Nutrition guidelines need to be modified from time to time to remain current with research findings, but revisions are generated by sluggish processes involving scientific and governmental committees. The mismatch between the current speed of research on the health effects of various nutrients and the speed of guideline modification leaves health professionals and the public with imperfect information for making decisions about the safety of incorporating micronutrients into a treatment plan. This problem becomes more complex when one considers the 'non-healthy population,' as population guidelines were not developed to include these individuals. Nowhere is this challenge greater than with formulae containing more than one nutrient (complex nutrient formulae). Some believe that the strongest verification that micronutrient combinations are safe is the evidence from thousands of years of human food habits, as most preparations are primarily nutrients that have been in the human diet for millennia; however, their amounts and combinations differ from the way the nutrients occur in food. Consequently, safety and tolerability information on formulae that combine various micronutrients (vitamins, minerals, amino acids, essential fatty acids) could have potential value for many people who suffer from illnesses for which there are currently no (or severely limited) effective cures.
The Dietary Reference Intakes in North America (DRIs) provide guidance on the quantities of vitamins and minerals thought to be safe for long term ingestion by the healthy population, called the Tolerable Upper Intake Levels (ULs). But the DRIs pertain only to single-nutrient consumption, and their application to composite formulae can result in peculiar interpretations. For instance, the UL for folate is 1 mg/day because a higher level might mask a B12 deficiency. This effect may be a concern, but likely only to a specific group in the population at risk of B12 deficiency and only when an individual takes a single nutrient supplement. Most complex formulae with B vitamins would contain both, so the risk of masking a vitamin deficiency would be minimized. In addition, the DRIs and ULs are based on the healthy population and their application to individuals with a clinical diagnosis is not known. As there is an incomplete understanding of the nutrient needs of those not considered to be 'healthy' North Americans, by default the DRIs become the guidelines for everyone. Knowing the safety profile of a complex formula used by people with mental health diagnoses would add value beyond DRI information.
The potential unsuitability of applying the upper limits of the DRIs to multi-ingredient formulae aimed at those who might fall outside the definition of the 'healthy population' is important because the study of the health benefits of micronutrients has increased rapidly in the past decade. Various mixed or single nutrient formulae have been shown to increase resistance to communicable diseases [1
], decrease the risk of birth defects [2
], be effective in treating specific problems such as sexual dysfunction [3
], prevent hip fractures [4
], and improve immune function [5
]. A randomized controlled trial (RCT) in 445 hospitalized elderly patients revealed significantly fewer re-admissions in those who received a broad-based vitamin-mineral treatment [6
]. Recently, Shea and colleagues have been reporting positive benefits from a six-ingredient formula in patients with Alzheimer's [7
]. Positive findings such as these increase the likelihood that research and clinical use of complex micronutrient formulae will continue to expand in the coming years. Hence, information on safety and tolerability is important for public health.
To further establish the relevance of the safety of multi-ingredient formulae to psychiatry, it is useful to address the available evidence on efficacy. Several RCTs of multi-ingredient formulae have demonstrated an impact on psychiatric symptoms such as antisocial and violent behavior. Schoenthaler reported a 28% decrease in rule violations in 62 imprisoned delinquents given a daily micronutrient formulation when compared to those who received a placebo [9
]. Research on delinquent behavior in 80 schoolchildren aged 6-12 yielded similar results [10
]: those receiving a complex micronutrient formula had a 53% lower rate of antisocial behavior requiring discipline (average 1/child) than the placebo group (average 1.875/child). In an RCT often erroneously cited as an investigation of a single ingredient (essential fatty acids; EFAs), there was a 35.1% decrease in disciplinary incidents (from 16 to 10.4 per thousand person-days) for 231 young offenders receiving a formula with 25 vitamins and minerals plus some EFAs, compared with a reduction of only 6.7% in those receiving a placebo [11
]. Using a similar 26-ingredient formula in 221 young offenders, Zaalberg and colleagues partially replicated the results, finding 34% fewer reported prison 'incidents' for the group receiving the active formula, and a 14% increase in those who were taking the placebo [12
In a study of 225 hospitalized elderly patients suffering from various acute illnesses [13
], those receiving a complex micronutrient formula displayed fewer signs of depression on a 15-item geriatric depression scale than those receiving placebo, regardless of whether they had been clinically depressed. In other words, there was evidence of improved mood in everyone receiving the micronutrients, those with severe or mild depression, as well as others. A nonclinical sample of adults given a complex formula exhibited significant improvement on all psychometric measures of stress during a 30-day placebo-controlled trial [14
]. In other research, decreases in anxiety and perceived stress were found in 80 normal healthy men who consumed a complex micronutrient formula compared to a placebo control [15
Benton's extensive review article on nutrition and behavior covered both EFAs and other micronutrients [16
]. In children with ADHD, there was no clear evidence of benefit from EFAs alone. In contrast, the studies that combined EFAs with vitamins and minerals (albeit in samples of young offenders) reported beneficial effects [11
]. The reason multi-nutrient formulae demonstrate benefits may in part be due to underlying dietary inadequacy, but the results of the above studies where sometimes nutrients were given in relatively high amounts suggest that the mechanisms are more complex and likely relate to some of the underlying etiology or pathophysiology of psychiatric disorders.
With two exceptions, each of the studies mentioned above has used a unique combination of ingredients. One exception is the work of Shea and colleagues [7
] who have reported more than one study using a single formula in various geriatric samples; the other is the study by Zaalberg [12
] which used a very similar formula to the one studied by Gesch [11
]. The formulae have varied considerably across studies, consisting of anywhere from three micronutrients to over 20.
There is only one complex micronutrient formula, EMPowerplus (EMP+), which has been studied extensively in mental health, by several research teams. The purpose of this paper is to provide safety and tolerability information on EMP+. In terms of PICOS (participants, interventions, comparisons, outcomes, and study designs), the review was all-inclusive and excluded no known source of data on this formula. Based on the theoretical issues mentioned above, there is reason to predict that this formula will not result in nutrient-related complications. However, it contains 36 ingredients, in a combination that likely does not occur naturally in the habitual intake of North Americans. Prior to any conclusions on potential efficacy, empirical data on its safety is essential for evaluating its potential for harm. With respect to the DRIs, there are four ingredients that exceed the ULs (cf. Table for dose details and comparison to ULs), but none exceeds the Lowest Observed Adverse Event Level, and as explained in Table , surpassing the ULs for those four nutrients appears to be of no concern with respect to a complex formula's safety.
Comparison of EMPowerplus ingredients with Tolerable Upper Intake Levels (ULs)