Natural Product-Derived Treatments for Attention-Deficit/Hyperactivity Disorder: Safety, Efficacy, and Therapeutic Potential of Combination Therapy

Table 2

Clinical trials evaluating safety and efficacy of nutritional supplements for ADHD.

Study	Supplement	Method	Participants	Outcomes	Proposed mechanism of action	Comments (side effects, etc)
Torrioli et al. [34]	Acetyl-L-carnitine (LAC); LAC (500 mg, 2 times/day) or placebo for 12 months	Randomized, double-blind, placebo- controlled, parallel, multicenter study	51 children (ADHD and Fragile X syndrome), 6–13 years old ( ALC versus placebo)	Reduction of ADHD symptoms versus Placebo on Clinical Global Impressions Parental Rating	Modulation of neural transmission by increasing acetylcholine synthesis, stimulating its release and release of dopamine in the striatum in various brain regions	No adverse events/side effects reported
Arnold et al. [35]	Acetyl-L-carnitine (ALC); ALC in weight-based doses from 500 to 1,500 mg b.i.d. or placebo for 16 weeks	Multisite parallel-group double-blind randomized pilot trial	112 children, 5–12 years old ( Acetyl-L-carnitine versus placebo)	Acetyl-L-carnitine superior to placebo in inattentive subtype		No adverse events/side effects reported
Richardson and Puri [36]	Essential fatty acids; Highly unsaturated fatty acid (HUFA): EPA 186 mg/day, DHA 480 mg/day, -linolenic acid 96 mg, vitamin E 60 IU, cis-linoleic acid 864 mg, AA 42 mg, and thyme oil 8 mg or olive oil (placebo), for 12 weeks	Randomized, double-blind, placebo- controlled study	41 children, 9 participants withdrew before the end of 12-week period, 8–12 years old ( HUFA versus placebo)	Attenuation of ADHD symptoms, for example, inattention, hyperactivity, improvement in cognition and emotion	Influence on signal transduction relevant to neuronal structure, development, and functions	Upset stomach and difficulty swallowing
Stevens et al. [37]	Essential fatty acids; PUFA supplement comprised of 480 mg DHA, 80 mg EPA, 40 mg arachidonic acid (AA), 96 mg GLA, and 24 mg alpha-tocopheryl acetate or an olive oil placebo for 4 months	Randomized, double-blind, placebo- controlled study	50 children (girls and boys), PUFA supplementation, placebo	Clear benefit for all behaviors characteristic of ADHD was not observed; Treatment effects for; conduct and attention as well as with clinical; improvements in oppositional/defiant behavior	Mediation of abnormal neuronal signaling that results in aberrant behaviors	Not specified
Sinn and Bryan [38]	Essential fatty acids; LC-PUFA capsules containing 400 mg fish oil and 100 mg evening primrose oil with EPA (93 mg), DHA (29 mg), GLA (10 mg), and vitamin E (1.8 mg) or placebo. Six active or 6 placebo capsules per day for 15 weeks	Randomized, double-blind, crossover, placebo-controlled study	132 children (data available for 104 and 87 children) 7–12 years old ( PUFAs versus PUFA + micronutrients versus placebo)	Significant treatment effects based on parental rating of core ADHD symptoms in both PUFA groups versus placebo	Modulation of neural cell signaling and neurotransmitter processes; PUFAs with other nutrients such as vit. C, B3, and B6 modulates PUFA’s role in the synthesis of prostaglandins and chemicals important for biological and brain function	No adverse events/side effects
Sinn et al. [39]	Essential fatty acids; LC-PUFA capsules containing 400 mg fish oil and 100 mg evening primrose oil with EPA (93 mg), DHA (29 mg), GLA (10 mg), and vitamin E (1.8 mg) or placebo. Six active or 6 placebo capsules per day for 15 weeks	Randomized, one-way crossover, placebo- controlled study; Phases 1 and 2	Phase 1: children with ADHD (PUFA versus PUFA + multivitamins/minerals versus placebo for 15 weeks); Phase 2: children with ADHD (PUFA, PUFA + multivitamin/minerals, and placebo for 15 weeks)	Improved ability on attention control and vocabulary performance during phase 2	Influence on metabolic and neural activities; Increasing dopamine activity in the frontal lobe	Two cases of nausea and one episode of nose bleed
Manor et al. [40]	Essential fatty acids; 2 capsules twice a day of phosphatidylserine (PS) containing omega-3 (300 mg of PS and 120 mg of EPA + DHA) or cellulose capsules as placebo, for 15 weeks	Randomized, double-blind, single-center, placebo- controlled trial	200 children (6–13 years old) randomly assigned to PS-omega-3 capsules or placebo; children completed 15 weeks of treatment (PS-omega-3,   placebo)	Improvement of ADHD symptoms (impulsivity, inattention, mood, and behavior issue)	Maintenance of integrity of cell membranes; Influence on dopaminergic and cholinergic systems; Increasing omega-3 LC-PUFA which improves behavioral, sensory, and neurological dysfunction	Mild adverse event profile: GI discomfort, atopic dermatitis, nausea, tics, and hyperactivity
Raz et al. [41]	Essential fatty acids; EFA capsules containing 240 mg of linoleic acid (LA) 60 mg of alpha-linolenic acid (ALA), 95 mg of mineral oil, and 5 mg of a-tocopherol (as an antioxidant) 2 times/day or placebo: vit. C (500 mg ascorbic acid) 2 times/day, for 7 weeks	Randomized, double-blind, placebo-controlled trial	73 children, 7–13 years old, 63 children completed the study; ( EFA supplement versus 39 placebo vitamin C)	Both treatments ameliorated some ADHD symptoms. No difference in efficacy between treatments	Improvement in behavioral, sensory, and cognitive functions	No adverse events/side effects reported
Voigt et al. [42]	Essential fatty acids; 345 mg of DHA per day () or a placebo capsule () for 4 months	Randomized, double-blind, placebo controlled study	54 children 6–12 years old ( docosahexaenoic acid (DHA) versus placebo)	DHA supplementation did not significantly improve in any objective or subjective measure of ADHD symptoms		Well tolerated and no adverse effects were reported
Hirayama et al. [43]	Essential fatty acids; DHA group: fermented soybean milk (600 mg DHA/125 mL, 3/week), bread rolls (300 mg DHA/45 g, 2/week) and steamed bread (600 mg DHA/60 g, 2/week) or placebo foods containing olive oil instead of DHA-rich fish oil for 2 weeks	Randomized, double-blind, placebo-controlled study	40 children with ADHD 6–12 years old ( docosahexaenoic acid (DHA) versus placebo)	DHA supplementation did not improve ADHD-related symptoms		No serious side effects were reported in the study
Konofal et al. [44]	Iron; 80 mg ferrous sulfate tablets or placebo once daily in the morning for 12 weeks	Randomized, double-blind, placebo-controlled, pilot trial	23 ADHD children with low serum ferritin level (<30 ng/mL) 5–8 years old ( iron versus placebo)	Improvement of hyperactive/impulsive and inattentive symptoms in the ADHD rating scale	Iron is a cofactor in the synthesis of both norepinephrine and dopamine	Minor side effects were reported, such as nausea, constipation, and abdominal pain
Mousain-Bosc et al. [45]	Vitamin B6 and magnesium; ADHD children: magnesium-vitamin B6 (Mg-B6) regimen (6 mg/kg/d Mg, 0.6 mg/kg/d vit-B6) for six months Controls did not receive Mg-B6	Open study	76 children (mean age: 6.9 years; 13 girls and 27 boys) (40 ADHD children & 36 healthy children)	Attenuation of hyperactivity and aggressiveness School attention was also improved	Vitamin B6 facilitates the production of the serotonin; Magnesium is a nonspecific inhibitor of calcium and NMDA channels; Magnesium can influence catecholamine signaling	No reported side effects
Bilici et al. [46]	Zinc; 150 mg zinc sulfate or 150 mg sucrose (placebo) daily for 12 weeks	Randomized, double-blind, parallel-group placebo-controlled trial	400 children 6–14 years old ( zinc versus placebo)	Zinc sulfate better than placebo in decreasing hyperactivity and impulsivity and improving socialization, but not inattention	Increased zinc levels necessary for cognitive development	No serious side effects reported. Metallic taste was a common complaint
Akhondzadeh et al. [47]	Zinc; Zinc sulfate (55 mg/day) + methylphenidate (1 mg/kg/day) or sucrose (placebo) 55 mg + methylphenidate (1 mg/kg/day) for 6 weeks	Randomized, double-blind, clinical trial	44 children, 5–11 years old ( methylphenidate + zinc versus methylphenidate + placebo)	Significantly greater treatment effects (as per parent and teacher rating scale scores) in zinc sulfate with methylphenidate treatment over placebo with methylphenidate	Zinc regulates dopamine function indirectly, through its action on melatonin	Nausea and metallic taste were common complaints. Overall, it was well tolerated
Arnold et al. [48]	Zinc; Zinc_1: 15 mg/day (once a day) or Zinc_2: 30 mg/day (twice a day) or placebo (8 weeks); amphetamine 5–15 mg/daily (based on the weight); Duration of experiment was 13 weeks (8 weeks controlled; + 5 weeks amphetamine add-on)	Randomized, double-blind, placebo-controlled, pilot trial	52 children 6–14 years old ( Zinc_1 or Zinc_2 versus placebo)	No appreciable difference between both dosages of zinc and placebo		Gastrointestinal discomfort reported by 1 patient