11th April 2014, Volume 127 Number 1392

Julia J Rucklidge, Amy Harris, Ian C Shaw

There is a plethora of micronutrient supplements for children available over-the-counter in New Zealand (NZ). They are regulated under the NZ Dietary Supplements Regulations1 (amended 20102; under revision). Since they are not covered by medicines legislation they cannot have medicinal claims; despite this their use in the general population is substantial. Indeed, a 1997 study in the USA reported that 54% of three year olds were given a dietary supplement, and of these, 85.4% were given a micronutrient supplement.3

Similarly, in a sample of 100 New Zealand children under 12 years old, 70% were given complementary or alternative medicines (CAM), of which multivitamins were among the most common types of CAM given.4

Doses of dietary supplements are set in accordance with the recommended daily intakes for the vitamin and minerals they contain, and since experimental efficacy data are often limited to specific age groups, setting maximum daily doses for children is usually achieved by extrapolation from adult studies using recommended daily doses from North American Daily Recommended Intake (DRI) panels.5 Whether supplement doses are clinically effective or not is a subject of much debate.

Even though dietary supplements are not regulated as medicines, some commercial products infer clinical benefits by referring to published studies that report benefits. Given the current rise in studies being published looking at the effectiveness of micronutrients in the treatment of psychological/psychiatric disorders,6 it is important to determine to what extent commercial products are comparable with respect to the components that might be effective in the management of these psychological disorders, and whether the amounts of these components in the supplements’ formulations are sufficient to result in beneficial psychological effects when administered in accordance with the manufacturer’s instructions.

Perceived benefits of multi-micronutrient supplements have been reported in autism, Attention-Deficit/Hyperactivity Disorder (ADHD), mood disorders, and antisocial behaviours, with the evidence supporting their use ranging from case controlled studies, open label (OL) trials, database analyses to randomized controlled trials (RCTs).7-15 Acknowledging the relative newness of the field and therefore limited evidence base, and that the perceived benefits are not definitive in the context of properly conducted clinical trials, researchers have proposed a variety of mechanisms by which micronutrients could be beneficial in mental illness including the correction of in-born errors of metabolism,16 regulating emotions and behaviour,17 exerting an effect on the dopamine inhibitory system,18, 19 improving mitochondrial function,20 promoting healthy gastrointestinal functioning and reducing inflammation,21, 22 and acting as cofactors for various metabolic processes.23

A key challenge associated with micronutrient supplement clinical effectiveness research is the applicability of the findings to commercial products available over-the-counter. Are commercial products comparable with formulations used in research? Can the reported research benefits be extrapolated to over-the-counter products? Such a comparison is important in order for the public to be aware that perceived benefits noted in research may not apply to products purchased in the supermarket, even if those products were not necessarily developed for the treatment of psychological disorders.

The present study identifies a broad range of over-the-counter micronutrient products for children, and compares their ingredients and recommended doses with supplements used in research studies that reported benefits in psychological disorders. Such an investigation may determine whether over-the-counter supplements sold in New Zealand are likely to provide psychological benefits in children.

Methods

Inclusion of research micronutrient formulation data in the study—Only published studies investigating psychological/psychiatric variables (e.g. stress, ADHD, psychosis) in children (<18 years) were included in our study. It is appreciated that this breadth of symptoms introduces heterogeneity in samples; however, as this is the first study of its kind, restricting inclusion to only diagnosed psychiatric disorders may conceal a body of literature that could well inform the direction of the field.

The selection criteria for inclusion of research formulations required that a) the formulae must include ≥4 vitamins and/or minerals, and b) botanicals, amino acids and fatty acids were not included unless they were part of a formula including ≥4 vitamins and/or minerals and it was evident that the main ingredients were the vitamins and minerals (this excluded supplements that were predominantly composed of amino acids).

Preparations that indicated that vitamins and minerals were contained within the formulation but that did not provide information on specific ingredients along with some information on dose were excluded. As there are so few RCTs using micronutrients, we included four experimental designs: RCTs, OL trials, case-control studies, and case studies with within-subject crossovers (ABAB). Such breadth also ensures that there was not bias towards RCT data because this can be problematic24 and acknowledges that single case research designs have been accepted as establishing empirical validity of therapies.25 No restrictions were placed on studies reviewed (e.g. sample size, trial length); however, it was a requirement of inclusion that the research report provided information about treatment responses.

Only micronutrient supplements that conferred a treatment benefit were included; the rationale for only including those supplements with an observed treatment benefit was because the intent was to determine whether products sold over-the-counter, depending on how comparable they are to the research products in ingredients and doses, could equally confer a treatment effect for children with psychological disorders. Details of the full search can be found elsewhere.6

Eighteen child trials were identified that met our inclusion criteria: five for the treatment of bipolar disorder,8,12,15,26,27 three for autism,11,13,28 seven for cognitive functioning,9,29-34 one for antisocial behaviours,10 and one for ADHD.7 Three studies were excluded as no effect was reported.35-37 This search resulted in 13 different micronutrient supplements being identified (referred to as the research supplements).

Over-the-counter micronutrient products—Over-the-counter micronutrient products were purchased from New Zealand supermarkets, health food stores, pharmacies and online. A micronutrient supplement was defined as any product that was labelled as a ‘multi-nutrient, multivitamin and/or multi-mineral, or micronutrient supplement’ and included ≥4 vitamins and/or minerals. For each micronutrient supplement, both the dose and largest recommended daily dose were recorded. The amount of each nutrient at the largest daily recommended dosage for a child was calculated. When recommended doses were based on age, the dose was calculated for the age range 3– 13 years. When the recommended dose was body weight based, the weight bracket ≤45 kg was calculated. Twenty-two over-the-counter supplements were sampled (Table 1).

Table 1. Over-the-counter micronutrient supplements included in the present study (daily doses of individual vitamins were calculated from amounts taken from the product labels)

Healtheries Fizz Bomb

Healtheries Kidscare Chewables

Healtheries Tongue Fizzer

Blackmores Kid's Multivitamin

Centrum Kid’s Complete

Nature’s Own Child Care Multivitamin & Mineral

Nature’s Sunshine Heroes Multiple Vitamin & Mineral

Thompson’s Animals Junior Immunofort

Radiance Kid’s Multivitamin

Solgar Kangavite’s Complete Multivitamins & Minerals

Emergen-C Kid’s Multi-Vitamin Fizzy Drink Mix

Iceberg Labs’ KIDZ Multivitamins

Rainbow Light Essential Gummies Multivitamin & Multimineral

Essentials Children's Multi with Acidophilus

Healtheries Teen Multi

Flinstone’s Gummies Complete (Bayer)

Children's Probiotic & Multivitamins (Lloyds Pharmacy)

Kindervital Tonic (Floradix)

Every Day Please (Microgenics)

Yummi Bears Multi-Vitamin & Mineral (Hero Nutritionals)

Kordel's DHA Smart Multi

Nature's Plus Animal Parade Chewable

Establishing equivalency across ingredients and doses—The dose of each ingredient across all supplements was normalised to either mcg or mg. This normalisation was done to allow for ease of comparison across the supplements. For example, using the 30% International Unit (IU) conversion rate for vitamin A (retinol), 1 IU vitamin A was = 0.3 mcg.

Supplement ingredients were listed on the labels in a number of different ways for each vitamin or mineral. For example, Vitamin C was listed in four different forms: ascorbic acid, sodium ascorbate, calcium ascorbate and mixed mineral ascorbates.

To enable equitable comparison across the micronutrient supplements, the dose of the active compound (e.g. ascorbic acid) in each of the different forms was calculated. For example, if ascorbic acid (molar mass = 175 g/mol) was present in a particular formulation as sodium ascorbate (molar mass = 198 g/mol), the dose of ascorbic acid in the latter would be (175/198) x (sodium ascorbate dose mcg) = ascorbic acid dose mcg.

Due to the difficulty of establishing consistent values across the minerals due to the complexity of identifying the correct chemical form used in each mineral variation, only the vitamins were selected for conversion. The active compound doses were calculated for vitamins A, B1, B2, B3, B5, B6, B7, B9, B12, C, and D.

Statistical analyses—Following conversion of each of the supplement vitamins to their active compound doses, the median, maximum and minimum daily dose were calculated. In order to provide the most accurate picture of the data, the median was chosen as the measure of central tendency due to a number of top end outliers.

Because the data did not follow a normal distribution, the two groups were compared using the non-parametric, two-tailed Mann-Whitney test, to identify whether the mean daily doses of the research and over-the-counter supplements were significantly different. The effect size was calculated for each Mann-Whitney test using N (total number of supplements) and the Z score.

The standard value of r for a weak effect size is 0.1, 0.3 for a medium effect size and 0.5 for a large effect size. Outliers were removed before conducting non-parametric tests and dose distribution graphs to improve the test accuracy and reduce the errors of inference.38 For each vitamin, no more than one outlier was removed from each of the supplement categories. Six outliers were removed from the research supplements and five were removed from the over-the-counter supplements.

Results

Ingredients and doses—Table 2 shows the frequency with which each vitamin appeared in the research and over-the-counter supplements. The ingredients in the research and over-the-counter supplements did not differ greatly. For example, vitamin B1 (thiamine) appeared in 78% of the effective research supplements, and 86% of the over-the-counter supplements. Vitamin B6 (pyridoxine) was an ingredient in all of the supplements.

Table 3 shows the median doses and dose ranges for the vitamins.

Table 2. Percentages of over-the-counter micronutrient supplements and research supplement formulations containing specific vitamins

Vitamin

% of research supplements containing specific vitamin

% of over-the-counter supplements containing specific vitamin

Vitamin A

78%

95%

Vitamin B1 (Thiamine)

78%

86%

Vitamin B2 (Riboflavin)

78%

82%

Vitamin B3 (Niacin)

85%

91%

Vitamin B5 (Pantothenic Acid)

78%

95%

Vitamin B6 (Pyridoxine)

100%

100%

Vitamin B7 (Biotin)

46%

77%

Vitamin B9 (Folic Acid)

78%

86%

Vitamin B12 (Cyanocobalamin)

92%

100%

Vitamin C

78%

100%

Vitamin D

78%

91%

Vitamin E

78%

95%

Vitamin K

23%

14%

Choline

54%

41%

Inositol

54%

36%

Table 3. Median daily doses and dose ranges for vitamins in research supplement formulations and over-the-counter micronutrient products calculated from label and published formulations, showing that the doses of the research supplements tended to be higher than the doses of the over-the-counter supplements

Vitamin

Research supplements

Over-the-counter supplements

Daily dose

median±SD

Dose range

Daily dose

median±SD

Dose range

B1

14.59±11.52 mg

0.7–243.18 mg

1.22±0.89 mg

0.6–40.84 mg

B2

13.5±12.84 mg

0.85-200 mg

1.7±2.11 mg

0.55–10 mg

B3

63.75±36.87 mg

10–750 mg

13.5±5.43 mg

2.5–20 mg

B5

22.08±54.76 mg

0.92–450.8 mg

7.5±2.56 mg

1.5–10 mg

B6

23.04±18.87 mg

0.9–287.95 mg

1.78±1.61 mg

0.7–8.23 mg

B7

400±429.31 mcg

10–150 mcg

50±90.65 mcg

10–1000 mcg

B9

560±703.48 mcg

35–2048.5 mcg

100±132.52 mcg

5–400 mcg

B12

900±490.71 mcg

1–500 mcg

5±2.04 mcg

0.64–750 mcg

A

1500±1416.36 mcg

300–4512.8 mcg

900±861.27 mcg

15–3000 mcg

C

600±386.8 mg

26.6–1500 mg

60±25.73 mg

20–500 mg

D

10±13.59 mcg

2.5–40 mcg

7.5±3.5 mcg

2.5–360 mcg

 

Comparison of research supplements with over-the-counter supplements—The non-parametric comparison of the research and over-the-counter doses are presented in Table 4.

Table 4. Nonparametric tests of group differences in daily dose between research formulations and over-the-counter products (note that not all supplements were included in each analysis if the particular nutrient was not contained in its formulation); effect sizes are provided to highlight the magnitude of the group difference

Vitamin

U

(Mann-Whitney)

Z

p

(2-tailed)

r*

(effect size)

B1

36.5

-2.96

0.003

.55

B2

62.5

-2.42

0.16

.43

B3

41.5

3.16

0.002

.56

B5

21

-3.95

0.001

.69

B6

79

-2.88

0.004

.47

B7

26

-3.08

0.002

.59

B9

44.5

-3.25

0.001

.57

B12

75

-2.68

0.007

.45

A

120

-1.06

0.289

.18

C

56.5

-3.06

0.002

.52

D

74.5

-2.19

0.029

.38

 

*Pearson’s r: weak effect size = 0.1, medium effect size = 0.3, large effect size = 0.5.

The research supplement vitamin doses were larger than the corresponding over-the-counter supplement doses. For example, the median vitamin B1 daily dose for research and over-the-counter supplements was 14.59 mg and 1.22 mg respectively, U(29) = 36.5, p<0.01, r=0.55.

All of the doses, with the exception of vitamins A and B2, were significantly higher in the research supplements when compared with the over-the-counter supplements.

Figure 1 shows the dose distribution across the vitamins with research doses on the left side of the graph and over-the-counter doses on the right, ordered in increasing magnitude of dose. It does not show an exhaustive list of the ingredients of all the products.

Figure 1. Individual daily doses of the vitamins for research formulations and over-the-counter products showing the consistent and significantly higher doses in the research formulations compared to over-the-counter-products

Rucklidge-1

Rucklidge-2

Rucklidge-3

 

Discussion

The empirical composition of research and over-the-counter supplements did not differ greatly. However, the doses of the vitamins were significantly greater in the research supplements compared with the over-the-counter supplements for all the vitamins studied except vitamins A and B2.

The most important ramification of these differences may be the inability to extrapolate micronutrient research findings to over-the-counter supplements. Therefore, research indicating a positive effect of supplements on, for example, ADHD, may not apply to patients treated or self-medicating with over-the-counter supplements. Similarly, claims or inferences on over-the-counter supplements’ labels relating to their benefits based on research studies published to date might be misleading unless specific studies are conducted on that specific product providing the evidence of efficacy.

Vitamin B6 was included in all the supplements studied, indicating that it might have an important role in the combination of nutrients used in micronutrient supplements. Vitamin B6 is involved in the synthesis of a number of neurotransmitters including serotonin, dopamine, acetylcholine, norepinephrine and GABA;39 these are all neurotransmitters known to affect depression, mood, sleep, attention, appetite, and anxiety. Although vitamin B6 was included in all of the supplements studied, the median dose of this vitamin was significantly higher in the research compared to the over-the-counter supplements.

The median over-the-counter supplement daily dose of vitamin B6 was close to the recommended daily intake (RDI) of 1 mg for New Zealand children aged between 9 and 13;5 the median daily dose in research supplements was much higher (approx. 23 mg). The higher research supplement dose may indicate that vitamin B6 levels significantly above the RDI are necessary to effectively impact on psychological symptoms and cognitive functioning.

Vitamin B12 was also included in the formulations of all over-the-counter supplements studied, and almost all of the research supplements, indicating that vitamin B12 might also play an important role in the combination of ingredients used in micronutrient supplements. The psychological effects of vitamin B12 deficiency include adverse effects on cognition from adolescence years onwards,40 indicating that vitamin B12 might have a role in improved cognition.

The RDI for New Zealand children aged between 9 and 13 is 1.8 mcg,5 which is lower than the 5 mcg over-the-counter supplement daily dose median and significantly lower than the research median dose of 900 mcg. This large difference indicates that achieving a significant change in psychological symptoms might require vitamin B12 doses significantly greater than the RDI for New Zealand children.

The greatest differences in doses between research and over-the-counter supplements were for vitamins B5 and B9. The significantly higher doses of vitamin B5 and B9 in research supplements are unsurprising given their roles in modulating mental health.41 As a component of coenzyme A (CoA), vitamin B5 plays an important role in the synthesis of vitamins A and D as well as supporting adrenal function and cortisol production.41 Acetyl CoA is the acetyl group donor in acetylcholine synthesis and the latter is a neurotransmitter with important roles in memory, attention and cognitive functions.5

The median dose of vitamin B5 in research supplements (22 mg) is approximately four-times the RDI of 5 mg for boys and 4 mg for girls, whereas the vitamin B5 dose in over-the-counter supplements was much closer to the RDI, with a median daily dose of 7.5 mg. The median daily dose of vitamin B9 in research supplements of 560 mcg is 260 mcg above the RDI5 for children aged between 9 and 13. Although much higher than the 100 mcg over-the-counter supplement median, the research daily dose is still well below the human Lowest Observed Adverse Effect Level (LOAEL) of 5 mg/day.5

These findings indicate that over-the-counter micronutrient supplements available in supermarkets, health food stores and pharmacies are unlikely to be as effective, if effective at all, compared with the supplements formulated specially for research when targeting behavioural changes. Despite this, some micronutrient products available in New Zealand advertise that their ingredients have psychological benefits (such as improved concentration).

Although the information of the nutrient effect that they present is correct, the inferred claim may be misleading because of the differences between the research and over-the-counter doses and the fact that the claims are likely to be based on research dose studies. Based on research supplement composition, we suggest that the psychological benefits that might result from micronutrient administration would only be obtained from doses much higher than those found in over-the-counter micronutrient supplements. It is the doses of the micronutrients, not simply their presence, that is important in predicting their biological effects.

It is likely that the over-the-counter products have lower doses of some nutrients because of statutory limits set in the Dietary Supplements Amendment Regulations 2010.2 For example, the Act specifies that a daily dose of vitamin B9 (folic acid) in a supplement manufactured in New Zealand must not exceed 500 mcg even though the Tolerable Upper Intake Level (UL) is 1000 mcg. However, since the UL was set at 1000 mcg to prevent vitamin B12 deficiency, if vitamin B12 is consumed alongside vitamin B9, that statutory limit could be much higher without adverse effects.

The statutory limit is currently being reviewed in light of proposals for fortification of bread with folic acid and the development of the Natural Health Products Bill 2011, where the upper limit may increase to 1000 mcg or may even possibly be removed. However, in the meantime, the current commercial products reflect these statutory limits (median 100 mcg) whereas research products often exceed the statutory limit for folic acid (560 mcg).

Likewise, the statutory daily dose limit for vitamin B12 is 50 mcg despite the fact that there is no evidence of harm associated with higher doses.5 Again the research supplements exceeded this dose (median 900 mcg) whereas the over-the-counter products were substantially lower (median 5 mcg) and within the statutory limit. Again, these values are being reviewed as part of the Natural Health Products Bill; however, the regulations may indeed have prevented manufacturers from providing the necessary dose to confer health benefits. This thinking is speculative due to the great number of ingredients contained within the products and the potentially complex biological interactions between them in the context of health benefits; however, it is possible that the government legislation of commercial products results in products that cannot reflect research and knowledge on biological effects, safety and ULs.

This research calls into question the usefulness of RDIs and Recommended Dietary Allowances (RDAs). Indeed, Fletcher et al42 showed that the North American diet, as reflected by food intake, while sufficient to prevent vitamin deficiency diseases, is inadequate to support optimal health.

The United States (US) RDA guideline levels in 2002 were similar overall to those set by the National Health and Medical Research Council (NHMRC)5 guidelines, with the RDA of some vitamins in the New Zealand guidelines set marginally higher, and others marginally lower. The US RDA levels were established to prevent acute vitamin deficiency disorders; however, this current study suggests that higher doses of some vitamins and minerals may be necessary to achieve optimal mental health for some people. The assessment made by Fletcher et al42 that RDA values are set too low, is supported by the higher median vitamin daily doses (with the exception of vitamins B3 and B9 in the over-the-counter supplements) found in both the research and over-the-counter supplements. This difference was most evident in the median research vitamin B12 dose which was 500 times greater than the NHMRC RDA5 guidelines.

This high B12 vitamin intake is unlikely to produce adverse effects, possibly because of the body’s ability to decrease absorption in response to high vitamin intakes.5 The over-the-counter median daily dose of vitamin B12 was also greater than the RDA (i.e. 2.8 times greater than the recommended daily dose).

It is possible that the doses in over-the-counter supplements are significantly lower than the doses in research supplements because of the high cost of micronutrients. There were 13 effective research supplements and the prices were available for two of these. Using these supplements as a cost guide, the average cost of a research supplement when used in a treatment setting would be NZ$6.90/day.

The average price of the 22 commercial products studied was NZ$0.64/day. This large difference in the daily cost of providing a child with a micronutrient supplement is likely to explain the low doses found in commercial products; it is unlikely consumers would be willing to pay for higher doses. This might, however, change if consumers were aware that the supplements they are buying are unlikely to have biological effects with respect to mental health symptoms.

Limitations—First, the frequency of nutrient inclusion comparison did not account for the different forms of each nutrient in micronutrient formulations. Indeed, vitamins and minerals were found in a number of different chemical forms across the spectrum of supplements.

In-depth analysis of the forms of each mineral and vitamin may provide further information to guide a decision as to whether or not these ingredients are comparable. This in-depth analysis is important because the form of a nutrient indicates the amount of specific mineral or vitamin contained. For example, retinyl palmitate which is a form of vitamin A, contains 54.7% vitamin A compared to retinol acetate, which contains 87%.5

Also, the chemical form of the micronutrient is very likely to affect the absorption efficiency and thus bioavailability of the compound. For example, the palmitoyl ester of vitamin A is more hydrophobic than vitamin A itself and is therefore likely to be better absorbed from the gastrointestinal tract. Clearly these differences are important in the context of biological activity of micronutrients and should be further studied in order to understand fully their implications.

Finally, the range of study methodologies included to determine effectiveness of the ingredients and doses of the research supplements was broad given the dearth of RCTs that have been conducted. Given that this is the first comparison of its kind, we felt comfortable including a broad range of methodologies to identify potential effective nutrient levels and as the field becomes more rigorous, we should gain a greater understanding of optimal doses required in order to effect change in psychological symptoms.

Conclusions—There is significant debate about the usefulness and efficacy of micronutrient-based dietary supplements in the management of psychological disorders. The preliminary evidence that supports their use is mostly based on studies using formulations that contain significantly higher micronutrient doses than over-the-counter products.

Therefore, even if published efficacy data support the use of micronutrients in psychological disorders, it is not clear whether over-the-counter products will have benefits because of their significantly lower micronutrient doses. 

Abstract

Aim

To investigate whether micronutrient supplements shown through research to have perceived benefits in the treatment of psychological/psychiatric symptoms in children have similar vitamin ingredients and doses to over-the-counter dietary supplements.

Method

We conducted a systematic review to identify studies that used micronutrients for the treatment of psychological/psychiatric symptoms in children with documented benefits; 13 different supplements were identified that included vitamin ingredients. They were compared with the vitamin composition of 22 over-the-counter child-targeted supplements available in New Zealand.

Results

The vitamin ingredients were comparable across the research and commercially available supplements. However, the median vitamin daily doses in research supplements were found to be greater than those of over-the-counter supplements, with most mean differences being significant, including vitamins B1, B3, B6, B7, B12, C and D (p<0.05), B5 and B9 (p<0.001), but not vitamins A or B2.

Conclusion

Micronutrient supplements found to show potential benefit in research with a focus on improving psychological/psychiatric symptoms in children have a significantly greater vitamin dose than over-the-counter supplements. Therefore, the results found in micronutrient research studies cannot be extrapolated to over-the-counter supplements. Comparing the myriad ingredients and dosages in micronutrient supplements is, however, a complex process and further investigation is required to understand fully the importance of our findings.

Author Information

Julia Rucklidge, Professor of Clinical Psychology, Department of Psychology; Amy Harris, (former) Master’s Student, Department of Psychology, University of Canterbury; Ian C Shaw, Professor of Toxicology and Director of Biochemistry, University of Canterbury, Christchurch

Correspondence

Professor Julia Rucklidge, Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand.

Correspondence Email

julia.rucklidge@canterbury.ac.nz

Competing Interests

Nil

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