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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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Effect of Montmorency tart cherry juice on cognitive performance in older adults: a randomized controlled trial.
Chai, SC, Jerusik, J, Davis, K, Wright, RS, Zhang, Z
Food & function. 2019;10(7):4423-4431
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A previous study demonstrated that tart cherry juice can lower blood pressure and improve inflammation and oxidative stress, which are risk factors for dementia, in older adults. This study, by the same authors, explored whether tart cherry juice could improve memory and cognitive function. In this randomised controlled trial, 37 adults between the ages of 65-80 with normal cognitive function were given two cups of either Montmorency tart cherry juice or a control drink every day for 12 weeks. At the end of the study, those that consumed the tart cherry juice showed significant improvements in several of the measures of memory and cognitive function, including contentment with memory function and spatial working memory, compared to the control group. The authors concluded that daily tart cherry juice consumption may improve cognitive abilities, possibly through the antioxidant and anti-inflammatory properties of tart cherry and its ability to lower BP.
Abstract
Hypertension, inflammation and oxidative stress are important factors in the development of cognitive impairment. Our previous study demonstrated that tart cherry juice can lower systolic blood pressure (BP) and improve inflammatory and oxidative stress status in older adults. As part of our previous trial, we explored whether daily consumption of tart cherry juice would improve cognitive abilities. In this randomized controlled trial, 37 adults between the ages of 65-80 with normal cognitive function were recruited and randomly assigned to consume two cups of Montmorency tart cherry juice for 12 weeks. Subjective memory and objective cognitive performance were assessed at baseline and after the 12-week juice supplementation using a validated subjective memory questionnaire and a standardized battery of tests. Daily caloric intake and physical activity levels were assessed throughout the study period. After the intervention, participants in the tart cherry group had higher contentment with memory scores (mean difference of 2.7; 95% CI: 1.2 to 4.2; p = 0.02), lowered their scores of movement time (mean difference of -10.4; 95% CI: -13.4 to -7.5; p = 0.03) as well as performed better on the paired associates learning task (mean difference of -8.5; 95% CI: -12.5 to -4.5; p = 0.02) compared to the control group. The within-group analysis showed that the visual sustained attention (p < 0.0001) and spatial working memory (p = 0.06) improved after the 12-week consumption of tart cherry juice compared with corresponding baseline values. Daily tart cherry juice consumption may improve cognitive abilities. This may be through anti-oxidative and anti-inflammatory properties of tart cherry and its ability to lower BP. Further research is needed to confirm these findings.
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Effect of yerba mate and green tea on paraoxonase and leptin levels in patients affected by overweight or obesity and dyslipidemia: a randomized clinical trial.
Balsan, G, Pellanda, LC, Sausen, G, Galarraga, T, Zaffari, D, Pontin, B, Portal, VL
Nutrition journal. 2019;18(1):5
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Yerba mate is a popular tea-like beverage, traditionally consumed in Latin and South America. Yerba mate contains a range of plant compounds that may have beneficial effects on health, such as weight loss and antioxidant activity. This study aimed to evaluate the effect of the intake of yerba mate and green tea on serum levels of leptin, a hormone involved in regulating appetite, and paraoxonase-1 (PON-1), an enzyme that can destroy harmful oxidised fats in the blood. 142 overweight or obese adults aged 35-60 years, with abnormal levels of fats in the blood and no history of coronary artery disease took part in this controlled, randomised clinical trial. Participants drank 1 litre of either yerba mate, green tea or apple tea daily for eight weeks. Blood PON-1 and leptin levels were measured at the beginning and end of the study. The group drinking yerba mate showed a significant 9.7% increase in blood levels of PON-1, but no difference in leptin levels. The consumption of green tea resulted in no significant differences in the levels of PON-1 or leptin. The increase in PON-1 levels in the yerba mate group was significantly associated with increased levels of high-density lipoprotein (HDL-c - often called ‘good’ cholesterol). The authors concluded that drinking yerba mate increased antioxidant capacity by increasing blood levels of PON-1 and was positively associated with increased HDL-c, demonstrating a protective role of this beverage against thickening and hardening of the arteries.
Abstract
BACKGROUND This study aimed to evaluate the effect of the intake of yerba mate (YM) and green tea (GT) on serum levels of leptin and paraoxonase-1 (PON-1), compared to control. METHODS Controlled, randomized clinical trial (RCT) that evaluated 142 men and women affected by overweight or obesity aged 35-60 years, untreated dyslipidemia and no history of coronary artery disease. Participants were randomized to ingest 1000 mL GT, YM or apple tea (AT, control group) daily, during eight weeks. Serum PON-1 and leptin levels were analyzed by ELISA immunoassay at the beginning (baseline) and after eight weeks of intervention. RESULTS The intake of 1 l of YM/day resulted in significant increase in serum levels of PON-1 (9.7%; p = 0.005). The consumption of GT induced no significant difference in the levels of PON-1 (p = 0.154) and leptin (p = 0.783). Intergroup analysis showed a significant difference (p = 0.036) in the variation of PON-1 levels in the YM group when compared to GT and AT groups. In addition, the increase in PON-1 levels in the YM group was significantly associated with increased HDL-c (p = 0.004). CONCLUSIONS The intake of yerba mate increased the antioxidant capacity by increasing serum levels of PON-1 and was positively associated with increased HDL-c, stressing the protective role of this beverage against atherosclerotic diseases. GT intake had no significant effect on serum levels of PON-1 and leptin. TRIAL REGISTRATION This study is registered with ClinicalTrials.gov under protocol number NCT00933647.
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Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial.
Mastroiacovo, D, Kwik-Uribe, C, Grassi, D, Necozione, S, Raffaele, A, Pistacchio, L, Righetti, R, Bocale, R, Lechiara, MC, Marini, C, et al
The American journal of clinical nutrition. 2015;101(3):538-48
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Flavanols and polyphenolic compounds have been found to produce neuroprotective effects that counteract many aspects of cognitive decline. Recent evidence has shown that cocoa flavanol (CF) consumption improves cognitive function in elderly adults with mild cognitive impairment. The aim of this study was to evaluate the effect of flavanol consumption on cognitive performance in 90 cognitively healthy elderly adults. Participants were randomly assigned to consume a drink containing either a high or low cocoa flavanol concentration for eight weeks. Various cognitive function tests were performed at the baseline and end of the study. The findings of this study indicate that regular CF consumption reduced measures of age-related cognitive dysfunction as well as improved blood pressure and glucose tolerance. These results suggest that habitual intake of flavanols can support healthy cognitive function with age, and indicate a role of glucose metabolism in modulating cognitive function.
Abstract
BACKGROUND Recent evidence has indicated that flavanol consumption may have many health benefits in humans, including improved cognitive activities. OBJECTIVE The aim was to evaluate the effect of flavanol consumption on cognitive performance in cognitively intact elderly subjects. DESIGN This was a double-blind, controlled, parallel-arm study conducted in 90 elderly individuals without clinical evidence of cognitive dysfunction who were randomly assigned to consume daily for 8 wk a drink containing 993 mg [high flavanol (HF)], 520 mg [intermediate flavanol (IF)], or 48 mg [low flavanol (LF)] cocoa flavanols (CFs). Cognitive function was assessed at baseline and after 8 wk by using the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT) A and B, and the Verbal Fluency Test (VFT). RESULTS The changes in MMSE score in response to the 3 different treatments were not different. In contrast, there was a positive impact of the intervention on specific aspects of cognitive function. Mean changes (±SEs) in the time required to complete the TMT A and B after consumption of the HF (-8.6 ± 0.4 and -16.5 ± 0.8 s, respectively) and IF (-6.7 ± 0.5 and -14.2 ± 0.5 s, respectively) drinks significantly (P < 0.0001) differed from that after consumption of the LF drinks (-0.8 ± 1.6 and -1.1 ± 0.7 s, respectively). Similarly, VFT scores significantly improved among all treatment groups, but the magnitude of improvement in the VFT score was significantly (P < 0.0001) greater in the HF group (7.7 ± 1.1 words/60 s) than in the IF (3.6 ± 1.2 words/60 s) and LF (1.3 ± 0.5 words/60 s) groups. Significantly different improvements in insulin resistance (P < 0.0001), blood pressure (P < 0.0001), and lipid peroxidation (P = 0.001) were also observed for the HF and IF groups in comparison with the LF group. Changes in insulin resistance explained ∼17% of changes in composite z score (partial r² = 0.1703, P < 0.0001). CONCLUSIONS This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age.
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Intake of red wine in different meals modulates oxidized LDL level, oxidative and inflammatory gene expression in healthy people: a randomized crossover trial.
Di Renzo, L, Carraro, A, Valente, R, Iacopino, L, Colica, C, De Lorenzo, A
Oxidative medicine and cellular longevity. 2014;2014:681318
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The traditional Mediterranean diet is known to reduce the risk of developing several chronic diseases including cardiovascular disease (CVD). The major underlying factors of CVD are oxidative stress and chronic inflammation, and oxidised low-density lipoprotein (ox-LDL) particles have been associated with increased CVD risk. The aim of this crossover trial was to evaluate the impact of various meal combinations on ox-LDL status and genetic expression of oxidative stress and inflammation. A total of 24 participants were analysed after consumption of four different meal combinations with washout periods in between: Mediterranean meal, McDonald’s meal, both with and without red wine. The findings of this study showed a significant reduction of ox-LDL depending on the quality of meal consumed, and found red wine to have a protective effect. The results of this study indicate that the antioxidant potential of nutrients found in the Mediterranean diet and red wine may be important for reducing inflammation and oxidative stress in chronic disease.
Abstract
Several studies have found that adherence to the Mediterranean Diet, including consumption of red wine, is associated with beneficial effects on oxidative and inflammatory conditions. We evaluate the outcome of consumption of a McDonald's Meal (McD) and a Mediterranean Meal (MM), with and without the additive effect of red wine, in order to ascertain whether the addition of the latter has a positive impact on oxidized (ox-) LDL and on expression of oxidative and inflammatory genes. A total of 24 subjects were analyzed for ox-LDL, CAT, GPX1, SOD2, SIRT2, and CCL5 gene expression levels, before and after consumption of the 4 different meal combinations with washout intervals between each meal. When red wine is associated with McD or MM, values of ox-LDL are lowered (P < 0.05) and expression of antioxidant genes is increased, while CCL5 expression is decreased (P < 0.05). SIRT2 expression after MM and fasting with red wine is significantly correlated with downregulation of CCL5 and upregulation of CAT (P < 0.001). GPX1 increased significantly in the comparison between baseline and all conditions with red wine. We highlighted for the first time the positive effect of red wine intake combined with different but widely consumed meal types on ox-LDL and gene expression. Trial Registration. This trial is registered with ClinicalTrials.gov NCT01890070.