||St. John's Wort|
Hypericaceae (Plant Family)
Medicinal use of St. John's wort dates back to ancient Greece. The renowned
physicians Dioscorides and Hippocrates used this herb to treat a variety of
illnesses, and it was long believed to rid the body of evil spirits. Belief in
the herb's powers continued through the Middle Ages, but by the end of the 19th
century, interest in St. John's wort—and most other
medicinal plants—had waned. Recent research on St.
John's wort has refocused attention on the herb, and it has become extremely
popular with consumers in the United States. In Europe, where St. John's wort
has a longer history of use, it is used to treat wounds, gastritis, kidney and
lung disorders, insomnia, and depression.
Most clinical studies of St. John's wort have focused on its use in treating
mild to moderate depression. In a 1996 meta-analysis, researchers examined 23
randomized trials of St. John's wort in a total of 1,757 patients with mild to
moderate depression. Acknowledging the limitations of using pooled data from
studies using different preparations and dosages, varying experimental designs
and patient populations, the researchers still concluded that St. John's wort is
better than placebo in treating mild to moderate depression. However, from the
trials reviewed, they could not draw firm conclusions about whether St. John's
wort is as effective as standard antidepressants. The analysis did suggest that
St. John's wort causes fewer side effects than standard antidepressants.
The National Institute of Mental Health (NIMH) does not currently recommend
the use of St. John's wort for treatment of depression and has called for more
rigorous research on the herb. Along with two other branches of the National
Institutes of Health—the Office of Alternative Medicine
and the Office of Dietary Supplements—NIMH has funded a
three-year controlled clinical study of the herb in clinically depressed
patients. Patient enrollment for the study began in the spring of 1999.
In at least one controlled trial, patients with seasonal affective disorder
(SAD) responded well to treatment with St. John's wort, and the herb seems to be
even more effective when used in combination with light therapy.
Studies from the early 1990s revealing antiretroviral activity of St. John's
wort had raised hopes for using this herb to treat human acquired
immunodeficiency virus (HIV). Results of small pilot studies have been
promising, with patients showing stable or increased helper T cell counts,
improved helper-to-suppressor T cell ratios, and low incidence of opportunistic
infection, but larger and longer-term studies are still needed. However, recent
data suggest a potential interaction with protease inhibitors; please refer to
the section entitled "Interactions" for more information.
Topical preparations of St. John's wort have shown antibacterial and
wound-healing activity and have been used to treat burns, muscle pain, and
hemorrhoids. Topical preparations also have been used to reduce pain,
inflammation, and to promote nerve-tissue regeneration. Interestingly, debate
continues over the most active ingredient in St. John's wort.
St. John's wort is a shrubby perennial with flat-topped clusters of bright
yellow flowers. The plant is native to Britain and Europe but now grows wild in
many other parts of the world, including the United States. It grows best in
sunny sites with dry, gravelly, or chalky soil.
The best-studied active components are hypericin and pseudohypericin, found
in both the leaves and the flowers. There has been recent research, though, to
suggest that these best-studied components may not be the most active in the
plant, with significant debate ensuing within the industry. Other components
include flavonoids, xanthones, phenolic carboxylic acids, essential oils,
carotenoids, alkanes, phloroglucinol derivatives, phytosterols, and medium-chain
fatty acid alcohols.
St. John's wort is available in various forms, including dried herb (chopped
or powdered), capsule, liquid extract, tincture, infused oil, and tea
The recommended preparation of St. John's wort currently accepted by the
industry is an extract standardized to contain 0.3% hypericin.
- Anxiety, depression, apathy, anorexia, and feelings of worthlessness
- Sleep disturbances including insomnia and hypersomnia
- Wounds and burns; topical application promotes healing
- Possible adjunctive therapy for viral infections such as herpes
simplex, influenza, mononucleosis, and HIV, (See Overview and Interactions
sections for controversial issues)
- Hemorrhoids (topically)
- Antidepressant activity. Early studies suggested that hypericin may
act as monoamine oxidase inhibitor (MAOI) but more recent evidence suggests that
it has weak MAOI activity. It has also been suggested that the antidepressant
activity of St. John's wort may mimic that of a selective serotonin reuptake
inhibitor (SSRI); however, the actual mechanism of antidepressant action remains
unclear and controversial. Xanthones and flavonoid components may also be
responsible for the antidepressant activity of this herb; most recent studies
indicate that hypertorin, a phoraglucinal, is partly responsible for the
- Antibacterial activity. Extracts show broad-spectrum antimicrobial
activity against such organisms as Escherichia coli, Staphylococcus aureus,
Streptococcus mutans, Pseudomonas aeruginosa, and Proteus vulgaris in
vitro, but the specific ingredients responsible for this action have not been
- Antiviral activity. Active components hypericin and pseudohypericin
show antiviral activity against herpes simplex virus types 1 and 2,
Epstein–Barr virus, and influenza types A and B. These
components have also demonstrated activity against a number of retroviruses,
including the human immunodeficiency virus (HIV).
|Dosage Ranges and Duration of
As an antidepressant, the recommended amount is 300 to 500 mg (standardized
to 0.3% hypericin extract), tid with meals, for a minimum of four to six
St. John's wort causes severe photosensitivity in grazing animals that eat
large amounts of the plant. Such reactions are rare in humans and have been seen
only in people taking very large doses for HIV infection. However, as a
precaution, people with fair skin and people taking other medications such as
tetracycline or piroxicam that can also cause photosensitivity should use a
sunscreen with a skin protection factor (SPF) of at least 15; they should also
not use sun-lamps, tanning beds or booths while taking St. John's wort.
Other side effects are usually mild. They may include:
- Abdominal pain, bloating, constipation
- Nausea, vomiting
- Dry mouth
- Itching, hives, skin rash
- Sleep problems
- Elevated blood pressure
- Unusual tiredness
- Take with food to reduce chances of gastric upset.
- Do not take during pregnancy or while breast-feeding.
Two cases of heart transplant rejection in patients who took St. John's wort
while being treated with cyclosporin have been reported (Ruschitzka et al.
2000). One patient had been maintained uneventfully on a regimen of cyclosporin
(125 mg bid), azathioprine, and corticosteroids for 11 months. The other patient
had also been stable on an immunosuppressive regimen that included cyclosporin
(125 mg bid). Although cyclosporin levels had been within the therapeutic range
for both patients, ingestion of St. John's wort (300 mg tid) for three weeks
diminished blood concentrations of cyclosporin to subtherapeutic levels and
prompted episodes of rejection in each of these patients. Cyclosporin
concentrations returned to therapeutic range with discontinuation of St. John's
wort in both of these cases.
Additional reports of 30 interactions between cyclosporin A and St. John's
wort in kidney transplant recipients were recently described (Breidenbach et al.
2000). After beginning St. John's wort therapy, cyclosporin blood levels fell by
an average of 47%; cyclosporin dosages were increased 46% to account for this
drop. Upon discontinuation of St. John's wort, cyclosporin blood levels
increased by an average of 187%. While the mechanism for this interaction is not
entirely clear, St. John's wort may either decrease cyclosporin absorption,
induce cytochrome P-450 in the liver and/or small intestine, or induce
P-glycoprotein (a drug transporter) in the small intestine. Because cyclosporin
has a narrow therapeutic range, the researchers caution against concomitant use
of St. John's
The interaction between the hypericum extract of St. John's wort (900 mg/day)
and digoxin (0.25 mg/day) was investigated in a single-blind, placebo-controlled
parallel study in 25 healthy volunteers (Johne et al. 1999). The combination
resulted in decreased plasma concentrations of digoxin over the 10-day period.
This interaction was thought to involve induction of transport proteins,
There is a report in the literature of a possible interaction between
loperamide and St. John's wort (Khawaja et al. 1999). A 39-year-old woman was
admitted to the hospital in a state of delirium. She had been taking St. John's
wort and valerian for 6 months, and she had recently ingested loperamide for
diarrhea. Because the patient's clinical condition resembled a MAOI reaction,
this interaction was thought to occur as a result of a MAOI-induced mechanism,
possibly associated with an interaction either between the herbal agents or the
herbal agents and
Oxidase Inhibitors (MAOIs)
Research regarding interactions between St. John's wort and MAOIs remains
incomplete and controversial. A recent report suggested that St. John's wort and
phenelzine, a MAOI, should not be used concomitantly (Miller 1998).
Eight women between the ages of 23 and 31 who had used St. John's wort while
taking oral contraceptives reported breakthrough bleeding or changes in
menstrual bleeding (Yue et al. 2000). There have been additional reports cited
in the literature of breakthrough bleeding in women taking oral contraceptives
with St. John's wort (Ernst 1999). Because oral contraceptives are metabolized
via the cytochrome P450 pathway, enzyme induction is thought to be the mechanism
The Food and Drug Administration (FDA) has issued a public health advisory
concerning an interaction between indinavir and St. John's wort that resulted in
significantly decreased plasma concentrations of this protease inhibitor (FDA
2000). This advisory warning was based on results of an NIH-conducted open-label
study of eight healthy volunteers receiving indinavir (800 mg) and later
indinavir with St. John's wort (300 mg tid standardized to 0.3% hypericin) for
14 days (Piscitelli et al. 2000). Plasma concentrations of indinavir dropped
significantly from levels obtained prior to the introduction of St. John's wort.
This interaction may be secondary to induction of the cytochrome P450 metabolic
The FDA recommends against concomitant administration of St. John's wort with
antiretroviral medications that are protease inhibitors or nonnucleoside reverse
transcriptase inhibitors because this interaction could lead to subtherapeutic
plasma concentrations of these medications with the potential for lack of
efficacy and/or resistance (FDA
St. John's wort antagonized the effect of the sympatholytic agent reserpine
in animal studies (Okpanyi and Weischer
Serotonin Reuptake Inhibitors (SSRIs)
In five cases, elderly patients receiving St. John's wort and prescription
antidepressants (SSRIs) developed symptoms of serotonergic syndrome, including
headache, dizziness, nausea, agitation, and anxiety (Lantz et al. 1999). A
washout period of two weeks has been recommended when switching between SSRIs
and St. John's wort because the combination of St. John's wort (600 mg) and
paroxetine (20 mg) reportedly resulted in symptoms of incoherence and lethargy
in a patient (Gordon 1998). Concomitant use of SSRIs with St. John's wort is not
recommended. If these agents are used concomitantly, patients should be
monitored very closely. Patients must be carefully weaned from one before
starting on the
Use of St. John's wort supplement (300 mg bid standardized to 0.3% hypericin)
decreased a patient's theophylline concentration, requiring an increase in
dosage to 800 mg bid (Nebel et al. 1999). Discontinuation of St. John's wort
caused the theophylline concentration to more than double in this individual
case. St. John's wort may enhance hepatic enzyme (CYP1A2) activity, leading to
Unpublished data suggest that St. John's wort may lower plasma concentrations
of amitriptyline (De Smet and Touw 2000). This lends support to the possibility
that the mechanism of drug interactions with St. John's wort involves induction
of hepatic enzymes that are part of the cytochrome P450
There have been seven case reports filed with the Medical Products Agency
(MPA) in Sweden involving reduced effectiveness of warfarin when taken
concomitantly with St. John's wort as evidenced by clinically significant
decreases in INR values (Yue et al. 2000). Adjustments in warfarin doses or
discontinuation of St. John's wort resulted in a return of INR values to desired
levels. This interaction may be due to induction of hepatic enzymes,
specifically cytochrome P450 2C9. In addition, there was a literature report of
lower serum concentrations of warfarin in a 75-year-old woman who also took St.
John's wort (Ernst 1999).
|Regulatory and Compendial
St. John's wort is labeled as a dietary supplement by the U.S. Food and Drug
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Profound drop of cyclosporin A whole blood trough levels caused by St. John's
wort (Hypericum perforatum) [letter]. Transplantation.
Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum
perforatum extract. Pharmacopsychiatry. 1997;30(suppl 2):108-112.
Degar S, et al. Inactivation of the human immunodeficiency virus by
hypericin: evidence for phytochemical alterations of p24 and a block in
uncoating. AIDS Res Hum Retroviruses. 1992;8:1929-1936.
De Smet P, Touw D. Safety of St. John's wort (Hypericum perforatum)
[letter]. Lancet. 2000;355:575-576.
De Smet PAGM, Nolen WA. St. John's wort as an antidepressant. Br Med J.
Ernst E. Second thoughts about safety of St John's wort. Lancet.
Food and Drug Administration. Risk of Drug Interactions with St John's
Wort and Indinavir and Other Drugs. Rockville, Md: National Press Office;
February 10, 2000. Public Health Advisory.
Furner V, Bek M, Gold JA. A phase I/II unblinded dose ranging study of
hypericin in HIV-positive subjects. Int Conf AIDS. 1991;7:199.
Gordon JB. SSRIs and St. John's Wort: possible toxicity? [letter] Am Fam
Gulick R, et al. Human hypericism: a photosensitivity reaction to hypericin
(St. John's wort). Int Conf AIDS. 1992;8:B90.
Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I.
Pharmacokinetic interaction of digoxin with an herbal extract from St John's
wort (Hypericum perforatum). Clin Pharmacol Ther. 1999;66(4):338-345.
Khawaja IS, Marotta RF, Lippmann S. Herbal medicines as a factor in delirium.
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Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug
interactions in the elderly. J Geriatr Psychiatry Neurol.
Lavie G, et al. Studies of the human mechanism of action of the antiviral
agents hypericin and pseudohypericin. Proc Natl Acad Sci USA.
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seasonal affective disorders. J Geriatr Psychiatry Neurol. 1994;7(Suppl
Meruelo D, Lavie G, Lavie D. Therapeutic agents with dramatic antiretroviral
activity and little toxicity at effective doses: aromatic polycyclic diones
hypericin and pseudohypericin. Proc Natl Acad Sci USA.
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known or potential drug-herb interactions. Arch Intern Med.
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the Wonders of Medicinal Plants. Rocklin, Calif: Prima Publishing; 1995.
Nebel A, Schneider BJ, Baker RK, et al. Potential metabolic interaction
between St. John's wort and theophylline [letter]. Ann Pharmacother.
Okpanyi SN, Weischer ML. Experimental animal studies of the psychotropic
activity of the Hypericum extract. Arzneim-Forsch.
Piscitelli S, Burstein A, Chaitt D, Alfaro R, Falloon J. Indinavir
concentrations and St John's wort [letter]. Lancet. 2000;355:547-548.
Rasmussen P. St. John's wort: a review of its use in depression.
Australian Journal of Medical Herbalism. 1998;10:8-13.
Ruschitzka F, Meier P, Turina M, Luscher T, Noll G. Acute heart transplant
rejection due to Saint John's wort [letter]. Lancet.
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Related Remedies. Binghamton, NY: Pharmaceutical Products Press; 1993.
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perforatum) [letter]. Lancet.
Copyright © 2000 Integrative Medicine
CommunicationsThis publication contains
information relating to general principles
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The reader is advised to check product information (including package inserts)
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