INTRODUCTION

The consequences of micronutrient deficiencies in the general population are widespread. With respect to the potential association between micronutrient status and neurological health, epidemiological studies have revealed a correlation between low biochemical levels of micronutrients and poor cognitive function and mood, leading to a range of symptoms (¹,²). Optimal nutrition is known to positively contribute to both mental and physical performance, with data indicating that the impact of certain micronutrients, specifically B and C vitamins, calcium, magnesium and zinc, may be of particular importance in supporting cognitive function (²-⁴). Deficiencies in folate, vitamin B12 and other B vitamins are also known to contribute to physical fatigue (²-⁵).

Vitamins and minerals are not synthesised endogenous to the human body and therefore must be consumed as part of a ba­lanced diet. In support of this, the governments of most deve­loped nations provide recommended dietary intakes of vitamins and minerals. Such recommendations are intended to guide populations on the advised intake of individual micronutrients that should prevent micronutrient deficiency in the vast majority of the population (¹,⁴). However, despite the availability of this guidance (which generally only reflects the bare-minimum levels to mitigate deficiency-based diseases, and not for optimal health), low intake of micronutrients is prevalent even in apparently healthy populations in developed countries (³,⁴). Evidence suggests that this is particularly the case in the young and elderly, and in mi­ddle-aged adults exposed to high occupational pressures. These include students, working professionals, multi-tasking parents, and those with an active lifestyle (³,⁴). Reasons for not achieving sufficient micronutrient intake may include lifestyle-associated behaviours, such as rushed meals (related to poor digestion), unhealthy food choices, chronic or periodical dieting, and stress-related activities, such as smoking and excessive consumption of coffee or alcohol (³,⁴). The prevalence values for B vitamin deficiency differs across age groups, sex, socioeconomic groups, and developed geographies, with evidence suggesting that insufficiency can vary vastly, with values of less than 5 % reported in the UK population and 10.5 % reported in the United States, compared with up to 54 % in the Netherlands (⁴,⁶,⁷).

Micronutrients play an important role in normal physiology and healthy bodily functions, with B vitamins performing coenzyme functions essential to the biochemistry that underpins energy, fat and protein metabolism, cell growth and function, and nucleic acid synthesis and repair (¹,³,⁴). In addition, adequate levels of micronutrients are required to maintain optimal functioning of the central nervous system (CNS) and facilitate cognitive processes, with insufficient levels of micronutrients known to impair cognitive and physical function (²-⁴). Inadequate levels of micronutrients can also result in reduced neurotransmitter levels, diminished structural and functional integrity of neuronal membranes and receptors, and impaired energy production that can affect cognition (¹-⁴,⁸). Deficiency of vitamins B6, B9 and B12 have also been linked to the potentially neurotoxic accumulation of homocysteine, which may impair cognitive function and mood, and has been observed in a range of pathologies (⁴). The essential cofactor role of B vitamins in the one-carbon cycle, specifically, has contributed to the hypothesis linking B vitamin levels with mood (⁹). Mitochondrial functions are also compromised by insufficient dietary intake of B vitamins and/or increased B vitamin needs (⁴). While there is limited clinical data on the interactions between micronutrient metabolism and physical performance, it has been shown that deficiencies in certain B vitamins can contribute to physical fatigue (²-⁴).

The clinical importance of even mild micronutrient deficiencies should not be underestimated, due to the risk of predisposing individuals to increased risk of poor health. Specifically, while overt micronutrient deficiency is known to contribute to changes in behaviour, a marginal B vitamin deficiency can potentially lead to symptomatic changes in psychological parameters (³,⁴). Such symptoms of marginal micronutrient deficiency include fatigue, weakness, loss of concentration, depressed mood, neurological disturbances, and anxiety (³,⁴). Therefore, one might not be surprised to learn that deficiencies of micronutrients may have wide reaching consequences on a population level, translating to loss of productivity in the workplace and increased healthcare costs, with subsequent economic implications (¹⁰-¹²).

Therefore, it stands to reason that micronutrient supplementation may in part assist in attenuating a negative health status in the general population. In support of this, evidence suggests that supplementation with multivitamins/minerals may enhance cognitive and physical function in both healthy and ‘at-risk' populations, including those with suboptimal nutritional status for any reason (¹,³,⁴,⁹). While the effect of intervention with a single or restricted range of micronutrients is limited, nutritional supplementation has already been shown to enhance cognitive and psychological functioning (²,⁴). In fact, the benefit of supplementation with multiple B group vitamins on stress in healthy and at-risk populations has been observed in a recent systematic review and meta-analysis (⁹).

To our knowledge, there are a vast array of products sold worldwide that provide differing formulations of vitamins and minerals; however, we believe there is generally little research conducted to determine the clinically meaningful benefits that these provide to healthy populations. Thus, our systematic review aimed to investigate the effects of supplementation with a high-dose B-complex multivitamin/mineral supplement on mental and physical health, by assessing physical, mental and energy performance outcomes. The supplement (Berocca^® Performance, Bayer Consumer Health) is designed to support mental and physical performance and energy. Its specific formulation was amended in 1998 to include vitamins B1 (15 mg), B2 (15 mg), B6 (10 mg), B12 (10 mcg), C (500 mg), biotin (150 mcg), folic acid (400 mcg), nicotinamide (50 mg), and pantothenic acid (23 mg), and minerals calcium (100 mg), magnesium (100 mg), and zinc (10 mg). A review paper authored by Maggini and colleagues in 2014 evaluated the evidence available on the effect of both the previous and current formulations of Berocca^® on cognitive function (²). Our review aimed to update and extend these findings by evaluating more recent evidence from randomised controlled trials (RCTs) on the effects of supplementation with the newest, currently available formulation of Berocca^® on mental but also on physical parameters, and the close interdependence of the two in healthy subjects.

METHODS

The primary focus of this review was to evaluate the effects of the high-dose B-complex multivitamin/mineral supplement on health status, including mental and physical domains. PubMed was searched for randomized controlled trials until January 2020 by using the following search string: (multivitamins[Title] OR multivitamin[Title] OR b vitamin complex[Title] OR multi-vitamin[Title] OR Multi-Vitamin/Mineral[Title] OR multi vitamin[Title]) (mental OR psychological OR cognition OR cognitive OR neurocognition OR neurocognitive OR energy OR stamina OR performance OR fatigue). Search results were manually filtered to remove all non-human and in vitro studies. For the selection process, see figure 1.

Figure 1.  Flow diagram depicting the selection process for the articles analysed in this review. 

The initial search captured 136 records. After screening of titles and articles, 68 in vitro and non-human studies were excluded. Following this, 68 full-text articles were manually filtered to remove articles focussed on unspecified multivitamins or which did not consider a physical, mental or energy performance outcome. Seven articles fulfilled the inclusion criteria and were included in this review (Table I).

Table I.  Short synthesis of the seven trials investigating supplementation with a high-dose vitamin B-complex multivitamin/mineral formulation (Berocca® Performance, Bayer Consumer Health) 

*ANCOVA including additional fruit/vegetable consumption covariate. †Significance was reached during post-work assessments, except for physical stamina, where significance was reached across both pre- and post-work assessments. ANCOVA: analysis of covariance; A-X CPT: A-X continuous performance task; CDB: cognitive demand battery; fMRI: functional magnetic resonance imaging; GHQ: General Health Questionnaire; HADS: Hospital Anxiety and Depression Scale; IT: Inspection Time; POMS: Profile of Mood States; PSS: Perceived Stress Scale; RVIP: rapid visual information processing; SST: steady-state topography; SSVEP: steady-state visual evoked potential; STAI-S:s State-Trait Anxiety Inventory – State Portion; VAMS: visual analogue mood scales; VAS: visual analogue scale.

RESULTS

COGNITIVE PERFORMANCE

The supplement has been investigated in seven RCTs in healthy populations, with outcomes demonstrating enhanced mental performance that may be supported by parameters of brain activity, cognitive performance and concentration, as discussed below.

Supplementation for 28 days may improve the ability to concentrate, as demonstrated by 80 healthy men who reported an improvement in concentration via rating scales (¹³). In addition, healthy males receiving this high-dose B-complex multivitamin/mineral supplement for 33 days presented with improved cognitive performance and reduction in mental tiredness during a 60-minute cognitive demand battery (CDB) of tasks designed to assess the impact of treatment on speed/accuracy and mental fatigue, and which has been shown to be sensitive to a number of different supplements (¹⁴). A concomitant study that involved these same male participants required them to complete intense cognitive tasks in a ‘Mobile Phone Battery' study, a form of testing shown to be sensitive in assessing aspects of cognitive performance and delivering mood visual analogue scale (VAS). Following supplementation for 28 days, this concomitant cohort presented with results revealing significant improvements in concentration and significant, sustained increases in alertness and mental stamina (¹⁵).

Brain mapping studies have shown that the effects of su­­pple­mentation on functional brain activity can be seen as soon as 30 minutes after one dose (¹⁶,¹⁷), although long-term su­pple­mentation of four weeks appears necessary for significant improvements in cognitive outcomes, such as mental fatigue, mental stamina, and concentration (13-15,18), which may translate into clinically important improvements.

Whole-brain analysis of participants during a working memory/vigilance task (rapid visual information processing; RVIP) and following supplementation indicated significantly increased functional brain activity in regions associated with working memory and attention, including the right precentral gyrus, and the left and right cerebellum (Fig. 2) (¹⁶). Furthermore, the high-dose B-complex formulation resulted in response patterns in the frontal cortex that are indicative of greater activation of task-relevant frontal brain regions, as measured by significant, transien­tly reduced amplitude and phase advance in the steady-state vi­sually evoked potential (SSVEP) response during completion of the active continuous performance task (A-X CPT; Fig. 3) (¹⁷).

Figure 2.  Brain activation patterns associated with supplementation with the high-dose vitamin B-complex multivitamin/mineral formulation (Berocca^® Performance, Bayer Consumer Health) compared with placebo during the rapid visual information processing (RVIP) task. Posterior (left) and left lateral surface (middle) and dorsal (right) views of brain surfaces showing significantly greater activation during the RVIP task for Berocca^® Performance compared with placebo (p < 0.01) (¹⁶). Figure adapted from Scholey et al., 2013 (DOI: 10.3390/nu5093589; open access article distributed under the terms and conditions of the Creative Commons Attribution license). 

Figure 3.  Topographic maps of differences in steady-state visual evoked potential (SSVEP) amplitude and phase for the A-X continuous performance task (A-X CPT) at the su­­pplementation (Berocca^® Performance, Bayer Consumer Health) and placebo visit. Each column shows topographic maps of SSVEP amplitude and phase differences with supplementation versus placebo, with the bottom map showing the p-values resulting from the Hotelling's T2 contrast of the two treatments. Warm colours indicate amplitude and latency reductions (phase advance) and lower p-values, respectively, and cool colours represent amplitude increases and latency increases (phase lag). Supplementation was associated with a pattern of frontal SSVEP amplitude reduction and phase advance during the hold (p < 0.01) and target (p < 0.05) segment of the A-X CPT (¹⁷). Figure obtained from White et al., 2017 (DOI: 10.1179/1476830514Y.0000000157; permission not required for use in this publication). 

The narrow-band characteristics of the SSVEP permitted reduced susceptibility to noise contamination, and improved detection.

In a pilot ‘brain mapping' study, participants undergoing neurocognitive assessment 30 minutes after intake of this high-dose B-complex multivitamin/mineral supplement experienced an increased efficiency of cortical functioning, as determined by steady-state topography (SST) (¹⁶). In a subset of participants, this formulation was also shown to increase activation in brain regions that constitute a well-established fronto-parietal wor­king memory network (²,¹⁶). Furthermore, converging evidence from functional magnetic resonance imaging (fMRI) and SSVEP recordings in another brain mapping study demonstrated brain activity patterns consistent with centro-parietal regions following supplementation (¹⁸). To our knowledge, Berocca^® was the first multivitamin/mineral preparation to be studied for neurocognitive benefits using fMRI, which enables simultaneous capture of both behavioural data and brain activity, with high spatial resolution that surpasses that of functional near-infrared spectroscopy (¹⁶,¹⁸). We also understand that the use of fMRI to specifically examine the effects of multivitamin/mineral supplementation on brain activation was first employed by Scholey et al., then in a further two studies (¹⁶-¹⁸). Overall, findings from these mapping studies support acute activation of the human brain regions linked to attention, executive control and working memory (¹⁶-¹⁹).

Perceived energy levels

In a large study of 215 healthy participants, 33 days of supple­mentation was associated with a significant increase in self-reported physical vigour, as assessed by the Profile of Mood States (POMS) questionnaire, a highly reliable, valid and well-established measure of psychological distress (¹⁴). Furthermore, a significant and sustained increase in physical stamina in the morning and evening was self-reported via VAS by 198 male participants receiving the supplement for 28 days (¹⁵). Data from a study in 80 healthy males also indicated that it may protect against minor illness, as those receiving placebo for 28 days registered a significant increase in somatic symptoms that was not observed in those receiving the high-dose B-complex formulation for 28 days (¹³). Somatic symptoms assessed during the study included watery eyes, upset stomach, congested nose, headache, feverishness, aches, ringing in the ears, eye strain and sore throat, amongst others (¹³).

Stress, mood, and biochemical outcomes

Dietary supplementation with this high-dose, B-complex multivitamin/mineral supplement has been associated with significant improvements in mood, compared with baseline and placebo, as demonstrated by increased vigour-activity and decreased depression-dejection (¹⁴,¹⁹). Significant reductions in stress, subjective stress and anxiety and numerical reductions in stress-related symptoms have also been observed across psychometric instruments known to reliably assess psychological status, including the General Health Questionnaire (GHQ), POMS and Hospital Anxiety and Depression Scale (HADS) questionnaires (¹³,¹⁴). While a direct link between supplementation and enhanced performance was not measured in all of these studies, the findings suggest an improvement in wellbeing and ability to effectively cope with stress and anxiety in daily life (¹³,¹⁴,¹⁹).

White et al. conducted a blood biochemical assessment in which significantly greater levels of vitamins B6 and B12 and significantly reduced levels of homocysteine were observed following 28 days of supplementation compared with placebo (¹⁹). Non-significant increases in levels of red blood cell folate and plasma zinc have also been observed following 28 days of supplementation (¹⁸,¹⁹). Of interest, the findings from White et al. corroborate those of a previous study, in which participants also experienced significant reductions in homocysteine levels (²⁰). These fin­dings appear promising, given the evidence that a deficiency in certain B vitamins can lead to accumulation of homocysteine and decreased synthesis of monoamines, which may ultimately affect mood (⁵,²¹,²²).

Finally, adverse events were either not reported or those reported were not serious and did not result in any treatment discontinuations.

Real-world studies may be considered an increasingly credible study type, as they are often able to examine large, heterogenous populations for long durations. There is certainly a need for such studies on the use of multivitamin/mineral supplementation in large patient populations and subpopulations/at-risk groups (with suboptimal nutritional status or subclinical symptoms at baseline) (¹). Despite some obvious methodological limitations, such as their typically observational or retrospective nature, these studies would strengthen the current understanding of the influence of micronutrient status and dietary habits on the effects of supplementation. One such study followed 300 male and female university students preparing for upcoming examinations who were taking either Berocca^® or no vitamin/multivitamin supplement at all. Participants were asked to complete questionnaires for assessment of their memory, concentration and stamina. Two hundred also completed 10-15-minute cognitive assessments via a verbal reasoning task to assess verbal learning, a stroop task to assess focus, and a digital span task to assess working memory and attention. Overall, the high-dose B-complex formulation provided support in fulfilling their noted priorities, particularly those related to handling multiple exams, and having confidence to perform well. In addition, participants receiving the supplement claimed that it gave them better memory, improved their mental stamina and significantly improved their ability to focus. Overall, these results complement the evidence generated with the controlled interventional studies.

DISCUSSION

Healthy functioning of the CNS is known to depend on a wide range of micronutrients, particularly B and C vitamins, calcium, magnesium and zinc (¹-⁵). Micronutrient deficiencies may arise from an imbalanced diet that does not satisfy micronutrient requirements, which can also be exacerbated by factors such as a stressful lifestyle, loss of sleep and missed meals (³,⁴).

Supplementation with multivitamins/minerals may improve mental and physical performance by replenishing levels of essential micronutrients that are not, or are insufficiently, consumed via the diet. Meta-analyses have presented consistent findings across a range of studies carried out in different countries that support the role of such supplementation in improving overall mood or aspects of mood (⁹,²³). Currently available evidence has also sugges­ted links between multivitamin supplementation, levels of blood micronutrients, homocysteine and C-reactive protein and clinical outcomes (¹,⁴,¹⁹), which warrant further investigation. Our review indicates that the high-dose B-complex supplement Berocca^® is the most studied multivitamin formulation to date. Multiple double-blind, placebo-controlled RCTs that have specifically investigated this supplement demonstrate its beneficial effects on brain function and mental and physical performance (¹,¹³,¹⁴,¹⁶-¹⁹). The supplement also led to significant improvements in fatigue, concentration, total mood disturbance and perceived stress, although not in all studies (¹³-¹⁵,¹⁸,¹⁹). Given its ease of administration and tolerability, which may be suggested by a compliance rate of at least 80 % in participants receiving the supplement (¹³,¹⁵,¹⁹), the potential for Berocca^® to restore micronutrient deficiencies not met through a balanced diet is promising, and offers a simple approach to promote optimal mental and physical performance in adults. In turn, improvements in mental and physical energy would be expected to contribute to increased productivity, with associated economic benefits at a population level.

As detailed above, the breadth of results indicate that this supple­ment may be beneficial for mental and physical performance in healthy populations. However, it is recognised that not all research discussed is supportive of this, and further study of this topic is certainly warranted. It is important to recognise both the strengths and weaknesses that each presents with. For example, the inter-study variation due to the different methodologies and designs employed can be a barrier to the generalisability of fin­dings. In particular, the studies considered different target populations, were generally limited in duration (≤ 33 days), and sample sizes were small and variable across studies (20-300 participants). In addition, some outcomes were only investigated in small participant subsets (¹⁶), and overall differences in the assessed outcomes across studies makes it challenging to draw comparisons and similarities between findings and make firm conclusions. Nevertheless, no serious adverse events were reported in any of the studies (if at all). Appropriate controls were performed where able, which included assessing or overseeing participant com­pliance with Berocca^® intake using a sensitive paradigm to assess treatment-related effects (serial 3s and serial 7s tasks), elimination of inter-individual variance, and minimising the possibility of type 1 errors (¹⁶,¹⁷). Moreover, studies employed a sensitive paradigm to assess treatment effect on differing cognitive facets; the serials 3s task can gauge psychomotor function, attention and working memory, while the serial 7s task can assess working memory and is better able to assess attentional and executive resources than the serial 3s task (¹⁴,¹⁶). Certainly, the use of clinically objective methodologies, such as fMRI for brain mapping, also constitute a strength of some of these studies, particularly as these appear to corroborate or supplement findings achieved with the objective questionnaires and CDB described above, which indicate improvements in mental performance. The role of high-dose B-complex multivitamin/mineral supplementation in improving physical performance is a potential benefit that was not explored in the review by Maggini et al. (²). In this review, significant increases in self-reported physical vigour and stamina and protection from minor illness were revealed, which we believe may extend to potential improvements in physical performance.

Micronutrient deficiencies can be present in up to 50 % of some populations (⁴,⁶,⁷,²⁴-²⁸). Epidemiological data have shown an association between poor B-vitamin status and reduced cognitive function, which can be characterised by impaired energy metabolism in the brain, synthesis of neurotransmitters, and neuronal membrane ion pump and neuronal receptor binding (¹-⁴,⁸). Evidence also suggests that B and C vitamins, calcium, magnesium, and zinc may be particularly important in supporting cognitive function (²-⁴), and low-normal concentrations of B vitamins (folate, vitamin B12 and vitamin B6) have arisen as candidate risk factors for both Alzheimer's disease and vascular dementia in the elderly (²⁹). In addition, deficiencies in some B vitamins may have impact on physical parameters, by contributing to physical fatigue (²-⁴). Therefore, one might consider that the impact of micronutrient deficiencies can extend across different populations, and result in heterogenous, yet clinically relevant outcomes.

The influence of supplementation on the quality of life of populations has yet to be investigated. To address this, a large-scale, multi-country research was conducted to investigate how the intake of Berocca^® for 28 days impacts the daily quality of life of participants, with results showing increases in the perceived energy levels and feeling healthier as compared to before supplementation.

CONCLUSION

Given the prevalence of suboptimal micronutrient intake in people with poor diets and/or low micronutrient levels, even in other­wise healthy populations and developed geographies, there is a potential application of a multivitamin/mineral supplement that can re-esta­blish healthy micronutrient levels and provide specific neurochemical mo­dulatory assistance in some instances. To our knowledge, the cu­rrent formulation of Berocca^® is the most widely studied multivitamin/mineral to date, with the evidence demonstrating beneficial effects on cognitive performance and potential increase in physical energy levels. As detailed in this review, there is also a potential clinical application for use in the management of stress, anxiety, and mood.

ANNEX 1.