Herbalists, Scientists and Trade Organizations Criticize JAMA Report
Of NIH Study of St. John's Wort
Wort Study Misinterpreted
TX, 9 April 2002
American public may be receiving misleading information about the
effectiveness of the popular herbal dietary supplement St. John's
wort, says the nonprofit American Botanical Council (ABC).
ABC and some of its scientific advisors noted that a new clinical
study being released to the media is being misinterpreted.
long-awaited government-sponsored study on the effectiveness of
the popular herb is being published April 10 in the Journal of
the American Medical Association. The study, conducted by researchers
at Duke University and 11 other medical centers in the US, concludes
that neither St. John's wort nor the drug sertraline showed any
measurable benefit in patients with more severe forms of depression.
Although the study was conducted in patients with moderate to severe
depression, the herb has been tested and used mainly in patients
with less severe forms of depression.
study conducted from December 1998 to June 2000 included 340 moderate
to severely depressed patients who were randomly assigned to three
groups. Over an eight-week period, one group received a dose between
900Ð1500 milligrams of a leading brand of St. John's wort extract,
one group took the antidepressant drug sertraline (50Ð100 mg), popularly
know by its trade name Zoloft®, and the third group took a placebo,
a sugar or dummy pill. Patients who responded to treatment continued
to receive their assigned treatment for an additional 18 weeks.
Curiously, fewer of the patients in both the herb and the drug groups
responded to the treatments than did those in the placebo group.
sensitivity and accuracy
to Jerry Cott, PhD, former Chief of the Psychopharmacology Research
Program at the National Institute of Mental Health, the NIH designed
this trial to include a standard anti-depression drug (sertraline)
as "an active comparator" to document the sensitivity
of the trial, that is, the ability of this trial to detect an actual
treatment effect. "The fact that the sertraline was not effective
in the primary measures of depression demonstrates (according to
the NIH's own design protocol) that this trial lacked assay sensitivity
and should not be considered a successful study." Dr. Cott
was involved in the original design of the trial when he worked
for the NIMH.
added that "this study does not invalidate the use of St. John's
wort in clinical depression. There are still many well-controlled
trials supporting the use of St. John's wort in mild to moderate
depression, and additional studies with more appropriate patient
populations are in progress."
fails to show effectiveness rather than shows ineffectiveness
Dr. Cott's estimation, this study could be considered "neutral",
one that simply fails to show effectiveness of either treatment
rather than proving the test drug doesn't work. "This result
is not uncommon in pharmaceutical industry-sponsored studies, though
normally they are not published. The study simply lacked the sensitivity
to detect a difference." Dr. Cott is an expert on the effects
of herbs and conventional drugs on mental disorders, including depression.
He also formerly worked at the Food and Drug Administration where
he evaluated clinical studies on new antidepressant drugs.
Steven Bratman, a physician-author in Fort Collins, Colorado agrees.
"The conclusion of the study is taken too far. Both treatments
have been found effective in the majority of clinical trials. This
study, while not supporting the use of St. John's wort, doesn't
discredit it either."
facing trials of antidepressants
Bratman, co-author of The Natural Pharmacy: Clinical Evaluation
of Medicinal Herbs, explained the intricacies of the interpretation
of clinical studies of this type. "In many studies of antidepressants,
perhaps as many as one-third, the tested drug doesn't do any better
than placebo. The cause is probably a combination of the high placebo
effect often seen in studies testing antidepressants and the relative
coarseness and subjectivity of the type of rating scales that must
be used to evaluate severity of depression." Dr. Bratman explained
that these rating scales are by their very nature less precise than
biomedical tests, such as those that measure cholesterol levels.
"In consequence, it is quite easy for a truly effective antidepressant,
such as sertraline, to fail to prove efficacy in a given double-blind,
placebo-controlled trial. The problem is not the treatment itself,
but in the difficulties of studying such treatments."
this study included sertraline, a drug that previously has been
shown effective, the inescapable conclusion is that details of the
patient group and the methods by which the ratings were determined
were such that this study could not discern the effectiveness of
a known effective treatment. This also applies to St. John's wort
(which has also been shown effective in many studies) as it does
conclusions based on "secondary measures" are challenged
took issue with the authors of the study when they used a secondary
outcome measure to conclude that sertraline was more effective than
placebo and therefore better than St. John's wort. According to
the standard rules of interpreting clinical studies, one should
take only the primary outcome measures as meaningful, he explained.
On those measures, neither sertraline nor St. John's wort was effective.
Digging into secondary measures is widely accepted as being inappropriate,
when the authors conclude that St. John's wort is ineffective for
moderate depression and shouldn't be used, noted Bratman, "it
would be equally valid to say that sertraline is ineffective for
moderate depression, and shouldn't be used. However, we know that
this is not the case; looking at the body of published research
as a whole, both sertraline and St. John's wort are effective."
of studies on St. John's wort
should be tested according to a reasonable expectation of their
previously documented benefits," said Mark Blumenthal, founder
and executive director of the nonprofit American Botanical Council.
He referred to 10 previous studies on St. John's wort extract where
the herb preparation was compared directly with pharmaceutical antidepressants
for treatment of mild to moderate depression. These studies indicated
a comparable efficacy with St. John's wort and the conventional
also noted, "In Germany many physicians use St. John's wort
as a first-line remedy for mild to moderate depression; if it doesn't
work, then they can always put the patient on more powerful, pharmaceutical
added, "It is important for the NIH to continue conducting
clinical trials on many popular herbal dietary supplements. This
adds to the growing body of scientific information on their safety
and efficacy. This process is a constructive contribution to the
maturation of the herbal movement. At the same time, however, it
is equally important that the results of these studies are accurately
interpreted and communicated to the public. Unfortunately, it appears
that some aspects of this first NIH-funded study are not being properly
characterized." He also noted that the full text of the study
is not available prior to its publication on 10 April, so it is
not possible to adequately evaluate all the details.
funding and background
study was funded with $4 million from the National Institutes of
Health's National Center for Complementary and Alternative Medicine.
It was the first clinical trial established by the NIH to test the
efficacy of herbal remedies. St. John's wort was chosen because
at the time the study was designed and funded in 1996, St. John's
wort had begun to significantly increase in popularity in the US.
This new awareness was based on media reports of a meta-analysis
(statistical review of clinical trials) of 23 European clinical
trials that showed that St. John's wort was safe and effective in
treating mild to moderate forms of depression.
study of St. John's wort and major depression
April, another US-based multi-center clinical trial on St. John's
wort also failed to show any activity for the herb, again in more
severely depressed patients. The placebo-controlled study was criticized
for targeting patients that were too chronically and severely depressed
and thus not consistent with the profile of patients normally included
in clinical trials. It was also criticized for not including an
active control, like the drug sertraline (Zoloft®, produced
by Pfizer, the funder of the study), to determine the level of response
by the patients. Both trials used the leading German St. John's
wort extract (known in Germany as Jarsin® 300, made by Lichwter
Pharma of Berlin, and sold in the US as Kira® by Lichtwer Pharma
St. John's wort and other research
John's wort, also known by its scientific name Hypericum perforatum,
is a traditional European herb that has drawn significant attention
for its ability to help elevate mood in mild or moderately depressed
people. At least 22 controlled clinical trials have been published
in European medical journals suggesting that St. John's wort extract
is a safe and effective remedy for mild to moderate depression.
An estimated 131 million doses of St. John's wort were prescribed
by psychiatrists in Germany in 1999, according to German sources.
Botanical Council (ABC).
On Depression Called Misleading
Washington DC, 9 April 2002
Council for Responsible Nutrition (CRN)
and expert scientists today questioned the value of a study of St.
John's wort on moderate to severe depression to be published in
the April 10 issue of the Journal of the American Medical Association
(JAMA), calling it "misdirected and inconsequential."
John's wort, the most commonly used antidepressant in Germany and
one of the top five selling botanicals in the United States, is
recommended and proven beneficial only for mild to moderate depression,
based on more than 30 published clinical studies and several meta-analyses
and systematic reviews. This new, multi-million dollar, NIH-sponsored
study was targeted at moderate to severe depression, a use not recommended
or supported for St. John's wort.
trial found no difference among St. John's wort, Zoloft®, and
placebo for severely depressed patients
NIH-sponsored clinical trial compared St. John's wort (an herbal
extract), sertraline (better known as Zoloft®, a prescription
antidepressant, used as a positive control), and placebo (dummy
treatment, used as negative control) for the treatment of moderate
to severe depression. The detailed results of this new study indicate
that the patient group was, in general, non-responsive to any treatment
offered. According to the studies' authors (Davidson et al.), "On
the two primary outcome measures, neither sertraline nor H. perforatum
[St. John's wort] was significantly different from placebo."
affirm value of St. John's wort for mild to moderate depression
to John Cardellina, PhD, vice president, botanical science and regulatory
affairs, CRN, "This new report dismisses the scientific fact that
St. John's wort has been proven safe and beneficial for the treatment
of mild to moderate depression, stress and anxiety, according to
a substantial body of evidence in the medical literature based on
more than 30 controlled clinical studies and three meta-analyses
or systematic reviews."
E. Rosenthal, MD, clinical professor of psychiatry at Georgetown
University and author of The Emotional Revolution, said,
"The findings of this study are of limited value, because St. John's
wort is not generally used for moderate to severely depressed people.
Instead, extensive research has demonstrated the herb's efficacy
for mild to moderate depression. It would be a shame if we discarded
St. John's wort as a treatment for mildly to moderately depressed
persons on the basis of these findings."
questions study's focus on severe depression
is difficult to understand why NIH chose to study this type of patient
population," said Jerry Cott, PhD, psychopharmacologist and former
chief of the Psychopharmacology Research Program at the National
Institute of Mental Health (NIMH), NIH. "It appears that they enrolled
a population of patients who were too depressed to respond to either
sertraline or hypericum. If they had designed the study to focus
on mild to moderate depression, then we likely would have seen a
very different result with both standard antidepressant and St.
John's wort. The lack of response in the standard treatment (positive
control) group prevents any valid conclusions from this study regarding
the effectiveness of St. John's wort."
for Responsible Nutrition (CRN),
via PR Newswire.
John's Wort Study Misleads Public
Silver Spring MD, 9 April 2002
study on the popular herbal remedy St. John's wort published in
the April 10 edition of the Journal of the American Medical Association
(JAMA) concluded that neither St. John's wort nor the widely
prescribed antidepressant Zoloft® are more effective overall
than placebo in treating severe forms of depression. The American
Herbal Products Association (AHPA)
and the National Nutritional Foods Association (NNFA)
are critical of the study saying that it ignores the traditional
use of St. John's wort and recent modern clinical trials that have
demonstrated conclusively that St. John's wort is effective in the
treatment of "mild to moderate" depression.
is a quintessential case of the Emperor's New Clothes," said Steven
Dentali, PhD, vice president for scientific and technical affairs
for AHPA. "It is inexplicable that JAMA has created such
fanfare over the fact that St. John's wort is not shown to be effective
for a condition that it was never intended to treat. The real story
here is that if this study is believable it showed that a blockbuster
drug, with sales of over $2 billion and prescribed to millions of
Americans for severe forms of depression, may be no more effective
John's wort is one of the top five selling herbal products in the
United States and is the number one antidepressant used in Germany
for the treatment of mild to moderate depression. The new multi-million-dollar
National Institutes of Health study was conducted on 340 patients
diagnosed as having major depression. The study broke patients into
three groups: assigning one group to take a leading brand of St.
John's wort, another group to take the anti-depressant pharmaceutical
Zoloft® and the third group a placebo (sugar pill). The researchers
reported that neither St. John's wort nor Zoloft® were significantly
different from placebo.
research in no way invalidates the scores of clinical studies and
analyses that have clearly demonstrated that St. John's wort is
effective for mild to moderate depression," said Phil Harvey, PhD,
director of science and quality assurance for NNFA. "In fact, contemporary
researchers have found evidence that St. John's wort extracts are
`therapeutically equivalent to' and `at least as effective as' some
commonly prescribed antidepressant drugs. Researchers also note
that people have better tolerance for the herb."
to Web MD, in the US, approximately 10% of people suffer from major
depression at any one time, and 20-25% suffer a major depressive
episode at some point during their lifetimes.
to Nutrition Business Journal, St. John's wort sales in 2000
were $180 million.
to Med Ad News, Zoloft® is the third best-selling selective
serotonin reuptake inhibitor and the leading antidepressant in terms
of share of new prescriptions. According to IMS Health Inc., 2000
Zoloft® sales reached $2.14 billion.
Herbal Products Association (AHPA).