Non-Pharmacological Treatments for ADHD in Youth

Abstract

Background

Complementary and alternative medicine (CAM) in psychiatry or integrative psychiatry covers a wide range of biological, psychological and mind-body treatments that enhance standard medical practices and patient outcomes. While CAM approaches are popular amongst patients in their practice as well as in self-report because of their ease of use, health professionals have received limited education in these interventions and often are unaware of their patients’ use of CAM treatments.

Method

This overview highlights evidence-based CAM treatments for attention deficit hyperactivity disorder (ADHD) including dietary interventions, phytomedicines, mind-body practices and neurofeedback.

Results

While conventional treatments are the mainstays for ADHD, there are a large number of available treatments that can be used to enhance treatment response.

Conclusion

With improved education and further scientific and clinical research, validated integrative treatments will provide more effective, lower risk and lower cost care for patients with ADHD.

INTRODUCTION

Complementary and alternative medicine (CAM) includes a wide range of biological, psychological and mind-body treatments that are used to enhance standard medical practices and thereby improve patient outcomes. Integrative Psychiatry (IP), a form of CAM, “seeks to enrich mainstream mental health care with valuable treatments from global healing traditions as well as from modern laboratories in related fields” (Muskin, Gerbarg, & Brown, 2013). Many patients with mental health disorders utilize these modalities, often without physician supervision (Elkins et al., 2005; Kessler et al., 2001). A 2000–2001 survey of adolescents diagnosed with ADHD or depression that was conducted at five community mental health clinics found that 15% of patients had taken herbal supplements within the past year and 20% over their lifetime (Cala, Crismon, & Baumgartner, 2003). Another study found that 54% of parents used CAM to treat their child’s attentional deficit hyperactivity disorder (ADHD), while only 11% had reported their use of complementary and alternative treatments to their child’s physician (Chan, Rappaport & Kemper, 2003). More than 90% of parents of children with ADHD hope to see more research on CAM conducted (Huang, Seshadri, Matthews, & Ostfeld, 2013). Understanding the growing evidence supporting the efficacy of certain CAM therapies will prepare clinicians to best advise patients when discussing integrative treatments.

Among the many available CAM treatments, a subset has been studied for efficacy in ADHD. This overview highlights evidence-based treatments, including dietary interventions, phytomedicines, mind-body practices and neurofeedback. Although behavioral therapies are an important treatment modality, because of space limitations they are not discussed in this review. For some treatments, there exists supporting evidence from animal studies and preliminary clinical trials. As for many other treatments, larger randomized controlled studies are necessary. Still, considering the favorable risk/benefit profile of many CAM treatments, clinicians should consider offering their patients complimentary interventions, particularly for patients who have experienced limited success or side effects with standard pharmaceutical treatments, or for those individuals who are averse to prescription medications for reasons such as concerns about their short- and long-term effects.

DIETARY INTERVENTIONS FOR ADHD

The role of diet as a contributor or modulator of ADHD symptomatology remains controversial (Millichap & Yee, 2012). In the Raine Study, a cohort of approximately 2800 Australian children were followed from birth to age 14 to determine whether certain dietary patterns were associated with ADHD. Adolescents with a high score for a “Western” dietary pattern were more likely to have been diagnosed with ADHD (odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.33, 3.80) even after adjusting for potential confounders. In contrast, those with a high score for a “Healthy” dietary pattern were less likely to have an ADHD diagnosis (Howard et al., 2011). While this study was the first to correlate the Western diet with ADHD, no conclusions regarding causality could be reached given its cross-sectional design. Dietary strategies evaluated in ADHD include elimination of synthetic food additives, sensitizing food allergens or sugar. Dietary supplementation studies in ADHD include the use of vitamins, minerals, omega-3 and omega-6 fatty acids, amino acids and natural metabolites.

MINIMIZING RISKS

In 1994, the Dietary Supplement Health and Education Act (DSHEA) defined the term “dietary supplement” to include herbs, vitamins, minerals and amino acids. Unlike most modern drugs, herbal and other dietary supplements are not subject to an FDA approval process. The FDA is responsible for post-marketing activities including monitoring of adverse events (Feucht & Patel, 2011). Few herbs relevant to psychiatric practice have clinically significant medication interactions. Nevertheless, risks for herb-drug interactions (HDIs) can be minimized by monitoring for side effects and obtaining serum levels of medications that have a narrow therapeutic window, for example insulin, warfarin, digoxin, immunosuppressants in transplant cases, antiretroviral drugs, and chemotherapy agents (Gerbarg & Brown, 2013; Gerbarg & Brown, in press).

The safety and efficacy of any product, whether a prescription drug or a supplement, depends upon its quality. This is especially true for herbs because the quality and potency can be affected by numerous factors including the growing conditions, time of harvest, processing, stability of constituents and testing for contaminants (Brown, Gerbarg, & Muskin, 2009; Gerbarg & Brown, 2013, Gerbarg & Brown, in press). Physicians may wish to visit websites such as www.herbalgram.org, www.fda.gov/medwatch, www.consumerlab.com, www.supplementwatch.com, www.drugs.com that provide results of impartial evaluations of many supplements and identify high-quality brands. Although these sites do not present every aspect of product quality, they do cover important characteristics of herbal products, vitamins and nutrients, such as the percentage of active ingredient and purity.

ELIMINATION DIETS

The hypothesis that synthetic food additives could induce hyperkinetic behavior was introduced in the 1970’s by Feingold (1975) who proposed that petroleum-based additives, including synthetic colors, flavors and preservatives as well as foods that contain natural salicylates could induce neurologic damage and trigger hyperactivity, as well as other behavioral problems. Consequently, a program was created to test whether removal of these additives from the diet could improve symptoms of ADHD. Among the food dyes that the Feingold program eliminates are Red 40 (Allura red AC), Yellow 5 (tartrazine), and Yellow 6 (sunset yellow). These three additives account for 90% of food dyes certified by the FDA each year and are commonly found in candies, cereals, desserts and other child-oriented foods. In addition, the Feingold diet eliminates artificial flavorings (e.g. vanillin), artificial fat preservatives (BHA, BHT, TBHQ) and natural salicylates.

Over the past three decades, studies of elimination diets for ADHD symptoms have shown mixed results. An early meta-analysis of Feingold diet studies found minimal clinical efficacy for hyperactivity (Kavale & Forness, 1983). Interest was again rekindled when a later study found a significant association between synthetic food colorings and parent-rated ADHD symptoms (Schab & Trinh, 2004). A 2011 qualitative review found that a subgroup of children diagnosed with ADHD may be sensitive to these additives and could benefit from a restricted diet (Stevens, Kuczek, Burgess, Hurt & Arnold, 2011). A meta-analysis including only double-blind, placebo-controlled randomized trials approximated that 33% of children with ADHD may respond clinically to dietary interventions, though only 8% have symptoms related to synthetic food colors (Nigg, Lewis, Edinger & Falk, 2012). Another meta-analysis found that when data from blinded assessments were segregated and analyzed apart from proximal unblinded assessments, the effect sizes of elimination diets on ADHD symptoms declined (standardized mean difference [SMD] 1.48 to 0.51), and remained modest for artificial food color exclusions (SMD 0.34 to 0.42) (Sonuga-Barke et al., 2013).

Genetic polymorphisms could explain differences in ADHD symptoms and the response to food additives. Polymorphisms of genes that regulate CNS dopamine levels, such as the dopamine transporter gene (DAT1), are associated with childhood ADHD (Gizer, Ficks, & Waldman, 2009). Polymorphisms in the histamine degradation gene (HNMT) result in impaired clearance of histamine which is released following a challenge with food additives (Murdoch, Lessof, Pollock & Young, 1987; Preuss et al., 1998). In a double blind, randomized placebo controlled study, children with ADHD with specific HNMT or DAT1 polymorphisms experienced worsening clinical symptoms when challenged with food additives compared to children lacking these polymorphisms. These findings provide a genetic link between histamine risk alleles and ADHD symptoms following exposure to food additives. The short term exposure to additives is one limitation of this study (Stevenson et al., 2010). Additional randomized controlled trials with genomic data are needed to better understand the effects of elimination diets on ADHD.

Considering that artificial food additives have no nutritional value and may exacerbate hyperactivity, parents and physicians may opt to do a trial by excluding these ingredients from the child’s diet for a three-month period. The use of objective assessments may help evaluate if an elimination diet was beneficial or not. Assessing the effects of these elimination diets can be challenging because it is particularly difficult to control adolescents’ food intake. Sample foods known to have additives include lemonade, flavored yogurt, bakery items, beverages, macaroni & cheese, candy, sodas, popsicles and colored vitamins. Parents can preferentially buy foods labeled “no artificial colorings or preservatives” and educate their adolescents on why additives are not good. Parents wishing to implement an elimination diet will need diligence, patience and guidance from physicians and dieticians.

DIETARY SUPPLEMENTATION

Minerals

Children with ADHD are at risk for nutrient deficiencies. Hyperactivity and inattention can interfere with the ability to sit and consume regular meals. Furthermore, stimulant medications can suppress appetite. The lack of a balanced diet, poor nutrient absorption due to medical conditions, co-morbid conditions such as anemia or restless leg syndrome (RLS) and country of origin should be considered when screening for mineral deficiencies in children with ADHD. Certain regions of the world are more prone to mineral deficiencies than others. There is evidence that ADHD is associated with low mineral levels in children living in Poland, Turkey, Israel, Canada and the United States (Kiddie, Weiss, Kitts, Levy-Milne & Wasell, 2010). The impact of supplementation of mineral cofactors is being studied to determine their impact on ADHD symptoms, especially in children with micronutrient deficiencies. (For an overview of the use of nutrients in mental health care see Akhondzadeh, Gerbarg, & Brown, 2013).

Iron

Iron imbalances have been associated with neurological diseases including ADHD (Jellen, Beard, & Jones 2009). Iron is an essential cofactor in the endogenous synthesis of monoaminergic neurotransmitters implicated in the pathogenesis of ADHD. Iron-deficient mice exhibit decreased striatal densities of D1 and D2 receptors (Erikson, Jones, Hess, Zhang, & Beard, 2001) and the dopamine transporter (DAT) (Erickson, Jones, & Beard, 2000) suggesting that iron is not only important for dopamine synthesis but also downstream dopaminergic receptor activity. In addition, mice that lack the DAT are phenotypically hyperactive (Gainetdinov et al., 1999). Studies show a correlation between low levels of serum ferritin and ADHD symptoms (Konofal, Lecendreux, Arnulf, & Mouren, 2004). In a controlled study of 23 children (ages 5–8 years) with low serum ferritin, iron supplementation (80mg/day) improved ADHD symptoms (Konofal et al., 2008). Another study showed that low serum ferritin not only correlated with baseline ADHD symptoms, but also with the dose of amphetamines required for clinical improvement (Calarge, Farmer, DiSilvestro, & Arnold, 2010). Iron deficiency can cause restless leg syndrome, easily mistaken as a symptom of ADHD in children. Serum ferritin levels should be checked in children with restless legs and in cases where there is reason to suspect a nutritional deficiency.

Zinc

The mineral cofactor zinc has also been implicated in regulating dopamine and norepinephrine neurotransmission (Lepping & Huber, 2010). In clinical studies performed in the Middle East, zinc supplementation significantly improved ADHD symptoms compared to placebo. For example, a 12 week controlled study of 400 children with ADHD living in Turkey found that zinc sulfate (40mg/day) significantly improved ADHD symptoms compared to placebo (Bilici et al., 2004). In a study performed in the United States, low serum zinc levels correlated with parent and teacher-rated scores of inattention, but not with the other core symptoms of hyperactivity and impulsivity (Arnold et al., 2005). A double blind study including 52 American children treated with either zinc glycinate or placebo for 8 weeks followed by 5 weeks of treatment with added d-amphetamine found that the clinical outcomes were equivocal with some measures favoring zinc and others favoring placebo (Arnold et al., 2011); however, a significantly lower dose of d-amphetamine was optimal for those receiving the zinc supplement (i.e. 37%) compared to those given placebo. Consequently, for ADHD patients residing in the United States, the clinical value of zinc supplementation remains to be determined.

Polyunsaturated Fatty Acids (PUFAS)

Omega-3 fatty acid deficiencies have been found in boys with ADHD (Antalis et al., 2006). Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids that maintain membrane fluidity (Simopoulos, 1991); serve as substrates in the biosynthesis of inflammatory eicosanoids (Simopoulos, 2002a; b); modulate dopaminergic neurotransmission (Chalon, 2006; Dervola et al., 2012; Baumgartner et al., 2012), and support other cellular functions. There are three omega-3 fatty acids relevant to human physiology: eicosapentanoic acid (EPA), docosahexanoic acid (DHA), and alpha-linolenic acid (ALA). The two omega-6 fatty acids are arachidonic acid (AA) and gamma-linolenic acid (GLA). Essential PU-FAs cannot be synthesized endogenously and must be derived from dietary sources.

The high ratio of omega-6/omega-3 fatty acids commonly found in western diets is believed to play a role in chronic inflammatory diseases (Simopoulos, 2002a; b). Supplementation with Omega-3 fatty acids or a combination of omega 3/6 fatty acids can improve symptoms of ADHD. One meta-analysis of 10 trials involving 699 participants found a small but significant overall improvement in ADHD with omega-3 fatty acid supplementation (standardized mean difference [SMD] = 0.31, confidence interval [CI] = 0.16–0.4, p~.0001) with similar results for both inattentive and hyperactivity symptoms. Higher doses of EPA were significantly associated with reduction of ADHD symptoms. (Bloch & Qawasmi, 2011). Another meta-analysis found that when data from blinded assessments were segregated from proximal un-blinded assessments, the effect sizes of free fatty acid supplementation on ADHD symptoms remained statistically significant (standardized mean difference [SMD] = 0.17, 95% CI= 0.01–0.34) (Sonuga-Barke et al., 2013).

A supervised trial of PUFA supplementation may be appropriate for certain children as a complementary treatment for ADHD. The daily use of a purified fish oil supplement has become more appealing due to concerns about contaminants such as mercury and polychlorinated biphenyls (PCBs) in fish. Essential fatty acid supplements have variable concentrations of omega-3 and omega-6 fatty acids. Most American diets contain excess omega-6 fatty acids. Based on clinical studies, a dose of 600–1000mg/day of omega-3 (with 2:1 ratio of EPA to DHA) is likely to be most effective (Antalis et al., 2006).

Phytomedicines and Nootropics for ADHD

For thousands of years, phytomedicine, the use of plants for healing, has been an integral part of traditional health systems worldwide (Aggarwal, Sundaram, Malani, & Ichikawa, 2007; Lai & Roy 2004). Bioactive compounds can be found in flowers, leaves, stem, roots, seed and berries. Hundreds of modern drugs were derived from plants (Fabricant & Farnsworth, 2001). In many cases, single active constituents have been used. However, whole plant extracts may contain bioactive compounds with synergistic and/or polyvalent properties such that more than one compound contributes to the clinical effect (Sarris, Panossian, Schweitzer, Stough, & Scholey, 2011; Panossian Hamm, Kadioglu, Wikman, & Efferth, 2013). Although scientific studies have shown that certain plant compounds improve attention and learning, only a few studies have been conducted with patients who have ADHD. While more data is needed, recent evidence and clinical experience indicates that certain herbs are beneficial as complementary and integrative treatments for ADHD.

Rhodiola Rosea

Rhodiola Rosea (Golden Root, Arctic Root), an herb with a long history in traditional medicine, is one of the most extensively studied herbs. It belongs to a group of plants called adaptogens, named after its capacity to protect organisms from numerous kinds of stressors—environmental, chemical, infectious, hypoxic, toxic, and others (Panossian et al., 2010; Brown & Gerbarg, 2004). R. rosea grows in extremely cold environments at high altitudes above 8,000 feet in the crevices of mountain rocks in the Arctic regions of Canada, Europe and the former Soviet Union. In order to fulfill increasing demand of this rare herb, widespread cultivation is developing in many of these regions. There are over twenty different species of the genus Rhodiola, many of which grow in the same regions and thus can be confused with the species R. rosea. While frequently used in traditional systems, there has been a marked increase in research and clinical interest in this herb over the last 10 years. High-performance liquid chromatography (HPLC) analysis of the root of R. rosea reveals hundreds of bioactive compounds including essential oils, fats, sterols, organic acids and phenolics (Panossian et al., 2010).

Dopamine and norepinephrine levels are deficient in cases of ADHD. In vitro, studies of R. rosea extract suggest that one of its mechanisms of activity is stimulation of the reticular activating system and elevation in levels of the neurotransmitters dopamine, serotonin and norephinephrine. (Petkov et al., 1986; Stancheva & Mosharrof, 1987; van Diermen, Marston, Bravo, Reist, Carrupt & Hostettman, 2009). Furthermore, R. rosea helps balance the stress-response system by preventing excessive release of stress hormones like cortisol (Panossian et al., 2010). Salidroside, an important neuroprotective constituent of R. rosea blocks apoptosis in rat neuronal cells (Cai et al. 2008), attenuates glutamate-induced apoptosis in primary hippocampal neurons (Chen et al. 2008), protects neuronal PC12 cells against amyloid peptide cytotoxicity (Jang et al. 2003) and protects human cortical cells against oxidative injury (Palumbo, Occhiuto, Spadaro, & Circosta, 2012). R. rosea extracts alone, salidroside, and a combination of R. rosea, Schizandra chinensis, and Eleutherococcus senticosus (Adapt232, Swedish Herbal Institute) exhibit metabolic and transcriptional effects on mediators of the stress response, homeostasis, energy metabolism, and the neuroendocrine-immune system (Panossian et al., 2013). While hundreds of pharmacological studies have been performed on R. Rosea extract and components, which particular bioactive components mediate specific therapeutic effects continues to be investigated.

In clinical trials, R. rosea has been studied as part of 11 RCTs evaluating its effects on mental health conditions, mental performance and physical performance in high school students, college students and military cadets. Studies have shown that R. Rosea can improve cognitive functions such as attention, accuracy and memory (Darbinyan et al., 2000; Shevtsov et al., 2003; Spasov, Mandrikov, & Mironova, 2000; Spasov, Wikman et al., 2000), reduce mental fatigue (Olsson et al., 2009) and exert anti-depressant effects (Darbinyan et al., 2007). The extracts were well tolerated across studies, including in elderly patients without any reports of significant adverse effects. Additional studies are needed to further explore potential benefits in neuropsychiatric disorders such as ADHD.

R. rosea root extracts have inhibited CYP3A4 enzyme systems in vitro (Hellum et al., 2010). However, subsequent studies have shown no significant effects on CYP3A4 isozymes in animal in vivo studies (Panossian, 2013). Furthermore, there have been no reports of significant herb-drug interactions (HDIs) in any human studies (Gerbarg & Brown, 2013; Brinker, 2010). Although R. rosea does not significantly affect metabolism of warfarin, it has a mild anti-platelet affect and may cause bruising, usually when taken in doses exceeding the recommended maximum dose (800 mg/day). Theoretically, this could increase the risk of bleeding in patients on warfarin or other anti-coagulant drugs. However, no cases of increased bleeding due to R. rosea HDIs have been reported to date. This is in contrast to numerous studies and reports of R. rosea extract enhancing the benefits of medications, including chemotherapy agents (Brown & Gerbarg, 2004; Brown, Gerbarg, & Muskin, 2009; Gerbarg & Brown, 2013; Brinker, 2010).

Physician supervision is advised when using R. rosea as a sole or complementary treatment for ADHD. In milder cases, R. rosea has been used as a solo treatment. It can be mentally stimulating while also emotionally calming. When used as an adjunct to pharmacologic stimulants, R. rosea is generally well tolerated. For pediatric use, small doses can be made by dissolving a capsule form of dry root extract, for example, Rosavin (Ameriden International) containing 100mg R. rosea, in 8-ounces of any liquid, labeled, stored in the refrigerator, and administered in appropriate amounts with one ounce containing 12.5 mg of extract. R. rosea should be given in the morning on an empty stomach to maintain its effect throughout the course of the day. For children 8–12 years old, very small doses can be helpful in ameliorating symptoms of ADHD, particularly in cases in which increases in prescription stimulant doses are problematic. For children 12–18 years old, R. rosea can be started at 50mg/day and increased by 50mg every 5–7 days, up to a maximum of 500mg/day and as long as it is well tolerated. Doses above 600mg per day are not recommended as these dosages have not yet been adequately studied nor have they proven clinically useful (Brown & Gerbarg, 2012a; Brown, Gerbarg, & Muskin, 2009).

Ginkgo Biloba

Ginkgo Biloba, extracted from the leaves of the maidenhair tree, has been used for centuries in traditional Chinese medicine to treat cognitive and memory impairments. The most studied standardized Ginkgo extract, EGb 761, contains hundreds of chemical constituents including 24% flavinoid glycosides, 6% terpenoids and 5–10% organic acids. The flavonoid and terpene fractions are believed to mediate bio-active properties.

Biological studies provide evidence that components of G. Biloba extract have anti-oxidant qualities (Ahlemeyer & Krieglstein, 2003; Smith & Luo, 2004; Wei et al., 2000), anti-apoptotic functions (Ahlemeyer, Möwes, & Krieglstein, 1999; Defeudis, 2002), protect against mitochondrial dysfunction (Shi et al., 2009), improve blood perfusion (Koltermann et al., 2007) and decrease ischemia-reperfusion injury (Saleem, Zhuang, Biswal, Christern & Doré, 2008). Administration of the flavonoid and terpene fractions of G. Biloba in rats increased extracellular dopamine levels in the prefrontal cortex; an area deficient in this neurotransmitter in ADHD patients (Yoshitake, Yoshitake & Kehr, 2010). Although in vitro and animal studies indicate that Ginkgo extracts inhibits MAO activity (Fehske, Leuner & Muller, 2009; White, Scates & Cooper, 1996), human imaging studies following ginkgo treatment did not detect any change in MAO A or B levels (Ponto & Schultz, 2003). This could be explained by differences in dosing, which tend to be higher in animal studies than in human studies (Diamond & Bailey, 2013) or by differences in the metabolism of humans compared to that of rodents.

Given G. Biloba extract’s neuroprotective activities, a number of studies have assessed its effects on cognitive functions in neuropsychiatric diseases. Meta-analyses indicate that Ginkgo significantly improved selective attention, fluid intelligence, memory, executive function and processing speed compared to placebo (Diamond & Bailey, 2013). These cognitive domains are often impaired in ADHD patients. Initial studies of patients with dementia using heterogeneous methodologies found mixed results (Herrschaft et al., 2012). In a small pilot study of adolescents (n = 6) with ADHD plus co-morbid disorders 200mg/daily of EGb 761 significantly improved arousal, hyperactivity, anxiety, frustration tolerance and cognitive aspects of attentional processing (Niederhofer, 2010). Another 6 week randomized, double-blind, placebo controlled study of 50 children with ADHD compared 80–120mg of G. Biloba T.D. to 20–30mg of methylphenidate. Methylphenidate was far more effective than G. Biloba T.D. for ADHD (Salehi et al., 2010). However, these results may be due to subtherapeutic doses and/or a less potent preparation called G. Biloba T.D. Additional RCTs using adequate doses of a preparation such as EGb 761 with an established record of efficacy in clinical trials are warranted.

Under physician supervision, G. Biloba can be used as a complementary treatment for patients with ADHD. It can be helpful for patients who are overly sensitive to and overly stimulated by prescription stimulants, R. rosea or other treatments. It can also reduce residual ADHD symptoms and be used concurrently with medications or other herbs. For example, in a four-week pilot study G. biloba combined with American Ginseng (Panax Quinquefolium) reduced symptoms in children with ADHD symptoms (Lyon et al., 2001). Ginkgo rarely causes side effects, but when it does, these can be minimized by starting with lower doses and gradually increasing until therapeutic effects are attained while monitoring for side effects such as nausea, headaches and skin rashes. Caution is advised when administering Ginkgo to patients taking anticoagulants such as heparin, warfarin and aspirin, and its use should be discontinued two weeks prior to surgery.

Neurohormones: Melatonin

Parents report sleep problems in 25–55% of ADHD patients (Corkum, Tannock & Moldofsky 1998). A meta-analysis including 16 clinical trials showed that children with ADHD are significantly more impaired in both subjective measures (bedtime resistance, sleep onset difficulties, morning awakening difficulties, etc) and objective measures (number of stage shifts/hrs sleep, apnea-hyponea index, etc) of sleep disturbances (Cortese, Faraone, Konofal, & Lecendreux, 2009). There are multiple causes of sleep problems associated with ADHD including side effects of stimulant medications, restless leg syndrome, sleep-disordered breathing, sleep onset insomnia, co-morbid psychiatric conditions and poor sleep hygiene. Patients with ADHD who have sleep problems need a diagnostic evaluation using clinical interviews, structured assessment tools and possibly sleep studies (Weiss & Salpekar, 2010). Whether common pathophysiological processes can explain both sleep problems and ADHD symptoms is an active area of investigation.

Melatonin is a natural hormone found in both plants and animals. In humans, it is secreted by the pineal gland in response to the 24-hour day-night cycle. Production of melatonin is inhibited by light and promoted in darkness. Once secreted, it binds to melatonin receptors in the suprachiasmatic nucleus of the hypothalamus resulting in reduced body temperature and sedation, possibly via increased GABAergic inhibitory effects (Bendz & Scates, 2010).

Chronic sleep onset insomnia can account for one third to one half of the cases of sleep disturbances among children with ADHD (Bendtz et al. 2010). These children with insomnia show both a delayed sleep phase as well as delayed secretion of melatonin compared with ADHD children without chronic insomnia (van der Heijden, Smits, van Someren, & Gunning, 2005). This suggests that ADHD patients with chronic insomnia may benefit from a trial of melatonin to promote sleep onset. In a four week double-blind, randomized, placebo-controlled study of 105 children (ages 6–12) with sleep onset insomnia and ADHD, those given melatonin showed significant improvements in sleep latency (p=.01) and sleep efficiency (p=.01) (van der Heijden, Smits, van Someren, Ridderinkhof & Gunning, 2007). A 3 year follow-up study of these children found that 65% continued to use melatonin every evening and 12% used it occasionally. Long term melatonin treatment was determined to be an effective treatment for sleep onset problems in 88% of cases. Temporal discontinuation of treatment resulted in delayed onset of sleep in 92% of children. While melatonin supplementation did not affect behavioral or mood symptoms after four weeks of use, parents reported improvements in both behavior (71%) and mood (61%) in the follow-up study. No adverse effects or safety concerns were noted (Hoebert, van der Heijden, van Geijlswijk & Smits, 2009). Thus, melatonin can be used as a complementary treatment for patients with ADHD and sleep onset insomnia. Melatonin, available as an over-the-counter supplement since 1993, causes few side effects (headache, dizziness, nausea, fatigue) and lacks a “hangover” effect unlike other sleep agents. Its use in patients with severe neurological deficits and epilepsy is controversial (Feucht & Patel, 2011). Use of melatonin products with proven efficacy in clinical trials and evaluated for potency and purity is advisable. Melatonin is available in tablet, capsule, liquid and sublingual forms. Dosing starts at 0.3–1mg with a final dose range of 1 to 3mg for children weighing 100 pounds (40 kg) or less and 3–6 mg for those over 100 pounds (40 kg). Melatonin comes in a fast-release formulation for sleep onset problems, slow-release for sleep maintenance, and a combination of both formulations.

Racetams

Nootrophic are a diverse group of drugs, supplements and nutraceuticals that enhance cognitive functions. The term was coined after the discovery of piracetam, the first member of a class of compounds called racetams, which contribute to multiple neurophysiological actions. For example, piracetam is a positive allosteric modulator of AMPA receptors (Copani et al., 1992; O’Neill & Witkin, 2007). AMPA receptors are ionotropic glutamate receptors involved in excitatory neurotransmission, learning and memory (Ahmed & Oswald, 2010). Racetams have also been implicated in neuroprotection, the release of brain-derived neurotrophic factor (BDNF), long-term potentiation, enhanced connectivity, and other potentially cognitive enhancing processes (Wu et al., 2004). A significant percentage of children with ADHD also have learning disabilities or language impairments. These children with co-morbid conditions perform worse on measures of cognitive function and academic achievement (Cohen et al., 2000; Jonsdottir, Bouma, Sergeant, & Scherder, 2005). Clinically, the racetams such as piracetam, aniracetam and pramiracetam have been found to be helpful in treating these impairments. A randomized, double-blind, placebo controlled study of 225 children with dyslexia (ages 7–12) found that administration of 3,600mg/day of piracetam resulted in significant improvements in reading and comprehension. The improvements were evident after 12 weeks and remained throughout the full 36 weeks of the trial. There were no adverse reactions to piracetam (Wilsher et al., 1987). Additional studies are needed to extend these findings to children diagnosed with ADHD and dyslexia.

Under physician supervision, racetams can be used as a complementary treatment for patients with ADHD who have co-morbid learning or language-related disabilities. Based on the authors’ clinical experience, pramiracetam tends to be more calming, whereas aniracetam is more stimulating. For aniracetam, 750mg twice a day can be particularly effective, well-tolerated and unlikely to cause agitation or other side effects. Additional trials for children with ADHD and learning or language disabilities would be worthwhile.

Mind-Body Practices for ADHD

Mind-body practices constitute a large and diverse group of mental and physical practices including yoga, tai chi, qi gong, meditation, and paced breathing, as well as many others. While there are plenty of unique mind-body practices, only a few have been studied in ADHD. This section focuses on those that have are evidence-based and have been found to be clinically helpful to patients with ADHD (For a more extensive discussion see Brown & Gerbarg, 2012b).

Patients with ADHD and co-morbid conditions such as conduct disorder (CD) and oppositional defiant disorder (ODD) can demonstrate detrimental externalizing behaviors such as physical aggression, bullying, defiance, theft and vandalism. Hyperactive/impulsive patients have a number of structural and functional abnormalities in the central nervous system (Castellanos et al., 2003; Durston et al., 2003; Valera, Faraone, Murray, & Seidman, 2007) and the peripheral nervous system (Scarpa & Raine, 1997; Crowell et al., 2006). These include imbalances in autonomic nervous system (ANS) activity associated with symptoms of impulsivity, hyperactivity, emotional reactivity and aggressiveness (Beauchaine, Gatze-Kopp, & Mead, 2007). Using cardiac physiological markers, autonomic nervous system activity was compared in children with either hyperactive/impulsive ADHD, aggressive CD or control adolescents. Those with ADHD or CD showed reduced vagal parasympathetic activity, which has been associated with impaired emotional regulatory control. These children also had lower thresholds for fight-flight reactions and when challenged with a videotaped conflict demonstrated increased vagal parasympathetic withdrawal compared to controls. (Beauchaine, Katkin, Strassberg, & Snarr, 2001, Beauchaine et al., 2013). A number of mind-body systems such as yoga postures, breathing techniques and meditation have been found to modulate autonomic nervous system activity (Bernardi, Porta, Gabutti, Spicuzza, & Sleight, 2001; Brown & Gerbarg, 2005; Raghuraj, Ramakrishnan, Nagendra & Telles, 1998; Telles, Gaur, & Balkrishna, 2009). Balancing the ANS and correcting such abnormalities may explain many of the beneficial effects of mind-body practices in patients with ADHD (Brown & Gerbarg 2012b, Brown, Gerbarg, & Muench, 2013). Using cardiac markers of ANS activity in a small study of 11 healthy yoga practitioners versus 11 matched healthy non-yoga practitioners, yoga practice induced significantly higher parasympathetic nervous system activity compared to a walking control intervention (Khattab, Khattab, Ortak, Richardt, & Bonnemeier 2007).

Mind-body practices can also affect neurotransmitter levels. For example, a Mass Resonance Spectroscopy (MRS) study revealed that thalamic GABA levels increased immediately after yoga sessions (Streeter et al., 2007) and over a 12 week period of yoga practice (Streeter et al., 2010).

Structural anatomic changes associated with mind-body practices are being studied. In small studies, cortical regions associated with attention, interoception, and auditory and visual processing were thicker in long-term meditators than in matched controls (Lazar et al., 2005). Following an 8 week mindfulness-based stress reduction program, increases in gray matter were observed in areas involved in learning, memory and emotion regulation (Hölzel et al., 2011).

Yoga

A preliminary randomized controlled trial assessing the effects of a multi-component, yoga-based program on adolescents (age 17–18) compared to a physical education control group found that the yoga treatment group showed significantly improved measures of mood and anxiety (Noggle, Steiner, Minami, & Khalsa, 2012). A study of another multi-component, yoga program with 445 adolescents (ages 14–18) found that the yoga treatment group showed significantly reduced measures of impulsivity as compared to the control group (Ghahremani et al., 2013).

Two randomized clinical trials have looked at the effects of yoga specifically on children and adolescents with ADHD. In a small randomized controlled study, 19 boys (ages 8–13) with hyperactive/impulsive ADHD stabilized on pharmacotherapy were randomized to a 20 session yoga program or to a control group comprising interactive games. The yoga group, but not the control group, showed significant improvements on the five subscales of the Conners’ Parents Rating Scales (CPRS). For the yoga group, the degree of improvement on the Conners’ Teacher Rating Scales (CTRS) correlated with the number of sessions. However, neither group showed statistically significant scores rated by teachers. The study was limited by a small sample size and by differences in assessment conditions between parents and teachers (Jensen & Kenny, 2004). In another randomized controlled study, 19 children with ADHD (ages 8–13) were assigned to either a yoga program (twenty weekly 1 hour yoga group) or a conventional program of motor exercises for 34 weeks. The yoga training was superior for all outcome measures of an ADHD rating scale for parents and teachers. The small sample size, attendance variability and exclusion of children with co-morbid behavioral conditions were among the limitations of this study (Haffner, Roos, Goldstein, Parzer, &Resch, 2006). Neither study reported any safety problems or adverse effects in the yoga treatment group. A recent review gave a Grade B for current evidence supporting the use of yoga as an adjunct to pharmacotherapy in children with ADHD (Balasubramaniam, Telles, & Doraiswamy, 2013).

Mindfulness

Mindfulness, a form of meditation, involves non-judgmental observation of the present moment (Ludwig & Kabat-Zinn, 2008). Mindfulness training for children and adolescents may be effective in the treatment of physiological, psychosocial and behavioral conditions (Black, Milam, & Sussman, 2009). A small pilot study of an 8-week mindfulness training program for 10 adolescents (aged 11–15) with ADHD, showed reduction in attention and behavioral problems and improvements in executive function as reported by parents and tutors. However, at 16-week follow-up, reductions in problem behaviors and attention performance did not persist (van der Oord, Bogels, & Peijnenburg, 2012). A review of meditation treatments for ADHD was unable to draw any conclusions regarding the effectiveness of meditation therapy for ADHD given the limited number of studies and sample sizes (Krisanaprakornkit, Ngamjarus, Witoonchart, & Pyakhatkul, 2010). More trials are needed to assess the role of different meditation treatments on ADHD symptoms.

Considering that initial reports of mind-body practices such as yoga training demonstrate benefits in children with ADHD; physicians and parents may consider a trial of yoga as a complementary treatment. Parents should learn about the yoga programs available in their area and identify teachers with experience in working with children with special needs. Assuming no physical contraindications and depending on the frequency of classes, a trial of yoga for several weeks or a month may be needed before assessing results. Children who are too symptomatic to participate in a class may be referred for individual sessions to a yoga therapist. In addition, some schools may offer or be willing to offer yoga programs as part of their curriculum.

Neurofeedback for ADHD

Neurofeedback (NF) utilizes real time electroencephalography (EEG) or hemoencephalography (HEG) recordings to allow patients to self-regulate and reinforce specific aspects of their own neuronal activity. The patient’s recorded EEG or HEG activity is entered into a computerized training program which then feeds the information back to the patient by through visual cues on a monitor or acoustic cues such as radio carrier waves. These cues enable patients to self-regulate specific aspects of brain activity using the training program.

Various neurofeedback training programs have been utilized in patients with ADHD to regulate aspects of brain activity (Larsen & Sherlin, 2013). A subgroup of patients with ADHD has excessive theta activity and/or reduced beta activity both at rest and while performing tasks (Gevensleben et al., 2014). In the theta/beta training protocol, patients learn to decrease EEG activity in the theta band (4–7 Hz) while increasing activity in the beta band (12–25 Hz). This corresponds to a relaxed yet attentive mental state. Sensorimotor rhythm training focuses on increasing activity in the mid-beta (12–15 Hz) band; an activity pattern associated with active concentration. In patients with ADHD, this training protocol has been used to improve sleeping problems and increase vigilance (Arns & Kenemans, 2012). Slow cortical potential (SCP) training involves the ability to self-regulate SCP activity. SCPs are EEG polarizations that reflect cortical excitability. When SCPs are shifted in the negative direction, cell assemblies have a lower threshold of excitation; when they are shifted in the positive direction, cell assemblies have a higher threshold of excitation (Leins et al., 2007). Children with ADHD have reduced shifts in the negative direction suggesting an overall higher threshold for brain activation when mental activity is required. In such cases, neurofeed-back aims to correct abnormal underlying SCP activity and cortical excitability.

Early studies on the effects of NF treatment in children with ADHD exhibited methodological limitations and mixed results. More recently, in a multicenter, randomized, controlled study of 102 children (ages 8–12) with untreated ADHD, the effect of neurofeedback training was compared to a computerized attention skill training program (Gevensleben et al., 2009). NF training included a block of theta/beta training and a block of slow cortical potential training (36 sessions, 50 minutes per session). The NF group demonstrated statistically significant improvements in parent and teacher ratings of ADHD symptoms with medium effect sizes of 0.4–0.6. Only 8 children discontinued the study. A 6-month follow-up study of 61 patients showed sustained superior scores for the NF group compared to the control group with improvements in both core ADHD symptoms as well as in other functional domains. For theta/beta training, decrease of theta activity in the resting EEG was associated with an improvement in ADHD symptoms. Similarly, change in alpha activity predicted clinical improvement following SCP training. These results suggest specificity of treatment effects (Gevensleben et al., 2010). Further studies using improved techniques and individualized treatments are expected.

Neurofeedback may be used as an alternative or complementary treatment for patients suffering from ADHD. While additional data is needed, patients who demonstrate increased theta or theta/beta ratios are more likely to benefit from treatment with NF. Moreover, NF is most effective for inattention and impulsivity (Sherlin et al., 2011). In practice, children treat NF interventions as if they were computer games and they rarely result in side effects. Still, there are some individuals who are sensitive to treatment. Side effects may include headache, nausea, dizziness, sleepiness or agitation. Furthermore, frequent (1–3/week) and prolonged (2–12 months) treatments are often required and may not be covered by insurance. The International Society for Neurofeedback (www.isnr.org) provides information as well as training workshops and certification for practitioners.

CONCLUSIONS

While conventional psychopharmacology and behavioral therapies are mainstays of ADHD treatment, more can be achieved when these standard treatments are integrated with complementary approaches. We have highlighted evidence-based alternative treatments shown to be particularly useful for ADHD. In addition, many promising approaches warrant further study. Interest in integrative psychiatry (IP) grows as practitioners discover a more diverse set of tools for helping their patients. While CAM approaches are popular amongst patients, health professionals have received limited education in these interventions and often are unaware of their patients’ use of CAM treatments. Through education and with further rigorous research, validated integrative treatments will provide more effective, lower risk and lower cost care for patients with ADHD.

Biographies

Anup Sharma, MD PhD is a PGY4 resident in the Department of Psychiatry at the University of Pennsylvania School of Medicine.

Patricia L. Gerbarg, MD is an Assistant Clinical Professor of Psychiatry at New York Medical College.

Richard P. Brown, MD is an Associate Clinical Professor of Psychiatry at Columbia University College of Physicians and Surgeons, NY