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Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youths: A Placebo-Controlled Randomized Clinical Trial.
Johnstone, JM, Hatsu, I, Tost, G, Srikanth, P, Eiterman, LP, Bruton, AM, Ast, HK, Robinette, LM, Stern, MM, Millington, EG, et al
Journal of the American Academy of Child and Adolescent Psychiatry. 2022;61(5):647-661
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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that affects about 5-7% of children. Characteristics of ADHD are age-inappropriate hyperactivity, impulsivity, and difficulties in focusing attention which arise from an impaired ability to regulate executive and emotional functions. The condition often persists into adulthood, where it presents an increased risk for poor educational achievements, substance abuse, incarceration, and mental health problems. In many cases, drug treatment can improve ADHD symptoms, yet concern remains about the side effects of these treatments. Some research has investigated the impact of nutrient supplementation on ADHD management, as many nutrients are essential for healthy brain function and are also involved in the production of neurotransmitters. In previous studies, supplementation with nutrients has shown some benefits but likewise also inconsistent results. This eight-week randomised placebo-controlled clinical trial evaluated the effects of a multi-nutrient supplement in 135 children with ADHD, aged 6-12 years. The study specifically focused on irritable mood symptoms. The multi-nutrient formula contained vitamins, minerals, amino acids, and antioxidants. Outcomes were measured by scores rated by clinicians (Clinical Global Impression-Improvement aka CGI-I) and scores rated by parents (Child and Adolescent Symptom Inventory-5 aka CASI-5). The multi-nutrient formula showed overall benefit in the blinded clinician rating but not by parental reports. According to the parents, overall improvement was reported, both in the placebo and intervention groups. The authors discussed how this absence of difference can be explained. Yet, on a subscale, the multi-nutrient group parents were more likely to report improvements. In addition, children with the additional micronutrients demonstrated greater height growth during the intervention. The supplement was well tolerated with good adherence and the monitored blood markers demonstrated safety of use.
Expert Review
Conflicts of interest:
None
Take Home Message:
This fully-blinded RCT of micronutrients addresses several concerns related to existing ADHD treatment, including the possibility of counteracting height suppression and treating associated irritable mood, emotional dysregulation, and aggression.
Although further research is needed, multinutrient supplementation should be considered for children with ADHD.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric condition that can result in low educational performance and achievement. Around 5-7% of children are believed to be affected. Alongside inattention and hyperactivity, emotional dysregulation is a common feature of ADHD. Psychiatric problems can continue into adulthood and an increased risk of incarceration and substance abuse have been reported.
Treatment with prescription medications may improve symptoms of ADHD, however, potential side effects include mild growth suppression, and mood and emotional dysregulation. Non-pharmacological treatments are therefore being investigated.
Previous research on single nutrients have shown mixed results for emotional dysregulation and mood issues in ADHD. The aim of this study was to test whether supplementation with a multi-nutrient could be beneficial to children aged 6-12 years with ADHD and irritability.
Methods
126 unmedicated children from North America with ADHD (mean age 9.8 years) completed this 8-week study. All participants had at least 1 symptom of anger, irritability, peer conflict or Disruptive Mood Dysregulation Disorder (DMDD).
Randomisation was into an intervention (n=71) or placebo (N=55) group with a 3:2 ratio to promote enrolment. Participants were required to take 6-12 capsules daily, depending on age and tolerance, of micronutrients or a placebo. Micronutrient dosages were above the recommended dietary allowance (RDA). Outcomes were measured using clinician and parent rated assessments and by a further adult who knew the child well.
The trial was blinded to all participants, parents and study staff.
Results
The clinician-rated results found 54% of the micronutrient group and 18% of the placebo group had improvements in irritability symptoms (Risk ratio =2.97, 97.5% CI: 1.5, 5.90, p<0.001). This was not replicated in the parent/adult rated results. Children in the micronutrient group grew on average 6mm more than the placebo group (p=0.002). No serious adverse treatment effects were reported. Adherence to protocol was met by >74% of participants (n=93).
Conclusions
In this study, clinicians reported that micronutrients showed greater benefits than placebo for treating irritability and supporting growth in children with ADHD.
The study and authors received funding from several research and association bodies. However, no funder was involved in the study design or reporting. No conflicts of interest were declared.
Clinical practice applications:
- Multinutrient supplementation including vitamins, minerals, amino acids, and antioxidants may support height growth in children who take pharmacologic treatment
- Multi nutrient supplementation may also help with irritable mood, emotional dysregulation, and aggression in ADHD children
- Micronutrients given at doses between the Recommended Dietary Allowance and Upper Tolerable Intake Level appear safe and may be developed into an alternative or complementary treatment for ADHD.
Considerations for future research:
- Further large scale research is needed into the potential benefits of micronutrients for children with ADHD and irritability
Abstract
OBJECTIVE To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample. METHOD A 3-site, 8-week, placebo-controlled, randomized clinical trial of micronutrients was conducted in nonmedicated children aged 6 to 12 years with ADHD and at least 1 impairing irritability symptom by parent report on the Child and Adolescent Symptom Inventory-5 (CASI-5). A priori-defined primary outcomes were Clinical Global Impression-Improvement (CGI-I) (CGI-I of 1 or 2 = treatment responder) and parent-rated CASI-5 composite score of ADHD, oppositional defiant, disruptive mood dysregulation, and peer conflict symptoms, including impairment scores. RESULTS Of 135 randomized (mean age 9.8 years), 126 youths (93%) comprised the modified intention-to-treat population. Blinding was maintained. For the CGI-I, 54% of the micronutrient and 18% of the placebo group were responders (risk ratio = 2.97, 97.5% CI = 1.50, 5.90, p < .001). CASI-5 composite scores improved significantly for both groups (p < .01), with a mean change of -0.31 (95% CI = -0.39, -0.23) in the micronutrient group and a mean change of -0.28 (95% CI = -0.38, -0.19) in the placebo group. However, the between-group difference was not significant (mean change = -0.02; 97.5% CI = -0.16, 0.12, effect size = 0.07, p = .70). The micronutrient group grew 6 mm more than the placebo group (p = .002). No serious adverse events or clinically significant changes from baseline in blood and urine tests occurred. CONCLUSION Micronutrients showed global benefit over placebo by blinded clinician rating, but not by parent-report CASI-5 composite rating in a population with ADHD and irritability. Micronutrients showed greater height growth. Micronutrients were well tolerated, and the majority of participants adhered to the number of capsules prescribed. This randomized controlled trial replicates safety and efficacy reported for ADHD in 2 smaller trials of a similar formula containing all vitamins and known essential minerals in amounts between the Recommended Dietary Allowance and Upper Tolerable Intake Level. CLINICAL TRIAL REGISTRATION INFORMATION Micronutrients for ADHD in Youth (MADDY) Study; https://clinicaltrials.gov; NCT03252522.
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Metabolic Syndrome Features: Is There a Modulation Role by Mineral Water Consumption? A Review.
Costa-Vieira, D, Monteiro, R, Martins, MJ
Nutrients. 2019;11(5)
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Metabolic syndrome, defined as having high blood pressure, triglycerides, blood glucose and being obese, is becoming an increasing worldwide health problem. It’s considered to be a result of modern-day life styles and there is no effective cure other than diet and life style interventions. This review paper looks at the mineral content and the alkalising effects of mineral water when consumed by participants with metabolic syndrome. The minerals within mineral water are thought to be more readily absorbed in the body than when consumed in foods and since Westernised diets are low in mineral content and high in acidity, consuming mineral water could help counteract mineral deficiencies and help to balance pH in those with metabolic syndrome. 20 studies, both animal and human, were selected for evaluation of the effect of mineral water on blood pressure, lipid profile, blood glucose and waist circumference. The authors conclude that mineral water is indeed beneficial to those with metabolic syndrome and can help counteract mineral deficiencies and balance pH. However, it is unclear whether mineral water in high quantities would be detrimental to a person with adequate mineral status and a pH within optimal range. Further studies are needed.
Abstract
Metabolic syndrome (MetSyn) promotes, among others, the development of atherosclerotic cardiovascular disease and diabetes. Its prevalence increases with age, highlighting the relevance of promoting precocious MetSyn primary prevention and treatment with easy-to-implement lifestyle interventions. MetSyn features modulation through mineral water consumption was reviewed on Pubmed, Scopus and Google Scholar databases, using the following keywords: metabolic syndrome, hypertension, blood pressure (BP), cholesterol, triglycerides, apolipoprotein, chylomicron, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein (HDL), glucose, insulin, body weight, body mass index, waist circumference (WC), obesity and mineral(-rich) water. Twenty studies were selected: 12 evaluated BP, 13 assessed total-triglycerides and/or HDL-cholesterol, 10 analysed glucose and/or 3 measured WC. Mineral waters were tested in diverse protocols regarding type and composition of water, amount consumed, diet and type and duration of the study. Human and animal studies were performed in populations with different sizes and characteristics. Distinct sets of five studies showed beneficial effects upon BP, total-triglycerides, HDL-cholesterol and glucose. WC modulation was not reported. Minerals/elements and active ions/molecules present in mineral waters (and their pH) are crucial to counterbalance their inadequate intake and body status as well as metabolic dysfunction and increased diet-induced acid-load observed in MetSyn. Study characteristics and molecular/physiologic mechanisms that could explain the different effects observed are discussed. Further studies are warranted for determining the mechanisms involved in the putative protective action of mineral water consumption against MetSyn features.
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Dietary Inflammatory Index, Dietary Non-Enzymatic Antioxidant Capacity, and Colorectal and Breast Cancer Risk (MCC-Spain Study).
Obón-Santacana, M, Romaguera, D, Gracia-Lavedan, E, Molinuevo, A, Molina-Montes, E, Shivappa, N, Hebert, JR, Tardón, A, Castaño-Vinyals, G, Moratalla, F, et al
Nutrients. 2019;11(6)
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This study aims to correlate the risk factors of inflammation and antioxidant capacity in cases of colon and breast cancer, using data from a large Spanish case-controlled study (1852 colon cancer subjects, 1567 breast cancer subjects and a total 4933 controls). The role of diet in colon cancer is widely accepted, however it is more controversial with breast cancer where genetic mutations and other lifestyle factors are cited as primary risk factors. What unites these cancers is the inter-related presence of both inflammation and oxidative stress. The dietary inflammatory index (DII®) and non-enzymatic antioxidant capacity (NEAC) were used to evaluate inflammation and oxidative stress using 30 nutrient parameters and 6 inflammatory blood markers. The results showed that colon cancer subjects typically ate a more pro-inflammatory diet compared to controls, with a higher odds ratio of men to women, and tended to be older, heavier and less physically active. The breast cancer subjects also had higher inflammatory scores versus controls but demographically were younger, premenopausal, frequently with a first-degree family link to breast cancer, and including a higher percentage of smokers. For both cancers, inflammation significantly and statistically increased risk factors. Adding in oxidative stress results showed a statistically higher risk of developing colon cancer whilst in breast cancer subjects the risk was increased but non-statistically valid. They did report that meat-eaters had a relative 9% increased risk of Breast cancer. Overall the study concluded that dietary components of inflammation and oxidative stress increased risk of colon cancer but were not statistically valid for breast cancer.
Abstract
Inflammation and antioxidant capacity have been associated with colorectal and breast cancer. We computed the dietary inflammatory index (DII®), and the total dietary non-enzymatic antioxidant capacity (NEAC) and associated them with colorectal and breast cancer risk in the population-based multi case-control study in Spain (MCC-Spain). We included 1852 colorectal cancer and 1567 breast cancer cases, and 3447 and 1486 population controls, respectively. DII score and NEAC were derived using data from a semi-quantitative validated food frequency questionnaire. Unconditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) for energy-adjusted DII (E-DII), and a score combining E-DII and NEAC. E-DII was associated with colorectal cancer risk (OR = 1.93, highest quartile versus lowest, 95%CI:1.60-2.32; p-trend: <0.001); this increase was observed for both colon and rectal cancer. Less pronounced increased risks were observed for breast cancer (OR = 1.22, highest quartile versus lowest, 95%CI:0.99-1.52, p-trend: >0.10). The combined score of high E-DII scores and low antioxidant values were associated with colorectal cancer risk (OR = 1.48, highest quartile versus lowest, 95%CI: 1.26-1.74; p-trend: <0.001), but not breast cancer. This study provides evidence that a pro-inflammatory diet is associated with increased colorectal cancer risk while findings for breast cancer were less consistent.
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Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder-A Randomized, Controlled 12-Month Trial.
Adams, JB, Audhya, T, Geis, E, Gehn, E, Fimbres, V, Pollard, EL, Mitchell, J, Ingram, J, Hellmers, R, Laake, D, et al
Nutrients. 2018;10(3)
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People with autism spectrum disorder (ASD) often have significant nutritional deficiencies, metabolic imbalances, and digestive problems. Many studies have previously looked at individual nutrients for ASD. This study was designed to look at the accumulative effect of using a wide range of dietary and nutritional interventions, including vitamin and mineral supplements, essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a gluten-free, casein-free, soy-free (HGCSF) diet. The objective being to see if combining multiple interventions for a 12-month period, had greater benefits versus single nutrient interventions, and shorter trials. This US study recruited a wide age range of participants from 3-58yrs because it targeted, and was funded, by family groups of the Autism Society of Greater Phoenix. The study was deliberately single-blinded (meaning the participants knew what they were being given, but the clinical evaluators did not), as it was thought this would be more compelling and lead to less dropouts, especially considering the 12-month timing. In total 67 participants with ASD were recruited and 50 controls. Blood and urine samples were taking at the beginning and end of the study alongside autism severity assessments. Results showed an improvement in nutrient profiles for vitamins, minerals, fatty acids and carnitine alongside a significant decrease in homocysteine. There was an improvement in non-verbal IG test and cognitive function, and gastro-intestinal symptoms. There were no significant differences in complete blood count, blood chemistry panels or markers for inflammatory C-reactive protein (CRP). There was no change to BMI. Three exceptional cases of improvement were recorded in the control group and made into case studies highlighting improved physical strength and ability to walk, and resolution of urinary issues and pica eating disorder. Because it was single blinded there may be some ‘placebo effect’ but overall the researchers conclude that the study demonstrates how interventions can be safely and effectively implemented in families, with minimal adverse effect. And that combined nutrient and diet interventions should be considered for use in clinical practice.
Abstract
This study involved a randomized, controlled, single-blind 12-month treatment study of a comprehensive nutritional and dietary intervention. Participants were 67 children and adults with autism spectrum disorder (ASD) ages 3-58 years from Arizona and 50 non-sibling neurotypical controls of similar age and gender. Treatment began with a special vitamin/mineral supplement, and additional treatments were added sequentially, including essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a healthy gluten-free, casein-free, soy-free (HGCSF) diet. There was a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group (+6.7 ± 11 IQ points vs. -0.6 ± 11 IQ points, p = 0.009) based on a blinded clinical assessment. Based on semi-blinded assessment, the treatment group, compared to the non-treatment group, had significantly greater improvement in autism symptoms and developmental age. The treatment group had significantly greater increases in EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10. The positive results of this study suggest that a comprehensive nutritional and dietary intervention is effective at improving nutritional status, non-verbal IQ, autism symptoms, and other symptoms in most individuals with ASD. Parents reported that the vitamin/mineral supplements, essential fatty acids, and HGCSF diet were the most beneficial.
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The relationship between nut intake and risk of colorectal cancer: a case control study.
Lee, J, Shin, A, Oh, JH, Kim, J
Nutrition journal. 2018;17(1):37
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Nut consumption has been shown to be associated with reduced risk of obesity, Type 2 diabetes and cardiovascular disease. This retrospective, case-controlled study aimed to examine the association between nut consumption and the risk of colo-rectal cancer in a cohort of Korean adults. 923 colorectal cancer patients and 1846 controls were included in the study. Each completed a validated food frequency questionnaire, including peanuts, pine nuts and almonds. A nut serving was considered to be 15g and was categorised as none, less than 1 serving per week, 1-3 servings per week and greater than 3 servings per week. Nut consumption was found to have a strong association with reduced colo-rectal cancer in both men and women, after adjusting for age, education level, alcohol consumption, BMI, regular exercise, red meat intake, fruit and vegetable intake and total energy intake. This association was found in all sub-sites of the colon for men and for the distal and rectum subsites for women.
Abstract
BACKGROUND Nut consumption is known to reduce the risk of obesity, diabetes mellitus, and cardiovascular disease. However, in previous studies, portion sizes and categories of nut consumption have varied, and few studies have assessed the association between colorectal cancer risk and nut consumption. In this study, we investigated the relationship between nut consumption and colorectal cancer risk. METHODS A case-control study was conducted among 923 colorectal cancer patients and 1846 controls recruited from the National Cancer Center in Korea. Information on dietary intake was collected using a semi-quantitative food frequency questionnaire with 106 items, including peanuts, pine nuts, and almonds (as 1 food item). Nut consumption was categorized as none, < 1 serving per week, 1-3 servings per week, and ≥3 servings per week. A binary logistic regression model was used to estimate odds ratios (OR) and their 95% confidence intervals (CI) for the association between nut consumption and colorectal cancer risk, and a polytomous logistic regression model was used for sub-site analyses. RESULTS High nut consumption was strongly associated with reduced risk of colorectal cancer among women (adjusted ORs: 0.30, 95%CI: 0.15-0.60 for the ≥3 servings per week group vs. none). A similar inverse association was observed for men (adjusted ORs: 0.28, 95% CI: 0.17-0.47). In sub-site analyses, adjusted ORs (95% CIs) comparing the ≥3 servings per week group vs none were 0.25 (0.09-0.70) for proximal colon cancer, 0.39 (0.19-0.80) for distal colon cancer, and 0.23 (0.12-0.46) for rectal cancer among men. An inverse association was also found among women for distal colon cancer (OR: 0.13, 95% CI: 0.04-0.48) and rectal cancer (OR: 0.40, 95% CI: 0.17-0.95). CONCLUSIONS We found a statistically significant association between high frequency of nut consumption and reduced risk of colorectal cancer. This association was observed for all sub-sites of the colon and rectum among both men and women, with the exception of proximal colon cancer for women.
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Dietary inflammatory index and risk of pancreatic cancer in an Italian case-control study.
Shivappa, N, Bosetti, C, Zucchetto, A, Serraino, D, La Vecchia, C, Hébert, JR
The British journal of nutrition. 2015;113(2):292-8
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Pancreatic cancer has the highest mortality rate amongst gastro-intestinal cancers and evidence suggests that diet plays a pivotal role in the aetiology of the disease. Chronic inflammation is often present with cancers however it is not known if inflammation has a causal role or is simply part of the body’s natural response mechanism. This 2015 case control study evaluated food frequency questionnaire (FFQ) data from 326 incident cases and 652 controls and indexed foods based on their inflammatory status using a global database derived from previous studies: the dietary inflammatory index (DII). The DII ranks foods against forty-five nutrient parameters to generate an overall score. The higher DII scores reflect a greater pro-inflammatory potential of the diet. Food parameters measured included: carbohydrate; protein; fat; alcohol; fibre; cholesterol; SFA; MUFA; PUFA; n -3; n -6; niacin; thiamin; riboflavin; vitamin B6; Fe; Zn; vitamin A; vitamin C; vitamin D; vitamin E; folic acid; β-carotene; anthocyanidins; flavan-3-ol; flavonol; flavonones; flavones; isoflavones; caffeine and tea. The DII is designed to consider all pro-inflammatory foods (such as red meat) and all anti-inflammatory foods (such as fruits and vegetables) to represent the potential inflammatory effect of diet as a whole. After adjustments for sex, age and other lifestyle factors the results showed that subjects with higher DII scores (i.e. representing a more pro-inflammatory diet) had a higher risk of developing pancreatic cancer.
Abstract
Previous studies have shown that various dietary components may be implicated in the aetiology of pancreatic cancer. However, the possible relationship between diet-related inflammation and the risk of pancreatic cancer has not yet been investigated. We examined the ability of a newly developed literature-derived dietary inflammatory index (DII) to predict the risk of pancreatic cancer in a case-control study conducted in Italy between 1991 and 2008. This included 326 incident cases and 652 controls admitted to the major teaching and general hospitals for non-neoplastic diseases, frequency-matched to cases by study centre, sex and age. The DII was computed based on dietary intake assessed using a validated and reproducible seventy-eight-item FFQ. Logistic regression models were used to estimate multivariable OR adjusted for age, sex, study centre, education, BMI, smoking status, alcohol drinking and history of diabetes. Energy adjustment was performed using the residual method. Subjects with higher DII scores (i.e., representing a more pro-inflammatory diet) had a higher risk of pancreatic cancer, with the DII being used as both a continuous variable (ORcontinuous 1.24, 95% CI 1.11, 1.38) and a categorical variable (i.e., compared with the subjects in the lowest quintile of the DII, those in the second, third, fourth and fifth quintiles had, respectively, OR(quintile2 v. 1) 1.70, 95% CI 1.02, 2.80; OR(quintile3 v. 1) 1.91, 95% CI 1.16, 3.16; OR(quintile4 v. 1) 1.98, 95% CI 1.20, 3.27; OR(quintile5 v. 1) 2.48, 95% CI 1.50, 4.10; P trend= 0.0015). These data suggest that a pro-inflammatory diet increases the risk of pancreatic cancer.