Skip to main content Accessibility help

Effect of folic acid supplementation on mood and serotonin response in healthy males

  • Emma Williams (a1), Barbara Stewart-Knox (a1), Ian Bradbury (a2), Ian Rowland (a1), Kristina Pentieva (a1), Anders Helander (a3) and Helene McNulty (a1)...


Evidence suggests that low folate status may be detrimental to mood and associated with depleted cerebrospinal fluid levels of the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT). A placebo-controlled trial was carried out to determine the effect of folic acid supplementation (100 μg for 6 weeks followed by 200 μg for a further 6 weeks) upon subjective mood (Positive and Negative Affect Schedule) and biochemical markers of mood (5-HT) in healthy males (n 23). Blood samples were obtained at baseline (week 0) and during the intervention at week 6 and week 12. Subjective mood assessments were obtained at week 0 and week 12. The results showed an increase in serum and erythrocyte folate concentrations (P=0·02 and P=0·003, respectively) and a corresponding decrease in plasma homocysteine (P=0·015) in response to the folic acid intervention. Neither subjective mood nor 5-HT levels, however, were significantly altered in response to the change in folate status. Folic acid given at physiological doses did not appear to improve the mood of healthy folate-replete individuals over a 12-week period. Further research is needed to address the effect of folic acid supplementation or of longer duration or increased dose, particularly in the face of sub-optimal folate status.

    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Effect of folic acid supplementation on mood and serotonin response in healthy males
      Available formats

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Effect of folic acid supplementation on mood and serotonin response in healthy males
      Available formats

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Effect of folic acid supplementation on mood and serotonin response in healthy males
      Available formats


Corresponding author

*Corresponding author: Dr Barbara Stewart-Knox, fax +44 28 70324965, email


Hide All
Agnoli, A, Ruggieri, S & Cerrone, GG (1977) The dopamine hypotheses of depression: results of treatment with dopaminergic drugs. In Depressive Disorders, pp. 447458 [Grattini, S, editors]. Stuttgart: FK Schatauer Verlag.
Alpert, JE & Fava, M (1997) Nutrition and depression: the role of folate. Nutr Rev 55, 145149.
Benton, D, Haller, J & Fordy, J (1995) Vitamin supplementation for 1 year improves mood. Neuropsychobiology 32, 98105.
Botez, MI, Botez, T, Levielle, J, Bielmann, T & Cadotte, M (1979 a) Neuropsychological correlates of folic acid deficiency: facts and hypotheses. In Folic Acid in Neurology, Psychiatry, and Internal Medicine. pp. 425461 [Botez, MI, Reynolds, EH, editors]. New York: Raven Press.
Botez, MI, Young, SN, Bachevalier, J & Gauthier, S (1979 b) Folate deficiency and decreased brain 5-hydroxytryptamine synthesis in man and rat. Nature 278, 182183.
Botez, MI, Young, SN, Bachevalier, J & Gauthier, S (1982) Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal fluid. Am Neurol Assoc 12, 479484.
Bottiglieri, T, Hyland, K & Reynolds, EH (1994) The clinical potential of ademethionine ( S -adenosylmethionine) in neurological disorders. Drugs 48, 137152.
Bottiglieri, T, Laundy, M, Crellin, R & Toone, BK (2000) Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 69, 228234.
Brattstrom, L, Israellson, B, Jeppson, J & Hultberg, B (1998) Folic acid – an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest 48, 215221.
Brewerton, TD, Flament, MF, Rapoport, JL & Murphy, DL (1993) Seasonal effects on platelet 5HT content in patients with OCD and controls. Arch Gen Psychiatry 50, 409.
Bryan, J, Calvaresi, E & Hughes, D (2002) Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr 132, 13451356.
Cantoni, GL (1953) S -Adenosylmethionine: a new intermediate formed enzymatically from l -methionine and adenosine triphosphate. J Biol Chem 204, 403416.
Carney, MWP (1967) Serum folate values in 423 psychiatric patients. Br Med J 4, 512.
Carney, MWP, Martin, R, Bottiglieri, T, Reynolds, EH, Nissenbaum, H, Toone, BK & Sheffield, BN (1983) The switch mechanism in affective illness and S -adenosylmethionine. Lancet 1, 820821.
Coppen, A & Bailey, J (2000) Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord 60, 121130.
Coppen, A, Turner, P, Rowsell, AR & Padgham, C (1976) 5-Hydroxytryptamine (5-HT) in the whole-blood of patients with depressive illness. Postgrad Med J 52, 156158.
Coppen, A, Chaudhry, S & Swade, C (1986) Folic acid enhances lithium prophylaxis. J Affect Disord 10, 913.
Costello, J, Benjamin, R, Angold, A & Silver, D (1991) Mood variability in adolescents. A study of depressed, nondepressed and comorbid patients. J Affect Disord 23, 199212.
Crawley, H (1988) Food Portion Sizes 3rd ed. London: HMSO.
Fava, M, Borus, JS, Alpert, JE, Nierenberg, AA, Rosenbaum, JF & Bottiglieri, T (1997) Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 154, 426428.
Ghadirian, AM, Anath, J & Engelsmann, F (1980) Folic acid deficiency in depression. Psychosomatics 21, 926929.
Godfrey, PSA, Toone, BK, Carney, MWP, Flynn, TG, Bottiglieri, T, Laundy, M, Chanarin, I & Reynolds, EH (1990) Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392395.
Guaraldi, G, Fava, M, Mazzi, F & LaGreca, P (1993) An open trial of methyltetrahydrofolate (MTHF) in elderly depressed patients. Ann Clin Psychiatry 5, 101106.
Harris, S & Dawson-Hughes, B (1993) Seasonal mood changes in 250 normal women. Psychiatry Res 49, 7787.
Herbert, V (1962) Experimental nutritional folate deficiency in man. Trans Assoc Am Physicians 75, 307320.
Jensen, E, Dehlin, O, Erfurth, EM, Hagberg, B, Samuelsson, B, Svensson, T & Hultberg, B (1998) Plasma homocysteine in 80-year-olds: relationships to medical, psychological and social variables. Arch Gerontol Geriatr 26, 215226.
Jung, RE, Yeo, RA, Love, TM, Petropoulos, H, Sibbitt, TL & Brooks, WM (2002) Biochemical markers of mood: a proton magnetic resonance spectroscopy study of normal human brain. Biol Psychiatry 51, 224229.
Kang, SSWong, PWK & Malinow, MR (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12, 279298.
Kema, IP, Schellings, AMJ, Melmorg, G, Hoppenbrouwers, CJM & Muskiet, FAJ (1992) Influence of a serotonin- and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem 38, 17301736.
Lapin, IP & Oxenkrug, GF (1969) Intensification of the central serotonergic processes as a possible determinant of the thymoleptic effect. Lancet 1, 132136.
Leino, A (1999) Fully automated measurement of total homocysteine in plasma and serum on the Abbott IMx Analyzer. Clin Chem 45, 569571.
Le Quan-Bui, KH, Plaisant, O, Leboyer, M, Gay, C, Kamal, L, Devynck, M & Meyer, P (1984) Reduced platelet serotonin in depression. Psychiatry Res 13, 129139.
McConville, C & Cooper, C (1992) Mood variability and personality. Pers Individ Dif 13, 12131221.
McConville, C & Cooper, C (1996) Mood variability and the intensity of depressive states. Curr Psychol 14, 329338.
McConville, C & Cooper, C (1999) Personality correlates of variable moods. Pers Individ Dif 26, 6578.
McNair, DM, Lorr, M & Dropplemann, F (1971) Profile of Mood States. San Diego, CA: Educational and Industrial Testing Service.
Molloy, AM & Scott, JM (1997) Microbiological assay for serum, plasma, and red cell folate using cryopreserved, microtiter plate method. Methods Enzymol 281, 4353.
Morris, MS, Fava, M, Jacques, PF & Selhub, J (2003) Depression and folate status in the US population. Psychother Psychosom 72, 8087.
National Statistics Socio-Economic Classification (2002) National Statistics Socio-Economic Classification User Manual London: HMSO, Office for National Statistics.
Ordonez, LA & Wurtman, RJ (1974) Folic acid deficiency and methyl group metabolism in rat brain: effects of l -Dopa. Arch Biochem Biophys 160, 372376.
Quintana, J (1992) Platelet serotonin and plasma tryptophan in endogenous depression. Clinical, therapeutic, and biological correlations. Affect Disord 24, 5562.
Reynolds, EH & Carney, MWP (1984) Methylation and mood. Lancet 28, 196198.
Reynolds, EH & Stramentinoli, G (1983) S -Adenosylmethionine and affective disorder. Psychol Med 13, 705710.
Reynolds, EH, Preece, JM, Bailey, J & Coppen, A (1970) Folate deficiency in depressive illness. Br J Psychiatry 117, 287292.
Sarrias, MJ, Artigas, M, Martinez, A & Gelpi, E (1989) Seasonal changes of plasma serotonin and related parameters: correlations with environmental measures. Biol Psychiatry 26, 695706.
Ward, M, McNulty, H, McPartlin, J, Strain, JJ, Weir, DG & Scott, JM (1997) Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. Q J Med 90, 519524.
Watson, D (2000) Mood and Temperament New York: The Guilford Press.
Watson, D & Clark, LA (1997) Measurement and mismeasurement of mood; recurrent and emergent issues. J Pers Assess 66, 267296.
Watson, D & Clark, LA (1994) The PANAS-X Manual for the Positive and Negative Affect Schedule – Expanded Form Ames, IA: University of Iowa.
Watson, D, Clark, LA & Tellegen, A (1988) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 54, 10631070.
Wesson, VA, Levitt, AJ & Joffe, RT (1994) Change in folate status with antidepressant treatment. Psychiatry Res 53 313322.
Xiao, R, Beck, O & Hjemdahl, P (1998) On the accurate measurement of serotonin in whole blood. Scand J Clin Lab Invest 58, 505510.
Zald, DH & Depue, RA (2001) Serotonergic functioning correlates with positive and negative affect in psychiatrically healthy males. Pers Individ Dif 30, 7186.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed