St. John's Wort Found Ineffective for Childhood ADHD CME
News Author: Marlene Busko CME Author: Penny Murata, MD Disclosures
Release Date: June 12, 2008; Valid for credit through June 12, 2009
June 12, 2008 — A randomized, controlled 8-week trial found that Hypericum perforatum (St. John's wort) was no more effective than placebo for improving symptoms of attention-deficit/hyperactivity disorder (ADHD) in 54 children and adolescents.
The findings by Wendy Weber, ND, PhD, MPH, a naturopathic doctor at Bastyr University in Kenmore, Washington, and colleagues, are published in the June 11 issue of the Journal of the American Medical Association.
The group writes that, to their knowledge, this is the first placebo-controlled trial of H perforatum in children and adolescents with ADHD and concludes that their results do not support further research of this formulation of this botanic agent for the treatment of ADHD symptoms. Adverse events were similar in the treatment and placebo groups.
Seeking Alternative Therapy for ADHD
Up to 30% of children with ADHD do not respond to pharmaceutical treatment, or they have adverse effects such as nausea, insomnia, or weight loss from the medications, the group writes. Parents of these children often seek alternative therapies, and in the United States, the most common herbal treatments used by children with ADHD are St. John's wort, Echinacea species, and Ginkgo biloba, they add.
In the last decade, atomoxetine, a new nonstimulant selective norepinephrine reuptake inhibitor, was approved by the US Food and Drug Administration (FDA) for ADHD. Because H perforatum is believed to act as a norepinephrine reuptake inhibitor, the group hypothesized that it might show benefit for ADHD, Dr. Weber told Medscape Psychiatry.
The researchers filed an Investigational New Drug application with the FDA for a clinical trial that aimed to determine if H Perforatum was effective in lessening the severity of ADHD symptoms.
They recruited participants from the general population and randomized 54 healthy children aged 6 to 17 years old who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for ADHD and who were not currently taking a pharmaceutical medication for ADHD.
After a 1-week placebo run-in, adherent participants were randomized to 8 weeks of the drug (which was standardized to contain 0.3% hypericin, a derivative of H Perforatum) or placebo. Participants were instructed to take a 300-mg capsule 3 times a day, ideally before school, after school, and at bedtime.
The 3 primary study outcomes were the following:
- Changes in ADHD symptoms, as measured by the ADHD Rating Scale-IV (ADHD RS-IV).
- Reduction in ADHD symptoms, as measured by the Clinical Global Impression (CGI) Improvement Scale.
- Adverse events.
The 27 children (20 boys) randomized to the treatment group had a mean age of 9.9 years, and the 27 children (14 boys) randomized to placebo had a mean age of 9.7 years.
The researchers did not find any significant difference in the change in the ADHD RS-IV scores from baseline to week 8 between the treatment and placebo groups.
Table. Change in ADHD RS-IV Scores After 8 Weeks of Placebo or H perforatum
| ADHD RS-IV* | Placebo Group Mean Score (95% CI) | H perforatum Group Mean Score (95% CI) | P |
| Hyperactivity score | –2.0 (–4.1 to 0.1) | –1.8 (–3.7 to 0.1) | .89 |
| Inattentiveness score | –3.2 (–5.7 to –0.8) | –2.6 (–4.6 to –0.6) | .68 |
| Total score | –5.2 (–9.4 to –1.1) | –4.4 (–7.9 to –0.9) | .76 |
There was also no statistical difference between the 2 groups in the proportion of participants who were rated as much or very much improved on the CGI scale (44.4% in the treated group vs 51.9% in the placebo group).
Similarly, there was no significant difference between the 2 groups in the proportion of participants who experienced 1 or more rash, nausea or vomiting, headache, or sunburn adverse event during the trial (40.7% in the treated group vs 44.4% in the placebo group).
Would a Different Formulation Be Effective?
"The results of this study do not support further research on the use of H perforatum as formulated in this study for the treatment of ADHD in children," the researchers write.
The H perforatum that was used in this study was formulated to contain 0.3% hypericin at the beginning of the study. Analysis revealed that at the end of the study, it contained only 0.13% hypericin and 0.14% hyperforin (another derivative of H perforatum, which is available in a "high hyperforin" format containing 3% to 5% hyperforin).
Hyperforin is very unstable and quickly oxidizes and becomes inactive. Most H perforatum products on the market are at risk for oxidation because of their delivery as 2-part capsules, the group writes.
"If an H perforatum product with a stable and high hyperforin content became available for investigation, it would be worthwhile to conduct a study to determine whether a clinically meaningful benefit could be achieved," they conclude.
Dr. Weber noted that their sample was too small to provide evidence that there are no adverse effects associated with the use H perforatum in children. It is important to remember that St. John's wort acts to decrease the circulating levels of other medications that are metabolized by the same isoenzymes in the liver, she added.
"A Noteworthy Example of a High-Quality Trial"
"Not only is this the first reported study of Hypericum for ADHD in children and adolescents, but it is also a noteworthy example of a high-quality randomized controlled trial evaluating a specific complementary and alternative medicine therapy in children," Eugenia Chan, MD, MPH, from Harvard Medical School, in Boston, Massachusetts, writes in an accompanying editorial.
Although it is challenging to design rigorous studies for complementary and alternative medicine therapies, this is what is needed to develop a strong evidence base, she concludes.
JAMA. 2008;299:2633-2641, 2685-2686.
Clinical Context
Children with ADHD might not respond to medication or might have adverse effects from the medication. Subsequently, the parents might turn to complementary or alternative treatment. Cala and colleagues reported in the February 2003 issue of Pharmacotherapy that St. John's wort, Echinacea species, and Gingko biloba are the most common herbal treatments used by children with ADHD.
Atomoxetine, a selective norepinephrine reuptake inhibitor, is used to treat ADHD in children. St. John's wort, known as H perforatum, also appears to inhibit reuptake of norepinephrine, as noted by Muller and colleagues in the September 1997 issue of Pharmacopsychiatry.
This randomized, placebo-controlled, double-blind trial evaluates the efficacy and safety of H perforatum in the treatment of children with ADHD.
Study Highlights
- Of 146 children aged 6 to 17 years recruited from offices and advertisements, 59 eligible children entered the placebo run-in phase.
- Inclusion criteria were score of more than 1.5 SD above age and sex norms on the ADHD RS-IV, ability to read English, ability to attend all visits, and ability to swallow pills.
- Exclusion criteria were severe depression, active suicide plan, bipolar disorder, severe conduct disorder, psychotic symptoms, risk for pregnancy, use of products metabolized by the cytochrome P3A4 isoenzyme of the cytochrome P450 system, or previous H perforatum use for more than 2 weeks.
- Children less than 80% adherent or who had placebo response during the placebo run-in phase were also excluded.
- 27 children were randomized to receive one 300-mg H perforatum capsule containing 0.3% hypericin and no heavy metals, pesticides, or adulterants 3 times a day for 8 weeks.
- 27 children received placebo capsules of rice protein powder and activated charcoal.
- Subjects had to discontinue stimulant medication for 1 week or other medications for 2 weeks before the start of the study.
- Permitted treatments were multivitamins, essential fatty acid supplements, and counseling if used for at least 3 months with no plans to change.
- Mean age of the children was 9.7 to 9.9 years.
- Previous ADHD medications were used by 41% of the H perforatum group and 44% of the placebo group.
- More boys were in the H perforatum vs placebo group (74.1% vs 51.9%).
- Baseline co-occurring oppositional defiant disorder was more common in the placebo vs the H perforatum group (55.6% vs 33.3%).
- Medication adherence was similar for both groups.
- Primary outcome measures were changes in ADHD symptoms measured by the ADHD RS-IV from baseline to week 8, changes in global functioning measured by the CGI Improvement Scale, and safety measured by the Monitoring of Side Effects Scale.
- Improvement in ADHD RS-IV scores from baseline to week 8 was not significantly different for the placebo vs H perforatum groups (5.2 vs 4.4 points).
- Changes in ADHD RS-IV hyperactivity and inattentiveness scales were not significantly different between groups.
- CGI Improvement Scale rating of much or very much improved occurred in a similar proportion of the placebo vs the H perforatum group (51.9% vs 44.4%).
- At least 1 or more adverse event (rash, nausea or vomiting, headache, sunburn) occurred for a similar proportion of the placebo vs the H perforatum group (44% vs 41%).
- Rash occurred in more subjects in the placebo vs the H perforatum group (15% vs 0%).
- Weight gain was similar for the placebo vs the H perforatum group (1.0 vs 1.5 kg).
- Change in height was similar for both groups.
- Adjustment for age, sex, household income, parental rating of ADHD severity, and co-occurring oppositional defiant disorder did not affect results.
- Placebo and H perforatum groups showed no differences in other measures of behavior: Parent-Reported Child Behavior Checklist or Child Behavior Checklist-Youth Self Report Form for ages 11 years and older (internalizing, externalizing, total, DSM-IV Affective, Anxiety, Oppositional, or Conduct scales), Conners Parent Rating Scale, and parent-report and child-report forms of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales.
- Blinding was adequate: medication status was correctly identified 52.9% of the time by parents, 43.1% of the time by children, and 56.9% of the time by the principal investigator.
- Limitations of the study included use of a product relatively low in hyperforin, baseline group differences, short duration, and small sample size.
Pearls for Practice
- Children with ADHD who use H perforatum for 8 weeks show no reduction in ADHD symptoms or improvement in global functioning.
- Frequency of adverse events is similar for H perforatum vs placebo in children with ADHD.
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