Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial) and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a “safer” approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments.
Attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder characterized by the core symptoms of hyperactivity, inattentiveness, and impulsivity [
A number of treatment strategies have been suggested for ADHD since its recognition as a specific disorder in the 1970s. Presently, typical treatment plans utilize a nonpharmacological (behavioral/psychosocial) and pharmacological interventions or a combination of both [
ADHD has been associated with abnormalities in catecholaminergic function in the brain [
While pharmacological treatments generally improve ADHD symptoms for most children, 20–30% of affected individuals are nonresponders or are unable to tolerate adverse side effects of these drugs [
Due to concerns over the safety and efficacy of current pharmacological ADHD interventions, there has been growing interest in the development of alternative treatments such as natural product-derived ADHD treatments including botanical or herbal medicines, vitamins, minerals, and amino acids [
Clinical trials evaluating safety and efficacy of botanical agents for ADHD.
Study | Botanical agent | Method | Participants | Outcomes | Proposed mechanism of action | Comments (side effects, etc.) |
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Dave et al. [ |
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Open-label study | 31 children, 6–12 years old with ADHD | Reduction of ADHD symptoms (restlessness, poor self-control, inattention, impulsivity, etc.) | Neuroprotection, regulation of dopamine, and inhibition of cholinesterase | Safe and well tolerated Mild gastrointestinal side effects |
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Uebel-von Sandersleben et al. [ |
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Open clinical pilot study | 20 children with ADHD | Improvement of ADHD core symptoms | Improvement in cerebrovascular blood flow, reversal of 5-HT1, and noradrenergic receptor reductions |
Very low rates of mild adverse events during observational period |
Salehi et al. [ |
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Randomized, double-blind controlled trial | 50 children, 6–14 years old with ADHD ( |
Improvement of ADHD symptoms. Less effective than methylphenidate | Lesser side effects (headache, insomnia, and loss of appetite) than methylphenidate | |
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Lee et al. [ |
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Observational study | 18 children, 6–14 years old with ADHD | Improvement in attention | Nootropic effect on CNS |
Taste aversion and repulsion to ginseng |
Ko et al. [ |
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Randomized, double-blind, placebo- controlled trial | 70 children, 6–15 years old with ADHD ( |
Improvement of hyperactivity and inattention symptoms |
No reported adverse events/side effects | |
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Li et al. [ |
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Randomized, double-blind, methylphenidate-controlled trial | 72 children, 6–13 years old with ADHD ( |
Similar efficacy to control (methylphenidate) | Regulation of dopamine by increasing HVA concentration in the sera | Hypersomnia |
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Akhondzadeh et al. [ |
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Double-blind, randomized, methylphenidate-controlled clinical trial | 34 children with ADHD | Improvement of ADHD symptoms | Not specified | Decreased appetite and anxiety/nervousness compared with methylphenidate group |
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Trebatická et al. [ |
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Randomized, double-blind, placebo-controlled study | 61 children, 6–14 years old with ADHD ( |
Attenuation of hyperactivity and improvement of attention, visual-motoric coordination, and concentration | Influence on catecholamine formation or metabolism |
Mild side effects including slowness and gastric discomfort |
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Chovanová et al. [ |
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Randomized, double-blind, placebo-controlled study | 61 outpatient children, 6–14 years old with ADHD ( |
Improved attention, reduction in oxidative damage | Antioxidant properties | No reported adverse events/side effects |
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Weber et al. [ |
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Randomized, double-blind, placebo-controlled study | 56 children, 6–17 years old with ADHD ( |
No significant improvement in ADHD symptoms | No reported adverse events/side effects | |
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Razlog et al. [ |
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Double-blind, placebo- controlled, clinical trial | 30 children, 5–11 years old with ADHD ( |
Improvement of ADHD symptoms in VOMT or 3x potency group, in comparison to placebo, in particular, inattention, impulsivity, and/or hyperactivity | Inhibition of the breakdown of GABA in the central nervous system | No reported adverse events/side effects |
Clinical trials evaluating safety and efficacy of nutritional supplements for ADHD.
Study | Supplement | Method | Participants | Outcomes | Proposed mechanism of action | Comments (side effects, etc) |
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Torrioli et al. [ |
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Randomized, double-blind, placebo- controlled, parallel, multicenter study | 51 children (ADHD and Fragile X syndrome), 6–13 years old ( |
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 |
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Arnold et al. [ |
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Multisite parallel-group double-blind randomized pilot trial | 112 children, 5–12 years old ( |
Acetyl-L-carnitine superior to placebo in inattentive subtype | No adverse events/side effects reported | |
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Richardson and Puri [ |
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Randomized, double-blind, placebo- controlled study | 41 children, 9 participants withdrew before the end of 12-week period, 8–12 years old ( |
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 |
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Stevens et al. [ |
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Randomized, double-blind, placebo- controlled study | 50 children (girls and boys), |
Clear benefit for all behaviors characteristic of ADHD was not observed |
Mediation of abnormal neuronal signaling that results in aberrant behaviors | Not specified |
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Sinn and Bryan [ |
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Randomized, double-blind, crossover, placebo-controlled study | 132 children (data available for 104 and 87 children) 7–12 years old ( |
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 |
No adverse events/side effects |
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Sinn et al. [ |
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Randomized, one-way crossover, placebo- controlled study |
Phase 1: |
Improved ability on attention control and vocabulary performance during phase 2 | Influence on metabolic and neural activities |
Two cases of nausea and one episode of nose bleed |
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Manor et al. [ |
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Randomized, double-blind, single-center, placebo- controlled trial | 200 children (6–13 years old) randomly assigned to PS-omega-3 capsules or placebo |
Improvement of ADHD symptoms (impulsivity, inattention, mood, and behavior issue) | Maintenance of integrity of cell membranes |
Mild adverse event profile: GI discomfort, atopic dermatitis, nausea, tics, and hyperactivity |
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Raz et al. [ |
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Randomized, double-blind, placebo-controlled trial | 73 children, 7–13 years old, 63 children completed the study |
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 |
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Voigt et al. [ |
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Randomized, double-blind, placebo controlled study | 54 children 6–12 years old ( |
DHA supplementation did not significantly improve in any objective or subjective measure of ADHD symptoms | Well tolerated and no adverse effects were reported | |
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Hirayama et al. [ |
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Randomized, double-blind, placebo-controlled study | 40 children with ADHD 6–12 years old ( |
DHA supplementation did not improve ADHD-related symptoms | No serious side effects were reported in the study | |
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Konofal et al. [ |
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Randomized, double-blind, placebo-controlled, pilot trial | 23 ADHD children with low serum ferritin level (<30 ng/mL) 5–8 years old ( |
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 |
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Mousain-Bosc et al. [ |
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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 |
No reported side effects |
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Bilici et al. [ |
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Randomized, double-blind, parallel-group placebo-controlled trial | 400 children 6–14 years old ( |
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 |
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Akhondzadeh et al. [ |
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Randomized, double-blind, clinical trial | 44 children, 5–11 years old ( |
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 |
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Arnold et al. [ |
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Randomized, double-blind, placebo-controlled, pilot trial | 52 children 6–14 years old ( |
No appreciable difference between both dosages of zinc and placebo | Gastrointestinal discomfort reported by 1 patient |
Clinical trials demonstrating efficacy of combination therapy of botanical agents and herbs/supplements with methylphenidate in treating ADHD.
Study | Methods | Participants | Outcomes | Comments | |
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Lyon et al. [ |
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Open, pilot study | 36 children, 3–17 years old with ADHD | Improvement of ADHD symptoms (hyperactivity, impulsiveness, and anxiety) | Five participants reported adverse events (increased ADHD symptoms, aggressiveness, sweating, headache, and tiredness), only 2 considered related to the study |
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Wang et al. [ |
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Randomized, blinded study |
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Significant improvement of ADHD symptoms, as well as tics | Combination therapy more effective than methylphenidate alone in improving ADHD and tic symptoms |
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Ding et al. [ |
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Randomized, methylphenidate-controlled trial | 210 children with hyperkinetic syndrome | Significant improvement in ADHD symptoms in those taking combination therapy compared to either given as monotherapy | Yizhi had fewer side effects when given alone or in combination than methylphenidate |
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Akhondzadeh et al. [ |
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Randomized, double-blind, and methylphenidate + placebo controlled trial | 44 children (26 boys, 18 girls), 5–11 years old with ADHD | Improved parent and teacher rating scale scores for those supplemented with zinc sulfate as an adjunct | Side effects reported: anxiety, loss of appetite, nausea, headache, abdominal pain, insomnia, and metallic taste |
Searches were made in the electronic databases PubMed, PyschINFO, and The Cochrane Library for English language articles from 2001 up to December 1, 2015. PubMed was used to search ADHD search terms in combination with particular natural product-derived treatments. The search strategy employed included combining these keywords: “natural products,” “plant”, “vitamins,” “minerals,” “essential fatty acids,” “amino acids”, “combination natural products,” or “combination with methylphenidate” and “ADHD” or “attention-deficit/hyperactivity disorder.” This process yielded 671 papers covering a wide range of research article types. As we were interested only in natural product-derived ADHD treatments which were evaluated in clinical trials, we concentrated on open-label, randomized controlled trials, as well as observational studies. Moreover, the inclusion criteria included samples consisting of children and adolescent ADHD patients (below 18 years of age), as well as sample size ≥ 10. The number of English language articles that were reviewed for this paper was 30.
Pycnogenol is a standardized extract derived from the bark of the French maritime pine (
Another randomized, placebo-controlled study investigating efficacy of Pycnogenol reported improvement in attention along with reduction in oxidative DNA damage and normalization of homeostatic antioxidant status in ADHD patients treated for 1 month with the compound [
This herb “
Ginseng contains ginsenosides, a class of phytochemicals with neuroprotective and antioxidant effects [
Another study (randomized, double-blind, and placebo-controlled) reported similar results in that participants (ADHD patients aged 6–15,
A unique species of tree native to East Asia,
Valerian (
Ningdong granule (NDG) is a widely used Chinese medicinal preparation for various medicinal purposes. NDG showed promise in treating Tourette’s syndrome, which invited studies to determine its efficacy in ADHD [
Bacopa (
Passion flower is comprised of the fragmented or cut, dried aerial parts of
Oroxylin A (5,7-dihydroxy-6-methoxyflavone) is a flavonoid isolated from the root of
YY162 is a combination pharmaceutical product consisting of terpenoid-strengthened
The genus
Rhodiola (
Previous studies showed that certain vitamins, minerals, and amino acids may contribute to the pathology of ADHD (discussed below). Thus, a wide range of nutritional supplements (vitamins and minerals) have been proposed as potential adjunct and alternative ADHD treatments. Because these agents are closer to food substances than drugs, they do not have similar rigorous restrictions by the Federal Drug Administration that drugs do have and can be purchased over the counter [
Vitamins have been used as potential adjuncts or alternative treatments for ADHD based on anecdotal evidence that they produced improvement in attentiveness and concentration in normal children [
The effects of vitamin C treatment with alpha linolenic acid- (ALA-) rich nutritional supplementation in the form of flax oil on blood fatty acids composition and behavior in children with ADHD were also examined [
Currently, there is another ongoing clinical study evaluating the effect of tocotrienols for children with ADHD, of which findings are not yet reported: Tocotrienols for School-going Children With ADHD (TOCAT). Tocotrienol is a form of vitamin E which is described to exert antioxidative properties [
While vitamins may not directly affect symptoms of ADHD, they have the added benefit of replenishing any deficiencies due to poor dietary habits [
Another proposed alternative intervention for ADHD is mineral supplementation. Mineral deficiencies have also been implicated in the etiology of this disorder, making supplementation a potential means of improving ADHD symptoms. Minerals, as cofactors, have a role in the synthesis, uptake, and breakdown of crucial neurotransmitters associated with ADHD [
A 12-week double-blind study found that children supplemented with zinc sulfate (150 mg) showed reduced impulsiveness, hyperactivity, and socialization difficulties [
Iron is another well-studied mineral that has undergone clinical trial for the treatment of ADHD. Iron is a cofactor in the synthesis of both norepinephrine and dopamine [
Another mineral shown to improve ADHD symptoms is magnesium. The involvement of this mineral in neurotransmitter synthesis supports its potentiality as an ADHD treatment [
In general, these findings indicate the worth of mineral supplementation in ADHD. Nevertheless, a strategy suggested to advance the use of minerals (as well as vitamins) in ADHD treatment is to combine these nutrients to adequately affect the complicated biochemical pathways that may be defective in ADHD patients [
A number of amino acids have been shown to exert direct or indirect effects on the levels of specific neurotransmitters. Thus, they have the potential to be used in treating ADHD. Amino acids, glycine, L-theanine, L-tyrosine, taurine, acetyl-L-carnitine (ALC), GABA, 5-hydroxytryptophan (5-HTP), and s-adenosyl-L-methionine (SAMe), are all considered potential complementary ADHD interventions [
Theanine is an amino acid found in both green and black teas [
The effects of essential fatty acids (EFAs, e.g., omega-3 and omega-6) in treating ADHD in children have been recently investigated. Supplementation with these fatty acids has shown modest success in controlling ADHD symptoms [
In contrast, other studies including randomized clinical trials reported no significant effects/benefits in ADHD patients treated with EFAs compared with the placebo group [
Given the multifactorial characteristic of ADHD, the management of this disorder may benefit from a multimodal approach. Presently, ADHD management trends are favoring treatment of ADHD with a combination of various treatment approaches [
Most multimodal treatment approaches employ the use of stimulant medications, given their wide use in managing ADHD, and behavioral/psychosocial therapy. A multisite clinical trial, the Multimodal Treatment of ADHD (MTA) study, revealed that combination (medicinal and behavioral treatment) and medicinal management (methylphenidate) interventions were significantly superior to behavioral or community care alone for managing ADHD symptoms [
In contrast, only a few studies have evaluated combination therapy utilizing nutritional/botanical supplements with behavioral therapy or pharmacological ADHD agents (Table
Two Chinese medicine herbal treatments have been previously evaluated as adjunct treatments to methylphenidate. A 2-week trial in children randomized to receive Yizhi mixture (a combination of 10 herbs designed to affect Yin/Yang liver functions), methylphenidate, or combination treatment reported more significant improvement of ADHD symptoms in children subjected to combination treatment than in those randomized to either individual treatment. There were also fewer side effects in children given Yizhi mixture alone or combination treatment than in those assigned to the methylphenidate group [
In another study, Akhondzadeh et al. [
The efficacy of combining American ginseng extract,
There are a number of available treatment options for ADHD; however, some of them may pose risks to patients [
Although the use of natural medications for ADHD has been considered as a “safer” approach, natural products are still far from being called as standard ADHD treatments due to the lack of comprehensive and appropriately controlled clinical studies that interrogate both their efficacy and safety. Moreover, it is challenging to compare efficacy profiles of herb therapy with conventional pharmacological ADHD treatments, mainly because herbal preparations are not standardized, and question regarding their purity, reliability, safety, and toxicity profiles will always arise [
The findings from recent, albeit few, studies which evaluated efficacy of adjunct therapy of botanical agents and nutritional supplements with a pharmacological ADHD treatment or another botanical agent suggest that combination therapy may be a promising approach in ADHD treatment. Nevertheless, positive findings from above-mentioned studies need to be replicated, and evidence for long-term effectiveness and safety should be aptly demonstrated. Efficacy of combining other botanical agents with pharmacological agents including other medications aside from methylphenidate (e.g., atomoxetine, guanfacine, and clonidine) or with behavioral therapy should also be explored in future studies. As herbs usually contain more than one psychoactive substance and may have additive or interactive effects with the combined treatment, the risk-benefit balance of natural product-derived ADHD treatments should be carefully considered when combined with other medications.
The authors declare that there is no conflict of interests regarding the publication of this paper.
James Ahn and Hyung Seok Ahn contributed equally to this work.
This research is supported, in part, by the School of Pharmacy of Loma Linda University (LLUSP-360034) and the Korea Health Technology R&D Project (Grant no. A120013).