What does Folate have to do with Depression?

What is Folate?

Folate, also called vitamin B-9 or folic acid, is a B vitamin found mainly in dark green leafy vegetables, beans, peas, nuts, oranges, lemons, bananas, melons and strawberries. Folate has important roles in red blood cell formation, cell growth, and cell functioning. It is also a very important vitamin during neurodevelopment. So what does this have to do with depression?

What does Folate have to do with Depression?

Folate and dihydrofolate are converted to L-Methylfolate in our bodies. L-Methylfolate is both directly and indirectly involved in a number of biochemical pathways, one of which is the production of monoamines like dopamine, serotonin, norepinephrine, and epinephrine. L-Methylfolate is an important regulator or “control operator” for the production of a biochemical called tetrahydrobiopterin (BH4). BH4, in turn, is an essential component of the machinery our bodies use to produce monoamine neurotransmitters such as dopamine, serotonin, and norepinephrine. The “machinery” for making these monoamines are tryptophan hydroxylase and tyrosine hydroxylase, which are the gatekeepers for serotonin and dopamine/norepinephrine/epinephrine production, respectively.

Confused yet? Here is an analogy:

It’s like making hot tea. L-Methylfolate is the electricity, tetrahydrobiopterin (BH4) is the electric stove, tryptophan hydroxylase (or tyrosine hydroxylase) is the tea kettle, and the hot tea is serotonin (or dopamine or norepinephrine). In order for the tea kettle to make hot tea (i.e., dopamine, serotonin, norepinephrine), we are going to need the stove (i.e., BH4) to “turn on” via electricity (i.e., L-Methylfolate). No electricity, no hot tea. No L-methylfolate, no dopamine, serotonin, or norepinephrine. 


This means that reduced levels of L-methylfolate could lead to “ineffective” BH4 and therefore reduced synthesis of the monoamines serotonin, dopamine, and norepinephrine. Reduced monoamines could contribute to both depressed mood and/or resistance to antidepressant medications.  Recall that selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors depend on the continued synthesis of monoamines. That is, if there is little to no serotonin available to be released, then reuptake blockade will be ineffective. Supplementing with L-methylfolate may increase production of monoamines and improve responsiveness to antidepressants and other medications that rely upon monoamine neurotransmission.

Formation of L-methylfolate (L-MF) from folic acid (F)

  1. Folic acid is converted to dihydrofolate (DHF) and then tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR).
  2. Serine hydroxymethyl-transferase (SHMT) then converts THF to methylene THF.
  3. Methylene THF is converted by methylene tetrahydrofolate reductase (MTHFR) to L-methylfolate.

Methylation and COMT

Recall that when DNA is methylated, it becomes more tightly coiled and prevents gene expression. In other words, methylation of genes silences them.

L-Methylfolate is considered a “methylator” as it provides a methyl group for this type of DNA methylation. COMT, or Catechol-O-methyl-transferase, is an enzyme that breaks down monoamines like dopamine. The more COMT, the more dopamine is broken down and therefore less is available for neurotransmission. If L-methylfolate is low, then perhaps this means less methylation of various genes such as COMT. Since methylation reduces genetic expression, decreased methylation of, say, COMT, would mean INCREASED genetic expression of COMT. The more COMT, the more breakdown of monoamines. Studies have shown genetic variability in the expression of COMT in patients with Schizophrenia. Some variants of the COMT gene result in greater expression of COMT and less dopamine availability in areas like the prefrontal cortex. Decreased dopamine levels in the dorsolateral prefrontal cortex (DLPFC) could potentially impair information processing and cause symptoms such as cognitive dysfunction. Therefore, L-methylfolate supplementation could result in higher dopamine levels in those brain areas and improve cognitive deficits in individuals with that gene variant of COMT.

Genetic Variants and MTHFR

Folate and L-methylfolate deficiency can occur from either a diet low in folate or a body that can’t convert folate to L-methylfolate. Recall that L-methylfolate is produced by the enzyme MTHFR (see figure above). In some individuals, the MTHFR gene is slightly different and less efficient.  Below are a few genetic variants of MTHFR:

Methylene tetrahydrofolate reductase: MTHFR C677T; MTHFR A1298C

If MTHFR is less efficient in some people, then their levels of L-MF may be reduced. Decreased levels of L-methylfolate may result in lower monoamine levels by impacting their synthesis and metabolism (remember the tea kettle analogy above?). This is why supplementing with L-methylfolate makes more sense than supplementing with folate. If we can’t convert folate to L-methylfolate efficiently, then supplementing with L-methylfolate makes more sense.

MTHFR, COMT, and Schizophrenia?

Studies of MTHFR and COMT in schizophrenia suggest that a variant of MTHFR combined with a variant of COMT in the same individual may be enough to decrease the efficiency of information processing in those patients’ dorsolateral prefrontal cortex (DLPFC). These findings have motivated researchers to look into these types of genetic interactions as playing a role in patients with other psychiatric disorders such as depression and may help identify those individuals who are better candidates for L-Methylfolate supplementation.

Folate and Drug Interactions

Anticonvulsants: Taking folic acid with fosphenytoin (Cerebyx), phenytoin (Dilantin, Phenytek) or primidone (Mysoline) might decrease the drug’s concentration in your blood.

Barbiturates: Taking folic acid with a drug that acts as a central nervous system depressant (barbiturate) might decrease the drug’s effectiveness.

Methotrexate (Trexall): Taking folic acid with this medication used to treat cancer could interfere with its effectiveness.

Pyrimethamine (Daraprim): Taking folic acid with this antimalarial drug might reduce the effectiveness of the drug.

Folate Facts

The recommended daily amount of folate for adults is about 400 micrograms (mcg). For adult women who are planning pregnancy or could become pregnant the recommended daily amount of folate is usually 400 to 1,000 mcg per day. Additionally, folate works together with other vitamins such as B-6 and B-12 to regulate high levels of something called homocysteine. Elevated homocysteine levels in the blood have been shown to increase the risk of cardiovascular diseases. Lastly, it is important to mention that increased intake of folate can mask the megaloblastic anemia associated with vitamin B-12 deficiency, which may go undiagnosed and cause irreversible nerve damage.


  1. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  2. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  3. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  4. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  5. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  6. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  7. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  8. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  9. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
  10. Charney and Nestler’s Neurobiology of Mental Illness. 5th Ed. Oxford University Press. 2017. 

Leave a Reply