Acute Effects of Multivitamins
Interestingly, the orthodoxy that vitamins have to be administered for an extended period of time in order to elicit any physiological effects is not based on any evidence that vitamins do not exert acute effects. Comparatively few studies have assessed the acute effects of vitamins, but from those studies that have, there is emerging evidence that vitamins have physiological and brain function effects following a single dose. For instance, single doses of a range of single vitamins, including folic acid (as well as vitamins C, E, A), administered at “mega-doses” of between five and 26 times the RDA for that micronutrient, have all been shown to increase vasodilation in groups with disease-related or experimentally induced endothelial dysfunction (1-5). Acute administration of vitamin B6 has also been shown to elicit increased serotonin synthesis in the primate brain (6), whilst, in a placebo controlled, double blind, cross-over study in humans, the higher of two single doses of vitamin B6 (100 mg, 250 mg) also engendered an increase in dream salience (vividness, bizarreness, emotionality, and colour) (7).
The direct acute effects of single doses of multi-vitamins (plus minerals) on brain function have also been assessed in several studies. Haskell et al. (8) investigated the effects of a multivitamin/ mineral on cognitive function in children after a single dose (and after four and eight weeks) and found that improvements in attention task performance and in a semantic memory task were evident as early as 3 h following the first dose. Two studies have also demonstrated that a single dose of a multi-vitamin/mineral can significantly modulate regional brain activity during a task measuring focussed attention as measured with functional magnetic resonance spectroscopy (fMRI) (9), and cerebro-electrical activity during an attention task as measured by electroencephalography (EEG) (10). In the latter study EEG changes following the multi-vitamin treatment correlated with changes in task performance. A recent study (11) also investigated the impact of two doses of multi-vitamins/minerals that differed on the basis of their water soluble vitamin content (1 RDA and 3 RDA) on cerebral blood-flow in the frontal cortex (using Near Infrared Spectroscopy) and overall energy expenditure and metabolism (using Indirect Calorimetry of exhaled gas) during difficult cognitive tasks. This study demonstrated significantly increased fat metabolism and overall energy expenditure during cognitive task performance within 2 h of consuming the higher dose (3 RDA) of water soluble vitamins, and increased cerebral blood-flow following the lower 1 RDA dose of vitamins.
Chronic Effects of Multi-Vitamins in Children
In terms of supplementation with multi-vitamins, Benton (12), reviewed the results of studies published within the preceding decade that had assessed the effects of supplementation with multi-vitamin/minerals on children’s intelligence (IQ). All of the treatments included a full range of B vitamins, typically administered at much higher levels than the adult RDA. Benton noted evidence of improved performance in 10 out of the 13 studies, with improvements exclusively restricted to non-verbal tests of intelligence (i.e., those “fluid” intelligence tasks that do not require knowledge or vocabulary and which could therefore be conceived as more closely reflecting the biological functioning of the brain). Eilander et al. (13) revisited the subject with a meta-analysis that included 15 multivitamin mineral studies, 12 of which had involved administration of a full range of B vitamins, with a further two of the remainder including folate and vitamins B12 and B6 alongside other vitamins. They concluded that there was evidence of a “marginal increase in fluid intelligence and academic performance in healthy schoolchildren”. Similarly, Frensham et al. (14) reviewed those studies from developed countries that included effect sizes and identified 10 studies that showed cognitive benefits, as opposed to four that did not. They concluded that these results show that multivitamin supplementation may engender benefits in nonverbal intelligence and in other behavioural measures.
Chronic Effects of Multi-Vitamins in Adults
With regards multi-vitamins and adults, Kennedy and Haskell (15) identified 10 studies involving chronic multi-vitamin supplementation, almost exclusively conducted in cohorts of non-elderly adults. Across these 10 studies, all but one study reported improved psychological/cognitive functioning following supplementation, although four studies found these effects were restricted to sub-groups within their sample. In a subsequent meta-analysis of some of the cognitive data from 10 controlled trials of multi-vitamins that employed several similar memory measures, Grima et al. (16) found that multi-vitamin supplementation improved performance of some memory tasks, with too little data on tasks assessing other cognitive domains to arrive at a conclusion. A subsequent meta-analysis of the data from eight studies that included an assessment of the effects of multivitamins on aspects of mood and psychological state (17) found that supplementation reduced clinical ratings of perceived stress, mild psychiatric symptoms and anxiety. Of particular interest, the studies included in this analysis could be subdivided into those that administered higher (4RDA) levels of B vitamins with lower levels of other micronutrients, or lower (1RDA) levels of B vitamins with higher levels of other micronutrients. This analysis suggested that higher B vitamins with lower levels of other micronutrients engendered stronger effects, suggesting both a dose-response and that the efficacy of the products lay primarily with the B vitamin constituents. These conclusions received further support from a more recent study that also demonstrated improved mood following four weeks of supplementation with a multivitamin containing high levels of B vitamins (18). Interestingly, several of the studies included in the reviews described above also included assessments of homocysteine levels before and after treatment, and demonstrated both that homocysteine levels were approaching levels indicating cardiovascular risk in the studies’ healthy, non-elderly samples, and also that multivitamins normalised these levels (19) including in a dose-related manner when 1RDA and 3RDA of B vitamins were administered (20). It is also worth noting that a number of other recent studies have also demonstrated improved psychological or cognitive functioning following products containing multi-vitamins (21-25), although the interpretation of these studies with regards their vitamin content is limited by the inclusion of multiple herbal extracts at potentially psychoactive levels in the formulations. However, it may be relevant that one of these studies demonstrated a correlation between improved performance in a focussed attention (Stroop) task and changes in blood levels of vitamin B6 following supplementation (25)
References
1. Doshi, S.N.; McDowell, I.F.W.; Moat, S.J.; Payne, N.; Durrant, H.J.; Lewis, M.J.; Goodfellow, J. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 2002, 105, 22–26.
2. Obad, A.; Palada, I.; Valic, Z.; Ivancev, V.; Bakovic, D.; Wisloff, U.; Brubakk, A.O.; Dujic, Z. The effects of acute oral antioxidants on diving-induced alterations in human cardiovascular function. J. Physiol. Lond. 2007, 578, 859–870.
3. Katz, D.L.; Nawaz, H.; Boukhalil, J.; Giannamore, V.; Chan, W.; Ahmadi, R.; Sarrel, P.M. Acute effects of oats and vitamin E on endothelial responses to ingested fat. Am. J. Prev. Med. 2001, 20, 124–129.
4. Title, L.M.; Cummings, P.M.; Giddens, K.; Nassar, B.A. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: An effect prevented by vitamins c and e. J. Am. Coll. Cardiol. 2000, 36, 2185–2191.
5. Usui, M.; Matsuoka, H.; Miyazaki, H.; Ueda, S.; Okuda, S.; Imaizumi, T. Endothelial dysfunction by acute hyperhomocyst (e) inaemia: Restoration by folic acid. Clin. Sci. 1999, 96, 235–239.
6. Hartvig, P.; Lindner, K.; Bjurling, P.; Långström, B.; Tedroff, J. Pyridoxine effect on synthesis rate of serotonin in the monkey brain measured with positron emission tomography. J. Neural Transm. Gen. Sect. JNT 1995, 102, 91–97.
7. Ebben, M.; Lequerica, A.; Spielman, A. Effects of pyridoxine on dreaming: A preliminary study. Percept. Mot. Skills 2002, 94, 135–140.
8. Haskell, C.F.; Scholey, A.B.; Jackson, P.A.; Elliott, J.M.; Defeyter, M.A.; Greer, J.; Robertson, B.C.; Buchanan, T.; Tiplady, B.; Kennedy, D.O. Cognitive and mood effects in healthy children during 12 weeks’ supplementation with multi-vitamin/minerals. Br. J. Nutr. 2008, 100, 1086–1096.
9. Scholey, A.; Bauer, I.; Neale, C.; Savage, K.; Camfield, D.; White, D.; Maggini, S.; Pipingas, A.; Stough, C.; Hughes, M. Acute effects of different multivitamin mineral preparations with and without guaraná on mood, cognitive performance and functional brain activation. Nutrients 2013, 5, 3589–3604.
10. White, D.J.; Camfield, D.A.; Maggini, S.; Pipingas, A.; Silberstein, R.; Stough, C.; Scholey, A. The effect of a single dose of multivitamin and mineral combinations with and without guaraná on functional brain activity during a continuous performance task. Nutr. Neurosci. 2014.
11. Kennedy, D.O.; Stevenson, E.; Jackson, P.; Wishart, K.; Bieri, G.; Barella, L.; Carne, A.; Dunn, S.; Robertson, B.; Forster, J.; et al. Multivitamins/minerals modulate cerebral blood-flow and whole-body energy metabolism during cognitive tasks of graded difficulty. J. Nutr. Metab. 2016,
12. Benton, D. Micro-nutrient supplementation and the intelligence of children. Neurosci. Biobehav. Rev. 2001, 25, 297–309.
13. Eilander, A.; Gera, T.; Sachdev, H.S.; Transler, C.; van der Knaap, H.C.M.; Kok, F.J.; Osendarp, S.J.M. Multiple micronutrient supplementation for improving cognitive performance in children: Systematic review of randomized controlled trials. Am. J. Clin. Nutr. 2010, 91, 115–130.
14. Frensham, L.J.; Bryan, J.; Parletta, N. Influences of micronutrient and omega-3 fatty acid supplementation on cognition, learning, and behavior: Methodological considerations and implications for children and adolescents in developed societies. Nutr. Rev. 2012, 70, 594–610.
15. Kennedy, D.O.; Haskell, C.F. Vitamins and cognition: What is the evidence? Drugs 2011, 71, 1957–1971.
16. Grima, N.A.; Pase, M.P.; Macpherson, H.; Pipingas, A. The effects of multivitamins on cognitive performance: A systematic review and meta-analysis. J. Alzheimer’s Dis. 2012, 29, 561–569.
17. Long, S.-J.; Benton, D. Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: A meta-analysis. Psychosom. Med. 2013, 75, 144–153.
18. White, D.J.; Cox, K.H.; Peters, R.; Pipingas, A.; Scholey, A.B. Effects of four-week supplementation with a multi-vitamin/mineral preparation on mood and blood biomarkers in young adults: A randomised, double-blind, placebo-controlled trial. Nutrients 2015, 7, 9005–9017.
19. Haskell, C.F.; Robertson, B.; Jones, E.; Forster, J.; Jones, R.; Wilde, A.; Maggini, S.; Kennedy, D.O. Effects of a multi-vitamin/mineral supplement on cognitive function and fatigue during extended multi-tasking. Hum. Psychopharmacol. Clin. Exp. 2010, 25, 448–461.
20. Grodstein, F.; O’Brien, J.; Kang, J.H.; Dushkes, R.; Cook, N.R.; Okereke, O.; Manson, J.E.; Glynn, R.J.; Buring, J.E.; Gaziano, J.M. Long-term multivitamin supplementation and cognitive function in mena randomized trial. Ann. Intern. Med. 2013, 159, 806–814.
21. Harris, E.; Macpherson, H.; Vitetta, L.; Kirk, J.; Sali, A.; Pipingas, A. Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: A randomised, placebo-controlled trial. Hum. Psychopharmacol. Clin. Exp. 2012, 27, 370–377.
22. Macpherson, H.; Ellis, K.A.; Sali, A.; Pipingas, A. Memory improvements in elderly women following 16 weeks treatment with a combined multivitamin, mineral and herbal supplement. Psychopharmacology 2012, 220, 351–365.
23. Harris, E.; Kirk, J.; Rowsell, R.; Vitetta, L.; Sali, A.; Scholey, A.B.; Pipingas, A. The effect of multivitamin supplementation on mood and stress in healthy older men. Hum. Psychopharmacol. Clin. Exp. 2011, 26, 560–567.
24. Pipingas, A.; Camfield, D.A.; Stough, C.; Scholey, A.B.; Cox, K.H.; White, D.; Sarris, J.; Sali, A.; Macpherson, H. Effects of multivitamin, mineral and herbal supplement on cognition in younger adults and the contribution of B group vitamins. Hum. Psychopharmacol. Clin. Exp. 2014, 29, 73–82.
25. Pipingas, A.; Camfield, D.; Stough, C.; Cox, K.; Fogg, E.; Tiplady, B.; Sarris, J.; White, D.; Sali, A.;Wetherell, M. The effects of multivitamin supplementation on mood and general well-being in healthy young adults. A laboratory and at-home mobile phone assessment. Appetite 2013, 69, 123–136.
