 15% with placebo.

Inadequate responders with BMI ≥30 taking L-methylfolate 15mg had nearly TWICE the reduction in depressive symptoms compared to the overall study population taking 15mg in 30 days.    Am J Psychiatry. 2012; 69(12):1267-1274   L-methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parrallel-Sequential Trials

Papakostas GI, Shelton RC, Zajecka JM, Etemad B, Rickels K, Clain A, Baer L, Dalton ED, Sacco GR, Schoenfeld D, Pencina M, Meisner A, Bottiglieri T, Nelson E, Mischoulon D. Alpert J, Barbee J, Zisook S, Fava M.


With atypical antipsychotics used adjunctively in major depressive disorder, the number needed to treat (NNT) ranged from 19 (quetiapine XR 150 mg per day) to 5 (aripiprazole)–to achieve response (>50% reduction in score).   Citrome L. Postgrad Med. 2010;122(4):39-48

The NNT for response with bupropion augmentation approximates 8– derived from a cost analysis from STAR*D data,

The NNT for L-methylfolate augmentation  is 6 for overall study population and 3 if BMI > 30.    Papakostas G, et al.  Am J Psychiatry, 2012;169(12):1267-74.  Raison C, et al.  (October 2013) ) Poster presented at the 26th Annual US Psychiatric and Mental Health Congress. Las Vegas NV.


Certain medications are associated with suboptimal levels of L-methylfolate, such as anticonvulsants. First generation anticonvulsants, such as valproate, phenobarbital, or carbamazepine can put the patients at risk for low levels of L-methylfolate through various mechanisms.  Of the second-generation anticonvulsants, lamotrigine is associated with low levels of L-methylfolate, because lamotrigine, like methotrexate, inhibits dihydrofolate reductase, the first step necessary to convert folic acid to a usable form.

Other medications that put the patient at risk for low levels of L-methylfolate include methotrexate, sulfa drugs, oral contraceptives, metformin, fenofibrates (used in cholesterol management), fluoxetine and warfarin.

Various diseases can also put the patient at risk for low levels of L-methylfolate.  Diabetes and GI disorders may affect absorption.  Renal failure is also associated with low levels of L-methylfolate, as is hypothyroidism.

Excessive alcohol intake, smoking, obesity, and poor nutrition are associated with low levels of L-methylfolate.

Age is also inversely correlated to CNS L-methylfolate levels.

Being homozygous (T/T) or heterozygous (C/T) for C677T can reduce available L-methylfolate.



  • Increased body weight is associated with a decreased response rate to antidepressants.1,2
  • Greater body weight increased the risk, severity and chronicity of major depression.3-5
  • A majority of psychiatric medications generate weight gain and ultimately obesity in some patients.6
  • Obese individuals with depression have higher risk of developing metabolic syndrome.7
  1. Oskooilar N, et al. J Clin Psychiatry. 2009 Nov;70(11):1609-10. 
  2. Kloiber S, et al. Biol Psychiatry. 2007 Aug 15;62(4):321-6.
  3. Luppino FS, et al. Arch Gen Psychiatry. 2010 Mar;67(3):220-9.
  4. Simon GE, et al. Gen Hosp Psychiatry. 2008 Jan-Feb;30(1):32-9. 
  5. Vogelzangs N, et al. J Clin Psychiatry. 2011 May;72(5):598-604. 
  6. Nihalani N, et al. J Obes. 2011;2011:893629.
  7. Skilton et al, 2007, Biol Psychiatry, 62(11): 1251-7.