Traditional Oriental Herbal Medicine for Children and Adolescents with ADHD: A Systematic Review

Objective. To evaluate the efficacy of traditional Oriental herbal medicines (TOHM) for children and adolescents with ADHD. Methods. Randomized clinical trials published from January 1, 1990, to December 31, 2010, in English, Chinese, Japanese, or Korean language which evaluated the use of TOHM on ADHD subjects of 18 years old or below, diagnosed based on DSM-IV, were searched from MEDLINE, EMBASE, PsyINFO, Cochrane Library, and 10 other databases. Results. Twelve studies involving 1189 subjects met the inclusion criteria. In general, the included studies claimed that TOHM has similar efficacy to methylphenidate and at the same time has fewer side effects compared to methylphenidate. Some studies also suggested that the effect of TOHM sustained better than methylphenidate. However, solid conclusions could not be drawn because the included studies were not of high quality. Risk of bias issues such as randomization, allocation, concealment and blinding were not addressed in most of the studies, and the risk of publication bias could not be ruled out. Conclusion. Currently, there is not strong evidence to say that TOHM is effective in treating the core symptoms of ADHD.


Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder of which patients display persistent pattern of inattention and hyperactivity/impulsivity or a combination of the two at an abnormal level that their social, academic, or occupational functioning is impaired [1]. While the etiology of ADHD is not clearly known, studies have suggested that the abnormality of the frontal network and dysregulation of catecholamines are the underlying pathophysiology [2]. Frontal lobes are involved in decision making to convert impulse to action, attention, and concentration, and they are primarily activated by the catecholamines, dopamine, and norepinephrine [3]. When frontal lobes are not fully activated, or when there are changes in the levels of dopamine and norepinephrine, the symptoms of hyperactivity and inattention are likely.
When making a diagnosis of ADHD, clinicians should determine that the diagnostic criteria have been met by assessing information obtained from primarily parents, guardians, and teachers [4]. For adolescents, information from at least two teachers and other sources should be assessed because adolescents usually have multiple teachers and parents have little direct contact to observe their strengths and problems [4,5]. Instruments such as the Revised Conners' Parent Rating Scale and Revised Conners' Teacher Rating Scale are useful for screening and assessing behavioral problems, and also helpful for assessing treatment effectiveness [6,7].
Behavioral therapy and pharmacotherapy are two kinds of treatments commonly used in ADHD. Recommendation of treatment for ADHD varies depending on the patient's age. While evidence-based behavioral therapy is recommended as the first line of treatment for preschoolaged children (4-5 years of age), school-aged children (6-11 years of age) and adolescents (12-18 years of age) are recommended a combination of medication and behavioral therapy [4].
Stimulants are reported to be highly effective for most children in reducing the core symptoms of ADHD and thus are used as first line medication for ADHD patients [2,4]. They are structurally similar to endogenous catecholamines 2 Evidence-Based Complementary and Alternative Medicine and are thought to work by enhancing dopaminergic and noradrenergic neurotransmission [2,8].
Methylphenidate (Ritalin) is the most commonly used stimulant for the treatment of ADHD [2,9]. Around 70% of ADHD patients who receive stimulant treatment are given methylphenidate [10]. It is shown to be effective, at least in short term, on improving the core symptoms of ADHD such as attention, distractibility, and impulsivity (effect size 0.75-0.84, mean 0.78). Methylphenidate has observable effects on improving social and classroom behavior (effect size 0.63-0.85, mean 0.8) [9]. Pemoline (Cylert) is a stimulant that is longer acting than methylphenidate, but due to its potential for hepatotoxicity, it is regarded as a third line treatment [2]. In some cases, nonstimulants are also used in the treatment of ADHD such as the norepinephrine specific reuptake inhibitors atomoxetine, and antidepressants such as Imipramine, Phenelzine, and Bupropion [2,11] but have been found to have significant differences in terms of efficacy compared to stimulants [8].
While stimulants are effective for many children with ADHD, they may cause side effects, with the most common ones being decreased appetite, insomnia, and headache (Cohen's d 0.67, 0.40, and 0.33 resp.) [12]. Other side effects such as motor tics, abdominal pain, irritability, nausea, and fatigue are also reported [9]. Therefore, many parents of ADHD children try to search for more natural and safe treatment options [13,14], which has resulted in a growing interest in complementary and alternative therapies (CAM), such as herbal remedies, dietary supplements, dietary modification, neurofeedback, homeopathic therapy, and chiropactic, in treatment of ADHD. Several surveys conducted on the use of CAM in ADHD showed over 50% of ADHD sufferers have used CAM [13,15].
Herbal medicine is a treatment measure used in traditional Oriental medicine. Although herb usually refers to materials from plant sources, in respect of traditional Oriental medicine, herbal materials can be originated from plants, animals, or minerals. In this review, traditional Oriental herbal medicine (TOHM) is defined as medicine made by materials used under traditional Oriental medical theory. Herbal materials that are not documented in the Korean Pharmacopoeia, the Japanese Pharmacopoeia, Pharmacopoeia of the People's Republic of China, Zhong Hua Ben Cao, and Zhong Yao Da Ci Dian (Chinese Medical Great Dictionary) are considered outside the context of TOHM. TOHM should be taken orally and studies employing other route of administration, such as intravenous or transdermal, are excluded from this review.
Even though ADHD was not described in literature of traditional Oriental medicine, in traditional Oriental medical theory, ADHD is related to congenital deficiency or insufficient postnatal nourishment that leads to imbalances in the body. It is suggested that the disorder is related to the heart, the liver, the spleen, and the kidneys [16]. TOHM is believed to work by adjusting the inner imbalances of ADHD patients and thereby relieving the symptoms.
A study on ADHD using an animal model of spontaneous hypertensive rat treated with an Oriental herbal decoction comprised of Caulis Polygoni Multiflori (stem of Polygonum multiflorum Thunb.), Radix Rehmanniae Preparata (processed Rehmannia root), Carapax et Plastrum Testudinis (Carapace and plastron of Chinemys reevsii (Gray)), Os Draconis (fossilized bones), Radix Polygalae (Polygala root), and Rhizoma Acori Tatarinowii (Grassleaf Sweetflag Rhizome) showed that the decoction increased the amount of dopamine at the frontal cortex and corpus striatum [17], suggesting that its possible mechanism in ADHD is to increase dopamine level and thereby enhance catecholaminergic neurotransmission.
This review aims to evaluate the efficacy of TOHM as a treatment for ADHD in patients under the age of 18. TOHM is natural and often perceived to have fewer side effects than conventional ADHD pharmacotherapy. Various research and clinical studies have been conducted on TOHM's efficacy on ADHD, but very few articles review the evidence of efficacy of the treatment. A systematic review on complementary medicines for ADHD suggested that a Chinese herbal medicine may be effective for ADHD [18] however in the review only one study about Chinese herbal medicine was included and analyzed. Further compilation and analysis of currently available data about TOHM on ADHD may help to understand the true effect of the treatment on the disorders, and provide insight into the direction of future research.

Database Searching.
English, Chinese, Korean and Japanese articles on randomized clinical trials (RCTs) of Oriental herbal treatment on ADHD published between January 1, 1990, and December 31, 2010, were searched from various databases. The details of search terms used in different databases are presented in the appendix. The following databases were searched: (1) Cochrane Library,
All of the studies included in this review were conducted in China as single-centre trials. Five results in Japanese and eighteen results in Korean were identified. Only one Japanese article was about a clinical trial; however the trial was not a randomized trial and was therefore not selected.
Among the twelve included studies, none included the information on how sample size was derived and whether the study was statistically powered. The length of study ranged from 4 weeks to 24 weeks. Six studies had followup observation on subjects, ranging from 2 weeks to 12 months after finishing treatment, to evaluate whether the intervention sustained effectiveness after treatment is stopped while the other six studies did not report if follow-up observations were conducted. Ten of the included studies reported homogeneity of baseline characteristics, but only seven [20,22,24,[26][27][28][29] showed relevant descriptive statistical data. Two studies [16,19] did not report if baseline characteristics of subjects were homogenous. Only one of the studies [27] specified the subtype of ADHD subjects included in the study. Characteristics of included studies are summarized in Table 1.

Assessment of Risk of Bias.
In general, the risk of bias in the included articles is unclear. Very limited information was revealed in the studies to enable the reviewers to tell if the included studies were at risk of bias.
Only one of the included studies [16] described how randomization was done, but the study used two randomization methods where part of the subjects were randomized using a random number table while part were allocated to the treatment or control groups by their patient record numbers. The allocation concealment issue was not addressed in any of the included studies.
The blinding method was also not addressed in most of the studies, and only two of the included studies [22,26] claimed to be a double-blind trial. Li et al. (1999) described the blinding method, which was to include a placebo resembling methylphenidate in the treatment group and a placebo that looked like the corresponding TOHM in the control group. Wang et al. (2003) did not describe how blinding was done.
Most of the studies indicated no missing data. However,   [25] did not specify the initial number of subjects so it could not be determined if there was any participant drop-out.   [16] reported seven drop-outs but no explanations were provided, and it was unclear whether the drop-outs were from the treatment group or the control group. In another study [23], three subjects were excluded and there were five drop-outs, but the reasons were not sufficiently provided. Among those eight subjects, it is only known that four of the drop-outs were reported to have terminated the study due to adverse effect of methylphenidate. Those three studies were considered to have unknown risk of bias on incomplete outcome data.
Study protocols were not available for any of the included studies, therefore it could not be discerned whether all prespecified outcomes were reported. Lai and Li (2006) [21] did not report the baseline score before treatment and score after treatment. Xu (2005) [27] did not report the baseline score of rating. The two studies were considered to have high risk of reporting bias.
The risk of bias graph and summary are presented in Figures 2 and 3, respectively.

Diagnosis and Assessment of the Disorder.
Although all included studies specified the diagnostic criteria and method to assess treatment effect, only one study [16] specified who completed the rating questionnaire or did the rating assessment. None of the studies addressed under which setting the assessment was done. Also, the language of   No side effects observed in treatment group but 10 subjects in control group reported nausea and loss in appetite, 2 subjects reported dizziness, and 1 subject reported sleeplessness.
8 Treatment group showed improvements in co-existing symptoms such as loss in appetite, recurrent flu, but no evident improvement in control group.     assessment tools was not specified. It was not clear if the assessment tools were validated in cases where they were translated into another language.

Treatment Effectiveness.
The herbal formulae used in the included twelve studies varied, and dosage forms of decoction, granules, oral liquids, pill, and so forth were used. Nine studies [16, 19-22, 25, 27-29] provided the ingredients of the formulae, but among them five [22,25,[27][28][29] did not specify the amount of each herb used in the formula, and therefore there was very little information on drug to extract ratio. Three studies [23,24,26] did not provide the formula at all. None of the studies mentioned how the herbal medicines used were standardized. The details of the herbal ingredients used in the included studies, their dosage form, and daily dose are presented in Table 2.
The remaining one of the twelve included studies [24] evaluated the net effect of TOHM by having a combined treatment group of TOHM and methylphenidate, and a methylphenidate control group. The study reported that TOHM and methylphenidate worked better in combination than methylphenidate alone, with statistically significant differences when comparing the rate of effectiveness of the two groups.

Follow-Up Observation on Effectiveness.
Among the included studies, six had follow-up observations to evaluate the sustainability of treatment effect of core symptom after stopping medication, while the other six studies did not specify if follow-up observation was done. The follow-up period varied from 2 weeks to 12 months after stopping the treatment. For the six studies with follow-up observation, five [20,23,24,27,28] compared the treatment effect of TOHM and methylphenidate after stopping medication and all reported the effect of TOHM sustained better compared to methylphenidate. The remaining one [25] only followed up on the effect of the TOHM treatment group.

Safety and Side Effects.
In general, TOHM was claimed to have fewer side effects than methylphenidate. Eight of the included studies [19-24, 27, 28] discussed side effects. In general, more cases of side effect were reported in the methylphenidate control group than the TOHM treatment group. Two studies [26,28] reported no cases of side effect in the TOHM treatment group. Cheng et al. (2006) reported that among the side effect cases in their study, dry mouth, sweating, nausea, weight loss, loss of appetite, and headache were significantly fewer in the TOHM treatment group compared to the methylphenidate control group (P < 0.05) [19]. Lai and Li (2006) reported that cases of loss of appetite and drowsiness were significantly fewer (P < 0.05) [21]. Lin et al. (2007) reported that cases of sleeplessness, dizziness/headache, sweating, dry mouth, nausea, loss of appetite, weight loss, and constipation were significantly fewer in the treatment group than the control group (P < 0.01) [24]. Xu (2005) compared the average score of Treatment Emergent Symptoms Scale (TESS) in the treatment group and the control group, and reported that the average score was significantly higher in the control group (P < 0.01) [27]. Four other studies [19,20,22,26] also claimed to have used TESS to evaluate side effects but scores were not reported.
Three studies [16,25,28] performed liver function tests, renal function tests, and/or ECGs on subjects after treatment  [20] Ingredients and amount: Fructus Lycii 9 g, Flos Chrysanthemi 9 g, Radix Rehmanniae Preparata 24 g, Fructus Corni 12 g, Rhizoma Dioscoreae 12 g, Rhizoma Alismatis 9 g, Cortex Moutan 9 g, Poria 9 g Dosage form: Pills. It was not clear how many pills were made out of the above amount of herbs.  and results showed that subjects had no impairment on liver function, renal function, and/or cardiac function after treatment with TOHM and methylphenidate, suggesting that both TOHM and methylphenidate do not cause any significant safety concern on treatment of ADHD, at least in the short term.

Discussion
This review included twelve studies, and though findings of this review suggested that the herbal preparations covered under the term TOHM may be effective in treating the core symptoms of ADHD; the overall evidence is not strong enough to draw solid conclusions, because in general the clinical trials were not of high quality and the herbal preparations far too different. Additionally, it cannot be ruled out that there is possibility of publication bias.
The included studies that discussed side effect issues all suggested that TOHM had fewer side effects compared to methylphenidate. However, such result should be interpreted with caution, because first of all it was not clear whether the side effect cases, both in the TOHM group and the methylphenidate group, were investigated to find out if they were related to the intervention. Secondly, it was not addressed in most studies whether blinding was done. As mentioned, since TOHM is indigenous to the study population, and is often perceived as natural with fewer side effects, if measures are not properly done to blind subjects from knowing what treatment they are getting, it may cause bias in reporting side effects.
In the future, should more clinical trials on ADHD using TOHM as treatment be conducted, clinical investigators should consider to address the issues discussed below in order to improve the robustness of data.
In the diagnosis of ADHD and assessment of treatment efficacy, tools such as rating scales are often used. In order to make precise assessment, information should be obtained from different parties including parents, guardians, and teachers under different settings, such as home and school [4]. However, among the included studies, eleven of them did not specify who completed the questionnaires for assessment or under which setting the assessment was done. It was difficult to tell whether sufficient information was obtained to facilitate an accurate assessment of the treatment effect. Also, since the studies were done in Chinese population, it was possible the questionnaires used were in Chinese, but no information was available to tell whether the questionnaires, in case written in another language, were validated or not. Investigators did not indicate whether the tool of assessment has been modified to suit the study purpose as well. Such information should be described in the study methods.
Among the included studies, the herbal medicines themselves varied. Some of the studies did not tell what herbs were used, some did not specify the amount of herbs used, and the treatment dosage was not clear in some studies. Also, the treatment period varied for each study. Due to such heterogeneity, it is not possible to deduce from the data which herbal formulae or ingredients may be effective for ADHD, nor to conclude that TOHM is effective for ADHD in children and adolescents. Although it is inevitable that different studies may use different herbs and have different treatment periods, the materials used and the amount should be stated clearly in the publication of clinical trial results. As various herbal treatments are used in different clinical studies the results even of the positive studies cannot be compared. Clinical investigators may have to consider repeating a study with the same herbal treatment, or to conduct a clinical trial in multiple sites.
Due to the complex nature of herbs, how the consistency of herbal treatment is maintained throughout a clinical study is often an issue to consider. Most of the studies included in this review used the herbal treatment substances in form of decoctions or other preparations such as granules or oral liquid prepared by the clinical sites. It was not addressed how the consistency of treatment substances was kept throughout the studies, or how the treatment substances were standardized to ensure quality. In addition, in three of the studies [16,21,29], prescriptions given to subjects varied according to their symptoms. Although one of the characteristics of traditional Oriental medicine is tailormade treatment according to the patient's condition, in a clinical study setting, this may introduce confounding variables. Investigators should make an effort to ensure the herbal treatment used in a study is of consistent quality