ST .J OHN'S WORT

Full text

St. John’s wort (SJW) is a com-
mon plant that has become popu-
lar in Europe and the US for
treatment of mild-to-moderate de-
pression. Research has shown it is
effective in alleviating symptoms
of depression with minimal side
effects and is also useful in pre-
menstrual syndrome. It has an
excellent safety profile, although
some known drug interactions.
Confusion has arisen recently re-
garding the appropriate use of
SJW and this review provides
clear guidelines. General consid-
erations for the use of herbs in
mental health, as well as a useful
summary, are also provided.
ST.JOHN’SWORT
AS AN HERBAL
TREATMENT FOR
DEPRESSION AND
GENERAL
CONSIDERATIONS
FOR THE USE OF
HERBS IN MENTAL
HEALTH
HYLA CASS
INTRODUCTION
St. John’s wort (SJW) is a common roadside plant that has
gained increasing popularity in the Europe and the United
States as an effective alternative to pharmaceutical antidepres-
sants. Research in treating patients with depression has shown
that it relieves symptoms of sadness, helplessness, hopelessness,
anxiety, headache, and exhaustion, all with minimal side effects. It
is also useful in seasonal affective disorder and premenstrual
syndrome. It has an excellent safety profile, but with some drug
interactions mentioned below. More information is needed on its
long-term efficacy and safety through studies, although it has been
historically used by many depressed patients in Europe for years
with no observed ill effects.
A metaanalysis published in the British Medical Journal in 1996
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191Seminars in Integrative Medicine, Vol 1, No 4 (December), 2003: pp 191-198

increased awareness and was associated with an
increase in its popularity in the United States. The
analysis evaluated 23 randomized trials (20 were
double-blind) of SJW in a total of 1,757 outpa-
tients with mild to moderate depression.
1
Most
trials were 4-8 weeks in duration. All groups
showed improvement in depressive symptoms
[usually measured by the Hamilton Depression
(HAM-D) or Clinical Global Impressions (CGI)
scales]. In 15 placebo-controlled trials, SJW was
found to be significantly better than placebo. In 8
trials comparing SJW to tricyclic antidepressants,
clinical improvement was similar, but with fewer
and milder side effects. Of those on SJW, 19.8%
reported symptoms compared with 52.8% of those
on tricyclic antidepressants.
The National Center for Complementary and
Alternative Medicine and the National Institute of
Mental Health funded a multicenter study com-
paring SJW to sertraline (Zoloft) and placebo in
patients diagnosed with major depression. While
the vast majority of these studies have demon-
strated that SJW extract is superior to placebo for
depression, there were notable exceptions with
two studies published in the Journal of the Amer-
ican Medical Association. The first of these neg-
ative trials was published in 2001. A randomized,
double blind, placebo-controlled clinical trial was
conducted with 200 patients diagnosed with major
depression and a baseline HAM-D score of at least
20. After a 1-week, single blind run-in of placebo,
participants were randomized to receive either
900 mg/d SJW extract (0.3% hypericin) or placebo
for 4 weeks. The dose could be increased to 1,200
mg/d for the remainder of the 8-week study if
there was not an adequate treatment response.
Response rates in the intention-to-treat analysis
were not significantly different between the two
groups: 26.5% for St John’s wort vs 18.6% for
placebo. The number of participants reaching re-
mission of illness was significantly higher with
SJW than with placebo (P⫽0.02), but the rates
were low in the full intention-to-treat analysis
(14.3 vs 4.9%, respectively). The authors con-
clude, “These results do not support significant
antidepressant or antianxiety effects for St John’s
wort when contrasted with placebo in a clinical
sample of depressed patients.”
2
The study was
challenged due to the very low placebo response,
an uncommon finding in antidepressant trials for
which placebo response is generally 25-30%.
The NIH-sponsored study is the longest and the
most rigorous SJW study conducted thus far.
3
Three hundred forty moderate to severely de-
pressed patients were randomly assigned to re-
ceive SJW extract, placebo, or sertraline for 8
weeks. Based on clinical response, the daily dose
of SJW extract could range from 900 to 1,500 mg
and sertraline from 50 to 100 mg. Patients who
responded at week 8 could continue on their
blinded treatment for an additional 18 weeks. The
two primary outcomes were change in the HAM-D
score from baseline to 8 weeks and rates of full
response (as determined by change in HAM-D and
CGI scores). For change in HAM-D score, neither
sertraline nor SJW extract was statistically signif-
icantly different from placebo. Full response oc-
curred in 31.9% of the placebo-treated patients vs
23.9% of the SJW extract-treated patients (P⫽
0.21) and 24.8% of sertraline-treated patients (P⫽
0.26). Neither sertraline nor SJW extract per-
formed as well as placebo in this primary out-
come. Sertraline was better than placebo on the
CGI improvement scale (P⫽0.02), which was
used as secondary measure in this study.
The media reports, based on this trial, that SJW
is ineffective for the treatment of major depressive
disorder, do not provide an entirely accurate pic-
ture. In studies of antidepressants, the tested drug
often fails to do better than placebo. This is due to
both the high subjectivity of the scales used and
the typically large placebo response. A review was
conducted of clinical trial data from the nine
antidepressants approved by the U.S. Food and
Drug Administration (FDA) between 1985 and
2000 and included 10,030 patients with depres-
sion who participated in 52 antidepressant clinical
trials evaluating 93 treatment arms. The research-
ers found that fewer than half (48%, 45/93) of the
antidepressant treatment arms showed superior-
ity to placebo.
4
To avoid a false-negative result
(type II error), antidepressant trials would have to
study 300 or more patients per arm, or more
sensitive research designs must be developed.
5
The appropriate conclusion from this trial is that
it wasn’t sensitive enough to detect the effective-
ness of either sertraline or SJW extract or that this
was primarily a group of “nonresponders”that
were not otherwise characterized biochemically.
MECHANISM OF ACTION
SJW has been reported to work by enhancing
the quantity of the antidepressant neurotrans-
mitters serotonin, norepinephrine, and dopamine
192 HYLA CASS

in vitro.
6
In reality, though, the concentrations
may be too low for these actions to be significant.
SJW’s most potent effect may be on the receptors
for the inhibitory neurotransmitter GABA
A
and
GABA
B
.
7
SJW was well reviewed in a monograph that
includes information about analytical methods for
active constituents, as well as a review of the
pharmacology and toxicology.
8
DOSE AND ADMINISTRATION
The recommended dose of SJW is 300 mg three
times per day of a standardized extract of 0.3%
hypericin, for a total of 900 mg daily. Higher doses
of 1,200 to 1,800 mg have been used successfully
in more seriously depressed patients, with no in-
crease in side effects.
9
If there is any gastrointes-
tinal discomfort from the herb, it can be taken
with food.
The 900 mg can also be taken 450 mg twice per
day, or all at once, in the morning for those who
find it stimulating (to keep it from interfering with
sleep) or in the evening for those who find it to be
sedating. A small percentage of patients may be-
come anxious on SJW. They should lower their
dose, or discontinue the herb altogether, and may
change to other natural antidepressant supple-
ments, including specific amino acids and essen-
tial fatty acids.
Many patients report positive effects almost im-
mediately, with a sensation of “a weight being
lifted,”decreased anxiety, and an enhanced abil-
ity to concentrate. As with most antidepressants,
though, it may take 3 or 4 weeks before one
notices significant effects.
There are generally no withdrawal effects from
St. John’s wort, so one can stop and restart as
needed. After a few months, rather than stopping
all at once, it’s a good idea to taper off gradually, to
assess continued need and dose level. SJW re-
mains a safe, effective alternative to prescription
antidepressants, with the appropriate cautions.
CHANGING FROM CONVENTIONAL
ANTIDEPRESSANTS TO ST.JOHN’SWORT
Changing from conventional antidepressants to
St. John’s wort can be done safely in mild
depression by using a withdrawal protocol appro-
priate to the specific drug and adding in one 300
mg dose of SJW each time the drug dose is low-
ered, usually every few days. By the end of 1-4
weeks, the patient can discontinue the antidepres-
sant completely. In more serious depression,
maintain the antidepressant at half strength for a
month while increasing the St. John’s wort to full
dose and then reevaluate. Taper off the medica-
tion as the full antidepressant effect of the herb
takes effect.
This protocol is generally well tolerated. No
reports have been published of serotonin syn-
drome or any other significant adverse effects
using these combinations. While there is no evi-
dence of danger, caution is indicated in changing
from an monoamine oxidase (MAO) inhibitor to
SJW as with other antidepressants, Conserva-
tively, one should observe a 2- to 4-week washout
period between stopping the drug and starting the
herb.
There are those who do best remaining on a low
dose of antidepressant in combination with SJW.
The latter can potentiate the drug, and the lower
dose has fewer drug side effects.
ADVANTAGES OF ST.JOHN’SWORT
COMPARED TO ANTIDEPRESSANT DRUGS
•Side effects are generally mild and infre-
quent
•Drug side effects include headaches, nau-
sea, sexual dysfunction, insomnia, seda-
tion, “drugged”feeling, agitation, heart ar-
rhythmias, weight changes, short-term
memory loss, and rashes
•St. John’s wort is nonhabituating, nonad-
dictive, and with no withdrawal symptoms
upon discontinuing use
•Does not interfere with REM sleep; most
often enhances sleep and dreaming
•No adverse effects when mixed with alco-
hol or most drugs
•Far less likely to cause drowsiness or agi-
tation
•There has not been a single reported death
from an overdose of St. John’s wort versus
one report of an annual rate of 30.1 deaths
by overdose per one million prescriptions of
antidepressant.
ST. JOHN’S WORT IN MENTAL HEALTH 193

SOURCES AND QUALITY
There is wide variation in the quality and con-
tent of commercially available SJW prepara-
tions. Such variability can effect clinical response
as well as the results of clinical studies. Patients
may do well taking one brand, then, upon chang-
ing to another brand, experience a decrease in
effectiveness, and vice versa. Side effects may vary
also. Similarly, some patients may experience side
effects such as gastrointestinal irritation from
lower quality brands, while tolerating higher qual-
ity brands.
SIDE EFFECTS
Although SJW was reputed to have some MAO
inhibition activity in vitro, this effect has not
been demonstrated in vivo in either animals or
humans nor are there any reported cases of MAOI-
associated hypertensive crises in individuals using
SJW.
1
Thus there is no need to restrict tyramine-
containing foods such as cheese and red wine.
Side effects reported for SJW are generally mild,
including gastrointestinal symptoms and fatigue.
1
Extreme sun sensitivity or “photosensitization”
may also occur, especially in fair-skinned peo-
ple.
10
Kasper and Schulz
11
reviewed efficacy and
safety from 20 controlled clinical trials, including
a total of 1,787 patients. They concluded that the
effective dosage is 600 to 900 mg/day, of 0.3%
extract, and that the risk of photosensitization is
insignificant.
Animal studies show low toxicity for SJW. Rats
fed SJW as 5% of their diet for 119 days experi-
enced no adverse effects.
12
In chronic toxicity
studies in rats and in dogs, only nonspecific symp-
toms of toxicity were seen, with no effects on
fertility or reproduction, and no birth defects in
offspring.
COMBINATIONS WITH OTHER HERBS
SJW has been combined with other herbs and
nutrients, such as kava and ginkgo. While SJW
may take as long as 2-6 weeks to reach its full
effect, kava’s rapid onset has been a historically
useful addition, acting immediately on any anxi-
ety or insomnia component. Recent concerns
about the potential adverse effects of kava on the
liver have placed clinical applications on hold and
will be addressed in a future issue of Seminars in
Integrative Medicine. In the elderly, ginkgo may
be an especially useful adjunct.
DRUG INTERACTIONS
Herbal products contain a number of pharma-
cologically active ingredients, some of which
may potentially participate in herb–drug interac-
tions.
A proposed mechanism for herb–drug interac-
tions has been through induction of the CYP 450
enzyme system, a family of enzymes concentrated
in the liver and intestinal mucosa, and on P-
glycoprotein (Pgp), an ATP-dependent pump that
moves substrates out of cells. These can be af-
fected by a range of naturally occurring com-
pounds, such as grapefruit juice and cruciferous
vegetables as well as by certain drugs.
13
Other
reports of interaction are only theoretical or are
solely based on in vitro studies.
Lists of substrates, inducers, and inhibitors of
the various enzymes systems are regularly up-
dated and can be found on the internet at: http://
www.georgetown.edu/departments/pharmacology/
clinlist.html.
There has been some media attention paid to
SJW interactions, from its reputed actions as an
MAO inhibitor (which it is not), to its reducing the
efficacy of a number of drugs. These include cy-
closporine (immunosuppressant for organ trans-
plant patients)
14
; digoxin
15
; the protease inhibi-
tors Indivar (used in HIV/AIDS)
16
; warfarin
17
;
theophylline (asthma), and oral contraceptives.
The last two merit further discussion, since they
affect a larger population and have less evidence
to support the claims.
Theophylline
Several authors have cited interaction between
the asthma medication theophylline and SJW.
18
However the published report
19
referred to is a
discussion of a single case of a 42-year-old woman,
smoking half a pack of cigarettes daily (tobacco
induces liver enzymes) also taking 11 other pre-
scription medications, who had been taking SJW
for 2 months. On cessation of SJW, her plasma
theophylline levels rose within 7 days. The case
obviously is hard to evaluate and does not consti-
tute definitive evidence of a SJW–theophylline
interaction.
194 HYLA CASS

Oral Contraceptives
Despite popular press articles, there are as yet
no reports of unwanted pregnancy caused by oral
contraceptive failure due to SJW consumption. A
letter to The Lancet by The Swedish Medical Prod-
ucts Agency reported eight cases of irregular or
breakthrough menstrual bleeding in women aged
23-31 years who had been taking long-term oral
contraceptives and had begun taking SJW. Such
reports have also been received from patients,
whose symptoms cleared upon stopping the herb.
The interaction is unclear and may reflect a low-
ering of concentration of the oral contraceptive. If
unwanted pregnancy is a concern, one should err
on the side of caution regarding this combination.
GENERAL CONSIDERATIONS FOR THE
USE OF HERBS
Changes in the practice of medicine are caus-
ing a shift to increasing self-care with more
benign, less invasive treatments. As such, it is
critical that practicing clinicians (and, in turn,
patients) be made aware of the indications, ac-
tions, and drug interactions of herbal remedies.
The World Health Organization estimates that
80% of the world’s population relies on herbal
medicine. Meanwhile, the use of herbs in the
United States is expanding rapidly, to the point at
which herbal products are readily found in most
pharmacies and supermarkets. From 1990 to
1997, as the use of complementary/alternative
medicine rose from 34 to 42%, herbal use quadru-
pled from 3 to 12%.
20
It is worth remembering that these rapid
changes have come by popular demand. The pub-
lic has discovered that natural medicines often
provide a safe, effective, and economical alterna-
tive, and research is increasingly validating this
finding. Many of those who use herbal and high-
dose vitamin products fail to tell their physicians.
Either they assume “natural”products are harm-
less and not worth mentioning or they fear telling
health professionals who may be skeptical about
their use. Health professionals, however, are be-
ginning to familiarize themselves with the subject.
Aside from some advantages of natural products,
herb–drug interactions are a growing concern:
almost one in five prescription drug users are also
using supplements.
20
In Europe, there is a less of a problem since
herbs are classified with other pharmaceutical
products and routinely prescribed by doctors. In
fact, in Germany prescriptions of SJW outnumber
those for all other antidepressants. Most of the
research to date is European, since industry has
had financial incentive to do the necessary re-
search. The United States has recently joined in
these efforts and the NIH National Center for
Complementary and Alternative Medicine and the
NIMH completed a $4.3 million joint clinical trial
to determine the efficacy of SJW in major depres-
sion. Herbal studies are now in progress at a
number of America’s major medical universities.
HERBS FOR MENTAL HEALTH
In the Eisenberg survey,
20
two of the top five
conditions for which consumers sought alterna-
tive treatment were anxiety and depression. Be-
sides SJW, there are other herbs with popularity
for these and related problems: kava for relief of
GENERAL GUIDELINES FOR THE USE OF
HERBAL MEDICINES
•The clinician should take a careful history
of the patient’s use of herbs and other sup-
plements
•An accurate medical diagnosis must be
made before using herbs for symptomatic
treatment
•Natural is not necessarily safe: Attention
should be paid to quality of product, dos-
age, and potential adverse effects, includ-
ing interactions
•Herbal treatments should, for the most
part, be avoided in pregnancy (and con-
templated pregnancy) and lactation
•Herbal usage in children should be done with
care, using the appropriate dosage based on
weight
•Adverse effects should be recorded, and
dosage reduced, or the product discontinued.
It can be carefully restarted to ascertain
whether it is the source of the problem
ST. JOHN’S WORT IN MENTAL HEALTH 195

stress and anxiety (until recent concerns about
potential effects on the liver), ginkgo biloba for
senile dementia or benign forgetfulness, and vale-
rian for sleep. A $20 million NIH trial comparing
ginkgo to placebo in the development of dementia
in older Americans began in 2000.
SAFETY
Side effects of psychiatric drugs can be serious,
the worst being death by overdose. According
to one report, overdoses yielded an annual rate of
30.1 deaths per one million prescriptions of anti-
depressant. On the other hand, to quote Norman
Farnsworth, PhD, Professor of Pharmacognosy at
the University of Illinois, Chicago: “Based on pub-
lished reports, side effects or toxic reactions asso-
ciated with herbal medicines in any form are
rare...In fact, of all classes of substances ...to cause
toxicities of sufficient magnitude to be reported in
the United States, plants are the least problem-
atic.”It is important to caution patients that if
they feel any ill-effects from an herbal product,
they should inform the prescribing doctor. Then,
depending on the severity, the patient should ei-
ther reduce the dose or stop taking the herb
altogether. Unlike pharmaceuticals, withdrawal
reactions are rarely an issue.
It is essential to obtain a complete drug and
herbal history. There are contraindicated combi-
nations, which will be covered individually. On
the other hand, there are many combinations that
work well together. For example, individuals tak-
ing a drug that is metabolized by the liver can be
protected by the liver-supporting herb, milk this-
tle (Silybum marianum).
PREGNANCY,BREASTFEEDING,AND CHILDREN
Many herbs have not been approved for use by
pregnant and nursing women in the guide-
lines of the German Commission E, the equivalent
of the FDA. Now available in English translation,
the German Commission E has published a col-
lection of reports based on safety and efficacy data
on over 200 herbs.
Herbs may often be a treatment of choice for
children. Despite lack of modern research, centu-
ries of use have shown many products to be safe
when dosed appropriately by weight.
AGING
Considering the phenomenon of polypharmacy
in the elderly and problems of impaired me-
tabolism and clearance, herbs may offer an alter-
native to drugs. On the other hand, we also must
be aware of herb–drug interactions. SJW can be
very useful for depression in the elderly, ginkgo for
GENERAL CONSIDERATIONS FOR THE
USE OF HERBS
Many current drugs are derived from
plants. Common examples are morphine,
from the opium poppy, digitalis from foxglove,
and reserpine from rauwolfia (Indian Snake-
root). In many cases, pharmaceuticals remain
the treatment of choice. However, when appro-
priate, herbs may be preferred for the following
reasons:
•Herbs are generally less likely to cause side
effects. When they do occur, they are gen-
erally milder. In fact, in the absence of side
effects, patients often don’t notice the sub-
tle improvements that occur as these nat-
ural medicines begin to take effect. This
contrasting lack of side effects may also
confound double-blind studies. A partial
explanation for the milder side effects may
be that the original plant constituents are
more compatible with metabolism and
body chemistry.
•Although the isolated active ingredient has
been assumed to be most effective, there
are advantages to using the whole plant.
While Western biomedicine seeks to iso-
late a single active ingredient, herbal med-
icine relies on the synergistic action of a
plant’s many constituents.
•These combinations may also yield a vari-
ety of effects. For example, by its action on
the brain, kava acts as an anxiety reliever,
while its relaxant effects are due to its
direct action on both smooth and striated
muscle.
•Herbs are working physiologically to re-
store balance rather than simply targeting
a symptom. As a result, herbs often tend
to take effect more gradually than pharma-
ceuticals.
196 HYLA CASS

cognitive decline, and kava, for sedation (but see
above), without the adverse effects of the benzo-
diazepines. These herbs can be used in combina-
tion with each other as well.
SELECTION AND USE OF HERBS
Standardized Extracts
For those new to the medicinal use of herbs,
dose selection can be confusing. As discussed
above, unlike synthetic drugs containing a single
compound, herbs often have a number of different
active ingredients. Even these will vary in propor-
tion, based on many factors, including where the
plant was grown and when (season or even the
time of day) it was harvested. The manufacturer
may adjust the mixture to help account for these
variations.
In order to standardize the product, that is, to
have a consistent, measured amount of product
per unit dose, one ingredient is selected as the
marker, usually the presumed active ingredient.
Though research may reveal different or addi-
tional active ingredients, for convenience the des-
ignated constituent will usually remain the ac-
cepted marker. This situation is demonstrated in
the example of SJW.
SJW is standardized to hypericin, the long-ac-
cepted active antidepressant ingredient. Further
research has found hyperforin to be a likely active
ingredient. Some SJW products are actually stan-
dardized for both. In any case, all compounds
(even as-yet-undiscovered contributors) remain
distributed throughout the plant, alongside the
hypericin. As a result, the standardization of hy-
pericin serves as a useful guidepost for the
strength of all the (active) ingredients.
Hypericin content is listed on the label, with
most products using a 0.3% concentration, so that
a 300-mg capsule contains 0.9 mg (0.3 ⫻300 mg)
of hypericin. In kava, the marker is kavalactones,
and in ginkgo, flavone glycosides.
Herbal Preparations and Dosing
Herbs can be purchased as teas, tinctures, tab-
lets, and capsules. Teas and tinctures, being liq-
uid, are absorbed more rapidly and with a shorter
duration of action. Tinctures are made by soaking
one part herbal material with 5 or 10 parts by
weight of alcohol, making a 1:5 or 1:10 concentra-
tion. To remove the alcohol taste, the tincture can
be placed in warm water or tea for a few minutes
to let the alcohol evaporate. Glycerin may also be
used instead of alcohol, but the resulting extract is
weaker.
Capsules and tablets are the most common de-
livery system. Gelatin- or vegetable-based cap-
sules are filled with powdered dried herb, while
tablets are powdered herbs, compressed into a
solid pill, often with a variety of inert ingredients
as fillers.
They are supplied in a variety of sizes and
strengths, so it is important to read the label
carefully. The label will also usually give an aver-
age suggested dose as a guideline, based on re-
search and clinical use. It is recommend to start at
the low end, watch for a response, including un-
wanted effects, and adjust the dose accordingly.
For example, patients may do well on 300 mg of
SJW once per day, while others need four times
that dose. Most will fall in the middle, with the
recommended 300 mg three times daily. Some
herbs such as kava take effect immediately, while
others take days, weeks (SJW, ginkgo), or even
months to do so, with individual variation.
Regulatory Issues
Most herbal products are regulated as “dietary
supplements.”In 1994, the U.S. Dietary Supple-
ment Health and Education Act (known as
DSHEA) set new guidelines with regard to quality,
labeling, packaging, and marketing of supple-
ments. It also sparked a surge of interest in herbal
products. DSHEA allows manufacturers to make
“statements of nutritional support for conven-
tional vitamins and minerals.”Since herbs aren’t
nutritional in the conventional sense, DSHEA al-
lows them to make only what they call “structure
and function claims,”but no therapeutic or pre-
vention claims. Thus, a SJW label can claim that it
“optimizes mood,”but cannot say “natural anti-
depressant,”which would be a therapeutic claim.
Since the labels (by law) give insufficient infor-
mation, it is particularly important for the health
practitioner to be well educated in this area. Ide-
ally, supplements would be labeled so that the
purchaser would know exact indications and pos-
sible side effects, as with over-the-counter medi-
cines.
Quality control is essential, with assurance that
the product contains the ingredients and quanti-
ties as labeled and without such contaminants as
bacteria, molds, or pesticides. There are trade and
ST. JOHN’S WORT IN MENTAL HEALTH 197

professional organizations, such as the American
Herbal Products Association, that are setting stan-
dards called “Good Manufacturing Practices”for
the herbal industry. In general, we recommend
buying herbal products from a recognized manu-
facturer.
There are a number of excellent websites on the
subject listed below.
WEBSITES
Alternative Medicine Foundation, Inc: HerbMed.
org
American Botanical Council: www.herbalgram.
org
Herb Research Foundation: www.herbs.org
Natural Product Research Consultants (NPRC):
www.nprc.com
The Natural Pharmacist: www.TNP.com
RESOURCES
McGuffin M, Hobbs C, Upton R, Goldberg A.
Botanical Safety Handbook. Boca Raton, FL, CRC
Press, 1997, p. 105.
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