Multivitamin/multi-nutrient formulas. A comprehensive nutritional supplement containing vitamins, minerals, and amino acids, may help improve symptoms of ADHD. In a fully blinded controlled trial of 93 children (ages 7&#;12) with ADHD not taking any medication, subjects were randomized to receive a nutritional supplement providing micronutrients (13 vitamins, 17 minerals, and 4 amino acids) or placebo for 10 weeks. Most of the nutrients in the formula were at doses between the recommended daily allowance (RDA) and the traditionally tolerable upper intake level (UL). There was a significant improvement on the Clinical Global Impression-Improvement (CGI-I) scale, a measure of a clinician&#;s view of the patient&#;s global function, in which 47% of those given the micronutrients were identified as improved versus 28% given placebo. Furthermore, 32% of subjects on micronutrients versus only 9% on placebo showed clinically meaningful improvements in attention. Clinician, parent, and teacher reports also identified that those on micronutrients showed greater improvements in emotional regulation, aggression, and general function compared with placebo.39 In a 1-year follow up of this trial, children who benefitted from micronutrients in the short-term maintained these improvements at follow up without side effects. Eighty-four percent of participants who remained on micronutrients were identified as having improved overall functioning relative to baseline, compared to 50% of participants who switched to psychiatric mediations and 21% who discontinued treatment, strongly supporting a role for micronutrient supplementation in improving ADHD symptoms.40 In the Micronutrients for ADHD in Youth (MADDY) study, 135 non-medicated children aged 6&#;12 were randomized to receive a nutritional supplement providing 36 micronutrients (vitamins, minerals, amino acids, and antioxidants) or placebo for eight weeks. On the CGI-I scale, 54% of the micronutrient group showed improvements compared with 18% of the placebo group; however, improvements reported by parents were similar in both groups.205
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The effect of nutritional supplements containing micronutrients on ADHD has also been evaluated in adults. In a double-blind controlled trial in 80 adults randomized to a broad-spectrum multivitamin/mineral and botanical formula or placebo for eight weeks, those taking micronutrients showed improvements in ADHD symptoms compared with placebo. The micronutrient group showed greater overall improvement as measured by the Global Assessment of Functioning (GAF) scale, and 64.3% of participants in the micronutrient group showed a &#;30% drop on at least one subscale of the Conners Adult ADHD Rating Scale (CAARS), a measure to assess various symptoms of ADHD such as inattention, memory issues, and hyperactivity, compared with 36.8% in the placebo group. More participants in the micronutrient group were also rated as improved on the CGI-I scale compared with placebo.41 A 1-year follow up on 72 of these subjects found that those who stayed on micronutrients still had significant improvement over the initial baseline and performed better than those who had switched to psychiatric medications or discontinued micronutrient treatment.42
B vitamins. B vitamins are a family of water-soluble nutrients that play a vital role in metabolism and maintaining homeostasis. Levels of B vitamins, namely vitamin B6 (pyridoxine) and B9 (folate), have been found to be reduced in children and adults with ADHD; additionally, vitamin B12 (cobalamin) levels in children with ADHD were found to be significantly lower than controls.43,44 Deficiency of B vitamins may contribute to disease pathology because of their essential role in production of serotonin, catecholamines, and other monoamines.
B vitamins are also of interest for their ability to lower blood homocysteine levels, as high levels of homocysteine have been observed in a variety of diseases, including ADHD, and may contribute to oxidative stress.45-47 Further studies are required to clarify the relationship between B vitamins and homocysteine in the pathology of ADHD.
Vitamin B6 and magnesium. Vitamin B6 (pyridoxine) is involved in the production of serotonin. Early research found that B6 supplementation increased serotonin levels and improved hyperactivity in ADHD.48 In a nutritional survey comparing 100 people with ADHD to 150 healthy individuals, vitamin B6 intake levels were significantly lower in those with ADHD. Studies have also shown that magnesium deficiency is common among individuals with ADHD.49,50 In a placebo-controlled trial, supplemental magnesium at a dose of about 200 mg per day for six months showed a significant decrease of hyperactivity in 7&#;12 year old children with ADHD.51
An 8-week study on 40 children with ADHD found that supplementation with magnesium (6 mg/kg/day) and vitamin B6 (0.6 mg/kg/day) led to improvements in hyperactivity and school attention. Interestingly, when the treatment regimen was discontinued, the children&#;s symptoms reappeared in a few weeks.32 A similar regimen of vitamin B6 and magnesium supplements improved hyperexcitability symptoms in a previous study by the same researchers. In this study, the magnesium-B6 supplement combination was given to 52 hyperexcitable children for six months; symptoms such as physical aggressiveness and attention in school improved in all subjects during treatment.52
Zinc. Zinc is involved in dopaminergic signaling and has been shown to be a common nutrient deficiency in individuals with ADHD.53,54 Children with ADHD treated with Ritalin for six weeks received better behavioral ratings from teachers and parents when they also took zinc supplements (55 mg zinc sulfate per day, providing 15 mg of elemental zinc) than children who received Ritalin and a placebo.37 As a monotherapy, 150 mg zinc sulfate daily for 12 weeks was shown to significantly improve hyperactive, impulsive, and impaired socialization symptoms versus placebo in a large study of 400 children with ADHD.
Iron. Iron is an essential trace element in the body that is important for growth, development, oxygen transport by red blood cells, and dopamine signaling.55 Iron is stored in the body by the protein ferritin, which can subsequently release iron in a controlled fashion as required by the body.56 Low ferritin levels have been observed in patients with ADHD, suggesting an important role of ferritin in ADHD pathology.57,58 Many children with ADHD are iron deficient, and the severity of iron deficiency correlates with symptom severity.59 Low iron levels have also been observed in children who have ADHD plus sleep disorders (eg, restless leg syndrome).57,58
A randomized placebo-controlled study in 23 children (aged 5&#;8 years) with ADHD as well as iron deficiency (defined by ferritin levels less than 30 ng/mL) showed that 80 mg of ferrous sulfate supplementation daily (providing 16 mg of elemental iron) for 12 weeks resulted in a significant decrease in symptoms.60 Another trial with 14 subjects (7&#;11 years old) showed that 5mg/kg (about 2.3 mg per pound of bodyweight) iron per day for 30 days significantly reduced parent ratings of ADHD symptoms.61 In a trial of 52 iron-deficient children on methylphenidate randomized to receive iron supplementation (ferrous sulfate 300 mg capsule containing 80 mg of elemental iron) or placebo for 12 weeks, parents reported significant improvement in ADHD symptoms for those receiving iron but not for those receiving placebo.62
Importantly, high doses of iron (such as those used in these trials) exceeding the RDA should only be used under the guidance of a healthcare practitioner, as accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age.
Vitamin D. Vitamin D is a fat-soluble vitamin obtained through the diet and synthesized by the body in response to sun exposure. Vitamin D deficiency has been suggested as a possible contributor to several neuropsychiatric disorders and may be a risk factor for ADHD. A meta-analysis of eight studies totaling 11,324 children (2,655 with ADHD) found that vitamin D serum levels were significantly lower in patients diagnosed with ADHD compared with healthy controls.63 In a separate meta-analysis of five studies, lower vitamin D status was significantly associated with a higher risk of developing ADHD.64 Vitamin D deficiency may also contribute to mood disorders, which commonly coexist with ADHD.65
Vitamin D supplementation has been examined in various clinical trials as a therapy to ameliorate ADHD symptoms. A double-blind trial randomized 54 children (5&#;12 years) to receive 2,000 IU (50 mcg) vitamin D or placebo for eight weeks as adjunctive therapy to methylphenidate. While ADHD symptoms decreased significantly in both groups, evening symptoms as observed by the Weekly Parent Ratings of Evening and Morning Behavior (WPREMB) standardized assessment were improved at four and eight weeks with vitamin D.66 In a separate trial including 96 children with ADHD randomized to receive 1,250 mcg (50,000 IU) vitamin D weekly or placebo for six weeks (along with a stable daily dose of methylphenidate), the vitamin D group saw an improvement in ADHD symptoms with a particular effect on symptoms of inattention.67 Further, a systematic review and meta-analysis of four randomized controlled trials including 256 children found that vitamin D supplementation demonstrated a small but statistically significant improvement in ADHD total scores, inattention scores, hyperactivity scores, and behavior scores.38A trial in 120 children with ADHD indicated that vitamin D (1,250 mcg [50,000 IU] weekly for 12 weeks) combined with neurofeedback therapy was more effective than either treatment alone, although both treatments alone were more effective than the control.207
The multifactorial origins of ADHD suggest that an intervention targeting multiple specific underlying contributing factors might be beneficial. To test this hypothesis, researchers at McLean Hospital in Massachusetts divided 20 children with ADHD into two groups. One group of 10 children received 5&#;15 mg of Ritalin 2&#;3 times daily and the other received a comprehensive multi-nutrient formula designed to target several factors that possibly play a role in ADHD development.68
The multi-nutrient formula used in this study included probiotics, amino acids (eg, tyrosine, histidine, glutamine, glycine, methionine, and cysteine), essential fatty acids and phospholipids (eg, EPA, DHA, and phosphatidylcholine), and vitamins and minerals.
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Impressively, ADHD symptoms among children who took the multi-nutrient formula improved in standardized ADHD assessments at four weeks just as much as those who received Ritalin. Upon concluding their study, the researchers noted &#;Improvements &#; were &#; found to be significant and essentially identical in both groups&#;&#;
In a placebo-controlled trial, 120 children recently diagnosed with ADHD were randomized to receive either an herbal preparation or placebo for four months. The herbal preparation contained the following:
After treatment, the children in the herbal group had significantly improved scores of variable attention and response times, while the placebo group had no improvement.208
L-theanine, a naturally occurring compound found in tea, has been shown to help ease anxiety, reduce stress, and improve focus and attention.69,70 L-theanine is structurally similar to L-glutamate and its effects are attributed to its ability to bind glutamate receptors, inhibit glutamate and glutamine reuptake, and elevate levels of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA).71 Sleep disorders, a common comorbidity in ADHD that also can be a factor in its etiology, have been shown to be improved with L-theanine. In boys (aged 8&#;12 years) diagnosed with ADHD, 400 mg L-theanine daily was shown to improve sleep.72
Conversely, studies suggest L-theanine alone and in combination with caffeine, another compound naturally found in tea, can also improve attention and focus in patients with ADHD.73 A study including five male children (ages 8&#;17) administered L-theanine (2.5 mg/kg), caffeine (2 mg/kg), L-theanine plus caffeine, or placebo found L-theanine and the combination improved cognitive function and decreased mind-wandering activity during functional magnetic resonance imaging (fMRI).74 These results were corroborated in a separate small trial involving five boys (age 8&#;15 years) with ADHD; administration of a drink containing L-theanine and caffeine (2.5 mg/kg and 2 mg/kg, respectively) improved cognitive function, inhibitory control, and reduced mind-wandering (&#;daydreaming&#;) compared with placebo, whereas L-theanine alone only improved cognition.75
Children with ADHD may have lower levels of omega-3 fatty acids in their blood.76 While the typical Western diet often contains excessive levels of certain omega-6 fatty acids, it is lacking in omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).77,78 Considering that dopamine-producing nerve endings are composed of up to 80% of the omega-3 fatty acid DHA,79 these molecules have an important role in the central nervous system and its functions. In children, the severity of ADHD symptoms is linked to lower levels of omega-3 and higher levels of omega-6 fatty acids. Hyperactivity and inattention in general are also linked to omega-3 fatty acid deficiency, thus indicating this may be a risk factor for ADHD.33 A UK-based study in 493 school children aged 7&#;9 years found omega-3 fatty acid insufficiency was very common and associated with ADHD-related symptoms (eg, oppositional behavior and emotional instability). Research from another group found that low blood levels of omega-3 fatty acids correlated with callous-unemotional behavior, antisocial traits, and impaired emotional processing.26,80
Swedish scientists studied the effects of fish oil supplements containing polyunsaturated omega-3 fatty acids (558 mg EPA, 174 mg DHA daily) and the beneficial omega-6 fatty acid gamma linolenic acid (GLA) (60 mg daily) in 75 children and adolescents with ADHD over a six-month period. They found that after six months, nearly half of subjects responded to the omega-3 and omega-6 supplements with a reduction in ADHD symptoms.81 In a subsequent analysis of these study data, the same researchers found that subjects with at least a 25% reduction in symptoms exhibited a significantly greater decrease in the ratio of omega-6&#;s to omega-3&#;s in their blood at three and six months.82 A comprehensive review conducted by researchers at Yale University examined evidence from 10 trials involving 699 children with ADHD. It was found that supplementation with omega-3 fatty acids modestly improved ADHD symptoms among study participants. In their concluding remarks, the researchers noted &#;&#;it may be reasonable to use omega-3 fatty supplementation to augment traditional pharmacological interventions&#;&#;83 An analysis of several published studies also found that supplementation with free fatty acids and exclusion of artificial food coloring from the diet had statistically significant effects on reducing ADHD symptoms.84
Flax oil, which provides high levels of the omega-3 fatty acid alpha-linolenic acid (ALA), a precursor to EPA and DHA, also may be of benefit. A study examining the benefit of supplementation with an emulsion of flax oil (providing 200 mg ALA) and vitamin C (25 mg) given twice daily to children with ADHD found a significant improvement in symptoms of ADHD, including impulsivity, restlessness, inattention and self-control, as reflected by a reduction in total hyperactivity scores.85
Fish oil is a good source of polyunsaturated omega-3 fatty acids. The balance of fatty acid levels can be measured with blood tests, and people taking fatty acid supplements can have repeat blood tests to measure their effect.
Phosphatidylserine (PS) is a major component of cell membranes and is considered one of the most important brain nutrients. PS has a variety of functions within the brain including supporting cell membrane fluidity and beneficially influencing neurotransmitter systems (eg, acetylcholine, dopamine, and serotonin). Researchers, patients, and their caregivers have long been interested in the potential of PS supplements for ADHD. A meta-analysis found that at a dose of 200&#;300 mg daily, PS had a significant effect on symptoms of inattention compared with placebo.86
In a randomized controlled trial, 36 children diagnosed with ADHD were given either 200 mg PS daily or placebo for two months. PS supplementation resulted in significant improvement in ADHD symptoms including inattention, impulsivity, and short-term memory. No adverse effects were reported and the supplement was well tolerated.87 Another randomized controlled trial of 15 weeks duration studied the effects of PS combined with omega-3 fatty acids. In this study, 200 children with ADHD were given either 300 mg PS plus 120 mg EPA and DHA or placebo. The treatment resulted in significant improvement in ADHD symptoms. A subgroup analysis revealed this treatment may be especially effective in children with ADHD with more pronounced hyperactive and impulsive behavior. In a 15-week open label continuation, the treatment showed continued efficacy as well as improvement in children who switched over from placebo.88
Acetyl-L-carnitine (ALC), a natural derivative of L-carnitine, serves a key role in the metabolism of fatty acids and cellular energy production and is a precursor to acetylcholine which plays a role in memory.89 Evidence from both animal and human studies suggests it may help alleviate ADHD symptoms. In an animal model of ADHD, long-term administration of ALC to rats consistently decreased impulsivity. This study also found that impulsive animals had altered levels of certain neurotransmitter metabolites, and ALC helped improve this imbalance.90 In a placebo-controlled trial in 112 subjects, 500&#;1,500 mg ALC twice daily (based on weight) improved symptoms in children with the inattentive ADHD subtype.91 In a separate randomized double-blind trial, ALC had a beneficial effect on hyperactivity and social behavior in 51 young boys with fragile X syndrome and ADHD.89 However, a study of boys and girls with ADHD found that 500&#;1,500 mg ALC daily did not have an effect when combined with methylphenidate.92
Ginkgo biloba contains compounds called terpene trilactones (eg, ginkgolides and bilobalide) that have various effects on the central nervous system.93 Ginkgo (80&#;120 mg daily in 25 children with ADHD for six weeks) was shown in a clinical trial to improve subjective teacher and parent ratings; however, it did not outperform methylphenidate (20&#;30 mg daily). Side effects of decreased appetite, headache, and insomnia were seen more frequently in the methylphenidate group.94 A 6-week placebo-controlled trial in 66 children with ADHD showed that ginkgo (80&#;120 mg daily) in combination with methylphenidate reduced parent- and teacher-rated inattention scores compared with placebo. The response rate for ginkgo was 93.5% versus 58.6% in the placebo group.209 In an 8-week trial, 18 children (6&#;14 years old) received a 1,000 mg dose of Korean red ginseng twice daily; at the end of the trial a significant reduction in inattentiveness, ADHD rating scale scores, and level of anxiety was observed.95 In a pilot study, the daily combination of 200 mg American ginseng extract and 50 mg ginkgo biloba also improved a range of symptoms from social problems to impulsivity in children being treated for ADHD.96
Pycnogenol, an extract from the bark of French maritime pine (Pinus pinaster), has antioxidant and vasodilatory properties and has been shown to benefit cognitive function in multiple human studies.97 A double-blind randomized trial in 61 children receiving 1 mg/kg Pycnogenol or placebo daily for four weeks showed a significant decrease in hyperactivity, improvement in attention, and increase in visual and motor coordination in the Pycnogenol group.98 Another double-blind, randomized, placebo-controlled trial showed Pycnogenol decreased hyperactivity and oxidative stress in children with ADHD.99
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