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L-Methylfolate: a Vitamin for Your Monoamines

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L-Methylfolate: a Vitamin for Your Monoamines L-Methylfolate: A Vitamin for Your Monoamines Stephen M. Stahl, M.D., Ph.D. Issue: Synthesis of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine is regulated by L-methylfolate, a derivate of the vitamin folate. olate (vitamin B ) is well acid or dihydrofolate to a usable form 9 Figure 1. Synthesis of L-Methylfolate F known as one of the 13 essen- in the body, L-methylfolate, that can From Folate tial vitamins, but perhaps what is not then pass through the blood-brain bar- as well known is that a derivative of rier where it modulates the formation Folate folate—known as L-methylfolate—is of the monoamines serotonin, norepi- actually the active form of the vita- nephrine, and dopamine.1–7 min.1 –3 One of L-methylfolate’s critical roles is to regulate the synthesis of the How Does L-Methylfolate Regulate 3 monoamine neurotransmitters seroto- the Synthesis of Monoamines? 1–6 nin, dopamine, and norepinephrine. L-Methylfolate acts to modulate the Dihydrofolate synthesis of monoamines in a 3-step H H What Is L-Methylfolate? process (Figure 2). First, L-methyl- Folic acid is the synthetic form of folate assists in the formation of a MTHFR the vitamin folate and is present in arti- critical cofactor, known as tetrahydro- ficially enriched foods such as bread biopterin, or BH4 (Figure 2A), for the and in over-the-counter multivitamins synthesis of monoamines.4–6 Second, CH3 HH as well as in prescription vitamins.3 BH4 activates the rate-limiting en- Dihydrofolate is the dietary form of zymes tyrosine hydroxylase and tryp- L-Methylfolate folate, derived from green vegetables, tophan hydroxylase for the synthesis of 3 4–6 yeast, egg yolk, liver, and kidney. monoamines. Note that when these HH A key regulatory enzyme known as enzymes lack BH4 (shown as an empty Abbreviations: C = carbon, H = hydrogen, methylene tetrahydrofolate reductase “4” in the blue tyrosine hydroxylase MTHFR = methylene tetrahydrofolate or MTHFR (Figure 1)1–7 converts folic and tryptophan hydroxylase enzymes reductase. Figure 2. Regulation of Monoamine Synthesis by L-Methylfolate A. B. C. L-Methylfolate Assists in the Tyrosine Hydroxylase and Tryptophan Hydroxylase BH4 Activates the 2 Enzymes Formation of Tetrahydrobiopterin (BH4) Are Inactive in the Absence of BH4 to Synthesize the 3 Monoamines BH Dopamine CH3 BH HH Tyrosine BH Norepinephrine L-Methylfolate Tyrosine Hydroxylase Tyrosine Hydroxylase HH BH BH Serotonin Tr yptophan Tr yptophan Hydroxylase Tr yptophan Hydroxylase J Clin Psychiatry 69:9, September 2008 PSYCHIATRIST.COM 13531352 Table 1. Characteristics of Patients With Depression Who Might Be the Best TAKE-HOME POINTS Candidates for L-Methylfolate Treatment ◆ L-Methylfolate is the centrally active derivate of the vitamin folate and is Documented low levels of folate and its active utilized not only for neurotransmitter synthesis, but also for many vital metabolites such as L-methylfolate methylation reactions in all cells. Inadequate responses to a standard antidepressant ◆ L-Methylfolate regulates the availability of the critical enzyme cofactor High risk for low folate levels resulting from BH4 (tetrahydrobiopterin), required by tryptophan hydroxylase for serotonin • Alcoholism synthesis and by tyrosine hydroxylase for dopamine and norepinephrine • Eating disorders synthesis. • Pregnancy ◆ Low levels of folate and L-methylfolate are linked to some forms of depression • Gastrointestinal disorders and to some patients who fail to respond to antidepressants, suggesting that • Documented low levels of MTHFR augmentation of antidepressants with L-methylfolate may be a useful (methylene tetrahydrofolate reductase) or being from a group (Hispanic and treatment option in these cases. Mediterranean populations) at high risk for decreased levels of this enzyme • Documented high homocysteine levels, which tend to rise when folate falls therapeutic action of antidepressants REFERENCES • Drugs that can interfere with folate dependent upon adequate levels of conversion to L-methylfolate such as monoamines. 1. Stahl SM. Stahl’s Essential Psychopharmacol- lamotrigine and valproate So, who might be the best candi- ogy. 3rd ed. New York, NY: Cambridge Preference for a natural product approach with University Press; 2008 few or no side effects dates to receive L-methylfolate? Re- 2. Stahl SM. Novel therapeutics for depression: search is still trying to answer this L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS question, but the current evidence Spectr 2007 Oct;12(10):739–744 in Figure 2B), they are inactive and suggests that the best candidates for 3. Paul RT, McDonnell AP, Kelly CB. Folic acid: cannot bind to their amino acid sub- L-methylfolate treatment might be de- neurochemistry, metabolism and relationship to depression. Hum Psychopharmacol 2004 strates, tyrosine and tryptophan, which pressed patients who have documented Oct;19(7):477–488 are the precursors for the monoamines. low levels of folate and its active me- 4. Turner AJ. The relationship between brain fo- Third and finally, when L-methylfolate tabolites, including L-methylfolate, and late and monoamine metabolism. In: Botez MI, Reynolds EH, eds. Folic Acid in Neurology, forms the critical amount of BH4, BH4 who fail to respond to treatment with a Psychiatry and Internal Medicine. New York, 1–8 can activate these enzymes (Figure standard antidepressant. Investiga- NY: Raven Press; 1979:165–177 2C), and tyrosine hydroxylase and tors are also determining whether those 5. Hamon CG, Blair JA, Barford PA. The effect of tetrahydrofolate on tetrahydrobiopterin metabo- tryptophan hydroxylase can now form at risk for low L-methylfolate levels, lism. J Ment Defic Res 1986 Jun;30(pt 2): the trimonoamines serotonin, norepi- such as those who have certain con- 179–183 nephrine, and dopamine.4–6 Specifi- comitant illnesses, have certain genetic 6. Bottiglieri T, Hyland K, Laundry M, et al. Fo- late deficiency, biopterin and monoamine cally, tyrosine can now bind with risk factors for low L-methylfolate lev- metabolism in depression. Psychol Med 1992 tyrosine hydroxylase and ultimately els due to inheritance of low MTHFR Nov;22(4):871–876 be converted into both dopamine and enzyme activity, or are taking certain 7. Gilbody S, Lewis S, Lightfoot T. Methylene- tetrahydrofolate reductase (MTHFR) genetic norepinephrine, and tryptophan can drugs that interfere with L-methylfolate polymorphisms and psychiatric disorders: a now bind with tryptophan hydroxylase formation (Table 1), might also be re- HuGE review. Am J Epidemiol 2007 and ultimately be converted into sponsive to antidepressant augmenta- Jan;165(1):1–13 1–8 8. Gilbody S, Lightfoot T, Shelton T. Is low folate serotonin. tion with L-methylfolate. a risk factor for depression? a meta-analysis and exploration of heterogeneity. J Epidemiol Therapeutic Implications? Summary Community Health 2007 July;61(7):631–637 One practical application of the L-Methylfolate modulates the syn- central action of L-methylfolate may thesis of the monoamines serotonin, BRAINSTORMS is a section of The Journal be for depressed patients who have in- norepinephrine, and dopamine. Some of Clinical Psychiatry aimed at providing adequate monoamine neurotransmitter depressed patients may have their dis- updates of novel concepts emerging from the neurosciences that have relevance to the synthesis, especially if caused by an order or their lack of response to an an- practicing psychiatrist. actual or functional deficiency in brain tidepressant linked to low levels of fo- From the Neuroscience Education Institute L-methylfolate (Table 1).1–8 In such late and L-methylfolate. Research is in Carlsbad, Calif., and the Department of Psychiatry at the University of California cases, administration of L-methylfo- currently working to establish which San Diego. late could theoretically boost mono- patients with depression would be Reprint requests to: Stephen M. Stahl, M.D., Ph.D., Editor, BRAINSTORMS, Neuroscience amine synthesis to the necessary levels the best candidates for L-methylfolate Education Institute, 1930 Palomar Point Way, and either treat depression or boost the treatment. ◆ Ste. 101, Carlsbad, CA 92009. 13541353 PSYCHIATRIST.COM J Clin Psychiatry 69:9, September 2008.
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