Herbal Medicines in Pediatric Neuropsychiatry

Herbal Medicines in Pediatric N e u ro p s y c h i a t r y Cynthia Feucht,

PharmD, BCPS

a,b,

*, Dilip R. Patel,

MD, FSAM

c

KEYWORDS  Herbal supplement  Neuropsychiatric  Pediatric  Adolescent  Complementary medicine

Mainstream medicine in Western society is based on conventional medicine, also referred to as allopathic or biomedicine.1 The National Center for Complementary and Alternative Medicine (NCCAM), a division of the National Institute of Health, was originally established in 1992 as the Office of Alternative Medicine and was promoted to a center in 1999.2 The goal of the Center is to sponsor and support research in complementary and alternative medicine (CAM), with funding appropriations increasing from 2 million US dollars in 1992 to 128 million US dollars in 2010.3 NCCAM has devised 4 domains for CAM therapy, recognizing that there is the potential for overlap as well as whole medical systems that may cover all 4 domains.1 Whole medical systems are based on systems of theory and practice and within the United States most commonly include homeopathic and naturopathic medicine.1 Mind-body medicine encompasses techniques including cognitive-behavioral therapy, meditation, and prayer, whereas biologically based practices include the use of herbal and dietary supplements.1 Manipulative and body-based practices include massage and chiropractic or osteopathic manipulation.1 Energy medicine revolves around the use of energy fields and includes Reiki, therapeutic touch, and use of electromagnetic fields.1 This article focuses on the review of just one aspect of CAM therapy, herbal supplements, which have been used for pediatric and adolescent neuropsychiatric disorders, and includes a discussion of the various supplements and limited literature surrounding their use. Herbal medicines have been used since the Greek and Roman era and gained popularity in the United States in the 1700s and 1800s.4 As allopathic medicine became dominant in the twentieth century, use of herbal therapies diminished. In the 1990s the US Food and Drug Administration (FDA) proposed stringent regulations a

Borgess Ambulatory Care, 1701 Gull Road, Kalamazoo, MI 49048, USA Department of Pharmacy Practice, Ferris State University College of Pharmacy, Big Rapids, MI 49307, USA c Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, MSU/Kalamazoo Center for Medical Studies, 1000 Oakland Drive, Kalamazoo, MI 49009-1284, USA * Corresponding author. Borgess Ambulatory Care, 1701 Gull Road, Kalamazoo, MI 49048. E-mail address: [email protected] b

Pediatr Clin N Am 58 (2011) 33–54 doi:10.1016/j.pcl.2010.10.006 pediatric.theclinics.com 0031-3955/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.

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for the marketing of herbal supplements. Opposition by consumers and supplement manufacturers led to a compromise and passage of the Dietary Supplement Health and Education Act by Congress in 1994.4 This Act led to the classification of herbal products as dietary supplements when manufacturers can make claims about health and nutrient content as well as about how the supplement affects structure and function of the body but cannot claim to cure, prevent, or treat specific diseases.5 Herbal and dietary supplements are not subjected to the approval process that traditional medicines undergo by the FDA. The manufacturer should ensure safety and accurate labeling of the product but does not have to register the product or notify the FDA of its production unless a new dietary ingredient is used.5 The FDA is responsible for postmarketing activities, including monitoring of adverse events via voluntary reporting and product information (eg, labels, claims, package inserts).5 HERBAL COMPONENTS

There are many different chemical constituents in herbal plants that can have therapeutic as well as toxic effects. Herbal supplements may come prepared as tablets/capsules, powders, tinctures, syrups, and brewed teas for oral consumption.6 Other preparations for topical application include salves, ointments, and shampoos. Parts of the plant that may be used include the flower, leaves, stem, roots, seeds, and berries.6 Bioflavonoids, one of the major herbal components, include flavonoids that can be found in flowers, citrus fruits, red wine, and tea and are believed to have antioxidant properties.7 Essential oils give the characteristic odor of the plants and are often referred to as volatile oils or essences.6,7 They have been used for treating skin and respiratory disorders and in aromatherapy.7 Glycosides are derived from plant chemicals containing a carbohydrate residue attached to a noncarbohydrate residue. Common glycosides include digoxin (used in allopathic medicine for cardiovascular conditions), anthraquinones (laxatives), and isothiocyanates (alliin in garlic, used for food flavoring and cholesterol-lowering properties).7 Resins are protective substances secreted by plants that when mixed with volative oils produce oleoresins and when mixed with cinnamic or benzoic acid produce a balsam.7 Other components include saponins (soaplike glycosides), which may be used for their mucolytic and expectorant properties, phytosterols (eg, soy), which claim to have antiinflammatory and antioxidant properties, and terpenes, which are the most common phytochemicals and are found in a variety of products including vegetables, soy, and grains.7 Terpenes are varied in chemical structure and are promoted for their antioxidant properties. Table 1 lists the various herbal components, examples, sources, and claimed benefits. PRODUCT QUALITY ASSURANCE

Quality control of herbal supplements within the United States remains largely unregulated. There are no standard governmental regulations that ensure good manufacturing processes and product reliability. Standardization of herbal supplements is challenging because of the chemical complexity of botanicals, which may contain multiple active ingredients, and because of uncertainty about which ingredient is contributing to the therapeutic effect.8 Laboratory analysis of multiple brands of a herbal supplement can reveal several-fold differences in the concentrations of the active components.8 A variety of factors can also contribute to differences in the concentrations of the active constituents, including the part of the plant used, growing conditions, timing of harvest, geography and soil conditions, processing methods, and storage conditions.6,8 Therefore, herbal supplements can vary in chemical composition,

Herbal Medicines in Pediatric Neuropsychiatry

Table 1 Chemical components of herbal supplements Classification

Chemical

Source

Potential Benefit

Imidazole

Ephedrine

Ma Huang

Asthma, weight loss

Indole

Yohimbine

Yohimbe

Aphrodisiac, benign prostate hyperplasia

Purine

Caffeine

Coffee, tea

Stimulant

Alkaloids

Bioflavonoids Flavonoid

Apigenin

Chamomile

Antiinflammatory

Isoflavonoids

Daidzein

Soy

Estrogenic, menopause

Flavonolignans

Silymarin

Milk thistle

Liver protection

Alcohols

Menthol

Mints

Antitussive

Phenols

Capsaicin

Capsicum

Counterirritant

Phenols

Thymol

Thyme

Antibacterial

Saponins

Glycyrrhizin

Licorice

Peptic ulcer

Anthraquinones

Sennosides

Senna

Laxative

Isothiocyanates

Alliin

Garlic

Cholesterol-lowering

Coumarins

Dicumarol

Sweet clover

Anticoagulant

Pure resins

Guaiac

Expectorant

Oleoresins

Turpentine

Expectorant

Balsams

Benzoin

Anesthetic

Essential Oils

Glycosides

Resins

Saponins Steroidal

Digitoxin

Foxglove

Cardiovascular

Terpenoid

Cycloartanes

Black cohosh

Estrogenic

b-Sitosterol

Soy

Cholesterol-lowering Antiinflammatory Benign prostate hyperplasia

Diterpenes

Capsianosides

Capsicum

Counterirritant

Diterpenes

Ginkoglides

Ginkgo

Antiinflammatory

Tetraterpenes

Carotene

Carrot

Antioxidant

Tetraterpenes

Lycopene

Tomato

Anticancer

Sterols Phytosterol

Terpinoids

Data from Chemistry of herbal medications. In: Rotblatt M, Ziment I, editors. Evidence-based herbal medicine. Philadelphia: Hanley & Belfus; 2002. p. 29–44.

concentrations of active ingredients, and overall quality, which give each brand its uniqueness.8 Contributing to the complexity of the problem is the potential for contamination or adulteration of herbal supplements. Production and harvesting of plants in contaminated soils or improper processing can lead to contamination, which if these substances are pharmacologically active can contribute to toxicity.6,8 Contaminants and adulterants that have been found in supplements include heavy metals, bacteria, and fungi.2,6,9–11 Chinese and Ayurvedic herbal medicines have been associated with

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contamination by heavy metals, with cases of lead poisoning being reported.6,11 A review of 319 children in Taipei who tested positive for increased blood lead concentrations found a significant correlation with the use of Chinese herbal medicine (specifically Ba-baw-san).12 Fungal contamination was observed in Croatia when 62 medicinal plant materials and 11 herbal tea samples were analyzed. The most common fungus species isolated included Aspergillus and Penicillium, with 18% of medicinal plants and 9% of herbal teas containing Aspergillus flavus.13 Herbal supplements have also been found to be adulterated with other substances. In Taiwan, 2609 samples of Chinese medicines were collected over 1 year and analyzed. Of the medicines, 23.7% were found to be adulterated and 52.8% contained more than one adulterant.14 The most common identified substances included acetaminophen, caffeine, indomethacin, hydrochlorothiazide, and prednisolone.14 Table 2 lists some of the contaminants and adulterants identified in herbal supplements. Misidentification of the plant, whether intentionally or inadvertently, can lead to serious consequences.10,11 A diet supplement that should have contained the Chinese supplement Fangji (Stephania tetrandra) may have contained Fangchi (Aristolochia fangchi), causing individuals in Brussels to develop interstitial nephritis.15 In Colorado, 3 children who had taken large quantities of the Chinese supplement Jin Bu Huan developed bradycardia and respiratory and depression of the central nervous system (CNS). The reaction was attributed to large quantities of levo-tetrahydropalmatine,

Table 2 Contaminants and adulterants found in herbal supplements Category

Examples

Heavy metals

Lead Aluminum Arsenic Cadmium Mercury

Bacteria

Staphylococcus aureus Salmonella Shigella Pseudomonas aeruginosa

Mycoses

Aspergillus Penicillium Mucor

Pesticides and herbicides

Chlorinated pesticides (eg, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, hexachlorobenzene) Organic phosphates Carbamate insecticides and herbicides Triazin herbicides

Other agents

Aspirin Caffeine Corticosteroids Diazepam Ephedrine Indomethacin Acetaminophen Theophylline Thiazide diuretics Chlorpheniramine

Data from Refs.2,9,11

Herbal Medicines in Pediatric Neuropsychiatry

which is found in the plant genus Stephania and not Polygala as noted in the package insert.16 Numerous nomenclature systems of identifying plants contribute to the problem, with multiple names that can identify a single product, including common name, scientific name, foreign name, and brand name.11 In 2000, the World Health Organization published a report evaluating 8985 case reports of adverse events associated with herbal supplements from 1968 to 1997.17 Of these adverse events, w1% were noted to occur in children up to 9 years old and an additional 1% in those 10 to 19 years old.17 Toxicity in children can occur because of the active ingredient itself, from contaminants or adulterants, and from interactions between the herbal supplement and other medications.10 Although there is no standardization and little regulatory oversight of herbal supplements and the potential for contaminants and adulterants exists, there are manufacturers that produce high-quality products. Trying to identify those brands that choose to undergo more rigorous testing to ensure quality can be challenging, and the following recommendations have been put forth. These include use of specific herbal supplements that have shown efficacy in rigorous controlled trials.8 If clinical trials do not exist, evaluate if the product has undergone independent laboratory quality-control testing.8 These tests seek to determine if the correct plant has been identified, that there are minimum concentrations of major constituents, and that impurities do not exist.8 One of the best sources for this is http://www.ConsumerLab.com, which performs product testing and provides supplement reviews and information regarding recalls and warnings; it requires a subscription for access to information.8 Additional quality control measures include the use of the United States Pharmacopeia (USP), which has established analytical standards (quality, purity, and potency) for a variety of botanic products.8,18 Products that meet these standards may include a USP Verified Dietary Supplement symbol on the label.18 The USP has a list of participating companies and verified products on their Web site (http://www.usp.org) and has also collaborated with the National Medicines Comprehensive Database and http://www.ConsumerReportsHealth.org in identifying USP-verified supplements alongside the drug information. Both of these systems require subscriptions for access to information. Currently all quality-assurance testing that manufacturers use for herbal supplements is on a voluntary basis. The other recommendations include use of herbal supplements that are manufactured by large pharmaceutical companies and researching manufacturers of herbal supplements.8 For proper evaluation, product labeling should include detailed information regarding ingredients, batch number, expiration date, and manufacturer contact information.8 USE WITHIN THE GENERAL PEDIATRIC AND ADOLESCENT POPULATION

Use of CAM therapy continues to gain in popularity, with numerous studies trying to quantify the numbers and types of individuals using CAM therapy. CAM therapy has been well documented in the adult population, and an increasing number of studies have sought to evaluate use within the pediatric population. Studies have been limited by small sample sizes and restriction to a locale or region and specific illnesses. In regards to specific illnesses, CAM use has been reported in patients with cystic fibrosis, juvenile rheumatoid arthritis, cancer, and asthma, with rates ranging from 46% to 70%.19 One of the first national studies involved a cross-sectional analysis of the 1996 Medical Expenditure Panel Survey, which is a subsample of the 1995 National Health Interview Survey.20 Of the 7371 children evaluated (age21 years), 2% reported having visited a CAM provider during the previous year, with only 12.3% reporting CAM use to their allopathic provider.20 Herbal therapies were the most common

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office-based therapy provided (22.4%), followed by spiritual healing/prayer (19.4%), homeopathic treatments (14.1%), and massage therapy (13.2%).20 The variable most highly associated with a child visiting a CAM provider was parents who visited a CAM provider. This study likely underestimates pediatric CAM use because there is no evaluation of self-administered CAM therapy and it relies on parental report. A prevalence study in 1999 evaluated the use of CAM therapy within a pediatric emergency department. Of the 525 questionnaires returned, 10.9% of the families reported using one form of CAM therapy for their child.19 Of those taking a herbal or homeopathic medicine, 40% reported using a prescription or over-the-counter product concurrently, 70.9% had informed their physician regarding the use of CAM therapy and only 35.8% noted that their physician had discussed the use of CAM therapy for treatment.19 Limitations to this study include wone-third of questionnaires were never returned, not all surveys were fully completed, the caregiver report was not reliable, and the study was limited to a single locale. Another survey in 2001 within an urban pediatric emergency department also sought to evaluate caregiver understanding and sources of information for herbal therapy in addition to patient use. Of the 142 families interviewed, 45% of caregivers noted use of herbal therapy within the past year.21 Within the previous 3 months, 61% had used a herbal supplement in conjunction with a prescription medication.21 Of all the caregivers interviewed, 77% did not believe that herbal supplements had side effects, or did not know if they had side effects, and 66% did not know if herbal supplements interacted with traditional medicines or believed that they did not interact with traditional medicines.21 Of those who provided supplements to their children, 80% received their information from family and friends, and only 45% reported use to their primary care provider.21 Although this study is limited by a small sample size and single location, it shows the prevalence of herbal use within the pediatric population and lack of knowledge on behalf of the caregivers, with underreporting to their primary care providers. Unlike most of the other surveys, one performed in 2002 sought to evaluate CAM and use of dietary supplements within adolescents by self-report. Respondents were drawn from a national sample and included 1280 adolescents aged 14 to 19 years.22 The study was conducted using an online self-administered survey, with incentives provided for completing the surveys. Of those surveyed, 46.2% reported using dietary supplements at least once in their lifetime, and 29.1% reported use within the past month.22 The most common supplements for current users included zinc, echinacea, ginseng, herbal or green tea, Gingko biloba, and creatine.22 Over their lifetime, 10.7% of the respondents had tried weight-loss supplements.22 Higher prevalence was noted in female respondents, and similar to previous studies, CAM use by adolescents was associated with parental use.22 This study indicates that adolescents are beginning to take an active role in their own health care and providers need to inquire about CAM use as well as provide education regarding risks and benefits. The most recent national survey was conducted as part of the 2007 National Health Interview Survey. The survey had expanded from the 2002 survey to include data regarding CAM use in children aged 0 to 17 years, and expanded the types of CAM therapy as well as the list of supplement products listed.23 Of the 9417 completed interviews of children, 3.9% reported use of supplements within the past 12 months.23 CAM therapies were most often used for musculoskeletal pain, colds, anxiety or stress, and attention-deficit/hyperactivity disorder (ADHD)/attention-deficit disorder.23 CAM use was more common among adolescents aged 12 to 17 years and White children, and increased with parental educational level.23 CAM use had a positive correlation with the number of health conditions and health provider visits within the previous

Herbal Medicines in Pediatric Neuropsychiatry

12 months as well as parental use of CAM therapy.23 CAM therapy was also more common when conventional care was unaffordable or worry about cost delayed conventional medical care.23 Unlike the other surveys, one study in 1997 sought out pediatricians’ views regarding CAM therapy, whether patients used or discussed CAM therapy, personal use, and referral practices for CAM therapy. Surveys were sent to fellows of the Michigan article of the American Academy of Pediatrics, and 348 were completed (40.5% response rate).24 Within the sample, 83.5% believed that their patients were using one form of CAM therapy but this comprised less than 10% of all their patients.24 Fifty-three percent of the respondents reported talking about CAM therapy with their patients but most was initiated by patients and families (84.7%).24 More than three-fourths (76.1%) believed that patients self-reported CAM use.24 With regards to personal use, only 37% used any type of CAM therapy, and referrals were most often for relaxation (56%), self-help groups (54.3%), acupuncture (51.1%), hypnosis (50.3%), biofeedback (49.1%), and massage therapy (46.3%).24 The data from the various studies and surveys indicate that pediatric patients do use CAM therapy and that this has been strongly correlated with parental use of CAM therapy. Communication between patient and provider is often lacking, with patients underreporting use and providers not inquiring about patient use of such therapy. Family and friends often serve as a source of information for CAM therapy, and many providers may feel uncomfortable discussing alternative therapy. Education is a critical component for both patients and providers in promoting safe and effective use of CAM therapy. HERBAL SUPPLEMENTS AND NEUROPSYCHIATRIC DISORDERS

It is not uncommon for patients to look to complementary therapy for the treatment of headaches, insomnia, depression, anxiety, and fatigue.25 Many supplements are promoted for treating these symptoms and patients may often self-treat before seeking professional treatment. As seen in the general population, a few surveys indicate that pediatric patients with neuropsychiatric disorders also turn to complementary therapy for treating a variety of ailments, including the primary neuropsychiatric disorder. A survey of adolescents with ADHD or depression in 5 community mental health centers in Texas found that 15% of the patients had taken herbal supplements within the past year.26 Herbal supplements were most commonly used to treat the behavior problem and included Gingko biloba, echinacea, and St John’s wort.26 Most patients did not discuss therapy with their health care providers. A cross-sectional survey was administered to caregivers of patients seen in neurodevelopmental pediatrics clinic in Hong Kong.27 Of the patients with autism spectrum disorder (ASD), 40.8% of patients had used CAM therapy in the past year, with acupuncture as the most common (47.5%) followed by sensory integration (42.5%) and Chinese medicine (30%).27 Over three-fourths of those interviewed believed that CAM therapy augmented traditional medicine.27 There are limited studies documenting CAM therapy in pediatric patients with neuropsychiatric disorders and even fewer studies evaluating herbal supplement use in treating these disorders.28 The following section reviews the most common herbal supplements (including St John’s wort, melatonin, valerian, kava, eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA], and those for weight loss) used within this patient population and briefly discusses the limited literature evaluating their use within the pediatric population.

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ST JOHN’S WORT

St John’s wort is likely the most heavily researched supplement, with the major focus on the treatment of depression. Other indications in which St John’s wort has been proposed to be beneficial but that lack sufficient supporting evidence include anxiety, obsessive-compulsive disorder (OCD), and seasonal affective disorder (SAD).29 The primary active ingredients of St John’s wort include naphthodianthrones (eg, hypericin), phloroglucinols (eg, hyperforin), flavonoids (eg, quercetin), proanthocyanidins (eg, catechin), and essential oils.30 Most products are standardized to include hypericin at concentrations of 0.1% to 0.4% and hyperforin at 2% to 4%.31 The exact mechanism of St John’s wort remains to be elucidated but it is believed to inhibit the reuptake of dopamine, serotonin, and norepinephrine.31,32 Hypericin has been shown to inhibit monoamine oxidase (MAO) in vitro, but in vivo it does not reach sufficiently high concentrations to show an effect.29,30 Studies of St John’s wort in pediatric patients have been limited by study design, small sample sizes, and short duration. Simeon and colleagues33 evaluated St John’s wort (300 mg 3 times daily) in 26 adolescents with major depressive disorder for 8 weeks in an open-label pilot study. Eleven patients completed the study and 82% of those showed clinically beneficial effects based on clinical global improvement change.33 Seven of the 15 who withdrew had persistent or worsening depression.33 A study by Findling and colleagues34 evaluated the use of St John’s wort in 33 children aged 6 to 16 years in an open-label design for 8 weeks. The initial dose was 150 mg 3 times daily and could be titrated up to 300 mg 3 times daily.34 Using the Children’s Depression Rating Scale (CDRS), 76% of the patients clinically improved and 93% continued therapy at the end of the study.34 St John’s wort has been fairly well tolerated in clinical studies, with the most common side effects reported as mild, including restlessness, insomnia, gastrointestinal (GI) upset, headache, fatigue, and dry mouth.32,33 Hypericin is believed to contribute to a photosensitivity reaction that has been observed with higher than usual doses of St John’s wort (2–4 g/d).29 Individuals with light or fair skin should use protective measures with sun exposure.29 Drug interactions continue to be a limitation to the use of St John’s wort. St John’s wort has been shown to induce the metabolism of drugs metabolized by cytochrome (CYP) 3A4, 1A2, and 2C9 and can result in reduced drug concentrations. Examples of drugs affected include oral contraceptives, cyclosporine, warfarin, tacrolimus, and protease inhibitors.29–31,35,36 In addition, St John’s wort has been found to induce the intestinal P-glycoprotein transporter, which can result in decreased absorption of the drug. Some examples of drugs potentially affected include digoxin, antifungals (eg, ketoconazole, itraconazole), corticosteroids, and erythromycin.29,30 Because St John’s wort increases serotonin, the risk of serotonin syndrome exists when combined with other agents that also increase serotonin.29,30,35,37 Agents that should be avoided because of the potential risks include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, tramadol, dextromethorphan, 5-HT1 agonists (eg, sumatriptan), MAO inhibitors, and meperidine.29,35 As seen with other antidepressants, St John’s wort may take several weeks to determine the full clinical effect and may induce a withdrawal syndrome on sudden discontinuation.30,31 Withdrawal symptoms may include GI upset, dizziness, confusion, insomnia, and fatigue.30 To avoid these symptoms, patients should gradually taper the dose before discontinuation. Table 3 gives a summary regarding St John’s wort.

Herbal Medicines in Pediatric Neuropsychiatry

Table 3 Supplement information: St John’s wort and melatonin St John’s Wort

Melatonin

Scientific Name

Hypericum perforatum

N-Acetyl-5-methoxytryptamine

Active components

Hypericin Hyperforin

Melatonin

Possible indications

Depression Anxiety ADHD OCD SAD

Insomnia Circadian rhythm disorder Benzodiazepine and nicotine withdrawal Cancer

Mechanism of action May inhibit reuptake of serotonin, Increase binding of GABA to dopamine, and norepinephrine receptors Inhibits GABA uptake Dosage

300 mg daily

0.3–9 mg daily

Adverse effects

Insomnia Vivid dreams Restlessness Agitation GI upset Dizziness Headache Photodermatitis Paresthesias Serotonin syndrome

Nausea Headache Dizziness Fatigue

Drug interactions

Induces CYP 450 3A4, 2C9, and 1A2 Substrate for CYP 1A2 Induces P-glycoprotein/multidrug resistance 1 (MDR-1) drug transporter

Additional comments Most supplements standardized to Use synthetic preparations to avoid risk of contamination with contain 0.3% hypericin animal-based products Increased risk of photosensitivity Avoid use in patients with immune with doses 2 gm/d (extract) dysfunction or taking Avoid abrupt discontinuation immunosuppressive agents because of risk of withdrawal Start with 0.3–1 mg and titrate effects accordingly Avoid use with other agents that increase serotonin (eg, SSRIs, TCAs, tramadol, dextromethorphan) Data from Refs.29–33,35–41

Although St John’s wort is one of the most commonly prescribed antidepressants in Germany, its use has been banned in France because of the potential for significant drug interactions.29,31 St John’s wort provides an alternative for treating depression in children and adolescents but still requires more well-designed studies to evaluate its benefits within the pediatric population. The side-effect profile and the potential for significant drug interactions should be considered before its initiation, and abrupt discontinuation should be avoided. MELATONIN

Endogenous melatonin is secreted by the pineal gland, along with other organs, to maintain a normal circadian rhythm.38 Production is regulated via a complex pathway,

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with stimulation occurring during periods of darkness and peak serum levels occurring before bedtime.38 Because of its ability to regulate the circadian rhythm, melatonin has been evaluated for a variety of conditions, including jet lag, night-shift work, and neuropsychiatric disorders.38 Melatonin is also believed to have immunomodulatory and antioxidant effects as well as antiproliferative properties.38 Melatonin is believed to exert its sedating effect by increasing binding of g-aminobutyric acid (GABA) to its receptors.38,39 Melatonin is rapidly absorbed on administration and undergoes extensive hepatic metabolism with a high first-pass effect.40 Bioavailability of exogenous melatonin is poor (10%–56%) and has a short half-life of 12 to 48 minutes.38 Evidence suggests that primary metabolism occurs via CYP1A2 and drugs that inhibit this isoenzyme (eg, fluvoxamine, cimetidine, ciprofloxacin) can lead to increased levels of melatonin.38,39 Additional drug interactions include the potentiation of warfarin (mechanism unknown) and decreased production of endogenous melatonin by nonsteroidal antiinflammatory drugs.38,39 Melatonin is fairly well tolerated, with the most common side effects reported as fatigue, headache, dizziness, and nausea.40,41 Melatonin lacks the hangover effect seen with other medications used to treat insomnia. Caution should be exercised when using melatonin in certain patient populations. Because of the immunostimulatory effects of melatonin, its use should be avoided in patients with immune dysfunction or who are taking immunosuppressive agents.41 Exogenous melatonin is known to affect several hormones, including prolactin, progesterone, and estradiol, and high doses have been shown to inhibit ovarian function.38,41 Use in patients with epilepsy has been controversial. A series of 6 patients with severe neurologic deficits received melatonin 5 mg nightly.42 Five patients subsequently developed new or increased seizure activity, with return to baseline on discontinuation.42 Three children were rechallenged with lower doses, and increased seizure activity was again noted.42 In contrast, 6 children with severe intractable seizures received melatonin 3 mg nightly to evaluate its antiepileptic effects in addition to their current antiepileptic therapy.43 Five of the 6 parents noted clinical improvement, and 2 of the 3 evaluated by polysomnography noted decreases in seizure activity.43 Because of the conflicting data and lack of controlled clinical trials evaluating its use in this patient population, caution should be exercised and patients monitored appropriately. Melatonin has been evaluated in children with primary and secondary sleep disorders. A meta-analysis by Buscemi and colleagues44 included 2 studies that evaluated the use of melatonin in children with chronic idiopathic sleep-onset insomnia. Melatonin 5 mg nightly was found to significantly reduced sleep-onset latency compared with placebo (difference: 16.7 minutes).40,44 Melatonin has also shown efficacy in treating insomnia in patients with developmental disabilities, ASD, and ADHD with or without concomitant stimulant medication.40,45,46 Phillips and Appleton45 performed a systematic review of exogenous melatonin in children with neurodevelopmental disabilities and sleep impairment. Only 3 randomized, double-blind, placebocontrolled studies were identified, which included a total of 35 children. The dosage of melatonin ranged from 0.5 to 7.5 mg daily across the 3 studies.45 Overall, sleep latency was significantly reduced in 2 studies and not reported in the third study.45 Total sleep time was increased in 4 of 6 patients in one study, with minimal effect in the other 2 studies, and no study reported an improvement in nighttime awakenings.45 Bendz and Scates46 performed a literature review and identified 4 studies evaluating exogenous melatonin in pediatric patients with ADHD. One open-label and 2 randomized, double-blind, placebo-controlled trials (sample size 24–105 patients each) found melatonin (3–6 mg daily) significantly reduced sleep latency, and one trial found an improvement in total sleep time.46 Two of the 3 trials evaluated patients taking

Herbal Medicines in Pediatric Neuropsychiatry

concurrent stimulant medications. The last trial was a follow-up to one of the previous trials and evaluated 94 stimulant-free patients who used melatonin (average 4 mg daily) for a mean duration of 18 months. Parent survey results noted a 90% efficacy for sleep-onset insomnia, 71% efficacy for behavior, and 61% efficacy for mood.46 Studies evaluating melatonin have noted benefit, most significantly for a reduction in sleep onset but have been limited by small sample sizes, differing doses, and varying methodology. Melatonin comes in a variety of formulations, including capsules, tablets, and liquid as well as immediate- and sustained-released products. Dosing guidelines have not been established within the pediatric population but if used, should begin with 0.3 to 1 mg and should be titrated accordingly.41 Recommendations for administration have ranged from 30 minutes up to 1 to 2 hours before bedtime. Patients should use synthetic formulations and avoid products produced from animal pineal gland to avoid the risk of contamination.39 See Table 3 for an information summary. VALERIAN

Valeriana officinalis is the most common species of the genus Valeriana that is used for medicinal properties.47 The root of the plant has been used for centuries for its purported benefits as an anxiolytic and sedative hypnotic. Valerian is also considered to have antispasmodic, anticonvulsant, and antidepressant effects.47 Volative oils and valepotriates may be the major components that contribute to the pharmacologic effects of valerian.47 Volative oils contain monoterpenes and sesquiterpenes (eg, valerenic acid) as well as giving valerian its characteristic odor.47–49 Valepotriates are unstable compounds and are quickly hydrolyzed in aqueous environments.41,47 Concern has been raised about the potential for cytotoxic and carcinogenic effects of valerian because many valepotriates have epoxide groups that can alkylate DNA.41 Although shown in vitro, these effects are unlikely to occur in vivo because of instability, minimal concentrations in marketed products, and poor absorption.41,48 The effects of valerian are believed to be mediated via an interaction with GABA receptors and are unlikely to occur from one single component.47–50 Other factors that can influence the effects of valerian and concentrations of active ingredients include species used, growing conditions of the plant, age of the herb, and method of extraction.41,49 The sedative and anxiolytic effects of valerian have been more extensively evaluated in adults than in pediatric patients. Most adult studies have used a valerian extract of 400 to 900 mg daily given 30 to 60 minutes before bedtime for the treatment of insomnia.49 Most but not all studies have shown a mild hypnotic effect, with a reduction in sleep latency and an overall improvement in sleep quality.41 A polysomnography study by Donath and colleagues51 evaluated valerian extract in 16 adult patients with insomnia. Patients were randomized to receive valerian extract 600 mg or placebo nightly and were evaluated after a single dose and after 14 days.51 Polysomnography results found no significant benefit after a single dose but after 14 days found a reduction in sleep latency (placebo 60 minutes vs valerian 45 minutes), onset to slow-wave sleep (SWS), and an increase in the duration of SWS.51 Only 2 studies have been conducted in pediatric patients: one evaluated its use for restlessness and dyssomnia, and the other for insomnia in children with intellectual deficits. For the treatment of restlessness and dyssomnia, 918 children (age<12 years) were given a combination product containing valerian and lemon balm.52 The study was an open-label, multicenter trial, and each patient received 2 tablets twice daily for 30 days (each tablet contained 160 mg dried valerian root

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extract and 80 mg of lemon balm).52 Analysis of the questionnaires revealed that symptoms changed from “moderate” and “severe” (66% at baseline) to “absent” and “mild” in 75% of those with restlessness at 4 weeks of treatment.52 In those patients with dyssomnia, symptoms changed from “moderate” and “severe” (77.1% at baseline) to “absent” and “mild” in 76.6% of patients at the end of the study.52 Investigators judged the tolerability to be “good” or “very good” in 96.7% of patients.52 Overall, 157 discontinued treatment early, with the most frequent reasons cited as treatment no longer needed and parent’s request.52 The second study evaluated the effects of valerian in 5 children (aged 7–14 years) with intellectual difficulties (IQ<70) and sleep problems in a double-blind, crossover fashion.53 The children received valerian (dried and crushed whole root of Valeriana edulis) 20 mg/kg each night 1 hour before bedtime.53 Sleep outcomes were measured at the end of each 2-week treatment period using diaries maintained by the parents. Valerian was found to significantly reduce time spent awake during the night, increase total sleep time, and improve parent-rated sleep quality.53 Studies assessing valerian suffer from the same issues seen with other herbal supplements, including a variety of formulations and dosages, small sample sizes, varying methodology, and short duration. Overall, valerian seems to be fairly well tolerated, with minimal side effects. Those side effects rarely reported include headache, GI discomfort, contact allergies, and vivid dreams.49,54 Valerian does not seem to produce a hangover effect, as noted in one study of 91 patients comparing placebo and valerian 600 mg each evening after 2 weeks of treatment.55 Four cases of acute hepatitis have been reported with valerian. Four women from England had been taking a herbal supplement believed to contain valerian and skullcap.56 Each patient subsequently discontinued treatment, and tests of liver function eventually showed a return to normal.56 Confirmation of ingredients in the 2 supplement products and evaluation for contaminants was not ascertained. No drug interactions with valerian have been noted in clinical trials.47,48 Because of the sedative properties, theoretically patients should use caution or avoid other CNS depressants.47,48 Valerian is available in a variety of formulations, including tablets, capsules, liquid, teas, and tinctures. Products may contain whole herb and/or a proprietary blend or may also be combined with other herbal supplements (eg, lemon balm, hops, skullcap, kava, St John’s wort). Some commercial products are standardized according to the content of valerenic acid but concentrations vary among products. Table 4 gives an information summary. Although evidence suggests some benefit in treating insomnia, conflicting data in the adult population and minimal studies in pediatrics warrant further investigation. Studies evaluating the benefit of valerian in treating anxiety are limited and need to be more clearly elucidated. KAVA

Kava originates from the South Pacific Islands and is derived from the roots, rhizomes, and root stems of the shrub Piper methysticum.57 In the South Pacific Islands it is used culturally as a social beverage as well as in ceremonial rituals.57,58 It also has medicinal implications, which include treating anxiety, insomnia, premenstrual syndrome, and stress.49 Kava is comprised of kavalactones (also known as kavapyrones), which are considered the pharmacologically active components. A variety of kavalactones exist, with most effect attributed to kavain (kawain), 5,6-dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin.58 Concentrations of kavalactones

Herbal Medicines in Pediatric Neuropsychiatry

Table 4 Supplement information: valerian and kava Valerian

Kava

Scientific Name

Valeriana officinalis

Piper methysticum

Active components

Monoterpenes Sesquiterpenes (valerenic acid) Valepotriates

Kavalactones: Kavain 5,6-Dihydrokavain Methysticin Dihydromethysticin Yangonin Desmethoxyyangonin

Possible indications

Insomnia Dyssomnia Anxiety Epilepsy Depression

Anxiety Insomnia Stress Premenstrual syndrome

Mechanism of action Interaction with GABA receptors

Blockade of voltage-gated sodium channels Enhance GABA transmission

Dosage

Adult: 400–900 mg at bedtime Pediatric: 20 mg/kg at bedtime (based on one study: see text)

Adult: 70 mg (kavalactones) 3 times daily (most common in Europe)

Adverse effects

Headache GI distress Contact allergies Vivid dreams

Headache Sedation GI upset Restlessness Tremor Allergic reactions Hepatotoxicity Kava dermopathy Extrapyramidal symptoms

Drug interactions

Avoid use with CNS depressants and alcohol

Potential inhibitor of CYP P-450 Avoid use with dopamineblocking agents Avoid concurrent use with CNS depressants and alcohol

Additional comments Available in a wide variety of formulations, dosages, and combination products Commercial products may be standardized to valerenic acid

Use products with concentrations standardized to kavalactones Avoid use in patients with preexisting liver disease or at risk

Data from Refs.47–50,53,54,58–64

can vary considerably among the subspecies of kava as well as within the same subspecies.57 Kava is most widely used and evaluated for the treatment of anxiety. Its anxiolytic and sedative effects are believed to be caused by blockade of voltage-gated sodium channels and enhancement of GABA transmission.58 Kavalactones have also been shown in vitro to inhibit MAO type B and block the reuptake of norepinephrine.58 Multiple studies have assessed the effects of kava in treating anxiety, with no reported studies occurring in the pediatric/adolescent population. A Cochrane review of kava in treating anxiety was updated in 2010 and included 12 studies, with 7 of the studies

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included in the meta-analysis.59 The 7 trials were randomized, double-blind, placebocontrolled clinical trials that used the Hamilton Anxiety Scale (HAM-A) to assess efficacy in treating anxiety.59 A total of 380 patients were evaluated, with 6 of the studies occurring in Germany, and duration ranged from 4 to 24 weeks.59 All except one trial used the same preparation, and dosages among the trials ranged from 105 mg to 280 mg kavalactones daily.59 Results indicated a statistically significant reduction in HAMA scores with kava compared with placebo, with a small effect size.59 The other 5 studies not included in the meta-analysis found similar results. Six trials reported minor side effects, with no cases of hepatotoxicity noted.59 The most common side effects seen are mild and include GI upset, sedation, restlessness, headache, tremor, fatigue, and allergic reactions.59,60 More concerning are the rare but potentially life-threatening reports of hepatotoxicity. Cases of hepatotoxicity, with most reports occurring in Europe, have ranged from increases found in liver-function tests and jaundice to severe hepatitis and liver necrosis, necessitating the need for liver transplantation.58 At least 11 cases of liver failure requiring transplantation have been documented, with doses ranging from 60 to 240 mg of kavalactones daily. Most patients used kava that was prepared from either alcohol or acetone extraction.60,61 Causality was not established in all cases because of concurrent use of other hepatotoxic medications and incomplete data. The FDA issued an advisory in March 2002 warning practitioners and consumers about the risk of hepatotoxicity associated with kava.49,61 Additional countries at that time also issued advisories or suspended sales of kava products.58 Given the risk for hepatic injury, it is recommended that patients with liver disease or at risk for liver disease avoid using kava-containing products.49,61 Kava dermopathy has been seen with higher than normal doses for prolonged periods.57,62 The syndrome is characterized by a yellow discoloration of the skin, bloodshot eyes, and a scaly dermatitis that can be seen on the palms, soles of the feet, forearms, shins, and back.57,62 Symptoms resolve with discontinuation of the kava-containing product.57,62 Dyskinesias have been reported in 4 patients, including one patient with Parkinson disease who consumed kava.60,63 Onset of symptoms ranged from 90 minutes after an initial dose to after 10 days of continual use, with symptom improvement after discontinuation of kava or initiation of biperiden.60,63 Because of the potential ability of kava to antagonize dopamine, patients susceptible to extrapyramidal side effects or on dopamine-blocking medications should avoid using kava.62 There is the potential for drug interactions with kava because of its ability to inhibit CYP P-450 isoenzymes but there is limited clinical evidence.62,64 Caution should be exercised if kava is used in conjunction with other medications or supplements. Patients should also avoid combining kava with alcohol or other CNS depressants because of the risk for additive effects.62 Because of variations in kavalactones among and within kava subspecies, products standardized to a kavalactone concentration are recommended over those containing raw ingredients.57 Typical dosing in European studies was 70 mg 3 times daily, and the most common formulation used was standardized to 70% kavalactones.62 Within the United States, most commercial kava products are standardized to 30% to 55% kavalactones and are available in capsule, tablet, and liquid formulation.62 See Table 4 for an information summary. Clinical trials support a mild anxiolytic effect of kava within adults and most patients experience only minor side effects. There are no data within the pediatric population, and the potential for hepatotoxicity precludes the use of kava in pediatrics and adolescents. See Table 4 for a summary.

Herbal Medicines in Pediatric Neuropsychiatry

DHA AND EPA

Omega-3 fatty acids (DHA and EPA) have been evaluated in several pediatric diseases, including asthma, Crohn disease, and eczema as well as ADHD, ASD, dyslexia, and juvenile bipolar disorder (JBD).65,66 Omega-3 fatty acids (also referred to as long-chain polyunsaturated fatty acids) can be derived from their precursor a-lineolic acid (ALA) within the human body, but this process is not efficient.65 ALA can be derived from plant sources, including green vegetables and some nuts, whereas omega-3 fatty acids are derived from fish and seafood.67,68 Conversion of ALA to DHA and EPA from food sources is also insufficient, and therefore marine life is the primary source.65,67 The Western diet has seen a shift, with a higher intake in lineolic acid and its derivative, omega-6 fatty acids, which are obtained from vegetable oils.68 Omega-6 fatty acids are believed to have proinflammatory effects, whereas EPA and DHA are considered antiinflammatory.65 Omega-3 fatty acids are considered to be an essential component in brain development. DHA is an integral structural component of cell membranes, including neurons, and is found in phospholipids.65 EPA is integrated into cholesterol esters, phospholipids, and triglycerides.65 These essential fatty acids (EFAs) are considered important in regulating eicosanoids (EFA metabolites), which are involved in a wide array of activities, including vasodilation/vasoconstriction, inflammation, platelet aggregation, and adhesion.67 EFAs are also considered important in regulating gene expression, affecting signaling pathways and synapse and nerve growth.67 Neuropsychiatric disorders have been associated with abnormalities in cell membrane fatty acid content. Using red blood cell membranes as a substitute for brain cell membranes, a decrease in omega-3 fatty acids or an increase in omega-6 to omega-3 fatty acids ratio has been shown in patients with depression, bipolar disorder, schizophrenia, ADHD, and ASD.68,69 In theory, the alteration in phospholipid content may alter neurotransmitter function, increasing the risk for neuropsychiatric disorders.68 Physical signs associated with low EFA include increased thirst and urination and rough, dry skin and hair.68 These symptoms have been reported in children with ADHD, dyslexia, and ASD, and studies in children with ADHD have suggested that physical signs correlated with low blood EFA concentrations.68 There are no established guidelines as to what is considered normal EFA blood levels, and even though supplementation in trials has resulted in an increase in EFA blood levels, supplementation does not always correlate to clinical improvement.68,69 Most of the data using omega-3 fatty acids in pediatric neuropsychiatric disorders have been in children with ADHD. Several reviews have been published evaluating the efficacy of omega-3 fatty acids in ADHD; please refer to these studies for more detailed information than can be provided in this article.65–68 Open-label trials have found omega-3 fatty acids to improve the behavioral aspects of ADHD as well as increase plasma EFA levels.67 One of the trials included is the only one to use a weight-based approach (2.5g/d per 10 kg), whereas the others used a variety of formulations and varying concentrations of EPA and DHA.66,67 The studies were also limited by small sample sizes, short duration, and lack of placebo effect. On the other hand, randomized, controlled clinical trials have produced mixed results. Overall, studies have had difficulty in substantiating an effect of omega-3 fatty acids in treating ADHD. Sample sizes were small (18–117 children) and treatment duration was short (4–18 weeks).65–67 A variety of formulations and doses (including ratio of EPA and DHA) were used, and those studies evaluating only DHA failed to provide any benefit.65–67 Studies also varied in their outcome measures, and benefit in more than one domain was not always found (eg, parent and teacher assessments).65–67

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Studies that did show a benefit for omega-3 were studies that included children without a diagnosis of ADHD or who had symptoms of ADHD without a confirmed diagnosis.65–67 Failure to find an overall benefit is limited by the varying methodologies, as noted earlier, as well as by high dropout rates in some studies. One randomized, controlled trial assessed the efficacy of omega-3 fatty acids (400 mg EPA and 200 mg DHA daily) in treating a first episode of depression in children.69 Twenty-eight children were randomized, with 20 completing at least 1 month of analysis.69 A 50% reduction in the CDRS was seen in 7 of 10 children receiving active treatment compared with 0 of 10 in the placebo group.69 Clinical global impression was also found to be significant for the group who received omega-3 fatty acids.69 Two open-label trials have evaluated the benefit of omega-3 fatty acids in JBD. One trial evaluated the use of 360 mg EPA and 1560 mg DHA daily for 6 weeks in 18 patients.70 Patients continued concomitant psychotropic medications throughout the study. Clinician rating of mania and depression significantly improved, and global functioning increased with treatment; 3 patients withdrew because of adverse effects.70 Improvement in mania symptoms was believed to be clinically modest compared with the improvement in depressive symptoms.70 The second study evaluated omega-3 fatty acids (1290–4300 mg/d EPA and DHA) in 20 children with JBD naive to therapy for 8 weeks.71 A significant reduction in mania and depressive symptoms was seen but patients continued to have residual symptoms.71 Four patients dropped out because of lack of efficacy.71 These 2 studies provide the impetus for better-designed studies to evaluate the benefit of omega-3 fatty acids in JBD. Two studies have been conducted in children with ASD and one study in children with dyslexia. The open-label trial evaluated omega-3 fatty acids in 9 children for 6 months.65 An improvement was seen for general health, sleep patterns, cognition, concentration, and behavioral symptoms.65 A randomized, controlled trial in 13 children evaluated 840 mg EPA and 700 mg DHA daily for 6 weeks.65,66 No significant benefit was found for the active treatment.65,66 The only study in dyslexia is an open-label trial evaluating 108 mg EPA and 480 mg DHA daily for 20 weeks.66 An improvement was seen for reading speed, general schoolwork, and subjective evaluations completed by the parent and child.66 Further studies are required to further elucidate the effect of omega-3 fatty acids in these conditions. Overall, omega-3 fatty acids are fairly well tolerated. Common side effects include nausea, diarrhea, heartburn, belching, and flatulence.72,73 Omega-3 fatty acids are also associated with a strong fishlike aftertaste.72,73 These adverse effects can contribute to lack of adherence with therapy. Omega-3 fatty acids can interfere with platelet activation and can increase the risk for bleeding when given at high doses.65,72,73 Patients receiving concomitant anticoagulants or antiplatelet therapy, as well as those with hematologic disorders, should use caution.72,73 Although omega-3 fatty acids are fairly well tolerated and have few drug/disease interactions, limited evidence exists (as shown by well-designed controlled clinical trials) regarding their efficacy in several neuropsychiatric disorders. Studies have been affected by the same limitations as discussed earlier with other herbal supplements. In addition, the varying ratios of EPA and DHA as well as high dropout rates in some studies provide additional limitations when evaluating the benefits of omega-3 fatty acids. HERBAL SUPPLEMENTS FOR WEIGHT LOSS

A variety of herbal supplements exist for the treatment of obesity but no clinical trials have been performed in children or adolescents. Table 5 lists supplements and

Herbal Medicines in Pediatric Neuropsychiatry

Table 5 Herbal supplements for weight loss Herbal Supplement

Mechanism of Action

Common Side Effects

Guarana/caffeine

Stimulant

Insomnia Nervousness Restlessness Tachycardia Nausea/vomiting Headache

Citrus aurantium (bitter orange)

Stimulant

Tachycardia Headache Hypertension Photosensitivity Cardiovascular events

Chromium picolinate

Insulin sensitizer Stimulate thermogenesis Decrease insulin release

Headache Insomnia Irritability Mood changes

Garcinia cambogia (brindleberry) Increase lipid oxidation Decrease carbohydrate use

Nausea GI upset Headache

Chitosan

Decrease absorption of dietary fats

Stomach upset Nausea Flatulence Constipation Increase stool bulk

Pyruvate

Increase fat oxidation

GI upset

Gingko biloba

Decrease glucocorticoid synthesis Antistress Neuroprotective

Stomach upset Headache Dizziness Palpitations Constipation Allergic skin reactions Spontaneous bleeding

Data from Refs.75–81

possible mechanisms of action. Many herbal supplements formerly contained ephedrine but because of its adverse effect profile, including sudden death, the FDA banned its use in 2004.74 Since then, Citrus aurantium has been substituted for ephedrine because of its stimulant properties (a-adrenergic agonist) and/or caffeine, which can be derived from guarana, green tea, or the cola nut.75 Many herbal products contain multiple ingredients, which increases the risk for toxicity as well as drug interactions. Herbal supplements should generally be avoided in the pediatric and adolescent population because of the risk of toxicity and lack of evidence for use. SUMMARY

Complementary medicine, including the use of herbal supplements, continues to grow even within the pediatric population. The ease of use associated with supplements, including access and self-administration, patients’ perceptions that herbals are safe, and consumer advertising, has led to an increased use in herbal supplements for prevention as well as treatment of chronic diseases. Parental use of CAM therapy is

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often associated with CAM use in pediatric patients, as noted in survey studies. Herbal supplements are not regulated by the FDA and it is up to the manufacturers to ensure safety and appropriate product labeling. Herbal supplements have been found to have been adulterated with medications, heavy metals, and bacteria/fungi. Manufacturers have the ability to undergo quality-assurance testing and it is recommended to use products from manufacturers who undergo this process. Herbal supplements have been evaluated for several pediatric neuropsychiatric diseases but the evaluation of data is limited because of methodological differences, small sample sizes, short duration, differences in dosage and formulation, and differences in outcome measures. Despite limited supporting evidence, it is likely that use will continue to increase. Because of increasing popularity and the potential for toxicity and drug interactions, practitioners should be knowledgeable regarding herbal supplements and inquire about patients’ use to provide the most meaningful discussions. REFERENCES

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