In 1999, British researchers from the University of Exeter undertook
the first systematic comparison of safety data on St. John's wort
(Hypericum perforatum L., Clusiaceae) and four antidepressant
drugs (Stevinson et al., 1999). In compiling the article, they
utilized data from meta-analyses and reviews from the Medline
database, manufacturers' clinical trials, drug monitoring studies,
and spontaneous adverse effect reporting schemes. Although St.
John's wort (SJW) was associated with fewer and milder side effects
than the drug therapies, it was difficult to make direct comparisons
due to the different forms in which data was presented. The authors
concluded that SJW is "at least as safe, or possibly more
safe" than conventional drug therapies. However, there is
still a need for safety data on potential herb-drug interactions.
For this review article, the researchers compared SJW with the
most widely prescribed drugs from the four main classes of antidepressants:
fluoxetine (Prozac®), a selective serotonin reuptake inhibitor
(SSRI); moclobemide, a monoamine oxidase inhibitor (MAOI); dothiepin,
a tricyclic antidepressant; and mirtazapine, a newer class of
drug known as a "noradrenergic and specific serotonergic
antidepressant (NaSSA)." In placebo-controlled studies, 4.1
percent of people taking SJW reported side effects, compared with
19.8 percent in studies that tested the plant against an antidepressant
drug. The researchers believe this difference may be due to patient
expectations, which may lead people to report more side effects
in trials involving a pharmaceutical drug. In clinical trials
of the antidepressant drug mirtazapine, 65 percent of patients
reported side effects. Safety statistics on the other three drugs
were more difficult to compare because the data was presented
as the percentage of patients experiencing individual side effects.
In general, SJW patients reported fewer and milder side effects
and withdrew from studies less frequently compared with those
taking antidepressant drugs. Problems associated with the four
drugs covered a wider range of symptoms. Participants taking dothiepin
and moclobemide reported the fewest side effects, while those
taking fluoxetine and mirtazapine had the greatest number of complaints.
The authors included tables of the incidence of side effects associated
with each form of treatment and related dropout rates.
The authors' analysis includes an in-depth assessment of problems
encountered while interpreting the data. One issue is that clinical
studies may fail to detect rare or delayed side effects or even
some common side effects, due to the studies' relatively short
duration, small sample size, and focus on efficacy rather than
safety. The authors also noted inconsistencies in the way safety
data is collected and reported, in the terminology used to describe
side effects, and in the methodologies used in different countries
for tracking adverse effects in clinical studies.
The study also included data from drug monitoring studies and
spontaneous reporting schemes, in which an FDA-type agency collects
voluntary reports of side effects from the public or health practitioners.
In SJW drug monitoring studies involving a total of 4,587 patients,
the side effect rate ranged from 2 percent to 6.1 percent, and
the rate of withdrawal was between 0.8 percent and 1.5 percent.
In these studies, the most commonly reported side effects were
gastrointestinal complaints, allergic reactions, fatigue, or restlessness.
Data from spontaneous reporting schemes, collected from Europe
and the World Health Organization, also revealed a low rate of
side effects among people using SJW products. However, according
to the authors, there are at least two major drawbacks to relying
on data from spontaneous reporting schemes. The first is it can
be challenging to establish a causal relationship between side
effect reports and the plant in question. Secondly, people may
tend to under-report problems experienced with herbal products.
The authors analyzed information related to potential overdose
and drug interactions for this article as well. Currently, there
is no data to suggest that SJW is dangerous in overdose. Although
increased photosensitivity is often cited as a concern with this
plant, there are only two documented cases of such reactions in
humans. Moreover, researchers estimate that a severe phototoxic
reaction would require a dose of SJW 30 to 50 times the standard
daily dose. Among the four antidepressant drugs, dothiepin presented
the biggest safety concern in terms of overdose.
At the time of the 1999 printing of this article, the authors
reported no known interactions between SJW and pharmaceutical
drugs. Since then, two letters published in the Lancet have raised
the concern that SJW may interfere with the metabolism of drugs
used in AIDS patients (Piscitelli et al., 2000) and heart transplant
patients (Ruschitzka et al., 2000). The authors pointed out that
there is a lack of information on possible interactions between
SJW and psychotropic drugs, because patients taking these drugs
are generally excluded from placebo-controlled studies of SJW.
On the other hand, there have been no reports from clinical trials
of interactions between SJW and medications for hypertension,
circulatory disorders, bronchial asthma, and menopausal symptoms.
The authors conclude the article with a discussion of some potentially
serious drug interactions associated with conventional antidepressant
drugs, including the rare but possibly life-threatening "serotonin
syndrome" that may result when SSRI drugs are used in combination
with other antidepressants. - Krista Morien, HRF
[Piscitelli SC, Burstein AH, Chaitt D, Alfara RM, Falloon J.
Indinavir concentrations and St. John's wort. The Lancet
2000; 355: 547-548.
Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. Acute
heart transplant rejection due to St. John's wort. The Lancet
2000; 355: 548-549.
Stevinson C, Ernst E. Safety of Hypericum in patients with
depression: a comparison with conventional antidepressants. CNS
Drugs 1999; 11(2): 125-132.]
