Current Drug Metabolism, 2008, 9, 1063-1120 1063

Clinical Evidence of Herb-Drug Interactions: A Systematic Review by the Natural

Standard Research Collaboration

C. Ulbricht*, W. Chao, D. Costa, E. Rusie-Seamon, W. Weissner and J. Woods

Natural Standard Research Collaboration, USA

Abstract: To evaluate the pharmacokinetics and adverse effects of medicinal herbs, as well as clinical evidence of herb-drug interactions.
Electronic searches were conducted in multiple databases, including MEDLINE, EMBASE, the Cochrane Library, CINAHL,
NAPRALERT, International Pharmaceutical Abstracts, CANCERLIT, CISCOM, and HerbMed. Search terms used included common
names, scientific names, and synonyms for the herbs and their primary active constituents. Bibliographies of relevant articles were also
searched by hand to obtain additional references. No restrictions were placed on language or quality of publications. All literature col-
lected pertained to adverse effects, pharmacokinetics, and suspected or confirmed cases of herb-drug interactions. Over 80 herbs or bo-
tanicals (including plants, fungi, algae, and common constituents) were identified that had clinically significant interactions with pre-
scription and over-the-counter drugs. Interestingly, herbs beginning with the letter “g” (garlic, ginger, ginkgo, and grapefruit) were
among the herbs most commonly involved in herb-drug interactions. Drugs with anticoagulant/antiplatelet activity (e.g. warfarin, aspirin)
were frequently implicated in herb-drug interactions, with documented interactions with over 30 herbs and herbal products. Because
many herbs have demonstrated adverse effects on the liver, the potential for interaction with hepatotoxic agents (such as acetaminophen)
is also significant. Clinical outcomes of reported herb-drug interactions ranged from mild to severe. Of note, fatalities (though rare) have
occurred with concomitant ephedra and caffeine use. As herbal products (and dietary supplements in general) continue to grow in popu-
larity, patients and health care providers should be vigilant of potential herb-drug interactions.
Keywords: Herbs, drugs, dietary supplements, interactions, pharmacokinetics, adverse effects.

INTRODUCTION
For over 5,000 years, since the dawn of Ayurvedic and tradi-
tional Chinese medicine, herbs and other natural products have
been principle sources of pharmacologically active compounds [1].
In fact, many conventional drugs used today come from natural
sources [2]. Aspirin, possibly the most widely used drug in the
world [3], is derived from salicylic acid, contained in willow bark
and some other herbs [2]. Other notable herb-based drugs include
the opiates (derived from the poppy), digoxin (extracted from the
foxglove plant), paclitaxel (isolated from the bark of the Pacific
yew tree), yohimbine (a constituent of yohimbe bark) and biguanide
antidiabetic drugs such as metformin (derived from the constituents
of French lilac or galega).
Even with modern medical advances, herbal products continue
to be widely used for health maintenance, disease prevention, and
even disease treatment. Herbal supplements have become increas-
ingly popular in recent years, and currently constitute a multi-
billion dollar industry. According to the National Toxicology Pro-
gram, headquartered at the National Institute of Environmental
Health Sciences, over 1,500 herbal products are currently on the
market [4]. Although herbal medicines have been used for centu-
ries, evidence of efficacy is largely anecdotal and unproven by con-
ventional clinical testing [1,2]. Furthermore, dietary supplements
(including herbal supplements) are not FDA-regulated and are often
not standardized. Therefore, safety and efficacy are difficult to
gauge when using herbal preparations. Though many herbs have
known pharmacological effects, the fact that they are “natural” has
led to a widespread and somewhat ironic notion that all herbs are
safe. Rather, adverse and toxic effects have been documented for
many herbal products – sometimes due to contaminants, but often
due to the constituents of the herbs themselves [2]. The potential
interactions between herbs and conventional drugs are often over-
looked – also ironic in light of the fact that many herbs not only
possess known pharmacological effects, but also serve as sources
for conventional drugs [2,5]. Multiple case reports and case series
of herb-drug interactions exist [6-9]. According to a recent cross-
*Address correspondence to this author at the Natural Standard Research
Collaboration, USA; E-mail: info@naturalstandard.com
sectional, point-of-care survey [10], the most common herbal prod-
ucts with potential drug interactions are garlic, valerian, kava,
ginkgo, and St. John’s wort. The survey also found the following
drug classes to be most likely to interact with herbs: anticoagu-
lants/antiplatelets, sedatives, antidepressants, and antidiabetic
agents.
This review contains information on pharmacokinetics, adverse
affects, and drug interactions for many common medicinal herbs.
This is not an all-inclusive comprehensive list of known or potential
interactions. Concurrent use of substances with similar effects (such
as anti-inflammatory, estrogenic, hepatotoxic, and other effects)
should be approached with caution. A qualified healthcare practi-
tioner should be consulted with specific questions or concerns re-
garding potential interactions.
METHODS
To prepare this review, electronic searches were conducted in
multiple databases, including MEDLINE, EMBASE, the Cochrane
Library, CINAHL, NAPRALERT, International Pharmaceutical
Abstracts, CANCERLIT, CISCOM, and HerbMed. Search terms
used included common names, scientific names, and multiple syno-
nyms for the herbs and their primary active constituents. Bibliogra-
phies of relevant articles were also searched by hand for articles not
found in electronic searches, and additional references were ob-
tained.
RESULTS
Pharmacokinetic data, as well as clinical evidence for adverse
effects and drug-herb interactions, are summarized below. When
available, evidence from basic science and theory are included.
Acacia (Acacia senegal)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
There are minimal reports of adverse effects associated with
acacia. The most common reported side effects are allergic asthma
and rhinitis [11-25] and gastrointestinal complaints [26]. Acacia
catechu contains high amount of tannins [27]; among the adverse

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1064 Current Drug Metabolism, 2008, Vol. 9, No. 10
effects of tannin use include increased risk of oral and esophageal
cancer and nephrotoxicity (kidney damage).
Interactions
Amoxicillin: Acacia has been shown to affect the absorption of
amoxicillin when taken concurrently [28]; this is likely attributable
to the fiber in acacia, which may impair the absorption of oral
agents. Doses should be separated by at least four hours.
Aloe (Aloe vera)
Pharmacokinetics
Aloe latex contains anthraquinone glycosides (aloin, aloe-
emodin and barbaloin). Anthraquinone glycosides, which are ab-
sorbed well only after digestion by intestinal bacteria, are elimi-
nated in the urine, bile, feces, and breast milk. The half-life of aloe-
emodin is approximately 48-50 hours [29].
Adverse Effects
Aloe leaf is used topically for burns and wound healing. Aloe
latex is used systemically (internally). Aloe latex is commonly used
as a laxative and may cause abdominal cramping and diarrhea [2].
Excessive use may cause potassium loss [30]. Combined use of oral
aloe latex and other laxatives and/or diuretics may exacerbate hy-
pokalemia, dehydration, metabolic alkalosis, or other electrolyte
abnormalities. Chronic use has been associated with an increased
risk of colorectal cancer [31]. Anecdotally, aloe has been linked to
thyroid dysfunction [32].
Interactions
Hypoglycemic agents: Oral aloe gel has been associated with
reduced blood glucose when used with glibenclamide (also known
as glyburide in the United States) [33]. Concurrent use of aloe with
other agents that lower blood sugar, such as insulin [33], may in-
crease the risk of hypoglycemia.
Antiretroviral agents: Acemannan, the major carbohydrate
fraction in aloe gel, has been shown in vitro to possess anti-
retroviral activities [34-36]. Preliminary clinical reports suggest that
azidothymidine (AZT) may be boosted by aloe ingestion [37].
Sevoflurane (Ultane®): Excess bleeding was reported when a
patient took aloe before surgery; a possible interaction was sug-
gested with the anesthetic agent sevoflurane, which also has anti-
platelet effects [38]. Aloe should be discontinued one week before
surgery.
Arnica (Arnica spp.)
Pharmacokinetics
The pharmacokinetics of arnica is not well understood. It ap-
pears that 30-50% of sesquiterpene lactones, the active constituents
of arnica, are bound to plasma [39].
Adverse Effects
Based on historical use and available research, it appears that
arnica is generally well tolerated when used in recommended ho-
meopathic doses for up to two weeks. Allergic reactions to the skin
and numerous cases of contact dermatitis have been reported [40-
47]. To avoid contact dermatitis, arnica should not be used on open
wounds or near the eyes or mouth. It should be avoided in patients
with known allergies to arnica or any plant in the Asteraceae or
Compositae families.
Ingestion of oral non-diluted Arnica montana-containing ex-
tracts has induced severe gastroenteritis, nervousness, accelerated
heart rate, muscular weakness, and death [48].
Interactions
Analgesic and anti-inflammatory agents: Arnica may have
anti-inflammatory and analgesic activity [49-52], and theoretically
may interact with similar agents. In clinical research involving
healthy humans, topical arnica was shown to increase hydroxyethyl
salicylate's analgesic effects [53].
Ulbricht et al.
Ashwagandha (Withania somnifera)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
There are few reports of adverse effects associated with ashwa-
gandha. Occasionally, human trials have reported dermatitis, diure-
sis, diarrhea, hypoglycemia, nausea, and abdominal discomfort [54-
57].
Interactions
Cholinergic agents: Ashwagandha has been associated with
cholinesterase inhibition in biochemical studies [58]. Due to the
presence of commonly used Parkinson’s disease drugs in some
combination ashwagandha products [59], it should be used cau-
tiously in patients with Parkinson’s disease.
Paclitaxel: Though clinical data is lacking, evidence from a
number of animal studies suggests that ashwagandha may enhance
the effects of paclitaxel [60-63]. Ashwagandha may also prevent
paclitaxel-induced neutropenia in mice [64].
Astragalus (Astragalus membranaceous)
Pharmacokinetics
The pharmacokinetics of astragalus is not well understood.
Clinical research indicates that Astragalus flavonoids may be ab-
sorbed in the gastrointestinal tract and that the major metabolites of
the flavonoid constituents are glucuronides [65].
Adverse Effects
Astragalus used in recommended doses is considered to be safe
and well-tolerated. The most commonly reported adverse events are
diarrhea and other mild gastrointestinal effects [66,67].
Interactions
Stanozolol: Clinical research has demonstrated astragalus to
enhance the effect of stanozolol in treating chronic aplastic anemia
[68].
Avocado (Persea americana)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Based on historical use and available research, it avocado ap-
pears to be well tolerated. Headache, migraine headache with fever,
and drowsiness have been reported [69]. One patient with severe
cardiovascular disease developed hemiplegia during a trial evaluat-
ing the effects avocado/soybean unsaponifiables (ASU) in the
treatment of osteoarthritis [69].
Cross-allergy between avocado and latex proteins has been
reported in several studies and case reports [70-78]. Allergy symp-
toms include urticaria, bronchospasm, and intestinal spasms. Re-
search also suggests potential cross sensitivity between avocado,
chestnut, and banana allergies [73,78,79].
Interactions
Monoaminergic agents: Large amounts of avocado may poten-
tiate effects of MAO inhibitors, and may lead to hypertensive crisis
as demonstrated by a clinical case report [80].
Beet (Beta vulgaris)
Pharmacokinetics
The pharmacokinetics of beet is not well understood. However,
research has shown that intact betalins (the water-soluble chro-
moalkaloids responsible for beet color) are excreted rapidly and in
relatively high volumes [81]. This suggests that either the bioavail-
ability of betalins is low or that renal excretion is the primary route
of elimination for these compounds. Sugar beet fiber increases cho-
lesterol and decreases bile acid excretion by the small bowel [82].
Clinical Evidence of Herb-Drug Interactions
Adverse Effects
Allergic skin reactions and skin diseases following exposure to
beets have been reported in the general population and among peo-
ple who work with beets in agricultural or factory settings [83-86].
Ingestion of beetroot is known to produce red or pink urine
(beeturia) in approximately 10%-14% of the population [87,88].
Several cases of occupational illness, including asthma, anaphy-
laxis, toxic poisoning, respiratory infections, and tularemia among
beet farmers and workers in beet sugar processing facilities have
been described in the literature [83-86,89-95]. Most of these ill-
nesses were not directly due to beet exposure, but rather to expo-
sure to the environmental bacteria, fungi, pollutants, or chemical
insecticides present in such settings.
According to the American Academy of Pediatrics, beets
should be avoided in infants younger than three months of age due
to the high nitrate content and the risk of nitrate poisoning. How-
ever, breastfed infants of mothers who ingest beets and other foods
high in nitrates are not at risk of nitrate poisoning because nitrate
concentration does not increase significantly in breast milk [96].
Interactions
Oral agents: As demonstrated by clinical research, the addition
of sugar beet fiber to the diet was shown to significantly decrease
gastrointestinal transit time [97]. Contrarily, increased secretion of
motilin, a gastrointestinal hormone, was observed after meals in a
subset of obese patients with non-insulin-dependent diabetes who
were taking a beet fiber supplement, suggesting that increased beet
fiber in the diet may increase transit time [98]. Increased or de-
creased transit time may potentially impact the absorption and
bioavailability of some orally ingested agents.
Belladonna (Atropa belladonna)
Pharmacokinetics
The belladonna constituent atropine has a reported half-life of
several hours and is rarely detectable in the plasma after 24 hours.
Elimination half-life of atropine from raw or cooked belladonna
berries was reported to be approximately 120-140 minutes [99].
Atropine is primarily excreted by the kidneys [99].
Adverse Effects
There is extensive literature on the adverse effects and toxicity
of belladonna, which is principally related to its known anticho-
linergic actions. Common adverse effects include dry mouth, con-
stipation, urinary retention, flushing, tachycardia mydriasis, photo-
phobia, blurred vision, dilation of pupils, constipation, dizziness,
lightheadedness, drowsiness, unsteadiness, confusion, hallucina-
tions, slurred speech, sedation, hyperreflexia, convulsions, and ver-
tigo [99-111]. Many of these effects may occur at therapeutic doses.
Tachycardia has been reported in cases of toxicity [99,102-
104,108,110]. Belladonna contains atropine, which is commonly
used in hospitals to increase heart rate. In one case report, infants
who received hyoscyamine sulfate developed heart rates of 155-220
beats per minute when given 2-4mL of hyoscyamine [112]. Death
in children may occur at 0.2mg/kg atropine [99].
Interactions
Cisapride (Propulsid®): Cisapride® enhances distal esophag-
eal motor activity, presumably by means of a muscarinic receptor
mechanism. In humans, these effects were completely blocked by
atropine when it was administered before cisapride; the effect did
not occur when atropine was administered after cisapride [113].
Beta-glucan
Pharmacokinetics
The pharmacokinetics of beta-glucan is not well understood.
The majority of ingested beta-glucan is excreted in feces [2].
Current Drug Metabolism, 2008, Vol. 9, No. 10 1065
Adverse Effects
Orally, yeast-derived beta-glucans seem to be well tolerated,
with minimal adverse effects. Rarely, it may cause constipation,
nausea, and vomiting. Beta-glucan is listed by the U.S. Food and
Drug Administration (FDA) as Generally Recognized as Safe
(GRAS) [114].
In a case series, six of 20 patients with acquired immunodefi-
ciency syndrome (AIDS) or AIDS-related complex developed kera-
toderma of the palms and soles after intravenous infusion of soluble
glucan (beta-1-3 polyglucose). Because none of the untreated 735
patients developed similar hyperkeratosis, the correlation to beta-
glucan was significant; however, it was suggested that this reaction
may be limited to patients with AIDS [115].
Interactions
Non-steroidal anti-inflammatory agents (NSAIDs): Although
clinical evidence is lacking, severe gastrointestinal damage result-
ing in enteric-induced bacterial peritonitis has been associated with
intake of beta-glucan and NSAIDs/aspirin in mice [116,117].
Beta-sitosterol, Sitosterol
Pharmacokinetics
Plant sterols are poorly absorbed because they are bound to the
fibers of the plant [118-120]. Plasma plant sterol contents change in
parallel with cholesterol and fat absorption; the lower the choles-
terol absorption, the lower the plasma beta-sitosterol level [121-
130]. Beta-sitosterol is structurally similar to cholesterol [131,132].
In vitro research suggests that beta-sitosterol is converted into
cholic acid in the intestinal tract [133]. Beta-sitosterol passes
through the intestine in the same physicochemical state as choles-
terol and is lost to the same extent as cholesterol in the feces [118].
Beta-sitosterol is also excreted in bile, with minimal urinary excre-
tion [134-139]. Data from some human trials suggest that beta-
sitosterol may reduce progesterone levels in healthy males and fe-
males, though the extent and significance of the reduction is unclear
[140,141].
Adverse Effects
Based on available data, it appears that beta-sitosterol is well
tolerated in recommended doses for up to six months [141-148].
Both diarrhea and constipation have been reported [142,149].
Interactions
Acarbose (Glucobay®, Prandase®, Precose®): In humans,
researchers investigated the impact of starch malabsorption on co-
lon carcinogenesis and found that the antidiabetic drug acarbose
decreased fecal concentration of beta-sitosterol by approximately
40%, indicating that absorption may be increased [150].
Activated charcoal: Data from clinical trials indicate that acti-
vated charcoal (8g given three times daily) may slightly decrease
serum levels of beta-sitosterol [151].
Alpha-adrenergic agents: Clinical studies suggest that beta-
sitosterol may relieve symptoms of benign prostatic hyperplasia
through mechanisms similar to those of finasteride and alpha-
blockers [152-154]. The combination of the sterols and these agents
may result in synergistic effects
Antibiotics: Beta-sitosterol has been demonstrated in vivo to
protect and improve the oral absorption of acid-labile antibiotics,
particularly, the potassium salts of penicillin G, penicillin V, and
erythromycin lactobionate [155].
Cholestyramine (Questran®): Cholestyramine (up to 32g
daily) has been shown to reduce beta-sitosterol concentrations in
patients with sitosterolemia [156-158].
1066 Current Drug Metabolism, 2008, Vol. 9, No. 10
Ezetimibe (Zetia®): Ezetimibe has been shown clinically to
decrease plasma plant sterol concentrations in individuals with
sitosterolemia [159].
HMG-CoA reductase inhibitors: In clinical research, simvas-
tatin has been shown to elevate the ratio of plant sterol to choles-
terol in patients with the highest baseline campestanol levels [160].
Simvastatin and niacin in combination have been shown in a ran-
domized controlled trial to elevate beta-sitosterol levels in patients
with low HDL [126]. Atorvastatin and simvastatin have been
shown to independently elevate the ratio of plant sterol to choles-
terol in patients with coronary heart disease, [161] and atorvastatin
has been suggested to increase levels of plasma plant sterols in
diabetics [162]. In vitro studies suggest that beta-sitosterol may
decrease the activities of HMG-CoA reductase and thereby have
synergistic effects if taken in combination with these agents [163].
Lifibrol: Lifibrol, a lipid-lowering drug used to treat hypercho-
lesterolemia, has been shown in clinical trials to reduce sterols
including lanosterol, lathosterol, beta-sitosterol, and campesterol
[164].
Betel nut (Areca catechu)
Pharmacokinetics
The pharmacokinetics of betel nut is not well understood. Min-
utes after mastication (chewing) of betel, the onset of effects oc-
curs, and may last for a mean period of 17 minutes [165].
Adverse Effects
Betel nut is not considered safe for human use (particularly
when used chronically or in high doses). Constituents of betel nut
are potentially carcinogenic [166-173]. Long-term use has been
associated with oral submucous fibrosis (OSF), pre-cancerous oral
lesions, and squamous cell carcinoma [174-183]. Wheezing, bron-
choconstriction, dyspnea, and pulmonary edema have been noted
anecdotally in users of betel nuts. Acute toxicity of betel nut has
resulted in tachypnea and dyspnea [184]. Aggravation of asthma
with a decrease in forced expiratory volume has been reported in
patients who chew betel nuts [185-187]. Patients chewing betel nuts
have reported acute chest pain, ventricular arrhythmias, tachycar-
dia, palpitations, and hemodynamic instability (hypotension/ hyper-
tension) [184,188-192]. Extrapyramidal symptoms (EPS), such as
tremor and stiffness have been reported in patients who chewed
betel while receiving anti-psychotic agents [193,194].
Interactions
Cholinergic agents: The betel constituent arecoline possesses
cholinergic properties [193]. Tremor and stiffness have been re-
ported in patients who chewed betel while receiving anti-psychotic
agents [195,196]; these are purported to result from the cholinergic
properties of the betel constituent arecoline [193].
Bilberry (Vaccinium myrtillus)
Pharmacokinetics
The gastrointestinal absorption of bilberry was reported to be
5% of the administered dose, and bioavailability appears to be low
[197]. Following oral doses in rats, plasma levels of bilberry
reached a peak at 15 minutes and declined rapidly within two hours,
and the absolute bioavailability was 1.2% of the administered dose
[197]. Anthocyanosides found in bilberry appear to have a high
affinity for tissues high in collagen concentration, including the
skin, liver and kidneys [198]. Bilberry appears to be eliminated in
bile (15-20%) and urine (25-30%) [199].
Adverse Effects
The long-term safety and side effects of bilberry have not been
extensively studied. Safety is often presumed based on bilberry's
history as a food source. According to post-marketing surveillance
data from 2,295 individuals who used bilberry extract, adverse ef-
fects were experienced by 4% of patients overall, with 1% com-
Ulbricht et al.
plaining of gastrointestinal discomfort and <1% experiencing nau-
sea or heartburn [200].
Interactions
Antidiabetic agents: In a recent cross-sectional, point-of-care
survey of 1818 patients, three cases were identified as potential
clinically significant interactions between bilberry and antidiabetic
agents [10].
Bitter melon (Momordica charantia)
Pharmacokinetics
The pharmacokinetics of bitter melon is not well understood. It
appears to be excreted in urine [201].
Adverse effects
A few adverse effects, including headache, have been associ-
ated with bitter melon in humans [202]. Individuals with glucose-6-
phosphate dehydrogenase deficiency are at risk of developing
"favism" following the ingestion of bitter melon seeds. Favism is
defined by the onset of hemolytic anemia with symptoms, including
headache, fever, stomach pain, and coma [202]. In animals, bitter
melon has been shown to exert abortifacient effects [203-205],
reduce fertility rates [206], or inhibit spermatogenesis [207]. Thus,
bitter melon may alter fertility.
Interactions
Antiviral agents: In HIV patients, MAP30 (isolated from bitter
melon extract) was reported to enhance the effects of dexametha-
sone and indomethacin [208].
P-glycoprotein substrates: P-glycoprotein is a cell membrane-
associated protein that transports a variety of drug substrates. Inter-
action with P-glycoprotein, including activation, inhibition and
induction, can lead to altered plasma or brain levels of P-
glycoprotein substrates.Based on in vivo research, 1-monopalmitin
found in bitter melon may inhibit p-glycoprotein-mediated efflux
[209,210] and may thus alter the levels of p-glycoprotein substrates.
Bitter orange (Citrus aurantium)
Pharmacokinetics
Meta-synephrine, an alkaloid constituent of bitter orange, is
readily absorbed after oral administration. Approximately 80% of
oral doses is excreted in the urine within 24 hours. After single oral
doses, peak plasma concentrations are typically reached in one to
two hours. Plasma half-life is approximately 2-3 hours.
Adverse Effects
Research evaluating the effects of a dietary supplement contain-
ing bitter orange (Advantra ZR® distributed by Nutratech, Inc.) on
exercise tolerance found no significant adverse events [211]. How-
ever, synephrine, a constituent of bitter orange, is similar to phen-
ylephrine and ephedra. Theoretically, synephrine may cause cardio-
vascular adverse effects that are similar to phenylephrine and ephe-
dra. In clinical research and case reports, tachycardia, tachyar-
rhythmia, QT prolongation, and myocardial infarction have been
noted with bitter orange use [212-215]. In young, healthy adults,
systolic blood pressure, diastolic blood pressure, and heart rate were
higher for up to five hours after a single dose of bitter orange
(900mg dietary supplement extract standardized to 6% synephrine)
compared to placebo [216]. Dizziness, concentration problems,
memory loss, syncope, seizure, and stroke have been noted in case
reports [213-217]. Photosensitivity may occur, particularly in fair-
skinned people [218]. Due to its synephrine content, bitter orange
may theoretically worsen glaucoma and alter thyroid function.
Interactions
Note: Interactions may be similar to those of ephedra.
Antidepressants: Based on preliminary animal and clinical
research, synephrine may have antidepressant effects, possibly by
promoting norepinephrine release [219,220]. Additionally, bitter
Clinical Evidence of Herb-Drug Interactions
orange contains MAO substrates - tyramine, octopamine, and
synephrine [221-224]. Concomitant use of MAO inhibitors with
bitter orange may increase the hypertensive effects of synephrine
and potentially cause hypertensive crisis.
Black Cohosh (Cimicifuga racemosa)
Pharmacokinetics
The pharmacokinetics of black cohosh is not well understood.
However, it does not appear to modulate P-glycoprotein (P-gp)
[225].
Adverse effects
Safety and efficacy data beyond six months are not available,
although recent reports suggest safety of short-term use, including
in women experiencing menopausal symptoms for whom estrogen
replacement therapy is contraindicated [226,227]. Nonetheless, due
to a lack of long-term follow-up, caution is advised until improved
safety data are available.
Reviews of the literature have reported black cohosh to be gen-
erally well tolerated in recommended doses for up to six months
[226,228-338]. The most common side effects seem to be gastroin-
testinal upset and rash [228]. The potential effects of black cohosh
on estrogen-sensitive conditions such as breast cancer, uterine can-
cer, or endometriosis are not known.
Various cases of liver damage have been reported with the use
of black cohosh [239-243]. Based on these data, the Dietary Sup-
plement Information Expert Committee determined that black co-
hosh products must be labeled with a warning statement [243].
Interactions
Estrogenic agents: The estrogenic activity of black cohosh
remains controversial. Specific estrogenic constituents have not
been identified, and it is not clear how (or if) black cohosh interacts
with estrogens/estrogen receptors and/or progestins. Recent publi-
cations suggest that there may be no direct effects on estrogen re-
ceptors, although this is an area of active controversy [228,244-
250]. Therefore, caution is warranted in individuals taking both
black cohosh and estrogens due to unknown effects and the lack of
interactions data.
Tamoxifen: Controversy surrounds the ability of black cohosh
to reduce tamoxifen-induced hot flashes as clinical trials have pro-
duced conflicting results [227,251].
Black pepper (Piper nigrum)
Pharmacokinetics
Insufficient Available Evidence
Adverse Effects
Black pepper has a long safety history when used as a spice.
However, according to clinical research, ingestion of black pepper
may cause dyspepsia and other gastrointestinal adverse effects
[252,253]. Based on case reports, inhalation of black pepper has
caused respiratory irritation and edema, and even respiratory arrest,
severe anoxia and death [254-256]. Based on reviews and case-
controlled studies, there may also be a link between ingestion of
black pepper and nasopharyngeal or esophageal cancer [257-259].
Caution is advised with excessive use. Black pepper may cause
adverse respiratory effects [254-256]. Caution is warranted in pa-
tients with asthma.
Interactions
Oral agents: Based on clinical research of intestinal peristalsis
in healthy volunteers, consumption of black pepper may increase
orocecal transit time [260], thus potentially improving the absorp-
tion and bioavailability of oral agents. Several clinical studies have
shown altered drug bioavailability with concomitant black pepper
use.
Current Drug Metabolism, 2008, Vol. 9, No. 10 1067
Phenytoin: Based on animal and clinical trials, piperine from
black pepper may significantly enhance the bioavailability of the
antiepileptic medication phenytoin, possibly by increasing its ab-
sorption [261-263].
Propranolol: Based on clinical research in healthy volunteers,
piperine may increase the bioavailability of the beta-adrenergic
agent propranolol [262].
Rifamipicin (rifampin): Based on clinical research in patients
with pulmonary tuberculosis, piperine may increase plasma concen-
trations of the antibiotic rifamipicin (rifampin) [262].
Theophylline (Bronkodyl®, Elixophyllin®, Slo-bid®): Based
on clinical research in healthy volunteers, piperine may increase the
bioavailability of the bronchodilator theophylline [262].
Borage seed oil (Borago officinalis)
Pharmacokinetics:
The pharmacokinetics of borage is not well understood. The
GLA constituent of borage is turned into dihomo-gamma-linolenic
acid (DGLA) [264]. Metabolites are primarily excreted in urine
[265].
Adverse Effects
Borage may cause diarrhea and bloating [266]. Numerous stud-
ies have suggested that borage may lower the seizure threshold
[267].
Interactions
Anticoagulants/antiplatelets: Borage seed oil has been sug-
gested to increase the risk of bleeding or potentiate the effects of
warfarin therapy [268,269]. However, in clinical research involving
healthy volunteers, the therapeutic dosage of 3g daily of borage oil
supplementation did not affect platelet aggregation [270]. Nonethe-
less, caution is still warranted when using borage with anticoagu-
lant/antiplatelet agents.
Bromelain (Ananas comosus)
Pharmacokinetics
Oral bromelain tablets have a bioavailability of 2%-4% in hu-
mans [271]. Bromelain is best taken an hour before or after food
[272]. Bromelain is distributed in plasma [273], but its metabolism
and excretion are not well understood. The elimination half-life of
bromelain was found to be 6-9 hours [273].
Adverse Effects
Bromelain appears to be well tolerated. Bromelain may cause
diarrhea and gastrointestinal upset [274]. Cases of bromelain al-
lergy have also been reported [275-277]. Bromelain should be used
cautiously in patients allergic to pineapple or related plants in the
Bromeliaceae family.
Interactions
Antibiotics: Clinical studies suggest that bromelain may in-
crease the absorption of some antibiotics (notably amoxicillin and
tetracycline), and increase levels of these drugs in the body [278-
280]. However, in one study, there was no effect on absorption of
tetracycline when patients were coadministered bromelain 80mg
with tetracycline 500mg [281].
Caffeine (Black Tea, Cola Nut, Green Tea, Guarana, Yerba
Mate)
Pharmacokinetics
Caffeine is well absorbed and distributed quickly. After absorp-
tion, caffeine passes into the brain. Caffeine is extensively metabo-
lized in the liver where primary metabolism is carried out by cyto-
chrome P450 1A2. Caffeine is metabolized to more than 25 me-
tabolites in humans. It is eliminated in urine. Less than 5% of caf-
feine is found in the urine as unchanged drug. The half-life of caf-
1068 Current Drug Metabolism, 2008, Vol. 9, No. 10
feine ranges from 1.5 to 9.5 hours, and studies have shown that
smoking nicotine cigarettes decreases the half-life of caffeine [282-
284].
Adverse effects
Caffeine is a stimulant of the central nervous system and may
cause insomnia in adults, children, and infants (including nursing
infants of mothers taking caffeine). Caffeine acts on the kidneys as
a diuretic (increasing urine and urine sodium/potassium levels, and
potentially decreasing blood sodium/potassium levels), and may
worsen incontinence. Caffeine-containing beverages may increase
the production of stomach acid, and may worsen ulcer symptoms.
Tannin in tea can cause constipation. Caffeine in certain doses can
increase heart rate and blood pressure, although people who con-
sume caffeine regularly do not seem to experience these effects
long-term.
An increase in blood sugar levels may occur after ingesting
high levels of caffeine. Caffeine-containing beverages such as black
tea should be used cautiously in patients with diabetes. People with
severe liver disease should use caffeine cautiously, as levels of
caffeine in the blood may build up and last longer. Skin rashes have
been associated with caffeine ingestion. In laboratory and animal
studies, caffeine has been found to affect blood clotting, although
effects in humans are not known.
The effects of caffeine are likely more pronounced at extreme
ages, such as in the elderly and in children [285]. The chronic use
of caffeine, especially in large amounts, may produce tolerance,
habituation, and psychological dependence. Abrupt discontinuation
of caffeine can result in physical withdrawal symptoms that include
headache, irritation, nervousness, anxiety, and dizziness.
Interactions
Anticoagulants/antiplatelets: Caffeine may have antiplatelet
activity [286,287] and may theoretically increase the risk of bleed-
ing when used with anticoagulant/antiplatelet agents.
Adenosine: Caffeine has been shown to inhibit the hemody-
namic and anti-arrhythmic effects of adenosine in humans [288].
Benzodiazepines: In humans, doses of 125-500mg of caffeine
counteracted the reduced anxiety and reduced mental performance
associated with 2.5mg lorazepam (Ativan®) [289].
Catecholaminergic agents: Caffeine overdose has been associ-
ated with elevated levels of plasma catecholamines [290]. An in-
crease in catecholamine levels was found when caffeine was admin-
istered as an adjunct to aerobic exercise [291]. A catecholamine test
may be performed to help diagnose a tumor in the adrenal glands
called a pheochromocytoma.
Dipyridamole (Persantine®): Caffeine has been shown to
inhibit dipyridamole-induced vasodilation in humans [292].
Ephedrine: Caffeine has been shown enhance the thermogenic
activity of ephedrine in clinical and animal studies [293-295]. Other
adverse effects caused by the combination of caffeine and ephed-
rine include abnormal heart rhythms, insomnia, anxiety, headache,
irritability, poor concentration, blurred vision, and dizziness. Fatali-
ties have been associated with simultaneous caffeine and ephedrine
use [296,297].
Estrogenic agents: Estrogen has been found to inhibit caffeine
metabolism in female patients [298].
Lithium: Caffeine withdrawal has been shown to increase se-
rum lithium levels in humans [299], and may increase the risk of
lithium toxicity.
Mexiletine (Mexitil®): In humans, mexiletine has been shown
to decrease caffeine elimination by 50% [300].
Quinolones: Caffeine clearance was decreased in patients
treated with norfloxacin [301]. Quinolones may inhibit the N-
demethylation pathway of caffeine. Ciprofloxacin slightly increases
Ulbricht et al.
the t
of caffeine from 5.2 hours to 8.2 hours [302,303]. Ofloxacin
had no effect on the clearance of caffeine [304,305].
Terbinafine (Lamisil®): Terbinafine has been shown in
healthy volunteers to decrease the clearance of caffeine [306], and
may increase the risk of adverse effects associated with caffeine.
Theophylline (Bronkodyl®, Elixophyllin®, Slo-bid®): In
healthy volunteers, caffeine has been shown to decrease clearance
of the bronchodilator theophylline, increase its elimination half-life,
and increase serum levels [307].
Verapamil (Isoptin®): Clinically significant interactions be-
tween caffeine and the calcium channel blocker verapamil have
been noted [308]. Verapamil may increase plasma caffeine concen-
trations and increase the risk of adverse effects associated with
caffeine.
Carob (Ceratonia siliqua)
Pharmacokinetics
Carob contains a large proportion of insoluble fiber, which is
not digested and passes through the gut unchanged. The pharma-
cokinetics of the other constituents of carob is not well understood.
Adverse Effects
Carob appears to be well tolerated. Hypersensitivity reactions,
including urticaria, asthma, and rhinitis, have been reported in
workers exposed to carob [309,310].
Interactions
Oral agents: Carob contains a large proportion of insoluble
fiber, which is not digested and passes through the gut unchanged.
Based on clinical and rat studies, carob bean gum may decrease
bowel transit time [311,312] and interfere with the absorption of
oral agents. It may be ideal to separate doses of carob bean gum and
oral agents by several hours.
Chaparral (Larrea tridentata, Larrea divaricata)
Pharmacokinetics
Nordihydroguaiaretic acid (NDGA) is the active metabolite of
chaparral [313]. Other metabolites include secoisolariciresinol,
enterodiol, enterolactone, matairesinol, and guaiaretic acid diqui-
none [313]. It was reported that NDGA is metabolized to an ortho-
quinone derivative [314,315] and could be further metabolized by
conjugation to glutathione [314]. NDGA is absorbed in the blood-
stream, filtered by the glomeruli, and retained by the proximal tu-
bules where it accumulates [313,315]. Free NDGA is not found in
the rat kidney, but is found in the feces [313].
In female mice, NDGA was administered intravenously at
50mg/kg to yield a primary half-life (T1/2) of 30 minutes and a
secondary half-life (T1/2) of 135 minutes with the peak plasma
concentration (Cmax) being 15mcg/mL [314,316].
Adverse Effects
Chaparral was removed from the U.S. Food and Drug Admini-
stration Generally Recognized as Safe (GRAS) list in 1970. Chap-
arral and NDGA are generally considered unsafe and are not rec-
ommended for use. Exposure to lignans, which may yield toxicity,
appears to be greater from capsule or tablets than from decoctions
of chaparral tea [317].
Multiple reports have been published of serious adverse reac-
tions associated with chaparral, including liver cirrhosis/failure,
kidney cysts/failure, and kidney cancer [313,318-327]. The most
serious outcomes of liver toxicity documented include several case
reports of cirrhosis. In most cases, symptoms arose 3-52 weeks
after initiating chaparral and resolved within 1-17 weeks after dis-
continuation [318]. Symptoms reported include fatigue, right upper
quadrant abdominal pain, dark urine, light stools, nausea, diarrhea,
anorexia, weight loss, icterus, fatigue, pedal edema, and increased
abdominal girth. Elevations in alkaline phosphatase, alanine
Clinical Evidence of Herb-Drug Interactions
aminotransferase (ALT), aspartate aminotransferase (AST), total
bilirubin and gamma-glutamyltranspeptidase (GGT) have also been
reported.
Interactions
Anticoagulants/antiplatelets: In theory, there may be an in-
creased risk of bleeding with concurrent use of chaparral and other
agents. The chaparral component, nordihydroguaiaretic acid
(NDGA), diminishes platelet aggregation in aspirin-treated patients
and delayed its onset [328].
Chlorella (Chlorella spp.)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Chlorella appears to be generally well tolerated. Long term
ingestion has been linked to manganese-induced Parkinsonism
[329]. Other rare but potential adverse effects include photosensi-
tivity [330], occupational asthma [331], and fatigue [332].
Interactions
Vaccines: Chlorella has demonstrated immunostimulating ef-
fects in vitro [333-335]; clinically, ONC-107 (Respondin®) ex-
tracted from Chlorella pyrenoidosa cells has been shown to boost
antibody response induced by influenza vaccine [334].
Anticoagulants/antiplatelets: In a case report, chlorella was
been suggested to interfere with warfarin therapy due to its vitamin
K content [336].
Clove (Eugenia aromatica)
Pharmacokinetics
The pharmacokinetics of clove is not well understood. It ap-
pears that eugenol (a constituent of clove) is metabolized in the
liver.
Adverse Effects
Clove has Generally Recognized as Safe (GRAS) status with
the United States Food and Drug Administration (FDA) for use as a
food. However, when clove is ingested in large doses, as undiluted
oil (eugenol), or in the form of clove cigarettes, it may cause nu-
merous adverse effects such as seizures, CNS depression, bron-
chospasm, pulmonary edema, disseminated intravascular coagulo-
pathy (DIC), and hepatotoxicity. Ingesting as little as 10mL of
clove oil has been implicated in hepatotoxicity [337].
The American Dental Association has accepted clove for pro-
fessional use but not non-prescription use because it may damage
soft tissues. Contact dermatitis has been reported after exposure to
clove [338-340]. Painful sensations are possible and are believed to
be mediated through TRPA1 (cold ion channel) activation [341].
Allergic stomatitis secondary to eugenol, a clove component, has
also been reported [342]. Some people may experience skin irrita-
tion or painful sensations from clove. This may lead to rash, hives,
burning, irritation, dry peeling lips, blanching, chemical burns, lack
of feeling, and sweating on skin exposed to clove.
Interactions
Anticoagulants/antiplatelets: Clove has been shown to inhibit
platelet aggregation in vitro [343-345], and was clinically impli-
cated in increased INR [346] Therefore, use with other anticoagu-
lants or antiplatelet agents may result in additive effects and in-
creased bleeding risk [268].
Cordyceps (Cordyceps sinensis)
Pharmacokinetics
The kinetics of two galactomannans (CI-P and CI-A) isolated
from cordyceps cicadae were studied in laboratory animals [347].
Current Drug Metabolism, 2008, Vol. 9, No. 10 1069
CI-P was found to have low affinity for concanavalin A (Con A)
and exhibited potent carbon-clearance activity in mouse.
Adverse Effects
Minimal side effects, such as dry mouth, nausea, loss of appe-
tite, diarrhea, and drowsiness, have been reported with the use of
cordyceps in humans [348,349].
Interactions
Antibiotics: Based on clinical research, concomitant admini-
stration of cordyceps and animoglycoside antibiotics may reduce
amikacin-induced nephrotoxicity in older people [350].
Cowhage (Mucuna pruriens)
Pharmacokinetics
The pharmacokinetics of cowhage is not well understood.
However, two does of Mucuna (15g and 30g) were compared with
the standard Parkinson’s disease treatment levodopa/carbidopa
[351]. Compared with standard levodopa/carbidopa, the 30g of
Mucuna preparation led to a considerably faster onset of effect
(34.6 vs. 68.5 minutes).
Adverse Effects
Few adverse effects have been reported. In humans, cowhage
has caused mild adverse effects that were mainly gastrointestinal in
nature [352]. In one human case report, cowhage has also caused
acute toxic psychosis, which may be due to its levodopa content
[353]. Presumably, in therapeutic doses, adverse effects are similar
to commercially available agents which contain levodopa.
Interactions
Dopaminergic agents: Because cowhage contains levodopa, it
may interact with dopamine agonists/antagonists. Based on clinical
research in Parkinson's disease patients [351], cowhage may in-
crease serum levodopa concentrations. Cowhage may also cause
hypotensive effects [354], which may interact with methyldopa
(Aldomet®). Patients being treated for Parkinson’s disease should
speak with their treating clinicians before taking prescribed Parkin-
son’s agents and cowhage simultaneously.
Cranberry (Vaccinium macrocarpon)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Consuming more than 3L daily of cranberry juice may cause
gastrointestinal distress and diarrhea [2]. Consuming more than 1L
daily may increase the risk of kidney stones [2]. Because cranberry
juice blends may contain high amounts of sugar (in the form of
high-fructose corn syrup), diabetic patients should drink sugar-free
or artificially sweetened juice.
Interactions
Anticoagulants/antiplatelets: Consumption of cranberry with
warfarin (Coumadin®) has been associated with increased INR,
suggesting a possible interaction [355,356]. In healthy subjects,
cranberry was found to alter the pharmacodynamics of warfarin,
potentially increasing its effects significantly [357]. Concurrent use
is cautioned.
Proton pump inhibitors: Cranberry juice has been noted to
increase the absorption of vitamin B12 in patients using proton
pump inhibitors [358], which are used to reduce gastric acid pro-
duction.
Dandelion (Taraxacum officinale)
Pharmacokinetics
Insufficient available evidence.
1070 Current Drug Metabolism, 2008, Vol. 9, No. 10
Adverse Effects
Historically, dandelion has been generally well tolerated. Dan-
delion should be avoided in individuals with known allergies to
dandelion [359,360], honey [361], chamomile, chrysanthemums,
yarrow, feverfew, or any members of the Asteraceae/Compositae
plant families (ragweed, sunflower, daisies) [362]. The most com-
mon type of allergy to dandelion is dermatitis, with itching, rash,
red/swollen or eczematous areas with direct skin contact [363-366].
Sesquiterpene lactones are the agents believed to be responsible for
these types of allergic reactions. A patch test has been developed to
assess a person’s likelihood for dandelion allergy [367-369].
Interactions
Antibiotics: Dandelion has high mineral content, which may
interfere with the absorption of quinolone antibiotics. Dandelion
been shown to reduce the effectiveness of ciprofloxacin in animals
[370]. Though clinical reports of antibiotic interactions are lacking,
concomitant use of dandelion with quinolone antibiotics should be
avoided.
Danshen (Salvia miltiorrhiza)
Pharmacokinetics
The pharmacokinetics of danshen is not well understood. Fol-
lowing oral administration, the extent of lithospermic acid recov-
ered from the entire gastrointestinal tract at 24 hours ranged from
23.3% to 41.2%. Danshen appears to be partially renally excreted
[371].
Adverse Effects
Danshen appears to be generally well tolerated. Reports of ad-
verse effects of danshen are rare, with the most common being
increased bleeding when used with anticoagulants or agents that
inhibit platelet aggregation and adhesion [372-374]. Danshen may
also cause stomach discomfort and reduced appetite [2].
Interactions
Anticoagulants/antiplatelets: In animals, prothrombin time
and steady-state plasma concentrations of warfarin increased when
used concomitantly with danshen [375]. In case reports, over-
anticoagulation due to danshen use [373] and prolonged prothrom-
bin time/international normalized ratio (INR) [374] were reported.
Caution is warranted when using danshen with blood thinning
agents.
Steroids: In children with primary nephritic syndrome, com-
bined use of steroidal agents and danshen decreased levels of serum
endothelin and soluble interleukin-2 receptor (sIL-2R) to a greater
extent than steroidal agents alone [376].
Devil’s claw (Harpagophytum procumbens)
Pharmacokinetics
Harpagoside is stable in artificial gastric juices for about three
hours and in intestinal juices for a period of six hours [377-380].
Nonetheless, it has been proposed that gastric digestion may de-
crease the potency of devil’s claw and that enteric-coated prepara-
tions may maintain efficacy despite exposure to gastric acids. Har-
pagoside elimination half-life has been reported as 5.6 hours [381].
Adverse Effects
Devil’s claw is generally well tolerated for up to 12 weeks.
Studies evaluating the long-term effects are currently lacking. Ad-
verse effects reported in clinical trials include mild gastrointestinal
upset, hypotension, diarrhea, loss of taste, anorexia, headache, and
tinnitus [382,383].
Interactions
Anticoagulants/antiplatelets: The combination of devil’s claw
and warfarin (Coumadin®) has been associated with purpura in a
case report [384]. Devil’s claw should be avoided with anticoagu-
lant agents due to the increased risk of bleeding.
Ulbricht et al.
Dong Quai (Angelica sinensis), Chinese angelica
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Although dong quai is accepted as being a safe food additive in
the United States and Europe, its safety in medicinal doses is not
known. There is currently a lack of reliable long-term studies that
evaluate its safety.
Interactions
Anticoagulants/antiplatelets: Due to anticoagulant and anti-
platelet effects [385-386], components of dong quai may increase
the risk of bleeding when taken with agents that are believed to
increase the risk of bleeding. In a recent cross-sectional, point-of-
care survey of 1818 patients, one case was identified as a potential
clinically significant interaction between dong quai and anticoagu-
lant/antiplatelet agents [10].
Echinacea (Echinacea angustifolia, Echinacea pallida, Echina-
cea purpurea)
Pharmacokinetics
The pharmacokinetics of echinacea are not well understood.
Echinacea may inhibit intestinal cytochrome P450 3A4, but induces
hepatic cytochrome P4503A4 [387-389].
Adverse effects
Echinacea has been well tolerated in clinical practice and in
trials, with few adverse events reported [390-392]. Gastrointestinal
upsets and rashes occur most frequently [390]. In rare cases, echi-
nacea can be associated with allergic reactions that may be severe
[390]. In children, three studies of 257 subjects total (infants to 14
year olds with whooping cough) found no adverse effects with 1-
2mL of squeezed aqueous extract (0.1g/2ml) given intramuscularly
twice daily for 3-21 days [393-398].
Interactions
Amoxicillin: In an obscure case study, a 19 year-old patient
ingesting amoxicillin and an unclear echinacea preparation devel-
oped rhabdomyolysis, shock, and death. Further details were not
provided [399].
Econazole nitrate (Spectazole®): There is preliminary evi-
dence to suggest that the use of echinacea with topical econazole
may decrease the recurrence rate of vaginal Candida infections
[400].
Ephedra (Ephedra sinica), Ma huang
Pharmacokinetics
Ephedrine is well absorbed after oral administration, with a
reported half-life of 3-6 hours. Following oral administration, 88%
is excreted in the urine within 24 hours, and 97% is excreted within
48 hours. Ephedrine and pseudoephedrine are excreted more rapidly
with urinary acidifiers (such as ammonium chloride) and more
slowly with urinary alkalinizers (such as disodium bicarbonate) [2].
According to anecdotal reports, the onset of bronchodilatory
effects with oral ephedrine occurs within 15-60 minutes and lasts
for 2-4 hours. Oral ephedrine causes pressor and cardiac effects for
4 hours. Intramuscular or subcutaneous administration of ephedrine
results in cardiac effects that last for 1 hour [2].
The natural and synthetic forms of ephedrine have similar
absorption and pharmacokinetics in adults, but the available natural
products contain considerably different concentrations of active
alkaloids [401]. Pharmacokinetics has not been extensively studied
in children.
Adverse Effects
The FDA has collected more than 800 reports of serious toxic-
ity, including more than 22 deaths. Ephedra is not considered safe
Clinical Evidence of Herb-Drug Interactions
despite its possible effectiveness for treating certain conditions.
Before the official ban of ephedra sales, the FDA issued a policy
that ephedrine products be labeled with possible adverse effects,
contain no more than 8mg of ephedrine per serving, and be used for
no longer than seven days [2]. When ephedra is used for prolonged
periods of time, even at recommended doses, chronic toxicity may
lead to weight loss, difficulty sleeping, high blood pressure, dry
mouth, irregular heart rhythms, rapid heartbeats, anxiety, obsessive-
compulsive disorder, flare, nervousness, and heart damage. A re-
view of 140 reports of adverse events between 1997 and 1999 re-
lated to ephedra use was submitted to the FDA [402]. A standard-
ized rating system for assessing causation was applied to each ad-
verse event; 31% of cases were considered to be "definitely" or
"probably" related to the use of supplements containing ephedra
alkaloids and an additional 31% were deemed to be "possibly" re-
lated. Among these adverse events, 47% involved cardiovascular
symptoms and 18% involved the central nervous system. Hyperten-
sion was the single most frequent adverse effect (17 reports); other
adverse effects included palpitations, tachycardia, a combination of
palpitations and tachycardia [403], stroke [404], and seizures [405].
Ten events resulted in death and 13 events produced permanent
disability. Both the ephedrine and pseudoephedrine constituents of
ephedra may induce hypertension, chronotropic, and inotropic ef-
fects in humans [406-409].
In 2003, a report was prepared by the RAND Southern Califor-
nia Evidence-based Practice Center for the Agency for Healthcare
Research and Quality, U.S. Department of Health and Human Serv-
ices [410,411]. This study reviewed available clinical trials, adverse
event reports to the FDA, and adverse event reports to the manufac-
turer Metabolife. Although most prospective trials were not suffi-
ciently large and most adverse event reports were not sufficiently
detailed, the authors identified three deaths, two myocardial infarc-
tions, two cerebrovascular accidents, one seizure, and three psychi-
atric cases that were considered to be "sentinel events" (i.e.,
strongly tied to ephedra use within 24 hours without other plausible
explanations). In addition, 50 other possible sentinel events were
identified.
A 2003 analysis published in the Annals of Internal Medicine,
showed that products containing ephedra account for 64% of all
adverse reactions to herbs in the United States, but only represent
0.82% of herbal product sales [405,412-416]. The relative risk for
an adverse reaction was extremely high in a person using ephedra
compared with other herbs, ranging from 100 (95% CI, 83-140) for
kava to 720 (95% CI, 520-1,100) for Ginkgo biloba. It was con-
cluded that ephedra use greatly increases risk of adverse reactions
compared with other herbs. A 2003 analysis published in Neurology
also demonstrated an increased risk of stroke associated with ephe-
dra-containing products [404,417].
Interactions
Anesthetics: In clinical studies, propofol anesthesia enhanced
the pressor response to intravenous ephedrine [418] and ephedrine
accelerated the regression of epidural block [419].
Cholinergic agents: Concomitant use of the tricyclic antide-
pressant amitriptyline and ephedrine was reportedly associated with
hypotension in a 61-year-old woman undergoing ovarian cancer
surgery [420]. Caution is warranted when ephedra is used with
tricylic antidepressants and other cholinergic agents.
Monoaminergic agents: When ephedra is administered in
combination with MAO inhibitors, increased sympathomimetic
activity may increase the risk of hypertension [421]. One case re-
port noted a 28 year-old woman who developed encephalopathy,
neuromuscular irritability, hypotension, tachycardia, rhabdomyoly-
sis, and hyperthermia after taking a combination tablet containing
ephedrine, caffeine, and theophylline (a "Do-Do") 24 hours after
discontinuing phenelzine treatment [421].
Current Drug Metabolism, 2008, Vol. 9, No. 10 1071
Caffeine: Use of ephedra with caffeine, theophylline, or other
methylxanthines may result in additive neurologic, cardiovascular,
and psychiatric adverse effects or toxicity. Fatalities have been
associated with simultaneous caffeine and ephedrine use [296,297].
A brief episode of acute psychosis in a 32 year-old male followed
the consumption of alcohol, caffeine, and Vigueur Fit® tablets
containing ephedra alkaloids [422]. Notably, many commercial
products contain both ephedra and caffeine. Theophylline combined
with ephedrine may induce insomnia, anxiety, and adverse gastroin-
testinal effects including vomiting [423].
Steroids: Ephedrine has been reported in clinical trials to in-
crease clearance and reduce effectiveness of dexamethasone
[424,425]. Caution is warranted when using ephedra with steroid
agents.
Essiac® Herbal Combination Tea
Pharmacokinetics
In general, pharmacodynamic/kinetic data for Essiac® are pri-
marily based on theoretical or empirical knowledge of the individ-
ual constituents.
The burdock constituent (arctiin) remains stable in gastric juice
and is rapidly transformed into an arctigenin metabolite by rat intes-
tinal flora [426]. Following an oral dose of 200mg/kg in rats, the
arctiin metabolite reaches its peak serum level after four hours
[426].
Only 2-5% of ingested oxalates have been shown to be ab-
sorbed in healthy human volunteers [427]. Oral oxalates given to
animals have been excreted unchanged in the urine within 24 to 36
hours after ingestion [427].
Anthraquinone glycosides are hydrolyzed in the gut to agly-
cones, which are reduced by bacteria to anthranols and anthrones.
Adverse Effects
In general, there are a lack of safety and efficacy data for Es-
siac®. Adverse effects and toxicities may be anticipated based on
theoretical or empirical knowledge of the tolerability of the individ-
ual constituents.
Interactions
Note: Drug interactions are primarily based on theoretical or
empirical knowledge of the individual constituents. In theory, pre-
cipitation of some agents may occur when taken concomitantly with
sorrel. Therefore, separate administration is recommended.
Alismatis orientalis: In a clinical trial, rhubarb showed hypolip-
idemic properties when used with Alismatis orientalis [428].
Alkaloid agents: Herbal textbooks suggest that herbs with high
tannin content should not be ingested in combination with agents of
high alkaloid content due to possibility of precipitate formation,
although this is largely theoretical [429].
ACE inhibitors: Tannins may possess inhibitory activity
against angiotensin converting enzyme (ACE), and may in theory
potentiate ACE inhibitors [430]. In a clinical trial, rhubarb synergis-
tically interacted with ACE inhibitors to decrease serum creatinine
levels [431].
Antibiotics: Concurrent use of doxycycline with Quanterra®
Sinus Defense or Sinupret® (which both contain sorrel) is reported
to synergistically improve outcomes in patients with acute bacterial
sinusitis [432]. Additional supporting evidence in this area is lim-
ited.
Antipsychotic agents: In a clinical trial, rhubarb and low doses
of anti-psychotic agents reduced the need for higher doses of anti-
psychotic agents in schizophrenic patients [433].
Captopril (Capoten®): In clinical trials, rhubarb has shown a
synergistic effect with captopril to reduce serum creatinine levels
[431,434-436].
1072 Current Drug Metabolism, 2008, Vol. 9, No. 10
Chlorhexidine (Periochip®): In a clinical trial, rhubarb re-
duced gingivitis when used with chlorhexidine [437].
Cytochrome P450 substrates: Based on a case report, a patient
taking the experimental drug DX-8951f (metabolized by CYP3A4
and CYP1A2) experienced toxic side effects and drug clearance
that was four to five times slower than in other patients [438]. This
patient was also reportedly taking "essiac tea," although further
details are not available, and it is not clear if the patient was taking
Essiac® or generic essiac formulations.
Glauber's salt (mirabilite): In a clinical trial, rhubarb en-
hanced Glauber's salt's laxative effects [439].
Nifedipine (Procardia®): In a clinical trial, rhubarb enhanced
nifedipine's anti-pre-eclampsia effects [440].
Evening Primrose Oil (Oenothera biennis)
Pharmacokinetics
After administration of evening primrose oil, tmax of linoleic
acid is approximately 3-5 hours [441]. Metabolic effects may occur
within hours of ingestion, and may persist for months. GLA (the
active constituent of evening primrose oil) is metabolized to di-
homo gamma linolenic acid (DGLA). DGLA may be broken down
further to arachidonic acid by delta-five desaturase in small
amounts. [264,442]. DGLA is cyclooxygenated into prostaglandin
E1 and thromboxane A1. It is also metabolized into 15-hydroxy-
dihomo-gamma-linolenic acid by 15-lipoxygenase [264, 443, 444].
Adverse effects
Evening primrose oil has been well tolerated when taken in
doses up to 3g daily for as long as one year [445]. Review of re-
search conducted in animals and clinical studies (involving ap-
proximately 500,000 users of evening primrose oil in the United
Kingdom) did not reveal significant toxicity [446]. There have been
several case reports of seizures associated with the use of evening
primrose oil in patients with/without known seizure disorders
[447,448].
Interactions
Anticoagulants/antiplatelets: In a recent cross-sectional,
point-of-care survey of 1818 patients, two cases were identified as
potential clinically significant interactions between evening prim-
rose oil and anticoagulant/antiplatelet agents [10].
Agents that lower seizure threshold: Due to several case re-
ports of seizures associated with the use of evening primrose oil in
patients with/without known seizure disorders [447,448], patients
taking antiepileptic drugs or agents that may lower the seizure
threshold should avoid EPO use.
Feverfew (Tanacetum parthenium)
Pharmacokinetics
An in vitro model of the human colonic cell line demonstrated
that parthenolide, the active constituent in feverfew, is absorbed via
a passive diffusion mechanism [449].
Adverse Effects
Feverfew appears to be generally well tolerated. Mild and tran-
sient side effects, including indigestion, nausea, flatulence, consti-
pation, diarrhea, abdominal bloating, and heartburn, have been
reported [450,451]. Feverfew may elicit allergic responses in pa-
tients who are sensitive to chrysanthemums, daisies, or marigolds.
There is potential cross-reactivity with other members of the Com-
positae family, including ragweed [452].
Interactions
Anticoagulants/antiplatelets: Feverfew has been shown to
inhibit platelet secretory and aggregation activity [453-459], and
may theoretically increase the risk of bleeding if used concomi-
tantly with anticoagulant or antiplatelet agents. In a recent cross-
sectional, point-of-care survey of 1818 patients, two cases were
Ulbricht et al.
identified as potential clinically significant interactions between
feverfew and anticoagulant/antiplatelet agents [10].
Flaxseed and Flaxseed Oil (Linum usitatissimum)
Pharmacokinetics
The pharmacokinetics of flaxseed is not well understood. Flax-
seed lignan metabolites appear to be excreted in the urine [460-
463].
Adverse Effects
Flaxseed and flaxseed oil appear to be well tolerated. Although
limited human safety data exist, there is long-standing historical use
with few reports of adverse events in the available literature.
Rarely, flaxseed (not flaxseed oil) may cause diarrhea, nausea,
vomiting, abdominal pain, and gastrointestinal distress [464-468].
Based on available research, consumption of flaxseed (not flaxseed
oil) may increase episodes of mania and hypomania in bipolar pa-
tients [464].
Interactions
Oral agents: Due to its fiber content, flaxseed (not flaxseed oil)
consumption may decrease the absorption of co-administered oral
agents/vitamins/minerals, due to the fiber content. Oral agents
should be taken an hour before or two hours after flaxseed to pre-
vent decreased absorption.
Garlic (Allium sativum)
Pharmacokinetics
The pharmacokinetics of garlic and all of its constituents is not
well understood. The pharmacokinetics of the vinyldithiins, trans-
formation products of allicin, have been described as having maxi-
mal concentrations 15-30 minutes after oral absorption [469]. S-
allyl cysteine sulfoxide (SAC) constituents of garlic have demon-
strated a first pass effect following rapid gastrointestinal absorption
with liver and kidney metabolism [470]. The elimination half-life of
N-Acetyl-S-allyl-L-cysteine (allylmercapturic acid, ALMA), a uri-
nary metabolite of garlic, was reported to be about six hours [471].
Adverse Effects
A review of 45 randomized trials and 73 other clinical trials of
garlic use found limited detailed information relating to adverse
effects [472]. One review noted that malodorous breath, body odor,
and allergic reactions appear to be the most commonly reported
effects [473]. Excessive use has been associated with spontaneous
epidural hematoma [474]. Potential reactions associated with oral
garlic use include bleeding (multiple case reports and a scientific
basis) and hypoglycemia (likely not clinically significant); topical
exposure may elicit dermatitis or burns (multiple reports).
Interactions
Anticoagulants/antiplatelets: Bleeding has been associated
with oral garlic use in several studies and case reports, including
intra-operatively, possibly related to impaired platelet aggregation
or increased fibrinolysis [474-486]. Reduced platelet aggregation
was observed in 308 cases of garlic use [487] There have been an-
ectodal reports of elevated international normalized ratios (INRs)
and prothrombin times in warfarin-stabilized patients after taking
garlic [488]. In a recent cross-sectional, point-of-care survey of
1818 patients, 25 cases were identified as potential clinically sig-
nificant interactions between garlic and anticoagulants/antiplatelets
[10].
Garlic should be used cautiously in patients taking warfarin or
other anticoagulants.
Protease inhibitors: Garlic supplementation was shown to
cause a significant decrease in plasma concentrations of the prote-
ase inhibitor saquinavir taken at a dose of 1,200mg three times
daily by 10 healthy volunteers [489-491]. Combination use may
Clinical Evidence of Herb-Drug Interactions
result in diminished effects of saquinavir (Invirase® or For-
tovase®).
Ginger (Zingiber officinale)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Ginger has a long history of oral and topical use with minimal
reports of toxicity or serious reactions. Adverse effects have usually
been reported for dosage amounts exceeding (usually far exceed-
ing) recommended doses [492]. According to a systematic review,
3.3% of 777 patients (from 15 studies) experienced slightly mild
side effects that mainly included mild gastrointestinal symptoms
[493]. Oral/esophageal irritation described as "pepper-like," heart-
burn [494], belching [495], bloating, flatulence, nausea, "bad taste,"
abdominal discomfort, and transient burning sensation of the tongue
have been reported occasionally, primarily with powdered forms of
ginger [496-501]. The mild gastrointestinal symptoms may be re-
duced by ingesting encapsulated (rather than powdered) ginger
[502]. According to a systematic review, up to 6g of ginger per day
does not appear to cause many side effects [493]. The U.S. Food
and Drug Administration (FDA) lists ginger on its Generally Rec-
ognized as Safe (GRAS) list, although this does not support ginger's
safety as a medicinal agent.
Interactions
Anticoagulants/antiplatelets: In theory, since ginger has been
observed to inhibit thromboxane synthetase and because decreased
platelet aggregation has been reported in clinical trials, concurrent
use of ginger with agents that predispose to bleeding could enhance
their effect and increase the risk of bleeding [503-506]. In addition,
there is also a European case report of a 75 year-old woman taking
chronic warfarin whose international normalized ratio/INR rose
after initiating therapy with ginger, complicated by epistaxis [507].
Her INR normalized after discontinuation of ginger and treatment
with vitamin K. It is not clear to what extent ginger was responsible
for this rise in INR. Another case report described a 76-year-old
woman who experienced erratic anticoagulation after taking ginger
[508]. In other clinical studies, normal and hypertensive patients
experienced synergistic anti-platelet effects when nifedipine (Ada-
lat®, Procardia®) and ginger were used. Nifedipine and ginger had
a synergistic effect on the inhibition of platelet aggregation [509].
In one clinical trial, ginger did not affect the pharmacokinetics or
pharmacodynamics of warfarin in healthy subjects [510]. However,
in a recent cross-sectional, point-of-care survey of 1818 patients,
seven cases were identified as potential clinically significant inter-
actions between ginger and anticoagulants/antiplatelets [10].
Ginkgo (Ginkgo biloba)
Pharmacokinetics
Oral bioavailability of the terpene lactones ginkgolide A, gink-
golide B, and bilobalide (constituents of Ginkgo) are 98-100%, 79-
93%, and 70%, respectively. Absorption has been found to occur
principally via the small intestine. Half-life of ginkgolide A, gink-
golide B, and bilobalide have been found to be 4.5, 10.6, and 3.2
hours, respectively, with peak plasma levels at 2-3 hours. Approxi-
mately 70% of ginkgolide A, 50% of ginkgolide B, and 30% of
bilobalide are excreted unchanged in urine, with seven other me-
tabolites (i.e., 4-hydroxybenzoic acid conjugate, 4-hydroxyhippuric
acid, 3-methoxy-4-hydroxyhippuric acid, 3,4-dihydroxybenzoic
acid, 4-hydroxybenzoic acid, hippuric acid, and 3-methoxy-4-
hydroxybenzoic acid (vanillic acid)) that are detectable in the urine
but undetectable in serum. Toxicity is low, with an oral LD50 in
mice of 7,725mg [511,512]. Duration of action has been reported as
seven hours.
Current Drug Metabolism, 2008, Vol. 9, No. 10 1073
Adverse Effects
Ginkgo appears to be well tolerated in most healthy adults at
recommended doses for six months to a year. In several reviews,
Ginkgo use was associated with similar rates of adverse effects as
placebo [513-517]. Post-market surveillance of >10,000 subjects
found a 1.69% incidence of minor symptoms, including headache,
nausea, and gastrointestinal complaints [518]. The most concerning
potential complication is bleeding, which has been life threatening
in a small number of case reports. Infrequent mild gastrointestinal
discomfort has been reported in clinical studies, particularly when
Ginkgo is taken with SSRIs [519]. Ginkgo may also alter blood
sugar levels. Rarely, Ginkgo may cause allergic hypersensitivity,
including Stevens-Johnson syndrome [520-522]. Eating Ginkgo
seeds may be deadly due to the risk of tonic-clonic seizures and loss
of consciousness [523,524].
Interactions
5-Fluorouracil (5-FU): 5-fluorouracil-induced adverse effects
may be alleviated by Ginkgo, as suggested by a Phase II clinical
trial [525].
Anticoagulants/antiplatelets: Based on several case reports of
spontaneous bleeding in patients using Ginkgo as a monotherapy or
concomitantly with warfarin or aspirin [526-530], concurrent use of
Ginkgo with agents that increase clotting time or inhibit platelet
function may increase the risk of bleeding. In a recent cross-
sectional, point-of-care survey of 1818 patients, 10 cases were iden-
tified as potential clinically significant interactions between Ginkgo
and anticoagulants/antiplatelets [10].
Thiazides: Although paradoxical hypertension was documented
in a male patient taking a thiazide diuretic and Ginkgo, it has been
found to decrease systolic and diastolic blood pressure in healthy
volunteers [531,532]. Caution is warranted with concomitant use.
Fluoxetine (Prozac®): Ginkgo has been used to treat erectile
dysfunction [533], and may interact with other agents used in the
management of vascular erectile dysfunction. Ginkgo has also been
reported to relieve sexual dysfunction associated with the selective
serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac®) [534].
Nifedipine (Adalat®, Procardia®): The effects of Ginkgo leaf
extract on the pharmacokinetics and pharmacodynamics of nifedip-
ine, a calcium-channel blocker, were studied in healthy volunteers
[535,536]. The maximal plasma nifedipine concentrations in two
subjects were approximately doubled by Ginkgo, and they had more
severe and longer-lasting headaches with Ginkgo than without
Ginkgo. Oral administration of nifedipine with Ginkgo also in-
creased heart rate over Ginkgo alone.
Ginseng (American ginseng, Asian ginseng, Chinese gin-
seng, Korean red ginseng, Panax ginseng: Panax spp. including
P. ginseng and P. quinquefolius, excluding Eleutherococcus sen-
ticosus)
Pharmacokinetics
The ginsenosides found in ginseng appear to be poorly ab-
sorbed after oral absorption [537-539]. Compound K is the main
metabolite of ginseng. The metabolism and excretion of the con-
stituents of ginseng have not been extensively studied. It appears
that ginsenosides are excreted in the urine only in trace amounts.
Adverse Effects
Clinical trials have indicated that Panax ginseng and American
ginseng used in recommended doses for a short period do not seem
to be associated with serious long-term side effects [540]. Based on
limited evidence, long-term use may be associated with skin rash or
spots, itching, diarrhea, sore throat, loss of appetite, excitability,
anxiety, depression, or insomnia. Less commonly reported side
effects include headache, fever, dizziness/vertigo, blood pressure
abnormalities (increases or decreases), chest pain, difficult men-
struation, heart palpitations, rapid heart rate, leg swelling, nau-
1074 Current Drug Metabolism, 2008, Vol. 9, No. 10
sea/vomiting, or manic episodes in people with bipolar disorder.
Stevens-Johnson syndrome has occurred in one patient and may
have been due to contaminants in a ginseng product. High intake of
American ginseng may result in hypoglycemia in both diabetics and
non-diabetics [541].
Interactions
Antibiotics: There is preliminary clinical evidence that ginseng
synergistically accelerate bacterial clearance of sputum in bacterial
bronchitis treated with antibiotics (amoxicillin and clavulanic acid)
[542];
Anticoagulants/antiplatelets: Ginseng may inhibit platelet
activity [543,544] and potentiate the action of NSAIDs, such as
aspirin. Based on in vitro research, non-saponin lipophilic fraction
from the roots of Panax ginseng inhibited the aggregation of human
platelets induced by thrombin (0.1units/mL) in a dose-dependent
manner [543]. Ginseng reduced platelet adhesiveness in rat studies
[544]; however, the mechanism is not entirely clear, as warfarin
pharmacokinetics have been shown to be unaltered by a single dose
of 2mg/kg ginseng in rats [545]. In humans, a ginseng-gingko
combination has been shown to reduce platelet aggregation [546].
One case report of a 47 year-old man stabilized on warfarin for a
mechanical heart valve experienced a drop in his INR from 3.1 to
1.5 four weeks after starting ginseng capsules three times daily
[547]. Two weeks after discontinuation of ginseng, the patient's
INR returned to 3.3 [548]. Due to conflicting data, it is unclear how
ginseng may act when used in combination with anticoagulants or
antiplatelet agents; it may increase bleeding or clotting risk. None-
theless, caution is warranted.
Antidiabetic agents: In a recent cross-sectional, point-of-care
survey of 1818 patients, six cases were identified as potential clini-
cally significant interactions between ginseng and antidiabetic
agents [10].
Digoxin (Lanoxin®): There is some clinical evidence that gin-
seng may enhance the effects of digoxin (Lanoxin®) in congestive
heart failure [549].
Estrogenic agents: Ginseng has been reported to have estro-
gen-like effects [550-552]. Mycotoxins in root extracts of American
and Asian ginseng bind estrogen receptors alpha and beta in vitro
[553]. However, one study found that no estrogenic activity was
evident in the sample of Panax ginseng extract tested, or in a sam-
ple of the combination product ArginMax® [554]. Clinical rele-
vance of this potential interaction remains unclear.
Furosemide (Lasix®): In one case report of a patient taking
furosemide (Lasix®), ginseng was suspected of inducing diuresis
resistance [555].
Monoaminergic agents: Panax ginseng or Panax quinquefo-
lius has been suggested to interact with MAO inhibitors [556].
Panax ginseng has documented clinical and theoretical interactions
with phenylzine (Nardil®) that cause mania, headache, tremors, and
insomnia [557-559].
Nifedipine (Procardia®): Based on case reports, ginseng may
interact with blood pressure or heart agents, including calcium
channel blockers such as nifedipine (Procardia®). Ginseng in-
creased serum levels of nifedipine in healthy volunteers [560].
Globe artichoke (Cynara scolymus)
Pharmacokinetics
Several metabolites detected in human plasma have been identi-
fied as being derived from mono- and dicaffeoylquinic acids, and
flavonoids that are known active phenolic constituents of artichoke
leaf extract. The metabolites caffeic acid, ferulic acid, and isoferulic
acid achieved peak plasma concentrations within one hour and de-
clined over 24 hours, demonstrating a near bi-phasic profile. The
hydrogenated metabolites dihydrocaffeic acid and dihyrdoferulic
acid were detected after six to seven hours, suggesting the involve-
Ulbricht et al.
ment of more than one pathway in processing caffeoylquinic acids.
Peak plasma concentrations of luteolin were reached within 30
minutes, with elimination showing a biphasic profile. The active
constituents of artichoke extract have not been detected in human
plasma or urine [561].
Adverse Effects
Patients should avoid globe artichoke if they have known aller-
gies or hypersensitivities to Cynara scolymus, its constituents, or
members of the Asteraceae or Compositae family, including chry-
santhemums, daisies, marigolds, ragweed, and arnica, due to possi-
ble cross-reactivity
The adverse effects associated with artichoke are generally mild
gastrointestinal symptoms including mild flatulence, diarrhea, hun-
ger, and nausea have been reported [562-564]. Severe asthma
[565,566] and nephrotoxicity [567,568] have also been reported.
Interactions
Anticoagulants/antiplatelets: Artichoke may increase the risk
of bleeding, based on a case report of significantly reduced platelet
aggregation (both spontaneous and ADP-induced) in 62 men taking
an artichoke extract (Cynarex®) for two years (dose not reported),
who were also chronically exposed to carbon disulfide [569]. It is
not clear whether artichoke or other agents were the cause of this
reaction.
Goji (Lycium spp.), Wolfberry
Pharmacokinetics
Plasma zeaxanthin concentrations increased significantly
(p=0.05) after volunteers consumed a 5mg dose of goji [570]. Peak
absorption occurred between 9-24 hours. Native 3R,3'R-zeaxanthin
from wolfberry was determined to be more bioavailable than the
non-esterified form.
Adverse Effects
There is a lack of available information on the adverse effects
of goji. According to anecdotal reports, high doses of goji berry
extract may induce alertness at bedtime, may interact with sleep,
and may cause nausea and vomiting [2].
Interactions
Anticoagulants/antiplatelets: Goji fruit was shown to elevate
international normalized ratio (INR) in a patient stabilized on war-
farin [571].
Goldenseal (Hydrastis Canadensis), Berberine
Pharmacokinetics
After receiving 500mg/kg of berberine, the whole blood con-
centrations were 0.8mcg/mL at eight hours in rabbits [572]. Berber-
ine appears to be metabolized in the liver, and undergo phase I he-
patic metabolism and phase II glucuronidation [573]. It also seems
to be a substrate of P-glycoprotein and organic cation transporter,
which may limit oral bioavailability [573,574]. Berberine is ex-
creted through the urine and feces [572]. Peak urinary excretion of
berberine is seen between 12-24 hours, while peak fecal excretion is
seen after 48 hours.
Adverse Effects
Berberine, the main constituent of goldenseal, may cause tran-
sient gastrointesintal effects including constipation [575,576].
Headache, bradycardia, nausea, vomiting, and leukopenia have
been noted in both animals and humans [577-582]. It has also been
associated with ventricular arrhythmias in subjects with congestive
heart failure (CHF) [583]. Rarely, it may cause drying of mucous
membranes, respiratory failure and paresthesias [584]. Functional
liver or kidney damage have not been observed in patients [575].
Berberine-containing herbs, such as goldenseal, have been sug-
gested, historically, as abortifacients, although there is a lack of
published research in this area.
Clinical Evidence of Herb-Drug Interactions
Interactions
Cyclosporine: In transplant patients, berberine has been shown
to elevate the blood concentration of cyclosporin A; this was attrib-
uted to inhibition of CYP3A4 by berberine [585]. This inhibition is
supported by in vitro studies, which demonstrate CYP3A4 inhibi-
tion by berberine [586,587]
Tetracycline: Based on clinical evidence, berberine may en-
hance the efficacy of tetracycline against Vibro cholerae [588].
Grapefruit (Citrus paradisi)
Pharmacokinetics
The pharmacokinetics of grapefruit is not well understood.
Grapefruit juice is a potent inhibitor of the intestinal cytochrome
P450 system (specifically, CYP3A4-mediated drug metabolism),
which is responsible for the first-pass metabolism of many agents.
It may also inhibit CYP1A2, CYP2C9, and CYP2C19, as well as
the drug transporters P-gp and organic anion transporting peptide
(OATP).
Adverse Effects
Grapefruit appears to be well tolerated. Consumption of large
amounts of grapefruit may increase the risk of breast cancer [589].
Grapefruit may increase or decrease the development of kidney
stones; research results are conflicting.
Interactions
General: Grapefruit juice appears to irreversibly inhibit the
intestinal cytochrome P450 3A4 system, which is responsible for
the first-pass metabolism of many agents. The inhibition of this
enzyme system leads to an elevation in blood serum concentration
of the drug when administered concurrently with grapefruit juice.
Antibiotics: The bioavailability of erythromycin was shown in
clinical studies to be increased by grapefruit, likely due to the in-
hibitory effect of grapefruit on CYP450 3A4-mediated metabolism
in the small intestine [590,591]. Grapefruit may increase the ab-
sorption and plasma concentrations of erythromycin.
Losartan: Concomitant use of grapefruit juice and the ACE
inhibitor losartan (Cozaar®) has been shown clinically to reduce
the effectiveness of losartan [592].
Anticoagulants/antiplatelets: Grapefruit has been reported to
potentiate the antiplatelet effects of cilostazol [593]. After ingestion
of grapefruit juice, urinary excretion of 7-hydroxycoumarin after
oral administration of 10mg coumarin were decreased for up to
eight hours [594]. It appears that grapefruit flavonoids inhibit cyto-
chrome P450 2A dependent metabolic pathways, but the mecha-
nism of this inhibition is not understood.
Anticonvulsant agents: Based on clinical evidence, grapefruit
may increase the absorption and plasma concentrations of some
(but not all) anticonvulsants [595,596]. In patients with epilepsy,
grapefruit juice has been shown to increase the bioavailability of
carbamazepine (Tegretol®) by inhibiting CYP450 3A4 enzymes in
the gut wall and the liver [596].
Antidepressants: Based on in vitro, in vivo, and preliminary
human evidence, grapefruit may inhibit the metabolism of antide-
pressants, thereby increasing drug levels and the risk of adverse
effects [597,598].
Antifungal agents: There is clinical evidence that grapefruit
decreases the systemic availability of itraconazole, possibly by
presystemic intestinal metabolism via CYP3A4 [599,600].
Antihistamines: Based on in vitro and human evidence, grape-
fruit may increase the bioavailability and side effects associated
with antihistamines [601-605]. In clinical studies, the administra-
tion of grapefruit juice concomitantly with terfenadine (Seldane®)
was shown to increase terfenadine bioavailability, thus increasing
the risk of cardiotoxicity [600,606,607].
Current Drug Metabolism, 2008, Vol. 9, No. 10 1075
Antimalarial agents: Grapefruit juice has been shown to in-
crease the bioavailability of antimalarial agents such as artemether
and halofantrine [608-610]. However, grapefruit juice has been
found to have no effect on quinine pharmacokinetics [611].
Antineoplastic agents: Based on human and in vivo studies,
grapefruit may reduce the effectiveness of some antineoplastic
agents [604,612,613]. There is some evidence from a human cross-
over study that grapefruit juice coadministered with oral etoposide
can reduce the AUC of etoposide (Etopophos®, Vepesid®): on
average by 26.2% [612]. Grapefruit juice may decrease the absorp-
tion and plasma concentrations of etoposide. According to the
manufacturer, grapefruit juice may inhibit CYP3A4 metabolism of
sunitinib (Sutent®) in the intestinal wall, possibly resulting in in-
creased drug levels and risk of adverse events.
Antipsychotic agents: Antipsychotic drugs, such as clozapine
[614-616] and haloperidol [617], have not been shown to be altered
by grapefruit ingestion in human studies. However, according to the
manufacturer of aripiprazole (Abilify®), due to the ability of grape-
fruit to inhibit CYP3A4, the levels/effects of aripiprazole may be
increased. It is recommended that the dose of aripiprazole be de-
creased by 50%.
Benzodiazepines: Grapefruit has been shown clinically to in-
crease the plasma concentrations of the benzodiazepines midazolam
[604,608,618-621] and triazolam [609,622]. However, the effects of
these drugs did not appear to be enhancd by grapefruit juice [623].
Beta-adrenergic agents: Grapefruit juice has been shown
clinically to decrease concentrations of beta-blocking agents [624-
626]. In clinical research, grapefruit juice has been shown to de-
crease in plasma concentrations of acebutolol (Sectral®) and diace-
tolol by interfering with gastrointestinal absorption [627].
Calcium channel blockers: Grapefruit has been shown in nu-
merous studies (biochemical, in vitro, in vivo, and clinical) to in-
crease the adverse effects associated with some calcium channel
blockers [628-650]. The basis for this interaction appears to relate
to both flavonoid and nonflavonoid components of grapefruit juice
interfering with enterocyte CYP3A4 activity.
Cardiac glycosides: Modest changes in digoxin pharmacoki-
netics have been observed following concurrent administration of
grapefruit juice in humans [651,652]. Inhibition of intestinal P-
glycoprotein does not appear to play an important role in drug in-
teractions involving grapefruit juice and digoxin [651,652].
Cholinergic agents: Theoretically, grapefruit juice may inhibit
the hepatic metabolism of oxybutynin (Ditropan®), leading to in-
creased drug levels and associated adverse events. A clinical study
showed that the AUC was increased to 30% when scopolamine was
administered with grapefruit juice; tmax and half-life were also
increased [653]. This interaction is likely due to CYP3A4 inhibition
in the intestine. Theoretically, grapefruit juice, a CYP3A4 inhibitor,
may increase the serum level and/or toxicity of tolterodine (De-
trol®), but unlikely secondary to high oral bioavailability.
Corticosteroids: In vivo evidence suggests that the dietary
flavonoids in grapefruit juice may inhibit the enzyme 11
-
hydroxysteroid dehydrogenase, which oxidizes cortisol to inactive
cortisone in a concentration-dependent manner [654,655]. Grape-
fruit juice has been shown to increase plasma concentration of
orally administered methylprednisolone in healthy subjects. Grape-
fruit juice (200mL three times daily) increased the half life of
methylprednisolone by 35%, Cmax by 27%, and total AUC by 75%
[656].
Cytochrome P450 substrates: Preliminary evidence suggests
that grapefruit juice may inhibit cytochrome P450 1A2 [657], cyto-
chrome P450 2C9 [642,657], or cytochrome P450 2C19 [657].
However, clinical evidence of these interactions is lacking. Grape-
fruit juice has been shown in vitro, in vivo, and clinically to inhibit
cytochrome P450 3A4 metabolism of drugs, causing increased drug
1076 Current Drug Metabolism, 2008, Vol. 9, No. 10
levels and potentially increasing the risk of adverse effects
[612,630,634,635,637,642].
Drug tests: Grapefruit juice decreases metabolism and in-
creases plasma concentrations and test results of various agents,
including praziquantel [658], clomipramine [659,660], artemether
and halofantrine [661-663], amiodarone [664], amlodipine [665],
diltiazem [666], felodipine [650,651,667-674], nifedipine [650,652,
674-678], nimodipine [679], verapamil [680-682], buspirone [683],
midazolam and triazolam [604,608,609,618-621], diazepam [684],
carbamazepine [685], dextromethorphan [686], cyclosporine [687-
689], methylprednisolone [690], tacrolimus [691], digoxin
[692,693], erythromycin [694], clarithromycin [695], sildenafil
[696,697], atorvastatin [613,630], lovastatin [698], simvastatin
[635,699-702], 17-beta-estradiol [703], ethinyl-estradiol [703],
methadone [704,705], cisapride [706-708], amprenavir [603],
saquinavir [638,639], terfenadine [606,607], quinidine [709], sco-
polamine [653], and theophylline [710].
Estrogenic agents: Grapefruit may increase the bioavailability
and side effects associated with estrogen therapy [618,620,711].
The most likely mechanism of action of the flavonoids of grapefruit
juice on 17 beta-estradiol metabolism is inhibition of the CYP450
3A4 enzyme, which catalyzes the reversible hydroxylation of 17
beta-estradiol into estrone and further into estriol [618].
HMG CoA reductase inhibitors: Grapefruit is known to in-
hibit P-glycoprotein-mediated transport of these agents in vitro
[610]. Grapefruit has been shown in numerous in vitro, in vivo, and
clinical studies to increase the absorption and plasma concentra-
tions of these agents [658,677,679,681,712-716]. Clinical studies
show that grapefruit increases plasma levels of simvastatin
[635,699-702]. The mean increase in simvastatin AUC was 3.6-fold
and the increase in mean Cmax was 3.9-fold [700].
Immunosuppressants: Based on animal and human studies,
grapefruit may increase the absorption and plasma concentrations
of immunosuppressants [622,657,666-669,682,717-719]. Animal
and human studies have reported increased blood levels of cy-
closporine when taken with grapefruit [622,657,666-669,717-719].
A furanocoumarin found in grapefruit, 6',7'-dihydroxybergamottin,
does not appear to be responsible for the effects of grapefruit juice
on cyclosporine; rather, inhibition of P-glycoprotein activity by
other compounds in grapefruit juice may be responsible [668]. The
bioavailability of tacrolimus (Prograf®) has been shown clinically
to double when coadministered with the CYP3A4 inhibitor keto-
conazole [691]. In one case report, a liver transplant recipient expe-
rienced a considerable increase in the trough blood concentration of
tacrolimus after concomitant ingestion of grapefruit juice [720].
Levothyroxine: In humans, grapefruit juice may slightly delay
the absorption of levothyroxine (Levoxyl®, Synthroid®), but it
seems to have only a minor effect on its bioavailability [721].
Theophylline (Bronkodyl®, Elixophyllin®, Slo-bid®):
Grapefruit juice seems to modestly decrease theophylline levels
when administered to subjects concurrently with sustained-release
theophylline [673]. The mechanism of action is not understood.
However, clinical studies show that the ingestion of grapefruit juice
should not cause any pharmacokinetic or pharmacodynamic interac-
tion when coadministered with another methylxanthine, caffeine
[616,617]. There was no significant difference in ambulatory sys-
tolic and diastolic blood pressure or heart rate when grapefruit juice
was coadministered with caffeine [617].
Opiates: Theoretically, grapefruit may interact with metabo-
lism of opioids by the liver and small intestine cytochrome P450
3A4 enzyme. Grapefruit has been shown to increase the bioavail-
ability of methadone [721,722] and alfentanil [619] in patients.
Grapefruit juice was not associated with any change in the intensity
of withdrawal symptoms by the patients [721].
P-glycoprotein substrates: P-glycoprotein is a cell membrane-
associated protein that transports a variety of drug substrates. Inter-
Ulbricht et al.
action with P-glycoprotein, including activation, inhibition and
induction, can lead to altered plasma or brain levels of P-
glycoprotein substrates. Grapefruit has been shown to inhibit P-
glycoprotein, which may explain its numerous drug interactions
[610,723].
Praziquantel (Biltricide): There is a documented interaction
between grapefruit and the antihelminthic drug praziquantel in hu-
mans [724]. The biotransformation of praziquantel appeared to be
mediated mainly by CYP3A4, which is inhibited by grapefruit;
thus, concomitant administration of grapefruit and praziquantel
resulted in significantly altered pharmacokinetcs of the drug.
Protease inhibitors: Based on clinical studies, grapefruit may
increase bioavailability and adverse effects of protease inhibitors
[619,672,725-727]. There is some clinical evidence that grapefruit
juice may lead to small changes in pharmacokinetic parameters
(Cmax and tmax) of amprenavir [603].
Sildenafil (Viagra®): Grapefruit has been shown to modestly
increase the absorption of sildenafil and plasma concentrations in
humans [676,728].
Greater celandine (Chelidonium majus)
Pharmacokinetics
After intraperitoneal administration, Ukrain™ (semi-synthetic
anticancer drug that contains alkaloids from the plant Cheladonium
majus conjugated with thiophosphoric acid) was distributed rapidly
throughout the body and into plasma with a biological half-life of
approximately 60 minutes [729]. It is excreted primarily unchanged
in urine [729].
Adverse Effects
There have been several reports of mild to severe hepatotoxicity
associated with the use of Chelidonium majus. It is not clear from
these reports what type of preparation of the herb was used, in what
manner the herb was administered, what quantity of the herb was
taken, or the duration of treatment. Patients appear to recover fully
upon discontinuation of the herb, and no cases of liver failure have
been reported [730-733]. Studies investigating the semisynthetic
anticancer drug Ukrain™ state that it is generally well tolerate"
with minimal side effects [734-737]. "No untoward side effects"
were observed when mice were treated intravenously, subcutane-
ously, or intraperitoneally with Ukrain™ [738]. Ukrain™ exhibits
toxicity toward malignant cells; however, some experts have pre-
sented evidence that Ukrain™ is equally toxic to normal, trans-
formed, and malignant cell lines [739,740].
Interactions
Cyclophosphamide (Endoxan®): In patients with advanced
esophageal cancer, the combination of Chelidonium majus and
endoxan appeared to mask the immunological response of the host
without causing the degeneration of cancer tissue seen in patients
who took Chelidonium majus alone [741].
Green Tea, Black Tea (Camellia sinensis)
Pharmacokinetics
The known pharmacokinetic parameters of black tea are largely
related to its caffeine content (see Caffeine).
Green tea is metabolized in the body to EGCG (epigallocate-
chin gallate), EGC (epigallocatechin) and EC (epicatechin). Cate-
chins from green tea are rapidly absorbed [742]. An increase in
catechins in the blood has been found to be rapid with an average
maximum change of 13% approximately two hours after ingestion
[742]. Blood levels rapidly decline with an elimination half-life of
4.8 hours for green tea [743].
Adverse Effects
Studies of the specific side effects of black and green tea are
limited. However, black and green tea is a source of caffeine, for
which multiple reactions are reported (see Caffeine).
Clinical Evidence of Herb-Drug Interactions
Interactions
General: Interactions associated with black and green tea are
predominantly theoretical and largely based upon the adverse effect
profile of caffeine. Interactions for caffeine are detailed separately
in this Pharmacokinetics and Safety Appendix.
Anticoagulants/antiplatelets: Both catechins in green tea and
caffeine in tea may have antiplatelet activity. Theoretically, black
and green tea might increase the risk of bleeding when used with
anticoagulants/antiplatelets. In one case report, large amounts (one
half to one gallon) of green tea antagonized the effects of warfarin,
possibly due to the small amounts of vitamin K in green tea
[744,745]. Dry green tea leaves contain significantly more vitamin
K than black tea leaves; green tea may contain 1,428mcg vitamin
K/100 grams leaf, while black tea may contain only 262mcg vita-
min K/100 grams leaf [746].
Guarana (Paullinia cupana)
Pharmacokinetics
The pharmacokinetics of guarana is unclear, and largely related
to its caffeine content.
Adverse Effects
Note: Because caffeine is a constituent of guarana, adverse
reactions associated with caffeine may be seen with guarana inges-
tion. See Caffeine.
Guarana is generally well tolerated. A majority of information
related to adverse effects of guarana is based in theory on the ad-
verse effect profile of caffeine.
Interactions
Note: Interactions associated with guarana are predominantly
theoretical and generally based upon the adverse effect profile of
caffeine. See Caffeine in this Pharmacokinetics and Safety Appen-
dix.
Ephedra: Use of concomitant ephedra and guarana has been
associated with a case of cerebral infarction [402].
Guggul (Commifora mukul)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Standardized guggulipid is generally regarded as being safe in
healthy adults at recommended doses for up to six months. Gastro-
intestinal upset is the predominant adverse effect that has been de-
scribed in humans, most commonly involving loose stools or diar-
rhea. Headache and restlessness are also frequent complaints.
Hypersensitivity skin reactions were noted in a clinical trial and
occurred in 5 of 34 patients (15%) receiving 50mg of guggulster-
ones three times daily and in 1 of 33 (3%) patients receiving 25mg
of guggulsterones three times daily. In most cases, reactions oc-
curred within 48 hours of starting therapy and resolved spontane-
ously within one week of therapy discontinuation, although one
patient required oral steroids [747].
Interactions
Anticoagulants/antiplatelets: Guggulipid administration has
been associated with inhibition of platelet aggregation and in-
creased fibrinolysis [748-751]. However, clinical reports of drug
interactions are lacking.
Beta-adrenergic agents: Co-administration of guggulipid to
humans has been reported to decrease the bioavailability of the
beta-blocker propranolol [752].
Diltiazem (Cardizem®, Dilacor®, Tiazac®): Co-administra-
tion of guggulipid to humans has been found to decrease the
bioavailability of the calcium channel blocker, diltiazem [752]. The
chemical structures of other calcium channel blockers are suffi-
Current Drug Metabolism, 2008, Vol. 9, No. 10 1077
ciently distinct that guggul may not affect other members of this
class.
Hawthorn (Crataegus spp.)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
While systematic analysis of hawthorn's safety profile in hu-
mans is lacking, limited adverse effects clearly associated with this
agent have been reported. Limited clinical research has reported no
side effects [753]; however, other study has reported side effects
associated with hawthorn. A 24-week multi-center observational
trial of 1,011 cardiac patients reported 14 total adverse events
[754]. A large surveillance study of 3,664 patients with class I or II
cardiac insufficiency confirmed a causal link to side effects in 22
patients [755]. Reported adverse events have been infrequent, mild,
and transient. They include abdominal discomfort, nausea, tachy-
cardia, palpitations, hypotension, dyspnea, headache, dizziness,
fatigue, sweating, mild macular skin eruptions, sleepiness, and agi-
tation [754-757].
Interactions
Antihypertensive agents: In a recent cross-sectional, point-of-
care survey of 1818 patients, one case was identified as a potential
clinically significant interaction between hawthorn and antihyper-
tensive agents [10].
Dixogin: A clinical study of healthy volunteers did not detect
statistically significant effects of hawthorn on digoxin, suggesting
possible safe coadministration [758]. Data on safe and efficacious
dosing in this setting is still limited.Hawthorn has been noted to
potentiate the inotropic effects (contraction stimulating or contrac-
tion decreasing) associated with cardiac glycoside agents without
toxicity in study of isolated guinea pig hearts [759]. Hawthorn has
been suggested and used concomitantly with cardiac glycosides to
decrease glycoside dosage and potential toxicity [760-762].
Hibiscus (Hibiscus spp.)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
There is limited reported safety data on hibiscus, although it is
popularly used as a tea. It should be avoided in patients allergic or
hypersensitive to hibiscus or its constituents.
Interactions
Acetaminophen (Tylenol®): A hibiscus drink has been shown
to alter the half-life of acetaminophen in human volunteers [763].
Quinines: A hibiscus beverage has been shown to reduce the
efficacy of quinine and chloroquine in human volunteers [764].
Kava (Piper methysticum)
Pharmacokinetics
The pharmacokinetic actions of kava are not well understood.
Metabolites and unchanged lactones of kava are excreted in urine
[765].
Adverse Effects
There is widespread concern regarding the potential hepatotox-
icity of kava [766-777]. There have been many cases of liver dam-
age reported in Europe, including hepatitis [778-780], cirrhosis,
fulminant liver failure [781,782], and reports of death [783,784].
These reports have been challenged, and researchers have main-
tained that kava is safe in most individuals at recommended doses
[785,786]. Kava, when used for less than one to two months, has
been generally regarded as safe and well-tolerated [787]. The most
common reported adverse effects are sedation, gastrointestinal
1078 Current Drug Metabolism, 2008, Vol. 9, No. 10
complaints and allergic rashes [788-798]. Chronic heavy use of
kava has been associated with increased red blood corpuscle vol-
ume, reduced platelet size, and decreased lymphocyte counts
[799,800]. Because kava may adversely affect the liver, it should be
used with extreme caution in patients taking hepatotoxic agents due
to an increased risk of liver damage.
Kava is still available in the United States, although the U.S.
Food & Drug Administration (FDA) has issued warnings to con-
sumers and physicians [770,771,801]. It is not clear what dose or
duration of use is correlated with the risk of liver damage. It is also
unclear if the safety profile of kava is comparable to other agents
used in the management of anxiety.
Interactions
Dopaminergic agents: Kava has been reported to antagonize
the effect of dopamine and elicit extrapyramidal effects in animals
[802-804]. Therefore, it may interfere with the effects of dopamine
or dopamine agonists and exacerbate the extrapyramidal effects of
dopaminergic antagonists such as droperidol, haloperidol, risperi-
dol, and metoclopramide. Kava (Piper methysticum) increases 'off'
periods in Parkinson patients taking levodopa and can cause a
semicomatose state when given concomitantly with alprazolam
[805].
Sedatives and CNS depressants: Kava may potentiate CNS
depressants, including barbiturates and benzodiazepines [806].
Lethargy and disorientation were reported in a 54 year-old man
taking kava in combination with alprazolam [807]. Kavalactones
have been shown to potentiate the effects of CNS depressants, such
as ethanol, benzodiazepines, low-potency neuroleptics, beta-
blockers, and barbiturates in animals with concurrent use being
potentially toxic [808,809]. In a recent cross-sectional, point-of-
care survey of 1818 patients, seven cases were identified as poten-
tial clinically significant interactions between kava and sedatives
[10].
Khat (Catha edulis)
Pharmacokinetics
When khat is chewed, absorption of cathinone is slow [810].
Cathinone is distributed in blood plasma [810]. Its plasma half-life
is 1.5 hours [810]. The primary metabolites are norpseudoephed-
rine, norephedrine, 3,6-dimethyl-2,5-diphenylpyrazine, and 1-
phenyl-1,2-propanedione [811-815]. After oral administration, 22%
to 52% of synthetic cathinone is excreted in 24-hour urine samples
[816]. The half-life of khat was documented to be 260 plus or mi-
nus 102 minutes [816].
Adverse Effects
Fresh khat leaves contain cathinone - a Schedule I drug under
the Controlled Substances Act; however, the leaves typically begin
to deteriorate after 48 hours, causing the chemical composition of
the plant to break down [810]. Once this occurs, the leaves contain
cathine, a controlled substance (Schedule IV) [810].
Based on historical and available research, khat may increase
blood pressure and heart rate [811-823] and cause insomnia, over-
alertness, constipation, dependency [824], and psychosis [825-827].
Hemorrhoidal disease [828], loss of appetite and anorexia [829],
gastritis, and malnutrition have also been associated with khat use
[825]. There is a case report of fasciola hepatica infection, a para-
site infection, after chewing of khat leaves [830]. Khat chewing has
also been associated with acute myocardial infarction [831] and oral
carcinoma [832].
Interactions
Antibiotics: In a human study, khat chewing reduced urinary
excretion of ampicillin and amoxicillin, possibly due to the result of
formation of insoluble compounds between the tannins found in
khat and the antibiotics [833]. These antibiotics should be adminis-
tered two hours after khat chewing [833].
Ulbricht et al.
Alpha-adrenergic agents: In one human study, the effects of
khat on urine flow rate were inhibited by indoramin (Baratol®), an
alpha-blocker [834].
Dopaminergic agents: Khat addiction has been successfully
treated with the dopamine agonist bromocriptine [835]. A dose of
1.25mg every 6 six hours, which was titrated downward over four
weeks, has been used [836].
Lavender (Lavandula angustifolia)
Pharmacokinetics
Topically, lavender oil is quickly absorbed through the skin.
The constituents, linalool and linalyl acetate, are detectable in the
blood five minutes after topical application, reach peak levels at 19
minutes, and largely dissipate from the blood within 90 minutes of
application [837].
Following oral administration, the constituents limonene and
perillyl alcohol (POH) are metabolized into perillic acid (PA) and
dihydroperillic acid (DHPA). In rats fed a diet containing POH or
limonene, peak levels of PA were seen at 1-2.5 hours, peak levels
of DHPA were noted at 2-3.5 hours, and half-lives for each metabo-
lite were 1-2 hours [838]. POH, PA, and DHPA are detectable in
subjects' urine following high doses of POH ingestion. Approxi-
mately 9% of the total dose can be recovered in the first 24 hours.
PA is the major metabolite found, with less than 1% of recovered
POH.
Adverse Effects
Common lavender usage is 1-2 teaspoons of the herb taken as a
tea (based on anecdote and expert opinion). The tea can be made by
steeping 2 U.S. teaspoons (10 grams) of leaves in 250mL (1 cup)
boiling water for 15 minutes. In recommended oral doses, lavender
is generally considered to be well tolerated, with minimal adverse
effects [839-841].
Central nervous system depression has been noted with laven-
der aromatherapy [842,843], including reports of significant deficits
in performance of working memory and impaired reaction times
[844]. Additive narcotic effects have been noted in rats when lav-
ender is taken orally concomitantly with barbiturates or chloral
hydrate [845,846]. Headache has been observed in patients taking
lavender tincture, which could be due to the alcohol in the formula-
tion (lavender 1:5 in 50% alcohol, 60 drops/day for 4 weeks) [847].
There have been case reports of mild dermatitis following the
use of topical lavender oil [848]. One individual developed an itchy
dermatitis on his face after using lavender oil on his pillow [849];
patch testing subsequently confirmed a positive allergy to lavender.
There have been reports of photosensitization and changes in skin
pigmentation after the use of topical products containing lavender
oil [850,851].
Interactions
Imipramine (Tofranil®): Lavender may enhance the effects of
antidepressant medications, as shown in a preliminary trial combin-
ing lavender with the tricyclic antidepressant imipramine (Tofra-
nil®) [847].
Sedatives and CNS depressants: Lavender should be used
cautiously in patients who are currently taking agents that depress
the central nervous system, as concomitant use of lavender and
pentobarbital or chloral hydrate has been shown to significantly
increase sleeping time and narcotic effects in animal studies
[845,846].
Licorice (Glycyrrhiza glabra), deglycyrrhizinated licorice (DGL)
Pharmacokinetics
After oral administration, glycyrrhizin (the active constituent of
licorice) is metabolized to glycyrrhetinic acid by intestinal bacterial
[852]. After intravenous administration of glycyrrhizin, both gly-
Clinical Evidence of Herb-Drug Interactions
cyrrhizin and glycyrrhetinic acid appear in the plasma. Intrave-
nously administered glycyrrhizin is metabolized in the liver by
lysosomal
-D-glucuronidase to 3-mono-glucuronide–glycyrrhe-
tinic acid. Human liver is unable to metabolize 3-mono-glucu-
ronide–glycyrrhetinic acid to glycyrrhetinic acid; 3-mono-
glucuronide–glycyrrhetinic acid is excreted with bile into the intes-
tine where bacteria metabolize it to glycyrrhetinic acid, which is re-
absorbed [853].
Adverse Effects
Licorice contains a chemical called glycyrrhizin, which is re-
sponsible for many of the reported side effects. Adverse effects
from glycyrrhizin are primarily a result from hormonal and electro-
lyte disturbances. Possible effects include hypokalemia, hyperna-
tremia, and metabolic alkalosis. Numerous cases of hypokalemia
and hypertention have been associated with licorice use [854].
Metabolic abnormalities may also lead to irregular heartbeats, heart
attack, kidney damage, muscle weakness, or muscle breakdown.
Reduced body fat mass, decreased libido in men, and temporary
vision problems or loss have also been reported. Serious, although
rare, side effects reported with licorice use include acute pseudo-
aldosteronism syndrome, paralysis [855], thyrotoxic periodic pa-
ralysis (TPP), metabolic alkalosis, seizure, and hypertensive en-
cephalopathy with stroke-like effects. Based on extensive in vivo
and clinical evidence, a proposed acceptable daily intake is 0.015-
0.229mg glycyrrhizin/kg body weight [856].
Deglycyrrhizinated licorice (DGL), which has been used in
many clinical trials, is free of glycyrrhizic acid and has had no sig-
nificant reported adverse effects.
Interactions
Cardiac glycosides: Concurrent use of licorice with cardiac
glycosides has been suggested increase the risk of cardiac toxicity
[857].
Corticosteroids: Numerous studies have shown that glycer-
rhyzin inhibits 11beta-hydroxysteroid dehydrogenase, the enzyme
responsible for deactivating cortisol. Thus, long-term ingestion or
overuse of licorice can produce hypermineralocorticoid-like effects
in both animals and humans [856]. Licorice has also been shown in
humans to potentiate the effects of topical hydrocortisone [858].
Cytochrome P450 substrates: There is conflicting evidence
regarding the effect of licorice on cytochrome P450 enzymes
[859,860]. Licorice has been shown to induce and inhibit cyto-
chrome P450 2B6, 2C9, and 3A4 [860].
Milk Thistle (Silybum marianum), Silymarin
Pharmacokinetics
Bioavailability of orally administered silibinin, a constituent of
milk thistle, ranges from 23% to 47% and appears to be higher
when administered in a softgel capsule [861]. About 10% of
silibinin was distributed in plasma [862]. The half-life of silibinin
and silymarin is reported as less than 4 hours [861]. Less than 3%
of the free or conjugated form of silibinin is recovered in the urine
[861].
Adverse Effects
In clinical trials and traditional use, oral milk thistle has gener-
ally been reported as well tolerated in recommended doses for up to
six years. Most reported adverse reactions, such as mild gastrointes-
tinal symptoms, have been reported in several studies and include
nausea, heartburn, diarrhea, epigastric pain, abdominal discomfort,
dyspepsia, flatulence, and loss of appetite [863-872]. Urticaria,
eczema, and headache have also been reported [864,868,873,874].
Hypersensitivity/anaphylactic reactions associated with milk thistle
ingestion have been published in case reports [857-878].
Because many of the patients in available clinical trials have
liver disease, it is not clear if adverse effects are due to milk thistle
Current Drug Metabolism, 2008, Vol. 9, No. 10 1079
or to underlying liver disease; the rates of adverse effects reported
are often similar to placebo.
Interactions
Indinavir (Crixivan®): Although preclinical research suggests
that milk thistle may inhibit CYP3A4 and potentially increase indi-
navir levels [879], milk thistle does not appear to affect the phar-
macokinetics of indinavir in healthy volunteers [880].
Mistletoe (Viscum album)
Pharmacokinetics
The pharmacokinetics of mistletoe has not been studied exten-
sively. However, a phase I clinical trial conducted in Germany re-
vealed a half-life of 13 minutes (and linear kinetics on doses

1,600ng/kg) for aviscumine [881].
Adverse Effects
Mistletoe is contraindicated in patients with protein hypersensi-
tivity and/or chronic progressive infections (e.g., tuberculosis). It
should also be avoided in patients with acute, highly febrile, in-
flammatory diseases [2]. Most clinical trials were performed with
unfractionated extracts, which contain numerous components, and
were standardized primarily by the ML-1 lectin content [882]. This
compound is believed to possess the properties of the active ingre-
dient, although it is not necessarily the cause of adverse reactions.
The minimal number of studies employing pure or purified ingredi-
ents make it difficult to ascribe adverse effects to any one compo-
nent of the mistletoe extracts. Parenteral administrations of mistle-
toe may be accompanied by mild side effects, most of which are
transient. The most common reactions were erythema and hypere-
mia [2]. Five patients in a phase III clinical trial using Iscador-M®
discontinued the study due to World Health Organization grade 3-4
toxicities (e.g. anorexia, general malaise, depressive moods, fever,
and local skin inflammation at the site of injection) [883]. Mabed et
al. observed in a Phase II trial with 23 patients the following: 34.8%
drug-related fever, 13.1% erthyma at injection site, and 17.4% pain
at the site of injection. No drug-related discontinuation or toxic
deaths occurred [884]. Anecdotal reports of seizures have been
reported in poison-control centers following the ingestion of crude
mistletoe plant material. Therefore, mistletoe may theoretically
increase the risk of seizures [881,885-890]. Mydriasis and my-
osis/myalgia has been observed in patients using mistletoe [886].
Alleged adverse side effects and complications with mistletoe use
also include dehydration [2]. Elevations of liver enzymes have been
reported with high doses of mistletoe [881].
Interactions
Busulphan: Busulphan and mistletoe extract (Helixor®) have
been implicated in one case study involving organ fibrosis and
death [891]. Though an interaction was possible, the mechanism
remains unclear.
Modified Citrus Pectin
Pharmacokinetics
Although pectins are not digestible by humans [892], modified
citrus pectin (MCP) is altered to increase absorption. Pectin from
citrus rinds is depolymerized through a treatment with sodium hy-
droxide and hydrochloric acid. The resultant smaller molecule is
comprised of predominantly of D-polygalacturonates, which may
be more easily absorbed by the human digestive system.
Adverse Effects
Few adverse effects associated with modified citrus pectin have
been reported. Because it is a dietary fiber, theoretically, modified
citrus pectin may cause gastrointestinal adverse effects.
Interactions
Oral agents: As a form of dietary fiber, modified citrus pectin
may slow or reduce the absorption of oral agents; however, clinical
1080 Current Drug Metabolism, 2008, Vol. 9, No. 10
evidence of such an interaction is lacking. It is recommended to
take modified citrus pectin one hour before or two hours after the
intake of other oral agents.
Neem (Azadirachta indica)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Oral neem bark extract for up to 10 weeks has been tolerated
well in adults [893].
Several cases of death in children from neem oil poisoning have
been reported. Other symptoms present in these children included
vomiting, drowsiness, loose stools, metabolic acidosis, anemia,
Reye-like syndrome, altered sensation and consciousness, seizures,
decreased responsiveness, and liver enzyme increases with evi-
dence of liver damage [894-897]. There are multiple case reports
that document the hepatoxicity of neem [894-897].
Interactions
Acetaminophen (Tylenol®): Concomitant use of acetamino-
phen and aqueous leaf extract of Azadirachta indica has been re-
ported to induce hepatotoxicity in rats [898]. Clinical reports of
drug interactions are lacking; however, due to multiple case reports
that highlight the hepatoxicity of neem [894-897], concomitant use
with acetaminophen should be avoided.
Omega-3 Fatty Acids, Alpha-Linolenic Acid
Pharmacokinetics
Omega-3 fatty acids are well absorbed [899]. Dietary omega-3
fatty acids are incorporated into fat tissues [900]. Alpha-linolenic
acid (ALA) – found mainly in green vegetables, canola oil and
soybeans – is the parent compound of all omega-3 fatty acids, in-
cluding eicosapentaenoic acid (EPA), and docosahexaenoic acid
(DHA). However, only a small percentage of ALA (<10%) is con-
verted to EPA and DHA making this an inefficient source of
omega-3 fatty acids in the body. DHA is retroconverted to EPA
[901,902].
Adverse Effects
The U.S. Food and Drug Administration (FDA) classifies intake
of up to 3g per day of omega-3 fatty acids from fish as Generally
Recognized as Safe (GRAS). Caution may be warranted in diabetic
patients due to potential (albeit unlikely) increases in blood sugar
levels, patients at risk of bleeding, or in those with high levels of
LDL [903-910].
Multiple human trials report small reductions in blood pressure
with intake of omega-3 fatty acids [911-916]. Reductions of 2-
5mmHg have been observed and effects appear to be dose respon-
sive (higher doses have greater effects) [912]. DHA may have
greater effects than EPA [917]. Caution is warranted in patients
with low blood pressure.
Interactions
Anticoagulants/antiplatelets: Diets containing salmon oil,
mackerel, or cod liver oil have been reported to significantly pro-
long bleeding times in healthy volunteers [905,918-921]. However,
in other studies, no effects of 3-omega fatty acid supplementation
have been observed [922,923]. Increased bleeding time is suggested
to be due to either less thromboxane (TXA2) or higher prostacyclin
I3 levels. It is unclear if omega-3 fatty acids affect coagulation.
Anecdotal evidence suggests that fish oil may increase INR [924].
However, clinical evidence suggests that fish oil does not affect
coagulation, even when taken with anticoagulant therapy [925,926].
Nevertheless, caution is warranted when omega-3 fatty acids (from
plant or fish) are taken with anticoagulant agents.
Ulbricht et al.
Papaya (Carica papaya), Papain
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Patients with known allergies/hypersensitivities to papain, pa-
paya (Carica papaya), or other plants or foods that may contain
papain [927] should avoid its use. Allergic sensitivity to papain may
cause symptoms ranging from an itchy palate to abdominal cramps,
diarrhea, and diaphoresis [928]. Other adverse effects of papain
include gastric ulcer, esophageal perforation, and hypernatremia
[929].
Interactions
Anticoagulants/antiplatelets: An interaction between papain
warfarin has been proposed [930]. In one case report, a woman
taking coumadin and Wobenzym® (containing pancreatin, bro-
melain, papain, lipase, amylase, trypsin, alpha chymotrypsin, and
rutin) experienced coumadin overdose; this may have been due to
coumadin contamination of the Wobenzym® [931].
Peony (Paeonia lactiflora, Paeonia officinalis, Paeonia suffruti-
cosa)
Pharmacokinetics
The pharmacokinetics of peony is not well understood. Paeoni-
florin (a bioactive monoterpene glucoside from peony root) is not
well absorbed. However its aglycone (nonsugar component of the
glycoside), paeoniflorgenin, is absorbed and circulated in the
bloodstream.
Adverse Effects
Based on traditional use and available research, it appears that
peony is well tolerated as part of Chinese herbal formulas when
used for up to three months [932-939]. Based on secondary sources,
peony may cause nausea and vomiting.
Interactions
Anticoagulants/antiplatelets: Theoretically, concomitant use
of peony with anticoagulants/antiplatelets may increase the risk of
bleeding. This is suggested by a case of easy gum bleeding, epis-
taxis, and skin bruising with an international normalized ratio (INR)
>6.0 in a 61 year-old man who was previously stable on warfarin
therapy [940].
Corticosteroids: Based on clinical evidence, a combination
product including peony may decrease the need for glucocorticoid
medication in some patients with nephritis [933].
Estrogenic agents: A combination product containing peony
has been shown to significantly increase estradiol (E2) levels in
postmenopausal women [936].
Policosanol
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Policosanol appears to be safe and well tolerated, even in popu-
lations with high use of concomitant agents [941]. No drug-related
clinical or biochemical adverse effects were observed in a number
of clinical trials [942-952]. Frequency of mild, moderate and seri-
ous adverse events, and mortality has been shown to be lower in
diabetic and non-diabetic individuals taking policosanol compared
with placebo [942,953,954].
Interactions
Anticoagulants/antiplatelets: Policosanol has been shown to
inhibit platelet aggregation in vitro [955,956]. Theoretically, con-
comitant use of policosanol with anticoagulants/antiplatelets may
increase the risk of bleeding. However, the addition of policosanol
Clinical Evidence of Herb-Drug Interactions
to warfarin therapy did not enhance the prolongation of the bleed-
ing time induced by warfarin alone in humans [957].
Levodopa: Increased dyskinesia has been reported in Parkin-
son’s disease patients taking octacosanol with levodopa [958]. Cau-
tion is advised when taking policosanol with levodopa and other
dopaminergic agents.
PSK (Coriolus versicolor)
Pharmacokinetics
According to research conducted in animals, radiolabeled PSK
is absorbed within 24 hours following oral administration [959]. It
is partially decomposed in the digestive tract. PSK or its metabo-
lites were detected in the digestive tract, bone marrow, salivary
glands, brain, liver, spleen, pancreas, and tumor tissue in sarcoma-
bearing mice [959]. Approximately 70% of radiolabeled PSK is
excreted in expired air, 20% in feces, 10% in urine, and 0.8% in
bile [959].
Adverse Effects
PSK generally seems to have a low incidence of mild and toler-
able side effects. Cases of liver impairment and toxicity have been
noted with PSK use. Gastrointestinal upset, darkening of the finger-
nails, and coughing have been reported with extended use of PSK
and with powdered supplemental forms.
Low blood cell counts like leukopenia, thrombocytopenia, and
albuminuria (protein in the urine) were observed in two clinical
trials. It should be noted that patients also received chemotherapy in
addition to PSK in these trials, which may have contributed to the
low blood cell counts. However, leukemia has also been associated
with PSK use.
PSK should also be used cautiously in patients with coronary
artery disease due to antiangiogenic properties (inhibition of new
blood vessel growth) in the heart.
Interactions
Chemotherapy: Numerous animal and human studies have
suggested that PSK may survival time in patients with lung cancer,
gastric cancer, stomach cancer, colon cancer, or leukemia when
used in conjunction with chemotherapy [960-968]. Clinical studies
have used PSK as an adjuvant with mitomycin C [969], tegafur
[969-972], 5-fluoruracil [970-973] and cisplatin [974]. An antiangi-
ogenic effect, in which inhibition of blood vessel growth theoreti-
cally slows tumor growth, has also been proposed.
Psyllium (Plantago ovata, Plantago isphagula)
Pharmacokinetics
Psyllium remains predominantly in the gut as a "bulk" agent. It
is somewhat resistant to fermentation, and is passed largely un-
changed through the gastrointestinal tract [975,976]. It has signifi-
cant "water-holding" capacity due to its high hemicellulose content
[977]. Onset of action is 12-24 hours; full effect may take 2-3 days
[978].
Adverse Effects
Psyllium-containing laxatives, cereal, or other products are well
tolerated and generally safe [979-985] with the important excep-
tions of individuals with repeated psyllium exposure, known hyper-
sensitivity, pre-existing bowel abnormalities or when psyllium
products are mixed with inadequate amounts of water [986-995].
Anaphylaxis, wheezing or difficulty breathing, skin rash, and
hives have been reported in patients who took psyllium or were
exposed to psyllium laxatives in the workplace [987,990,996].
Cross-sensitivity may occur in people with allergy to English plan-
tain pollen (Plantago lanceolata), grass pollen, or melon [997].
Gastrointestinal side effects are generally mild and have not
prompted discontinuation in clinical trials. Flatulence, bloating,
diarrhea, indigestion, loose stool, abdominal pain, dyspepsia, and
Current Drug Metabolism, 2008, Vol. 9, No. 10 1081
constipation have been reported [998-1003]. Fecal obstruction of
the gastrointestinal tract has been noted in many case reports of
patients taking psyllium-containing laxatives, and esophageal im-
paction and bezoars (indigestible mass) have also been reported
following the ingestion of psyllium products [988,1004-1007].
Interactions
Anticoagulants/antiplatelets: Theoretically, psyllium may
reduce the absorption of anticoagulant and anti-platelet agents.
However no effect on warfarin levels by co-administered psyllium
was found in one study [1008].
Antidepressant agents: Dietary fiber has been shown to lower
the blood levels and effectiveness of tricyclic antidepressant agents
in three patients [1009]. Reduced dietary fiber intake increased the
blood levels and improved symptoms in these patients.
Cholestyramine (Questran®): The psyllium plus cho-
lestyramine provided a modest but non-significant reduction in TC
(total cholesterol) and LDL in human subjects. This combination
significantly reduced constipation, abdominal discomfort, and
heartburn than the group that continued on cholestyramine alone
[1010]. In a different study, no statistically significant lipid reduc-
tion was found after the use of colestipol and psyllium [1011]. One
animal study showed a greater LDL reduction with high-dose cho-
lestyramine compared to a lower dose of that agent plus psyllium.
However, the study also found that the combination reversed cho-
lestyramine-induced LDL receptor suppression and reduced hepatic
cholesterol content [1012].
Carbamazepine: Psyllium can decrease the absorption and
concentration of carbamazepine [1013]. If patients are treated with
carbamazepine and psyllium, their administration times should be
separated as far as possible and plasma levels of carbamazepine
should be monitored.
Digoxin: There are mixed results regarding the effects of psyl-
lium on digoxin levels. Limited study suggests that psyllium may
lower digoxin levels [1014]. However, another study found no ef-
fect [1015].
Lithium: Psyllium can decrease the plasma levels and effec-
tiveness of lithium [1016,1017]. Psyllium should be separated from
lithium by at least two hours to reduce the likelihood of this interac-
tion. Lithium levels increased to therapeutic levels after stopping
psyllium [1017].
Orlistat (Xenical®, AlliTM): One study of psyllium co-
administered with orlistat vs. orlistat alone found dramatically
fewer gastrointestinal events, such as diarrhea and oily discharge, in
the combination therapy group [1018].
Pycnogenol® (Pinus pinaster spp. atlantica)
Pharmacokinetics
Pycnogenol® is rapidly absorbed after oral ingestion [1019].
Steady-state conditions have been reached after five days’ ingestion
of the pine bark extract [1019]. Pycnogenol® metabolites include
catechin, caffeic acid, ferulic acid, taxifolin and the metabolite, M1
(delta-(3,4-dihydroxy-phenyl)-gamma-valerolactone) [1019].
Pycnogenol® is excreted in the urine. Ferulic acid and taxifolin
were excreted within 18 hours, with the peak urinary excretion
occurring within two to three hours. Recovery of ferulic acid in
urine was 36-43% and recovery of taxifolin was 7-8% [1020].
Adverse Effects
Pycnogenol® is generally reported as being well tolerated. Low
acute and chronic toxicity with mild unwanted effects may occur in
a small percentage of patients following oral administration. Be-
cause of its astringent taste and occasional minor stomach discom-
fort, it may be best to take Pycnogenol® with or after meals. To
date, reports of serious adverse effects are lacking, although sys-
tematic study of its safety is not available. Possible side effects
include mild and transient gastrointestinal complaints [1021], de-
1082 Current Drug Metabolism, 2008, Vol. 9, No. 10
creased blood glucose levels [1022], vertigo, headache, and nausea
[1021].
Interactions
Anticoagulants/antiplatelets: Pycnogenol® should be used
cautiously with anticoagulants because of its potential to decrease
coagulation [1023]. Based on clinical research, Pycnogenol® sup-
plementation may significantly decrease serum thromboxane con-
centration [1024]. In vitro, Pycnogenol® was shown to improve the
efficacy of acetylsalicylic acid (aspirin) in platelet inhibition
[1023].
Quercetin
Pharmacokinetics
Quercetin is hydrolyzed in the small intestine and absorbed as
aglycone. Absorbed quercetin is conjugated in the liver and se-
creted in bile into the intestinal lumen [1025]. Quercetin does not
appear to be well absorbed by the gut; quercetin chalcone (a modi-
fied version of quercetin) appears be better absorbed [1026]. Phar-
macokinetic studies with dietary quercetin glycosides showed
marked differences in absorption rate and bioavailability. Flavon-
oids present in foods may be considered non-absorbable because
they are bound to sugars as beta-glycosides. Only free flavonoids
without a sugar molecule, the so-called aglycones, were thought to
be able to pass through the gut wall. Quercetin glucoside is actively
absorbed from the small intestine, whereas quercetin rutinoside is
absorbed from the colon after deglycosylation [1027]. In plasma,
quercetin is extensively protein bound [1028-1030]. Carbon dioxide
is the major metabolite of quercetin in humans [1031], and it is
eliminated in the urine [1032]. Plasma and urine levels reflect short-
term intake [1033].
Adverse Effects
Quercetin is a common food component, and is found in vari-
ous fruits, vegetables, and wine. It is generally safe and well toler-
ated at usual dietary intake. However, quercetin supplementation
has been associated with headache, gastrointestinal effects, hema-
toma, and nephrotoxicity. Concern had been expressed about the
possible tumorigenic effect of quercetin; however, it is not currently
classified as a carcinogen [1034,1035].
Interactions
Nifedipine (Adalat®, Procardia®): Food rich in flavonoids,
including quercetin, have been found to delay the first pass metabo-
lism of nifedipine in humans [1036]; however, this effect has not
been specifically attributed to quercetin.
Red Yeast Rice (Monascus purpureus)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Note: Red yeast rice is the product of yeast grown on rice, and
is a dietary staple in some Asian countries. It contains several com-
pounds collectively known as monacolins, substances known to
inhibit cholesterol synthesis. One of these, "monacolin K," is a
potent inhibitor of HMG-CoA reductase (HMG-CoA reductase is
the liver enzyme responsible for producing cholesterol is regulated
and the target of pharmaceutical intervention). This active ingredi-
ent is also known as the prescription drug lovastatin (Mevacor®),
approved for marketing in the United States for high cholesterol. Of
note, lovastatin can cause severe muscle, kidney, and liver damage.
In 2007, the FDA issued a warning to consumers to avoid red yeast
rice products promoted on the Internet since these products were
found to contain lovastatin. Although red yeast rice is still available
in the United States, it is fermented using a different process and
the active ingredient has been removed. Its ability to lower choles-
terol is now questionable.
Ulbricht et al.
There are limited data available on adverse events associated
with red yeast rice. Controlled trials report mild headache and gas-
trointestinal discomfort. In general, adverse effects, contraindica-
tions, and interactions for red yeast rice may be extrapolated from
controlled trials with low-dose "statin" agents. There are several
case reports in which patients using red yeast rice developed mus-
cular dysfunction (myopathy) and muscle breakdown (rhabdomy-
olysis) [1037-1039], which have been described in numerous case
reports of individuals taking statin agents [1040]. Though the fre-
quency of adverse effects appears to be low with moderate con-
sumption of red yeast rice, there is a lack of standardization or data
regarding the long-term safety of products containing red yeast rice.
Red yeast rice should not be used in people with liver problems or
in heavy alcohol users. Serious drug interactions have been reported
[1040].
Interactions
Note: Due to the the limited safety information for red yeast
rice, many of these interactions are based on known interactions for
statins. Whether these interactions are applicable to red yeast rice
preparations will depend on the levels of monacolin K present.
Antibiotics: Certain antibiotics, in particular the macrolide
antibiotics are known to increase the risk of muscle breakdown
(rhabdomyolysis) when taken with statins. A 2002 FDA report cited
42 cases (of 601 total cases of statin-associated rhabdomyolysis in a
29-month period) that also involved macrolide antibiotics [1040].
Some examples of macrolide antibiotics are azithromycin (Zithro-
max®, clarithromycin (Biaxin®), dirithromycin (Dynabac®),
erythromycin, roxithromycin (Rulid®). Because of the various
types of statins and antibiotics involved in these cases, as well as
the variable levels of statins in red yeast rice, this data should be
interpreted carefully. Nonetheless, caution is warranted when taking
red yeast rice and antibiotics concomitantly.
Anticoagulants/antiplatelets: The 2002 FDA report on statin-
associated rhabdomyolysis cited 33 cases (of 601 total cases in a
29-month period) that also involved warfarin [1040]. Because of
the various types of statins involved in these cases, the various
types of anticoagulants, and the variable levels of statins in red
yeast rice, this data should be interpreted carefully. Nonetheless,
caution is warranted when taking red yeast rice and anticoagulants
or antiplatelets concomitantly.
Azole antifungal agents: The 2002 FDA report on statin-
associated rhabdomyolysis noted 12 cases (of 601 total cases in a
29-month period) that also involved azole antifungals [1040]. There
are numerous types of azole antifungals, all with the suffix –azole –
such as clotrimazole (Lotrimin®). Because of the various types of
azoles and statins, as well as the variable levels of statins in red
yeast rice, this data should be interpreted carefully. Nonetheless,
caution is warranted when taking red yeast rice and antifungal
medicines concomitantly.
Cyclosporine: The 2002 FDA report on statin-associated rhab-
domyolysis noted 51 cases (of 601 total cases cases in a 29-month
period) that also involved the immunosuppressant cyclosporine
[1040]. Because of the various types of statins used in these cases,
as well as the variable levels of statins in red yeast rice, this data
should be interpreted carefully. Nonetheless, caution is warranted
when taking red yeast rice and cyclosporine concomitantly.
Cytochrome P450 substrates: Lovastatin is a substrate of cy-
tochrome P450 3A4 that is found in red yeast rice. Decreased lovas-
tatin metabolism from cytochrome P450 3A4 inhibition may in-
crease the risk of myopathy and rhabdomyolysis.
Digoxin: The 2002 FDA report on statin-associated rhabdomy-
olysis noted 26 cases (of 601 total cases cases in a 29-month pe-
riod) that also involved the cardiac glycoside digoxin [1040], which
is commonly used to treat heart conditions. Because of the various
types of statins used in these cases, as well as the variable levels of
statins in red yeast rice, this data should be interpreted carefully.
Clinical Evidence of Herb-Drug Interactions
Nonetheless, caution is warranted when taking red yeast rice and
cardiac glycosides concomitantly.
Fibric acid derivates (fibrates): The 2002 FDA report on
statin-associated rhabdomyolysis noted 80 cases (of 601 total cases
cases in a 29-month period) that also involved fibrates [1040]. Fi-
brates are carboxylic acids that are commonly used in conjunction
with statins to treat hyperlipidemia; there are various types, includ-
ing benzafibrate (Benzalip®), ciprofibrate (Modalim®), and fenofi-
brate (TriCor®). Because of the various types of fibrates and stat-
ins, as well as the variable levels of statins in red yeast rice, this
data should be interpreted carefully. Nonetheless, caution is war-
ranted when taking red yeast rice and fibrates concomitantly.
HMG CoA reductase inhibitors: Taking red yeast rice with
other HMG-CoA reductase inhibitors may increase the risk of ad-
verse effects [1041-1043].
Mibrefradil (Posicor®): The 2002 FDA report on statin-
associated rhabdomyolysis cited 99 cases (of 601 total cases cases
in a 29-month period) that involved mibefradil [1040]. Mibefradil is
a calcium channel blocker, which was used to treat hypertension
and angina prior to its withdrawal from the market due to serious
side effects [1044]. Though this drug is no longer available, caution
is warranted when taking red yeast rice and calcium channel block-
ers concomitantly.
Protease inhibitors: Many commonly used protease inhibitors
are metabolized by CYP3A, which also metabolizes many statins
(including lovastatin, simvastatin, atorvastatin and cerivastatin).
Due to the known interactions between protease inhibtors, use of
lovastatin is generally contraindicated in patients taking protease
inhibitors [1045].
Levothyroxine: Two case reports have described interactions
between simvastatin and levothyroxine (L-thyroxine) [1046,1047].
It was postulated that the excess formation of CYP3A4 in the liver
by simvastatin accerlerated the metabolic breakdown of levothyrox-
ine. Similar interactions are possible with lovastatin derived from
red yeast rice.
Rhodiola (Rhodiola rosea)
Pharmacokinetics
The pharmacokinetics of Rhodiola is not well understood. P-
tyrosol, a constituent of Rhodiola, appears to be dose-dependently
excreted in urine [1048].
Adverse Effects
In clinical research, reports of side effects from Rhodiola rosea
(SHR-5) are currently lacking in the available literature
[1049,1050]. Unsubstantiated reports suggest that Rhodiola rosea
might increase blood pressure, heart rate, and heart palpitations, as
well as cause restlessness, irritability, and insomnia.
Interactions
Antibiotics: There is clinical evidence from a Phase III study
that ADAPT-232 (a combination product containing Rhodiola ro-
sea, Schisandra chinensis, and Eleutherococcus senticosus) may
have additive effects with standard antibiotic therapy for pneumo-
nia (cephazoline, with bromhexine and theophylline) [1051].
Rhubarb (Rheum officinale, Rheum palmatum)
Pharmacokinetics
The pharmacokinetics of rhubarb is not well understood. An-
thraquinone glycosides in rhubarb are hydrolyzed in the gut to
aglycones, which are reduced by bacteria to anthranols and an-
thrones (the active compounds) [1052].
Adverse Effects
Chronic use of rhubarb may cause electrolyte loss (especially
potassium), hyperaldosteronism, edema, inhibition of gastric motil-
ity, pseudomelanosis coli, intestinal griping, colic, atonic colon
Current Drug Metabolism, 2008, Vol. 9, No. 10 1083
[1053-1060], nephropathies, albuminuria, hematuria, bone deterio-
ration and muscular weakness, arrhythmias, and cardiac toxicity
(especially if cardiac glycosides, diuretics, or corticosteroids are
used concomitantly) [1061-1064].
Short-term use of raw rhubarb may cause gastrointestinal com-
plaints, including abdominal pain, diarrhea, nausea, and vomiting
[1054,1055,1065]. Handling rhubarb leaves may cause contact
dermatitis [1065].
Oxalic acid in rhubarb may form insoluble calcium oxalate
crystals in the blood that may be deposited in the kidneys, and lead
to renal stones. Bright yellow or red discolored urine may occur
with rhubarb ingestion. Hyperkalemia has been reported in one case
of a person taking rhubarb (amount unspecified) [1066]. Abuse of
rhubarb may cause dependence with possible need for increased
doses.
Interactions
Captopril: Rhubarb root contains tannins that have been shown
in vitro to inhibit angiotensin converting enzyme (ACE) [1067]. In
clinical trials, rhubarb has shown a synergistic effect with captopril,
an ACE inhibitor, to reduce serum creatinine levels [1066,1068-
1071]. Hyperkalemia, corrected with furosemide, occurred in one
case of a person taking rhubarb and captopril [1066].
Antipsychotic agents: Rhubarb reduced the need for higher
doses of antipsychotic agents in schizophrenic patients [1072].
Chlorhexidine: In a clinical trial, rhubarb reduced gingivitis
when used with chlorhexidine [1073].
Nifedipine (Procardia®): In a clinical trial, rhubarb enhanced
the effects of the calcium channel blocker nifedipine [1074].
Rose hip (Rosa spp.)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Based on historical use and available research it appears that
rose hip preparations are well-tolerated in recommended doses for
up to three months [1075-1077]. It has been proposed that some
adverse effects are related to the amount of vitamin C present in
rose hips. However, individuals who work in rose cultivation or
manufacturing of rose products are susceptible to developing IgE-
mediated hypersensitivity to rose [1078-1081].
Interactions
Note: Secondary sources report several interactions between
vitamin C and agents, including aspirin, estrogens, fluphenazine,
salicylates, and warfarin. It is not clear how much vitamin C re-
mains in dried and stored rose hips, or whether the remaining vita-
min C may cause similar interactions.
Estrogenic agents: There has been a documented interaction
between ethinyloestradiol with vitamin C in humans [1082]; thus,
similar interactions are likely with rose hips.
Salicylates: Administration of 900mg of aspirin was found to
block gastrointestinal absorption of a single oral dose of 500mg
vitamin C in humans [1083]. Concomitant use of rose hips and
salicylates may increase urinary excretion of ascorbic acid and de-
crease the excretion of salicylates.
Rutin (C27H30O16)
Pharmacokinetics
Absorption of an oral dose of hydroxyethylrutosides was less
than 10% [1084]. Rutosides are distributed in the blood, lungs,
spleen, and muscles [1085]. Rutosides are metabolized by intestinal
flora [1084,1085] and liver [1084,1085], and are primarily elimi-
nated in the bile [1085]. A small amount is excreted in the urine
[1085].
1084 Current Drug Metabolism, 2008, Vol. 9, No. 10
Adverse Effects
Rutins, oxerutins and troxerutins have been used effectively and
safely in several clinical and equivalence trials. Numerous reports
have reported no adverse side effects with rutin treatment [1086-
1103]. Gastrointestinal disturbances, including diarrhea, dry mouth,
constipation, and vomiting have been reported [1104-1110].
Interactions
Anticoagulants/antiplatelets: Rutin is often used in combina-
tion with warfarin (Coumadin®) [1111-1113]. Clinical studies have
confirmed the anti-erythrocyte aggregation effect of troxerutin
[1114], a constituent of rutin, and suggest a favorable effect on
blood fibrinolytic activity [1115].
Docetaxel: Rutin (300mg hydroxyethylrutoside) has been given
to breast cancer patients to counteract docetaxel-fluid retention
[1116].
Safflower (Carthamus tinctorius)
Pharmacokinetics
The pharmacokinetics of safflower is not well understood. It
appears that safflower is metabolized by human intestinal bacteria.
Adverse Effects:
Safflower is a member the daisy family (Asteraceae/ Composi-
tae) and may cause allergic reactions in patients sensitive to daisies.
Other members of this family include ragweed, chrysanthemums,
marigolds, and many other plants. Rarely, safflower may cause
diarrhea, low blood pressure, tachycardia, loss of appetite, nausea,
bad aftertaste, stomach cramps, and a feeling of fullness [1117-
1123].
Interactions
Anticoagulants/antiplatelets: Based on clinical and laboratory
studies, safflower (taken orally) may have anti-platelet aggregation
activity [1124-1128] and may increase the effects of blood thinning
agents. However, there is clinical evidence that safflower infusion
may develop hypercoagulability of blood [1125]. Small does of
heparin added to large doses of Liposyn® 10% (an emulsion of
safflower oil) in total parenteral nutrition reversed hypercoagulation
caused by safflower oil [1125].
Lithium: Based on a case series, safflower oil may reverse the
symptoms of low-dose lithium neurotoxicity caused by inhibited
synthesis of prostaglandin (PG) EI [1129].
Saw palmetto (Serenoa repens)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Overall, there appear to be few safety concerns with short-term
use of saw palmetto, although large-scale and longer-term safety
studies are lacking [1130]. Saw palmetto appears to be well toler-
ated by most patients for up to 3-5 years. The most common com-
plaints are gastrointestinal, and include abdominal discomfort or
pain, nausea, vomiting, and diarrhea (anecdotally, lipidosterolic
extract of Serenoa repens [LSESR] may be a better-tolerated for-
mulation) [1131-1135]. Taking saw palmetto extract with food may
decrease these gastrointestinal side effects. There have been case
reports of clinically significant bleeding associated with saw pal-
metto products [1136,1137]. Erectile dysfunction and decreased
libido have also been reported [1132].
Interactions
Anticoagulants/antiplatelets: Based on case studies of severe
hemorrhage [1136,1137], saw palmetto should be used cautiously
with other agents that increase the risk of bleeding. However, clini-
cal reports of drug interactions are lacking.
Ulbricht et al.
Antibiotics: Saw palmetto, used in combitation with antibiotics
(ciprofloxacin/azithromycin), have been demonstrated to be clini-
cally effective in treating chronic bacterial prostatitis [1138].
Scotch broom (Cytisus scoparius)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Scotch broom contains sparteine, and alkaloid with anti-
arrhythmic properties and potential cardiac toxicity (reported as
similar to class 1A antiarrhythmics such as quinidine). Blood pres-
sure changes and circulatory collapse may occur with large doses
taken in any form, including by mouth or smoked in cigarettes.
There is a possibility of abnormal heart rhythms, heart attack, and
worsening of heart failure. Therefore, use of this herb should only
be under medical supervision, and extreme caution is warranted in
individuals with a history of heart disease, abnormal heart rhythms,
high blood pressure, or those taking heart agents [2].
High doses of scotch broom taken by mouth may cause toxicity
symptoms including dizziness, headache, weakness, fatigue, sleepi-
ness, blurry vision, sweating, and confusion. When smoked in ciga-
rette form, headache, confusion, relaxation, and euphoria may oc-
cur, and driving or operating heavy machinery should be avoided.
Interactions
Haloperidol (Haldol®): Sparteine is metabolized by the liver's
cytochrome P450 2D6 isoenzyme system. Therefore, agents that
inhibit cytochrome P450 2D6 can increase the potential toxicity of
scotch broom. The antipsychotic drug haloperidol has been shown
to substantially increase the levels of sparteine in the blood [1139].
Shiitake mushroom (Letinula edodes)
Pharmacokinetics
Insufficient available evidence.
Adverse Effects
Overall, side effects associated with shiitake are rare, and are
thought to be caused by lentinan. Side effects attributed to shiitake
include dermatologic effects (shiitake dermatitis or contact dermati-
tis) [1140-1146], fever and chills [1147-1151], hematological
changes [1152], and abdominal discomfort [1152].
Interactions
Antineoplastic agents: In clinical trials, lentinan has been
demonstrated to interact with cancer therapies TS-1 (tegafur-
gimeracil-oteracil potassium) [1148], tegafur [1153], tegafur and
cisplatin [1154], 5-fluorouracil (5-FU) [1155,1156], levamisole
[1157], uracil, mitomycin C, and other chemotherapeutic agents
[1158-1178]. It has also shown benefit in terms of survival rates in
cancer patients [1148,1179-1184]. Based on in vitro research, lentin
may inhibit proliferation of leukemia cells [1185]. Shiitake has
been proposed as an adjunct to standard antineoplastic therapy.
Didanosine (2’3’ ddI, Videx®): Concomitant use of the
antiretroviral drug didanosine (ddI, Videx®) with lentinan was
shown to augment drug-induced increases in CD4+ levels in HIV
positive patients [1186].
Sorrel (Rumex acetosa, Rumex acetosella)
Pharmacokinetics
There is limited reliable information on the pharmacokinetics of
sorrel. Approximately 2-5% of ingested oxalates are absorbed in
healthy human volunteers [1187]. Oral oxalates administered to
animals are excreted unchanged in the urine within 24-36 hours
after ingestion [1187].
Clinical Evidence of Herb-Drug Interactions
Adverse Effects
There is limited scientific evidence regarding the use of sorrel
alone. It is likely safe when used in very small amounts in foods.
However, toxicity may occur when taken in larger amounts, and
may include damage to the kidneys, liver, and the gastrointestinal
tract. These outcomes are likely related to oxalate (oxalic acid)
content in sorrel. Sorrel leaves contain 0.3% oxalate [1187]. There
is a case-report a 53-year-old man who died after ingestion of 500
grams of sorrel in soup (equivalent to approximately 6-8 grams of
oxalic acid) [1188]. The mean lethal dose of oxalic acid for adults is
estimated to be 15-30 grams, although doses as low as 5 grams have
been shown to be fatal [1187,1188]. Sorrel is possibly unsafe in
children due to its oxalic acid content (ingestion of rhubarb leaves,
another source of oxalic acid, is reported to have caused death in a
four-year-old child) [1187]. The combination formula Sinupret® is
anecdotally said to be well tolerated, and includes sorrel in combi-
nation with gentian root, European elderflower, verbena, and cow-
slip flower (infrequent gastrointestinal upset has been reported).
Interactions
Antibiotics: Concurrent use of doxycycline with Quanterra®
Sinus Defense or Sinupret® was reported in a human trial to syner-
gistically improve outcomes in patients with acute bacterial sinusi-
tis [1189]. There is limited additional evidence supporting this
observation.
Soy (Glycine max)
Pharmacokinetics
Upon ingestion, soy isoflavones are metabolized by intestinal
bacteria, absorbed from the intestinal tract, transported by the portal
vein, and then metabolically processed by the liver. About 10-22%
of soy isoflavones are excreted in urine [1190,1191]. The half-life
of soy isoflavones, daidzein and genistein, is approximately 7-8 hr.
[1192].
Adverse Effects
Soy is generally regarded as safe. The most frequent adverse
effects related to soy are allergic reactions and stomach and intesti-
nal difficulties such as bloating, nausea, and constipation. Soy al-
lergy is a common food allergy. People with soy allergy may also
cross react to certain foods including peanuts, legumes, wheat, rye,
and barley. The use of soy is often discouraged in patients with
hormone-sensitive malignancies such as breast, ovarian, or uterine
cancer, due to concerns about possible estrogen-like effects (which
theoretically may stimulate tumor growth). Other hormone-
sensitive conditions such as endometriosis may also theoretically be
worsened. In laboratory studies, it is not clear if isoflavones stimu-
late or block the effects of estrogen, or both (acting as a "receptor
agonist/antagonist"). Until additional research is available, patients
with these conditions should be cautious and speak with a qualified
healthcare practitioner before starting use [2].
Interactions
Estrogenic agents: Despite a large body of research on soy
phytoestrogens, it is not clear if isoflavones stimulate or block the
effects of estrogen or do both (acting as a "receptor ago-
nist/antagonist"). It is not known if taking soy or soy isoflavone
supplements increase or decrease the risk of adverse effects of es-
trogen on the body, such as the risk of blood clots [2].
St. John’s wort (Hypericum perforatum)
Pharmacokinetics
In 18 healthy male volunteers who received 612mg of dry ex-
tract of St. John's wort (STW-3, Laif 600), either as a single oral
dose or as a multiple once daily dose over a period of 14 days, con-
centration/time curves were determined for hypericin, pseudo-
hypericin, hyperforin, the flavonoid aglycone quercetin, and its
Current Drug Metabolism, 2008, Vol. 9, No. 10 1085
methylated form isorhamnetin for 48 hours after single dosing and
for 24 hours on day 14 at the end of the two weeks of continuous
daily dosing regimen. After single dose intake, results were as fol-
lows for hypericin: area under the curve (AUC(0-infinity)) = 75.96
hours x ng/mL, maximum plasma concentration (Cmax) =
3.14ng/mL, time to reach Cmax (tmax) = 8.1 hours, and elimination
half-life (t1/2) = 23.76 hours; pseudohypericin: AUC(0-infinity) =
93.03 hours x ng/mL, Cmax = 8.50ng/mL, tmax = 3.0 h, t1/2 = 25.39
hours; hyperforin: AUC(0-max) = 1009.0 hours x ng/mL, C max =
83.5ng/mL, tmax = 4.4 hours, t1/2 = 19.64 hours. Under steady state
conditions achieved through administration of the multiple dose
regimen, similar results were obtained [1193].
St. John's wort may have multiple effects on various enzymes
(inhibition and induction) of the liver cytochrome P450 system
[1194]. Human studies have reported that St. John’s wort is able to
induce CYP450 3A4 [1195-1199]. St. John's wort (hyperforin) has
also been shown to activate a regulator (pregnane X receptor) of
3A4 transcription and thereby induce the expression of 3A4 in hu-
man liver cells [1197]. There are mixed results regarding St. John’s
wort on other CYP450 isoenzymes [1200]. However, St. John’s
wort has been shown to induce 1A2, 2C9, 2D6, 2C19, and 2E1
[1198,1199,1201,1202].
Early work reported in vitro inhibition of monoamine oxidase
(MAO) A and B by hypericin and other components, such as xan-
thon and flavonols of St. John’s wort; however, it is widely agreed
that the magnitude of MAO inhibition was inadequate for its pur-
ported antidepressant activity [1203-1206]. Even at concentrations
up to 10uM, hypericin lacked significant MAO inhibition [1206].
Based on these data and other pharmacokinetic findings [1207], the
MAO inhibition may not be clinically relevant.
Adverse Effects
Multiple reports of headache have been documented with St.
John’s wort use [1208-1215]. Several cases of reversible photosen-
sitivity to St. John's wort have also been reported [1216].
In rare cases, St. John’s wort may cause serotonin syndrome
characterized by rigidity, hyperthermia, delirium, confusion, auto-
nomic instability, and coma. There is a case report of possible sero-
tonin syndrome associated with St. John's wort, manifested by tran-
sient flushing, diaphoresis, hypertension, disorientation, dyspnea,
and tremors in a 40 year-old man. The patient, who had a history of
depression and SSRI-induced mania, was not taking other agents
[1217]. Another report described a 33 year-old woman with mild
anxiety who experienced multiple anxiety episodes with autonomic
arousal (blood pressure maximum 195/110) following three doses
of St. John's wort [1218]. In a telephone survey, a woman reported
nausea, diaphoresis, muscle cramping, weakness and elevated pulse
and blood pressure after a single dose of combination containing St.
John's wort, kava, and valerian [1219].
Anorgasmia, decreased libido, orgasmic delay, and erectile
dysfunction have been some of the sexual side effects reported with
St. John’s wort use [1220-1222]. Inhibition of sperm motility has
been observed in vitro due to St. John's wort [1223]. Frequent uri-
nation has been rarely noted [1220].
Interactions
Anesthetic agents: It has been hypothesized that St. John’s
wort may interact with anesthetic agents [1224]. There is a case
report of cardiovascular collapse during anesthesia reported in a
healthy 23 year-old woman who had been taking St. John’s wort
daily for six months prior to surgery; the patient had undergone
uneventful general anesthesia two years earlier when she was not
taking St. Johns wort [1225].
Anticoagulants/antiplatelets: There have been several cases of
reduced International Normalized Ratio (INR) in patients using
warfarin and St. John’s wort concomitantly [1250]. This was con-
firmed in a trial in which healthy men were given 25mg of warfarin
1086 Current Drug Metabolism, 2008, Vol. 9, No. 10
[1281]. In most cases, the patients had been stabilized on warfarin
for some time prior to ingesting St. John’s wort. None of the pa-
tients in these cases developed thromboembolic events; however,
the decrease in INR was thought to be clinically significant. In-
creases in warfarin dose or discontinuation of St. Johns wort re-
sulted in the INR returning to target values.
Antidepressants: It has been widely suggested that St. John’s
wort may potentiate the effects of selective serotonin reuptake in-
hibitors (SSRIs) and MAO inhibitors, theoretically leading to clini-
cal toxicity such as serotonin syndrome or hypertensive crisis
[1203-1206,1226-1228]. There have been multiple case reports of
interactions between St. John’s wort and SSRIs, including sertraline
[1232] and paroxetine [1229-1231]. However, given the unclear
MAO inhibitory activity of hypericin [1203-1207,1226], the inter-
action with other MAOIs may not be clinically significant. None-
theless, caution is warranted with concomitant use. Possible interac-
tions between St. John’s wort and the serotonergic antidepressant
nefazodone have been noted [1232], as well as interactions with
tricyclic antidepressants; two 14-day studies of depressed patients
found a significant reduction in amitriptyline concentration with
concurrent ingestion of St. John's wort [1233,1234]. A number of
CYP enzymes including 1A2, 2C19, 3A4, and 2D6 are involved in
the metabolism of tricyclic antidepressants [1235]. In a recent
cross-sectional, point-of-care survey of 1818 patients, eight cases
were identified as potential clinically significant interactions be-
tween St. John’s wort and antidepressants [10].
Benzodiazepines: St. John’s wort has been reported to induce
the metabolism of benzodiaziepine agents. In humans, St. John’s
wort has been reported to reduce midazolam concentrations, pre-
sumed to be due to CYP 3A4 induction [1195,1196,1236,1237].
Verapamil (Isoptin®): Repeated administration of St John’s
wort was shown to significantly decrease the bioavailability of R-
and S-verapamil in humans; this was attributed to induction of first-
pass CYP3A4 metabolism, most likely in the gut [1238].
Digoxin: In humans, Hypericum extract was demonstrated to
decrease of digoxin levels by 25% [1239,1240]; this effect was
likely due to induction of the P-glycoprotein drug transporter
[1234,1239-1244]. Bigemeny was reported in an 80 year-old man
taking both digoxin and St. John's wort [1245]. The interaction of
St John's wort and digoxin varies within St John's wort preparations
seems to be dependent on the dose hyperforin [1246,1247].
Estrogenic agents: St John's wort causes an induction of
ethinyl estradiol-norethindrone metabolism, consistent with in-
creased CYP3A activity [1248]. In 16 healthy women treated with a
low-dose OC (Loestrin 1/20), treatment with St John's wort (300mg
three times daily) resulted in increased metabolism of norethin-
drone and ethinyl estradiol, breakthrough bleeding, follicle growth
and ovulation [1249]. There are multiple reports of reduced serum
levels/half-life of oral contraceptives in association with St. John's
wort use; alterations in hormone levels, and altered menstrual
bleeding (including breakthrough bleeding) [1248,1250-1254]. It
was suggested that bleeding irregularities may adversely effect
compliance to oral contraceptives; furthermore, together with St
John's wort-induced decreases in serum 3-ketodesogestrel concen-
trations, concomitant use may enhance the risk of unintended preg-
nancies [1252]. In early 2002, warnings emerged following several
reports, in Sweden and the UK, of unwanted pregnancies in women
taking oral contraceptives and St. John's wort. In a recent cross-
sectional, point-of-care survey of 1818 patients, one case was iden-
tified as a potential clinically significant interaction between St.
John’s wort and oral contraceptives [10].
Cyclosporine: There are numerous clinical reports of signifi-
cant reductions in cyclosporine drug levels and possible organ re-
jections with concomitant use of St. John’s wort [1236,1255-1266].
The mechanism for this interaction is likely due to induction of
Ulbricht et al.
cytochrome P450 3A4 and induction of intestinal P-glycoprotein
drug transporter.
Cytochrome P450 substrates: Concurrent use of agents
metabolized via the CYP450 liver enzyme system may result in
altered therapeutic levels of pharmacologic agents, due to induction
or inhibition of enzymes by St. John’s wort [1267]. Human studies
have reported St. John’s wort to induce CYP450 3A4 [1194-1197].
St. John’s wort (hyperforin) has been shown to activate a regulator
(pregnane X receptor) of 3A4 transcription and thereby induce ex-
pression of 3A4 in human liver cells [1197]. There are mixed re-
sults regarding St. John’s wort on other CYP450 isoenzymes
[1200]. However, St. John’s wort has been shown to induce 1A2,
2C9, 2D6, 2C19, and 2E1 [1203-1206]. Agents such as che-
motherapeutic agents (irinotecan, etoposide, vinblastine, vincristine,
vindesine), protease inhibitors (ritonavir, amprenavir), antifungals
(ketoconazole, itraconazole), and many others should be avoided
with St. John’s wort.
HMG-CoA reductase inhibitors: In healthy subjects, St.
John’s wort was shown to reduce the serum concentrations for sim-
vastatin (but not pravastatin), likely due to the induction of cyto-
chrome P450 3A4 by St. John’s wort and induction of P-
glycoprotein [1268].
Imatinib (Gleevec®): St John’s wort has been shown to in-
crease the clearance of the anticancer drug imatinib in humans
[1269,1270], thus possibly reducing its effectiveness. The mecha-
nism for this interaction is likely due to the induction of cytochrome
P450 3A4 metabolism of imatinib by St. John’s wort.
Irinotecan (Camptosar®): St. John’s wort has been shown to
reduce irinotecan effectiveness in humans, leading to treatment
failure [1271,1272]. The mechanism for this interaction is likely
due to induction of cytochrome P450 3A4 by St. John’s wort.
Methadone: Long-term usage of St. John’s wort has been
shown to reduce methadone levels and increase the risk of with-
drawal in humans; this has been attributed to cytochrome P450 3A4
induction by St. John’s wort [1273].
Non-nucleoside reverse transcriptase inhibitors (NNRTIs):
St. John's wort has been shown to decrease plasma concentrations
of the antiretroviral non-nucleoside reverse transcriptase inhibitors
(NNRTIs), possibly due to cytochrome P450 induction. The oral
clearance of the NNRTI nevirapine was significantly increased in
five HIV+ patients treated with nevirapine and concomitant St.
John's wort [1274]. Effects on these medications may also be due to
an induction of the drug pump P-glycoprotein [1202]. The U.S.
Food & Drug Administration (FDA) has issued an advisory dis-
couraging the concomitant use of St. John’s wort and certain
antiretroviral medications.
Opiates: In a recent cross-sectional, point-of-care survey of
1818 patients, one case was identified as a potential clinically sig-
nificant interaction between St. John’s wort and the opiate tramadol
[10].
Protease inhibitors: St. John's wort has been shown to de-
crease plasma concentrations of protease inhibitors (PIs) possibly
due to cytochrome P450 induction. An open-label study demon-
strated a significant reduction in concentrations of the PI indinavir
when taken concurrently with St. John's wort by healthy volunteers
[1275] Effects on these medications may also be due to an induc-
tion of the drug pump P-glycoprotein [1202]. The U.S. Food &
Drug Administration (FDA) has issued an advisory discouraging
the concomitant use of St. John’s wort and certain antiretroviral
medications.
Tacrolimus (Prograf®): There are several reports that St.
John’s wort may decrease the levels of the immununosuppressant
tacrolimus, likely due to induction of cytochrome P450 3A4 and P-
glycoprotein [1276-1278].
Clinical Evidence of Herb-Drug Interactions
Theophylline (Bronkodyl®, Elixophyllin®, Slo-bid®): It has
been suggested that St. John’s wort may affect serum levels of theo-
phylline or its metabolites; however, this remains unclear [1202]. In
one case report, lowered serum theophylline levels occurred with
concomitant St. John's wort (300mg daily); theophylline levels rose
after discontinuation of St. John’s wort [1279]. However, controlled
studies found it unlikely that St. John’s wort is sufficient to cause a
change in plasma theophylline concentrations [1280].
Strawberry (Fragaria spp.)
Pharmacokinetics
Based on human evidence, strawberry anthocyanins are recov-
ered in urine as glucuroconjugates and sulfoconjugates [1282].
Fours hours after strawberry consumption, more than two-thirds of
anthocyanin metabolites were excreted [1282].
Adverse Effects
Other than allergic responses, the literature reports compara-
tively few adverse effects due to strawberries. In sensitive subjects,
strawberry has caused contact urticaria [1283] and pruritic dermato-
ses (eczema and neurodermite) [1284].
Fresh strawberries and cut strawberry salads have been found to
be contaminated with pesticides [1285], fungi [1286], bacteria
[1287,1288], and other microorganisms [1289]. Strawberry jam has
been contaminated by pyrethroid insecticide residues [1290] and
possibly the norovirus, although the norovirus contamination was
most likely due to post-market food handlers [1291]. Part of the
problem may be due to the difficulty of removing contamination
either before or after strawberries go to the market.
Interactions
Salicylates: Based on tests performed in allergic patients, there
may be a connection between acetylsalicylic acid intolerance and
strawberry sensitivity [1292].
Sweet Annie (Artemisia annua)
Pharmacokinetics
In a pharmacokinetic study, artemisinin was absorbed faster
from herbal tea preparations than from oral solid dosage forms, but
bioavailability was similar. One liter of an aqueous preparation of
9g of Artemisia annua contained 94.5mg of artemisinin (active
constituent).
The elimination half-life (t1/2) of Artemisia annua is between 2
and 4 hours [1293,1294]. Its main metabolite, dihydroartemisin,
showed a half-life of approximately 40 minutes [1293].
Adverse Effects
Sweet Annie appears to be generally well-tolerated
[1293,1295]. A related species (Artemisia composita) may have
potential central nervous system and cardiovascular toxicities
[1296].
Interactions
Antimalarial agents: Constituents of sweet Annie (including
artemisin, arteether, artemether, artemotil, artenimol, artesunate,
and dihydroartemisinin) are currently being used to treat drug-
resistant and non-drug resistant malaria [1297-1304]. Because these
antimalarial compounds are found in sweet Annie, nteractions with
antimalarial treatments are likely; however, they have not been
throroughly evaluated.
Turmeric (Curcuma longa) and Curcumin
Pharmacokinetics
Animal research found that the absorption of curcumin after
oral administration varies from 25-60%, with most of the absorbed
flavonoid being metabolized in the intestinal mucosa and liver
[1305]. The remainder is excreted in the feces [1306].
Current Drug Metabolism, 2008, Vol. 9, No. 10 1087
Adverse Effects
The most common side effect with use of turmeric reported in
humans is gastrointestinal upset, including epigastric burning, dys-
pepsia, nausea, and diarrhea [1307,1308]. High doses of turmeric
are thought to be safe based on toxicology studies [1309]. Increased
bleeding risk is a concern with high doses of curcumin [1310-
1313].
Interactions
Anticoagulants/antiplatelets: In a recent cross-sectional,
point-of-care survey of 1818 patients, two cases were identified as
potential clinically significant interactions between turmeric and
anticoagulant/antiplatelet agents [10].
Valerian (Valeriana officinalis)
Pharmacokinetics
Valepotriates are poorly absorbed and subject to a significant
first pass effect when administered orally. Degradation may occur
in the presence of heat or alkaline conditions. Valepotriates and
their metabolites have reportedly been found in the stomach lining,
intestines, blood, liver, kidneys, heart, lungs, and brain. Valerian
appears to be metabolized in the liver [2]. The excretion of valerian
is not known.
Adverse Effects
Short-term mild impairments in vigilance, concentration, and
processing time for complex thoughts, as well as mild fatigue have
been reported in trials (lasting for several hours), although residual
sedative effects appear to be less pronounced than those associated
with benzodiazepines [1314-1317]. Preliminary evidence suggests
that valerian is non-sedating in recommended doses [1314, 1315,
1318]. In one trial, use of a combination product containing vale-
rian and lemon balm (Melissa officinalis) did not impair perform-
ance on psychometric tests that correlate with the ability to drive or
operate machinery [1319]. A drug “hangover” effect has been re-
ported in patients taking high doses of valerian extracts [1320]. A
“valerian withdrawal” effect has been reported with chronic high-
dose use; delirium, ameliorated by benzodiazepines, was reported
in a single patient undergoing withdrawal from high doses of vale-
rian [1321]. Dizziness and headache have been reported in human
studies, although they are rare [1322,1323]. Anecdotally, some
patients may develop a “paradoxical reaction” leading to nervous-
ness or excitability, and use for longer than 2-4 months may result
in insomnia.
It remains unclear if valerian is hepatotoxic. Hepatotoxicity has
been associated with some multi-herb preparations that include
valerian [1324]; however, the contribution of valerian itself cannot
be determined from these reports, due to the potential hepatotoxic-
ity of other ingredients (e.g., skullcap), as well as the possibility of
adulteration with unlisted herbs (such as the known hepatotoxic
herb germander, which is often mistakenly harvested as skullcap).
Valerian is not recommended for use in pregnant and lactating
women due to theoretical concerns over the teratogenic effects of
valepotriates, and theoretical properties as a uterine stimulant, abor-
tifacient, and emmenagogue. Valepotriates and baldrinals have been
shown to be cytotoxic and mutagenic in vitro [1325,1326]. How-
ever, these substances are unstable and generally not found in
commercial valerian products.
Interactions
Beta-adrenergic agents: In a randomized trial, a combination
of 100mg valerian extract and 20mg propranolol was found to im-
pair performance on a written concentration test more than valerian
alone (which was reported to slightly improve performance) [1327].
However, there was no comparison to propranolol alone, so it is not
clear if the effects were due to the beta-blocker only, or to the com-
bination with valerian.
1088 Current Drug Metabolism, 2008, Vol. 9, No. 10
Loperamide (Imodium®): A brief episode of acute delirium
was reported in one patient during concomitant use of loperamide
and valerian [1328]. However, causality could not be established, as
the patient was also taking St. John’s wort. The condition resolved
rapidly with discontinuation of treatment.
Sedatives and CNS depressants: Valerian may theoretically
potentiate the effects of CNS depressant agents, although studies in
patients taking CNS-active agents concurrently with valerian have
not revealed an increased rate of adverse effects [1314,1315,1329].
However, numerous animal studies have demonstrated valerian to
prolong barbiturate-induced sleeping time [1330-1335]. In a recent
cross-sectional, point-of-care survey of 1818 patients, 15 cases
were identified as potential clinically significant interactions be-
tween valerian and sedatives [10].
Serotonergic agents: A patient taking the selective serotonin
reuptake inhibitor (SSRI) fluoxetine (Prozac®) for a mood disorder
(in the setting of alcohol use) reported that approximately 12 hours
after taking valerian tablets, he experienced mental status changes
and lost control of his left arm [1336]. Other reported symptoms
included agitation and obsession which led him to self-inflict cuts
to his hand. After another 12 hours, his symptoms resolved. The
specific role of valerian in this isolated case is not clear.
Yohimbe (Pausinystalia yohimbe)
Pharmacokinetics
Yohimbine, the major alkaloid of the yohimbe plant, seems to
be poorly absorbed following oral administration. Bioavailability is
highly variable (between 7-87%) [1337]. Yohimbine is distributed
in liver, red blood cells, brain, and intestinal wall [1338,1339]. It
appears that yohimbine is eliminated through metabolism since
urinary excretion is minimal [1338]. Yohimbine has an elimination
half-life of less than 1 hour, while an active metabolite, 11-
hydroxy-yohimbine, has a half-life of about 6 hours [1340].
Adverse Effects
Because of the potential for serious side effects and interac-
tions, the FDA has determined yohimbine to be unsafe for over-the-
counter sale. Because yohimbe bark may contain clinically signifi-
cant amounts of yohimbine alkaloid, similar risks may apply. How-
ever, 1995 chemical analysis of 26 commercial yohimbe products
reported that most commercial yohimbe products contain virtually
no yohimbine [1341].
Yohimbine is likely to be safe when taken by adults in recom-
mended oral doses under the direction and supervision of a quali-
fied healthcare professional. In large doses, yohimbine may cause
severe hypotension and cardiac conduction disorders [1342-1351].
Yohimbine should be avoided in pregnancy because it may act as a
uterine relaxant and fetal toxin. It should also be avoided during
lactation and in children (there have been reports of death in chil-
dren).
Interactions
Note: Yohimbe bark extract contains approximately 6% indole
alkaloids, of which 10-15% is yohimbine. A 1995 chemical analysis
of 26 commercial yohimbe products reported that most commercial
yohimbe products contained virtually no yohimbine [1341]. The
pharmacological activity of yohimbine has been well characterized
in studies, although these effects may or may not apply to yohimbe,
depending on the concentration of yohimbine present.
Alpha-adrenergic agents: Yohimbine is an alpha-adrenergic
blocker, and has been reported to antagonize the effects of alpha-
adrenergic agents such as clonidine [1352-1354]. In theory, this
interaction may also apply to yohimbe bark extract, which contains
variable (albeit low) concentrations of yohimbine alkaloid. Con-
comitant use of yohimbe and phenothiazines is contraindicated due
to an increased risk of alpha-2 adrenergic antagonism.
Ulbricht et al.
Beta-adrenergic agents: Beta-blockers may possess a protec-
tive role against yohimbine toxicity.
Monoaminergic agents: Due to MAO inhibitory activity of
yohimbine, concomitant use may produce additive effects. Con-
comitant use of yohimbine and MAO inhibitors is contraindicated
due to an increased risk of hypertensive crisis. In theory, this inter-
action may also apply to yohimbe bark extract, which contains vari-
able (albeit low) concentrations of yohimbine alkaloid.
Opiates: Although yohimbine by itself does not appear to pos-
sess analgesic effects, yohimbine may enhance morphine analgesia,
based on the results of a controlled trial [1355,1356]. In theory, this
interaction may also apply to yohimbe bark extract, which contains
variable (albeit low) concentrations of yohimbine alkaloid. Yo-
himbine may increase or decrease naloxone-precipitated opiate
withdrawal symptoms [1357-1359]. In theory, this interaction may
also apply to yohimbe bark extract, which contains variable (albeit
low) concentrations of yohimbine alkaloid.
Physostigmine: In preliminary clinical research, concomitant
use of yohimbine and physostigmine in patients with Alzheimer's
disease has been associated with anxiety, agitation, restlessness, and
chest pain [1349]. In theory, this interaction may also apply to yo-
himbe bark extract, which contains variable (albeit low) concentra-
tions of yohimbine alkaloid.
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