Data on Mood and Vitamin B-9 (folate)

According to clinical nutritionist Blake Graham, all vitamins and minerals are involved in one or more biochemical pathways and/or physiological actions which influence the function of the human brain. Most vitamin and mineral deficiencies result in psychiatric symptoms in a significant number of people, and in people with psychiatric diagnoses these deficiencies are often associated with more severe symptoms and poorer outcome from conventional treatment. Vitamin and mineral deficiencies may act as an exacerbating factor secondary to malnutrition, alcoholism, etc. or may be a primary causative factor. Either way, optimisation of nutrient levels is in each patients best interest.

Several named vitamin deficiency diseases may result from the lack of sufficient B-vitamins.  Also, several unnamed, sub-clinical responses can result from B-vitamin deficiency.

A key observation by researcher Lucy Wills in 1931 led to the identification of folate as the nutrient needed to prevent anemia and other defects during pregnancy.  She demonstrated that the anemia could be corrected by brewer’s yeast. First called Wills factor and later called folate, the corrective substance in brewer’s yeast was extracted from spinach leaves in 1941. 

Since that time, there has been a great deal of data produced on this important B-vitamin and how it impacts mental health.

Depression is a common symptom of folate deficiency. (JE Alpert. 1997 & Howard JS. 1975) Of 1081 young men, those who were folate deficient were significantly more depressed based on ratings from the Adjective checklist, although not more depressed based on the Frieburg personality inventory scale. (Heseker H. 1992) Two more studies reported a significant association between folate level and depression ratings (Sachdev PS. 2005) (Bell IR. 1990), however, another investigating a group of 5948 subjects found no significant correlation between folate levels and depression or anxiety. (Bjelland I. 2003) The duration of current depressive episodes was also inversely correlated with serum folate levels in one study, which could be a reflection of dietary practices changing over the course of the illness. (Levitt AJ. 1989) Central nervous system abnormalities were found in two thirds of patients with megaloblastic anaemia due to folate deficiency with affective disorder being the most common association. (Shorvon SD. 1980)

Folates basic functions include methylation and DNA synthesis. (Mann. 2002) S-adenosylmethionine (SAMe) and tetrahydrobiopterin (BH4), both involved in monoamine synthesis, are lower in the presence of folate deficiency. (Young SN. 1989) (Bottiglieri T. 1992) Lower central nervous system levels of 5-hydroxytryptamine (serotonin) are also documented in folate deficiency. (Young SN. 1989) The most likely explanation for the association between folate status and psychiatric symptoms is its connection with monoamine metabolism via methylation, although other functions are also likely relevant. High plasma homocysteine levels have been shown to correlate strongly with low cerebrospinal fluid levels of folate, SAMe and monoamines. (T Bottiglieri. 2000) Homocystine levels are not raised in all cases of folate deficiency, so are not reliable marker for folate status. If elevated homocysteine levels are an innocent marker for folate, B12 and other deficiencies, or if elevated homocysteine also plays a direct role in major depression and anxiety disorders is unclear. (Bottiglieri T. 1996) Anemia and macrocytosis can be the result of folate deficiency, although they are only present in more severe cases so are also not a reliable predictor of folate status in psychiatric populations. (Mischoulon D. 2000)

A large body of research has examined the status of folate in psychiatric patients. 9/12 studies summarized below found folate deficiency in 17-31% of patients. The discrepancy between these 9/12 studies which reported high rates of deficiency and 3/12 studies reporting low rates, 0-3.4 %, is likely explained by different diets, alcohol consumption, laboratory techniques and reference ranges.

A prospective study followed 2,313 men aged between 42 and 60 for over 10 years. (T Tolmunen. 2004) At the beginning of the study, individual’s diets were analysed and divided into below and above the energy-adjusted median folate intake. Those below the median folate intake level had a relative risk of 3.04 (CI: 1.58-5.86) of receiving a diagnosis of depression.

Low serum folate levels were associated with a higher relapse rate in people with major depression being treated with fluoxetine. (Papakostas GI. 2004) In another study, high folate levels predicted greater improvement via SSRI’s in 22 depressed patients over 60 years old.(Murray. 2003) Low serum levels of 5-MeTHF, a biologically active form of folate, are not predictive of response to electroconvulsive therapy (ECT) in major depression. (Wilkinson AM. 1994)


Bonnie Kaplan points out that folate also impacts brain health in the following ways:

-Can heighten serotonin function by slowing destruction of brain tryptophan (Cousens, 2000). 

-Functions as a cofactor for enzymes that convert tryptophan into serotonin, and for enzymes that convert tyrosine into norepinehrine/noradrenalin (Cousens, 2000). 

-Contributes to the formation of compounds involved in brain energy metabolism (Selhub et al., 2000). Involved in the synthesis of the monoamine neurotransmitters (Hutto, 1997). 

-In folate deficient patients with depression (N=24) and schizophrenia (N=17), lower symptom scores were reported for treatment group than for placebo group (Godfrey et al., 1990).

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Bell IR, Edman JS, Marby DW, Satlin A, Dreier T, Liptzin B, Cole JO. Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population. Biol Psychiatry. 1990 Jan 15;27(2):125-37.

Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003 Jun;60(6):618-26.

Bottiglieri T, Hyland K, Laundy M, Godfrey P, Carney MW, Toone BK, Reynolds EH. Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med. 1992 Nov;22(4):871-6.

Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. 1996 Dec;54(12):382-90.

Bottiglieri T, M Laundya, R Crellinb, BK Tooneb, MWP Carneyc, EH Reynoldsa. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-232.

Cousens, G. (2000). Depression-free for life. New York: William Morrow.

Godfrey, P., Toone, B., Carney, M., Flynn, T., Bottiglieri, T., Laundy, M., et al. (1990, August 18). Enhancement of recovery from psychiatric illness by methylfolate. Lancet, 336, 392-395.





H, Kubler W, Pudel V, Westenhoffer J. Psychological disorders as early symptoms of a mild-to-moderate vitamin deficiency. Ann N Y Acad Sci. 1992 Sep 30;669:352-7.

Howard JS 3rd. Folate deficiency in psychiatric practice. Psychosomatics. 1975;16(3):112-5. 

Hutto, B. R. (1997). Folate and cobalamin in psychiatric illness. Comprehensive Psychiatry, 38, 305-314.

JE Alpert, M Fava. Nutrition and depression: the role of folate. Nutr Rev 55(5):145-9, 1997.

Levitt AJ, Joffe RT. Folate, B12, and life course of depressive illness. Biol Psychiatry. 1989 Apr 1;25(7):867-72.

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Mischoulon D, Burger JK, Spillmann MK, Worthington JJ, Fava M, Alpert JE. Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression. J Psychosom Res. 2000 Sep;49(3):183-7.

Murray A, Raul RS, Enrique RP. Prediction of Treatment Response in Geriatric Depression From Baseline Folate Level: Interaction With an SSRI or a Tricyclic Antidepressant. Journal of Clinical Psychopharmacology. 23(3):309-313, June 2003.

Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004 Aug;65(8):1090-5.

Sachdev PS, Parslow RA, Lux O, Salonikas C, Wen W, Naidoo D, Christensen H, Jorm AF. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med. 2005 Apr;35(4):529-38.

Selhub, J., Bagley, L, Miller, J., & Rosenberg, I. (2000). B vitamins, homocysteine, and neurocognitive function in the elderly. American Journal of Clinical Nutrition, 71, 6145-6205.

Shorvon SD, Carney MW, Chanarin I, Reynolds EH. The neuropsychiatry of megaloblastic anaemia. Br Med J. 1980 Oct 18;281(6247):1036-8.

Tolmunen T, Hintikka J, Ruusunen A, Voutilainen S, Tanskanen A, Valkonen VP, Viinamaki H, Kaplan GA, Salonen JT. Dietary folate and the risk of depression in Finnish middle-aged men. A prospective follow-up study. Psychother Psychosom. 2004 Nov-Dec;73(6):334-9.

Wilkinson AM, Anderson DN, Abou-Saleh MT, Wesson M, Blair JA, Farrar G, Leeming RJ. 5-Methyltetrahydrofolate level in the serum of depressed subjects and its relationship to the outcome of ECT. J Affect Disord. 1994 Nov;32(3):163-8.

Young SN, Ghadirian AM. Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13(6):841-63.


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