An increasing number of studies have evaluated the role of herbal supplements in pediatric disorders, but they have numerous limitations. This review provides an overview of herbal components, regulation of supplements, and importance of product quality assurance. Use of herbal supplements is discussed with reference to factors that influence use in the pediatric population. The remainder of the article discusses the use of St John’s wort, melatonin, kava, valerian, eicosapentaenoic acid, and docosahexaenoic acid, focusing on indications, adverse effects, and drug interactions, and providing a limited efficacy review. Herbal supplements used for weight loss are also briefly discussed.
Mainstream medicine in Western society is based on conventional medicine, also referred to as allopathic or biomedicine. 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. 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. 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. Whole medical systems are based on systems of theory and practice and within the United States most commonly include homeopathic and naturopathic medicine. Mind-body medicine encompasses techniques including cognitive-behavioral therapy, meditation, and prayer, whereas biologically based practices include the use of herbal and dietary supplements. Manipulative and body-based practices include massage and chiropractic or osteopathic manipulation. Energy medicine revolves around the use of energy fields and includes Reiki, therapeutic touch, and use of electromagnetic fields. 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. 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 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. 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. 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. The FDA is responsible for postmarketing activities, including monitoring of adverse events via voluntary reporting and product information (eg, labels, claims, package inserts).
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. 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. 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. Essential oils give the characteristic odor of the plants and are often referred to as volatile oils or essences. They have been used for treating skin and respiratory disorders and in aromatherapy. 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). 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.
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. 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.
| Classification | Chemical | Source | Potential Benefit |
|---|---|---|---|
| Alkaloids | |||
| Imidazole | Ephedrine | Ma Huang | Asthma, weight loss |
| Indole | Yohimbine | Yohimbe | Aphrodisiac, benign prostate hyperplasia |
| Purine | Caffeine | Coffee, tea | Stimulant |
| Bioflavonoids | |||
| Flavonoid | Apigenin | Chamomile | Antiinflammatory |
| Isoflavonoids | Daidzein | Soy | Estrogenic, menopause |
| Flavonolignans | Silymarin | Milk thistle | Liver protection |
| Essential Oils | |||
| Alcohols | Menthol | Mints | Antitussive |
| Phenols | Capsaicin | Capsicum | Counterirritant |
| Phenols | Thymol | Thyme | Antibacterial |
| Glycosides | |||
| Saponins | Glycyrrhizin | Licorice | Peptic ulcer |
| Anthraquinones | Sennosides | Senna | Laxative |
| Isothiocyanates | Alliin | Garlic | Cholesterol-lowering |
| Coumarins | Dicumarol | Sweet clover | Anticoagulant |
| Resins | |||
| Pure resins | Guaiac | Expectorant | |
| Oleoresins | Turpentine | Expectorant | |
| Balsams | Benzoin | Anesthetic | |
| Saponins | |||
| Steroidal | Digitoxin | Foxglove | Cardiovascular |
| Terpenoid | Cycloartanes | Black cohosh | Estrogenic |
| Sterols | |||
| Phytosterol | β-Sitosterol | Soy | Cholesterol-lowering Antiinflammatory Benign prostate hyperplasia |
| Terpinoids | |||
| Diterpenes | Capsianosides | Capsicum | Counterirritant |
| Diterpenes | Ginkoglides | Ginkgo | Antiinflammatory |
| Tetraterpenes | Carotene | Carrot | Antioxidant |
| Tetraterpenes | Lycopene | Tomato | Anticancer |
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. Laboratory analysis of multiple brands of a herbal supplement can reveal several-fold differences in the concentrations of the active components. 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. Therefore, herbal supplements can vary in chemical composition, concentrations of active ingredients, and overall quality, which give each brand its uniqueness.
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. Contaminants and adulterants that have been found in supplements include heavy metals, bacteria, and fungi. Chinese and Ayurvedic herbal medicines have been associated with contamination by heavy metals, with cases of lead poisoning being reported. 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 ). 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 . 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. The most common identified substances included acetaminophen, caffeine, indomethacin, hydrochlorothiazide, and prednisolone. Table 2 lists some of the contaminants and adulterants identified 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 |
Misidentification of the plant, whether intentionally or inadvertently, can lead to serious consequences. 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. 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, which is found in the plant genus Stephania and not Polygala as noted in the package insert. 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.
In 2000, the World Health Organization published a report evaluating 8985 case reports of adverse events associated with herbal supplements from 1968 to 1997. Of these adverse events, ∼1% were noted to occur in children up to 9 years old and an additional 1% in those 10 to 19 years old. 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. 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. If clinical trials do not exist, evaluate if the product has undergone independent laboratory quality-control testing. 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. 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.
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. Products that meet these standards may include a USP Verified Dietary Supplement symbol on the label. 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. For proper evaluation, product labeling should include detailed information regarding ingredients, batch number, expiration date, and manufacturer contact information.
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%.
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. Of the 7371 children evaluated (age≤21 years), 2% reported having visited a CAM provider during the previous year, with only 12.3% reporting CAM use to their allopathic provider. Herbal therapies were the most common office-based therapy provided (22.4%), followed by spiritual healing/prayer (19.4%), homeopathic treatments (14.1%), and massage therapy (13.2%). 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. 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. Limitations to this study include ∼one-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. Within the previous 3 months, 61% had used a herbal supplement in conjunction with a prescription medication. 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. 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. 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. 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. The most common supplements for current users included zinc, echinacea, ginseng, herbal or green tea, Gingko biloba , and creatine. Over their lifetime, 10.7% of the respondents had tried weight-loss supplements. Higher prevalence was noted in female respondents, and similar to previous studies, CAM use by adolescents was associated with parental use. 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. Of the 9417 completed interviews of children, 3.9% reported use of supplements within the past 12 months. CAM therapies were most often used for musculoskeletal pain, colds, anxiety or stress, and attention-deficit/hyperactivity disorder (ADHD)/attention-deficit disorder. CAM use was more common among adolescents aged 12 to 17 years and White children, and increased with parental educational level. CAM use had a positive correlation with the number of health conditions and health provider visits within the previous 12 months as well as parental use of CAM therapy. CAM therapy was also more common when conventional care was unaffordable or worry about cost delayed conventional medical care.
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). 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. Fifty-three percent of the respondents reported talking about CAM therapy with their patients but most was initiated by patients and families (84.7%). More than three-fourths (76.1%) believed that patients self-reported CAM use. 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%).
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. 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. Herbal supplements were most commonly used to treat the behavior problem and included Gingko biloba , echinacea, and St John’s wort. 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. 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%). Over three-fourths of those interviewed believed that CAM therapy augmented traditional medicine.
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. 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.
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). 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. Most products are standardized to include hypericin at concentrations of 0.1% to 0.4% and hyperforin at 2% to 4%.
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. 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. Studies of St John’s wort in pediatric patients have been limited by study design, small sample sizes, and short duration. Simeon and colleagues 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. Seven of the 15 who withdrew had persistent or worsening depression. A study by Findling and colleagues 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. Using the Children’s Depression Rating Scale (CDRS), 76% of the patients clinically improved and 93% continued therapy at the end of the study.
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. 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). Individuals with light or fair skin should use protective measures with sun exposure.
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. 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.
Because St John’s wort increases serotonin, the risk of serotonin syndrome exists when combined with other agents that also increase serotonin. 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-HT 1 agonists (eg, sumatriptan), MAO inhibitors, and meperidine. 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. Withdrawal symptoms may include GI upset, dizziness, confusion, insomnia, and fatigue. To avoid these symptoms, patients should gradually taper the dose before discontinuation. Table 3 gives a summary regarding St John’s wort.
Full access? Get Clinical Tree
