CLINICAL RESEARCH STUDY

Potential for Interactions Between Dietary Supplements

and Prescription Medications
Amit Sood, MD, MSc,a Richa Sood, MD,a Francis J. Brinker, ND,b Ravneet Mann, MBBS,c Laura L. Loehrer,a
Dietlind L. Wahner-Roedler, MD, MSca
a
Division of General Internal Medicine, Mayo Clinic, Rochester, Minn; bProgram in Integrative Medicine, University of Arizona
College of Medicine, Tucson; cChristian Medical College, Ludhiana, Punjab, India.

ABSTRACT

PURPOSE: The objective of this study was to assess the frequency of clinically significant interactions
caused by concurrent use of dietary supplements and prescription medication.
METHODS: We conducted a cross-sectional, point-of-care survey and combined the findings with a review
of patient medical records. Patients treated at Mayo Clinic (Rochester, Minn) in 6 different specialty clinics
were surveyed for their use of dietary supplements. Concurrent use of prescription medications was
obtained from patients’ medical records. We used the Lexi-Interact online medication and dietary sup-
plement interaction analysis program to assess the potential clinical significance of each interaction.
RESULTS: We surveyed 1818 patients; 1795 responded (overall response rate of 98.7%) and 710 (39.6%)
reported use of dietary supplements. In total, 107 interactions with potential clinical significance were
identified. The 5 most common natural products with a potential for interaction (garlic, valerian, kava,
ginkgo, and St John’s wort) accounted for 68% of the potential clinically significant interactions. The 4
most common classes of prescription medications with a potential for interaction (antithrombotic medi-
cations, sedatives, antidepressant agents, and antidiabetic agents) accounted for 94% of the potential
clinically significant interactions. No patient was harmed seriously from any interaction.
CONCLUSIONS: A small number of prescription medications and dietary supplements accounted for most
of the interactions. The actual potential for harm was low.
© 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, 207-211

KEYWORDS: Adverse effects; Complementary medicine; Dietary supplements; Herbal products; Interactions;
Medication

Complementary and alternative medicine treatments are
used by more than two-thirds of the US population, and
dietary supplements are some of the most popular treatments.1
Most of these treatments are not regulated tightly by the US
Food and Drug Administration and are available without a
prescription from a physician. Several treatments have the
potential for adverse effects, including medication interactions.
Dietary supplements typically have multiple active phar-
macologic constituents. Thus, the likelihood of interactions
is increased when compared with the likelihood of interac-
tions between 2 prescription medications.2 Currently, most
interactions involving dietary supplements are reported as
Requests for reprints should be addressed to Dietlind L. Wahner-
Roedler, MD, MSc, Division of General Internal Medicine, Mayo Clinic,
200 First Street SW, Rochester, MN 55905.
E-mail address: wahnerroedler.dietlind@mayo.edu
case series or individual case reports.3-6 The actual potential for
interaction in a large group of patients is not well understood.
This study was designed to assess the most common
clinically significant interactions among patients who con-
currently use dietary supplements and prescription medica-
tions. The study involved a point-of-care survey of patients
treated in 6 different specialty clinics. The potential for
interactions was defined on the basis of published evidence
of interactions.
PATIENTS AND METHODS
Survey
An 85-question survey was designed to determine the use of
complementary and alternative medicine therapies during
the 6 months before the survey date. Survey questions exam-
ined use of 52 listed dietary supplements, and a text entry field

0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2007.11.014
208 The American Journal of Medicine, Vol 121, No 3, March 2008

was provided for patients to document use of supplements not case report form was created for each participant. On the basis
included in the survey. Details of the survey have been de- of the participants’ reported use of dietary supplements, each
scribed previously.7,8 Briefly, a point-of-care survey was report included the list of potential dietary supplement–medi-
administered to 1818 patients in 6 different specialty clinics at cation interactions.
Mayo Clinic (Rochester, Minn) from September 2002 through
July 2003. The 6 specialty clinics Potential Medication
were the Departments of General Interactions
Internal Medicine, Oncology, and The information on the potential in-
CLINICAL SIGNIFICANCE
Physical Medicine; the Fibromyal- teractions was obtained by search-
gia Clinic; the Preoperative Clinic; ● Use of dietary supplements is common ing the MEDLINE database (using
and the Spine Center. These 6 spe- in the US population. PubMed),9 the Natural Medicines
cialties were chosen because of the Comprehensive Database,10 and a
high volume of patients and because ● Despite a high prevalence of potential
published textbook.11 Interactions
the patients in these specialties were interactions between dietary supple-
from the Natural Medicines Com-
more likely to use complementary ments and prescription medications, prehensive Database were in-
and alternative medicine treatments. the actual potential for harm is low. cluded if a published reference
A study assistant was available was available. In the MEDLINE
● A small number of prescription medica-
to answer questions and facilitate searches, we used generic names of
survey completion. Dietary sup- tions and dietary supplements account
for most potential interactions. the supplements as key search
plements were defined as products terms. All clinical trials, case re-
containing herbs or other botani- ● Antithrombotic medications were most ports, and case series for each prod-
cal components, amino acids, en- likely to interact with dietary supplements. uct were reviewed to create a master
zymes, organ tissues, glandular list of potential medication interac-
extracts, or metabolites. Vitamins tions. The potential for interaction
and minerals were not included in between 2 dietary supplements was
this definition. Prescription medications were defined as not considered in this study because of the relatively limited
pharmacologic agents that were available in the United States evidence-based information about these interactions.
only by prescription from a physician. Aspirin also was in-
cluded in this definition. For the purpose of this study, we
Clinical Significance of Interactions
analyzed the responses about the use of 52 listed dietary sup-
Clinical significance of individual interactions was assessed
plements separately from the additional products listed by the
using the Lexi-Interact online medication and dietary sup-
patients in the free text area. Informed consent was obtained
plement interaction analysis program, which provided up-
from each patient, and the study was approved by the Mayo
to-date information.12 The program provided a summary of
Clinic Institutional Review Board.
medication interactions with an assigned risk rating (range,
Use of Prescription Medication A-D and X). The risk rating and its interpretation were as
follows: A ⫽ no known interaction; B ⫽ no action needed
Patients at Mayo Clinic have a single integrated medical
(potential for interaction but of no clinical significance);
record that is shared by all health care providers, thus
C ⫽ monitor therapy (potential for interaction that may be of
ensuring complete and consistent data about the prescription
clinical significance and needs monitoring); D ⫽ consider
medication usage. The patient medical records were re-
therapy modification (potential for interaction that may be
viewed by 3 study investigators (AS, RS, DLW-R) after
of clinical significance and needs close monitoring, change
confirming research authorization for each patient. We ex-
in therapy, or both); and X ⫽ avoid combination.
amined concurrent use of prescription medication during the
6-month period covered by the survey of dietary supplement
usage. Medical records also were reviewed to determine Data Analysis
whether any patient was seriously harmed as the result of an Differences in baseline characteristics between participants
interaction between the dietary supplement and prescription who did and did not report use of dietary supplements were
medication. Serious harm was defined as hospitalization for compared using the chi-squared and log-rank tests. P values
aggravation of any underlying medical condition or for a ⬍.05 were considered statistically significant. Statistical
new medical problem that was a direct result of the analysis was performed using the SAS software package,
interaction. version 9.1.3 (SAS Institute, Cary, NC).
Electronic medical information was available for all pa-
tients who completed the survey. We collected baseline data, RESULTS
which included patient demographics, self-perceived stress
level (scale, 1-5; 5 was the highest level of stress), and number Survey Response Rate
of symptoms checked on the review of systems questionnaire, The overall response rate to the survey was 98.7% (1795/
a standard part of our electronic medical record. An individual 1818). Of the 1795 respondents, 710 patients (39.6%) re-
Sood et al Natural Product–Conventional Medication Interaction 209

ported use of dietary supplements. These data were reported Table 1 Baseline Characteristics
previously.7,8 Eleven patients did not have information
about the use of prescription medications in their electronic Use of Dietary Supplements*
medical records, and those patients were excluded from the
interaction analysis. Thus, the final sample comprised 699 Yes No P
Characteristic (n ⫽ 710) (n ⫽ 1085) Value†
patients. Of these, the medical records of 185 (26.5%)
showed use of dietary supplements. Age, years .56
Mean ⫾ SD 55.7 ⫾ 14.9 58.1 ⫾ 16.8
Median (range) 58.5 (18-90) 59.0 (18-95)
Baseline Comparisons Sex, no. (%) .003
The mean ages were similar between participants using Men (n ⫽ 704) 248 (35) 456 (65)
dietary supplements and participants not using these prod- Women (n ⫽ 1091) 462 (42) 629 (58)
ucts (Table 1). Women were more likely to use dietary Specialty, no. (%) —
supplements than men. Patients using dietary supplements General internal 103 (33) 205 (67)
had more symptoms on the review of systems than patients medicine
not taking these products. The mean stress level was statis- (n ⫽ 308)
Oncology 123 (40) 181 (60)
tically different between the 2 groups (P ⫽ .008), but the
(n ⫽ 304)
actual difference of 0.1 was not clinically meaningful. The Physical medicine 94 (32) 201 (68)
mean number of prescription medications per patient was (n ⫽ 295)
not significantly different between the 2 groups (P ⫽ .71). Fibromyalgia 147 (51) 141 (49)
Preoperative clinic 127 (42) 175 (58)
(n ⫽ 302)
Potential Medication Interactions Spine center 116 (39) 182 (61)
The most common dietary supplements with a potential for (n ⫽ 298)
interaction were garlic, valerian, kava, ginkgo biloba, St Stress level‡ .008
John’s wort, glucosamine, ginger, and ginseng (Table 2). Mean ⫾ SD 3.0 ⫾ 1.1 2.9 ⫾ 1.1
The most common prescription medication classes with a Median (range) 3.0 (1-5) 3.0 (1-5)
potential for interaction were antithrombotic medications, Symptoms, no. ⬍.001
sedatives, antidepressant agents, and antidiabetic agents Mean ⫾ SD 10.6 ⫾ 8.6 9.1 ⫾ 7.7
(Table 3). In total, 369 potential interactions were identified Median (range) 9.0 (0-59) 7.0 (0-46)
among 236 patients. Of these, 107 interactions were con- Prescription .71
sidered to have potential clinical significance (risk rating of medications, no.
Mean ⫾ SD 3.6 ⫾ 3.1 3.7 ⫾ 3.3
C or D) (Table 2). No potential interactions resulted in
Median (range) 3.0 (0-18) 3.0 (0-22)
serious harm to any patient during the study period.
*Excludes use of vitamins and minerals.
†P values were calculated by comparing means only.
DISCUSSION ‡Self-perceived stress level was rated from 1 (low) through 5 (high).

Principal Findings
The present study showed that approximately 2 of 5 sur-
complete data for most patients. These strengths increase
veyed patients reported use of dietary supplements. In total,
our confidence in the validity of the study results.
369 potential interactions were identified among 236 pa-
Our study had several weaknesses. First, like most sur-
tients. Of these interactions, only 107 (29%) had potential
veys, ours did not eliminate the possibility of recall bias.
clinical significance. The 5 most commonly used dietary
Recall bias was minimized, however, by providing the par-
supplements with a potential for interaction accounted for
ticipants with the names of all commonly used products.
68% of all possible interactions. The 4 most common pre-
Second, the medical record information about prescription
scription medication classes with a potential for interaction
medication use may have been incomplete or inaccurate. To
accounted for 94% of the possible interactions. No patient
increase the accuracy, we checked for documentation from
had serious harm from the possible interactions during the
multiple care providers at our institution and from patient-
study period (ie, no patient was hospitalized for an aggravated
provided information that was scanned into the medical
underlying medical condition or for a new medical problem
records (each patient at Mayo Clinic has a single integrated
that was caused by an interaction). Use of dietary supplements
electronic medical record). We also were able to obtain
was documented in only 26% of the medical records.
clinical data and a current list of medications for 98.5% of
our patients (699 of 710), thus increasing the validity of our
Study Strengths and Weaknesses findings. Third, the existing information about potential
The study had several strengths, including large sample interactions between dietary supplements and prescription
size, excellent response rate to the survey, inclusion of medications was incomplete. We relied primarily on the
patients from different specialty groups, and availability of medical literature to identify adverse interactions docu-
210 The American Journal of Medicine, Vol 121, No 3, March 2008

Table 2 Potential Interactions of Dietary Supplements and Prescription Medications*

Dietary Supplement Prescription Medication Risk Category C, No. of Patients† Risk Category D, No. of Patients‡
Garlic Antiplatelet agent 22
Warfarin 3
Valerian Sedative 15
Kava Sedative 7
Hepatotoxic medication 3
Ginkgo biloba Antiplatelet agent 9
Warfarin 1
St John’s wort Antidepressant agent 8
Tramadol 1
Oral contraceptive 1
Glucosamine Warfarin 9
Ginger Antiplatelet agent 7
Ginseng Antidiabetic agent 6
Bilberry Antidiabetic agent 3
Evening primrose oil Antiplatelet agent 2
Feverfew Antiplatelet agent 2
Tumeric Antiplatelet agent 2
5-hydroxy-l-tryptophan Antidepressant agent 2
Dong quai Antiplatelet agent 1
Hawthorne Antihypertensive agent 1
Olive leaf Antihypertensive agent 1
Pau d’arco Antiplatelet agent 1
*Excludes use of vitamins and minerals.
†Potential interactions in this category may have clinical significance. Patients should be monitored.
‡Potential interactions in this category may have clinical significance. Patients should be monitored closely or have the therapy modified.

mented in humans. However, these interactions may not survey to date, of 31,044 surveyed patients, 18.9% reported
always be a direct effect of a dietary supplement and could use of dietary supplements.1 The higher proportion of
be an effect of adulterants in the supplement (eg, heavy 39.6% in our study likely resulted from a combination of
metals or pesticides), prescription medications, or misiden- referral bias and inclusion of patients with medical condi-
tified plants.13-17 Finally, even though we surveyed patients tions such as cancer, fibromyalgia, and chronic pain, which
in 6 specialty clinics, the generalizability of our study find- increased the likelihood of use of dietary supplements.
ings to the community setting might be limited. In 1999, a point-of-care survey asked 458 veteran outpa-
tients about their current use of dietary supplements.18 Intake
Comparison with Other Studies of prescription pharmaceuticals was identified through a Vet-
Use of dietary supplements is extremely common in the erans Administration pharmacy database search. A total of 197
United States. In the largest point-of-care, population-based patients reported using dietary supplements. The potential for
prescription medication– dietary supplement interaction ex-
isted in 45% of these patients (89/197). The higher estimate
Table 3 Prescription Medications That Commonly Showed obtained in that study likely is attributable to the inclusion
Clinically Significant Interactions with Dietary Supplements* of vitamins and minerals when considering possible inter-
Medication Class No. of Patients actions. The most common products with a potential for
interaction in that study are among the most likely products
Antithrombotic medication
Warfarin 13
for interaction in the present study (ie, garlic, ginseng, and
Antiplatelet agent 46 gingko biloba).
Sedative 22 Other studies have documented concurrent use of herbal
Antidepressant agent 10 products and prescription medications. In a national survey
Antidiabetic agent conducted in the United States, concurrent use of herbal
Insulin 3 remedies and prescription medications was documented in
Oral medication 6 18.4% of prescription medication users.19 However, the
Other† 7 potential for interactions was not addressed. In a British
*Excludes use of vitamins and minerals. study involving 271 participants older than 50 years, a mean
†Antihypertensive agents, hepatotoxic medications, oral contracep- of 5.91 supplements and a mean of 2.26 prescription med-
tives, and tramadol.
ications were used concurrently.20 However, a specific eval-
Sood et al Natural Product–Conventional Medication Interaction
uation of the potential for interactions was not reported. In
a smaller survey of 76 patients with cancer, 27% were
reported to have a potential for herbal products or vitamins
interacting with chemotherapeutic agents.21 In a Canadian
study of 195 patients older than 65 years, 33 current users of
herbal medicines were identified.22 Among those patients,
11 potential herb-medication interactions were identified in
9 patients (27%). In a Canadian study involving seniors with
osteoarthritis, 214 potential interactions were identified. Of
these, 30 were considered clinically significant.23
Among all prescription medications, antithrombotic
agents are the best-described class of medications with a
potential for interacting with herbal products.24,25 In a study
involving a search of electronic databases, warfarin was the
most common medication documented to have a potential
for interaction with herbal products.14 Findings from the
present study, which surveyed a broad patient population,
confirmed that antithrombotic medications indeed were the
ones most likely to interact with dietary supplements. How-
ever, the actual potential for harm in quantitative terms is
unknown because well-designed studies to evaluate adverse
effects would be unethical and not feasible. Until further
data are available, patients receiving antithrombotic medi-
cations generally should be counseled to avoid dietary sup-
plements known to interact with warfarin or known to have
an antiplatelet effect.
Distinguishing between a real potential for harm and a
purely speculative interaction is important. Despite a high
prevalence of the potential for interaction, no serious ad-
verse events such as hospitalization or serious bleeding due
to interactions were documented in any of our patients.
Some interactions that were included in the study could be
considered speculative. However, it might be prudent to
take a balanced but cautious approach, even if some cause-
and-effect relationships are not well established, and partic-
ularly if the purported treatments are not proven to have a
beneficial biologic effect. Furthermore, dietary supplements
often are intended to be taken for long periods, and given
the high prevalence of their use, even a small potential for
harm might have public health consequences.
In summary, the present study showed that a small num-
ber of prescription medications and dietary supplements
accounted for most potential interactions. This information
likely will help educate patients and physicians about these
potential interactions.
ACKNOWLEDGMENT
Editing, proofreading, and reference verification were pro-
vided by the Section of Scientific Publications, Mayo
Clinic.
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