THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE

Volume 8, Number 3, 2002, pp. 293–308

© Mary Ann Liebert, Inc.

Herb–Drug, Food–Drug, Nutrient–Drug, and

Drug–Drug Interactions: Mechanisms Involved and
Their Medical Implications

JANINA MARIA SØRENSEN, M.Sc., M.H.

ABSTRACT

Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant fac-
tors responsible for patient morbidity and mortality. Significant studies on drug metabolism in
humans have been published during the last few years, offering a deeper comprehension of the
mechanisms underlying adverse drug reactions and interactions. More understanding of these
mechanisms, and of recent advances in laboratory technology, can help to evaluate potential
drug interactions when drugs are prescribed concurrently.
Increasing knowledge of interindividual variation in drug breakdown capacity and recent
findings concerning the influence of environment, diet, nutrients, and herbal products can be
used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should
be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed
diet and herbal remedies, could increase drug efficacy and lessen drug toxicity.
This review focuses mainly on recently published research material. The cytochrome p450 en-
zymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in
drug–drug interactions are discussed. Drug–food and drug–herb interactions have garnered at-
tention. Interdisciplinary communication among medical herbalists, medical doctors, and di-
etetic experts needs to be improved and encouraged. Internet resources for obtaining current in-
formation regarding drug–drug, drug–herb, and drug–nutrient interactions are provided.

INTRODUCTION published on the hazards of ADRs and fatal

consequences of comedication. These adverse

I dentifying the metabolic role of cytochrome

p450 (CYP) enzymes in adverse drug reac-
tions (ADRs) and drug–drug interactions is a
factor that has contributed significantly to un-
derstanding the mechanisms involved in drug
metabolism. Understanding these mechanisms
has the potential to contribute to much more
effective and safe management of medications.
During the last few years, many studies were
reactions have been identified as a significant
factor in patient mortality and serious morbid-
ity during the last decades. The personal cost
in quality and quantity of life is incalculable.
Current prescribing references are not suffi-
ciently updated and many medical practition-
ers and researchers are aware that, in order to
know about recent findings, we have to consult
current and updated published data continu-

Allinge, Denmark.

293
294
ously. Dissemination of recently published
findings can contribute to a decrease in ADRs
and interactions and result in increased patient
safety.
During the last decades, medication has be-
come more and more synthetic. For example,
petroleum-based pharmaceuticals can be syn-
thesized and commercially patented. Many of
these agents have displayed marked therapeu-
tic effects, prolonging human life, controlling
epidemics, and helping patients to live with
such chronic conditions as diabetes. However,
now, patients’ bodies are being subjected to
“cocktails” of xenobiotics (from the Greek,
meaning “strange to life”) that have an impact
on the metabolic processes responsible for
breaking down and eliminating chemicals from
the human system. These new drugs post a
challenge to the human metabolic system, es-
pecially when different substances are admin-
istered concomitantly.
Generally speaking, the human metabolic
system has evolved carefully to deal with tox-
ins. It evolved to eliminate biologic substances
from the body that are not useful or that would
be potentially dangerous if they were not me-
tabolized. For thousands of years, this ever-
evolving and adapting system has metabolized
chemical constituents from the human diet, as
well as metabolizing endogenous substances.
This system is adaptable to the lifestyles and
conditions of individuals. Racial, gender-spe-
cific, and genetic variations in metabolizing ca-
pacity have been reported along with environ-
mental, dietary, and habitual influences.
ADRS AND IATROGENIC DISEASES
A meta-analysis of data to estimate the inci-
dence of serious and fatal ADRs in hospital pa-
tients showed that fatal drug reactions might
be the fourth leading cause of death in the
United States (Lazarou et al., 1998), following
heart disease, cancer, and stroke. This data is
especially discouraging because it does not in-
clude mistakes, such as drug-administration er-
rors, drug overdoses, or drug abuse or reac-
tions occurring in nonhospitalized patients. If
these parameters were to be included, it is pos-
sible, that adverse drug reactions would be
SØRENSEN
noted as the third leading cause of death in the
United States (Lazarou et al., 1998).
In the United States, the yearly cost of caring
for patients with drug-induced illness was es-
timated as $136 billion (Johnson and Bootman,
1995), which is significantly more than the bill
for the treatment of heart disease or diabetes.
Adverse effects of medications are responsible
for approximately 106,000 deaths annually in
the United States and an estimated 2 million
hospitalized patients are experiencing serious
adverse drug reactions. These adverse reac-
tions occurred mainly at the manufacturers’
standard recommended doses for the drugs
concerned (Lazarou et al., 1998).
These reports were further verified by a re-
port in 1999 on medical errors (Charatan, 2000),
which was published by the United States In-
stitute of Medicine. This report prompted the
then U.S. President Clinton to call for a na-
tionwide system of registration for these errors.
More than 6000 U.S. hospitals will be required
to adopt a reporting system. For example, they
will have to report on the prescription and dis-
pensing of drugs. However, Clinton’s proposal
will require legislation, and despite its appeal
to consumers, the proposal has come under
strong opposition from the American Medical
Association and the American Hospital Asso-
ciation (Charatan, 2000).
Apart from adverse reactions occurring in
hospitalized patients, there are significant
records that indicate that patients are admitted
to hospitals because of adverse drug reactions.
Reviewing international data sources, Einarson
(1993) concluded, that an average of 5% of all
hospital admissions result from ADRs and, in
3.7% of cases, the outcome is fatal. An Aus-
tralian survey stated that 2.4%–3.6% of all hos-
pital admissions are drug-related (Roughead et
al., 1998). The authors of this survey also spec-
ified that drug-related admissions account for
6%–7% of all emergency admissions, for 12%
of all admissions to medical wards, and for
15%–22% of admissions among the elderly.
However, it has to be kept in mind that most
of the published data is extracted from volun-
tary reports of health care professionals and
several studies elucidate the inadequacy of the
reported data. Cullen et al. (1995) specified that
voluntary reporting identified only a small
ADVERSE DRUG REACTIONS
fraction of ADRs. Of 54 ADRs identified in their
study, only 3 patients had a corresponding in-
cident report submitted.
A recent study (Sweis and Wong, 2000) eval-
uated the shortcomings of hospital reporting
systems. Since 1997, U.K. hospital pharmacists
have been invited to report suspected ADRs to
a committee on Safety of Medicines. The re-
searchers investigated the factors that could af-
fect reporting ADRs and, despite the fact that
46% of hospital pharmacists had identified
ADRs that were considered to be reportable,
39% of these pharmacists did not report these
ADRs. The reasons for not reporting included:
“being busy at work”; lack of a written hospi-
tal policy regarding ADR reporting; lack of
confidence in recognizing ADRs; and fear of
breaching patient confidentiality (Sweis and
Wong, 2000).
A similar study was published concerning
the reporting of ADRs by poison-control cen-
ters in the United States. Although these cen-
ters manage some 30,000 ADRs every year, the
extent of reporting these is incomplete (Chyka
and McCommon, 2000). Reasons given for not
routinely reporting ADRs included: ADR re-
porting not being part of the regular routine;
lack of time to complete forms; and reporting
being too much work.
Drug complications among outpatients are
very common but are rarely documented, and
the impact on quality of life seems to be sub-
stantial (Gandhi et al., 2000). A recent study
suggested that periodic querying of patients
could help to detect adverse drug effect prob-
lems early (Wunsch, 2000).
In the United States, manufacturers spent in
excess of $1 billion in 1998 on direct-to-cus-
tomer advertising, often providing misleading
information (Waltermire, 1998). These adver-
tisements place minimal, low-key focus on po-
tential side-effects and raise unrealistic expec-
tations among consumers regarding quality of
life after using the drugs in question. Ulti-
mately, this can result in overreliance on drugs
at the expense of making lifestyle changes.
Some products that are coming onto the mar-
ket have not been thoroughly studied for po-
tential adverse drug reactions prior to patient
consumption, especially with regard to adverse
drug reactions from combinations with other
295
prescription and over-the-counter remedies
(Waltermire, 1998).
Two thousand dangerous drug interactions
have been identified to date (Lyle et al., 1998);
however, the effort to identify these interac-
tions and bring them to the attention of health
workers and consumers is neither systematic
nor coordinated. Although federal legislators
in the United States in 1990 voted for a state re-
quirement to introduce “drug use review pro-
grams,” these programs have fallen short of
their aim as have other efforts to safeguard con-
sumers. It would appear that, once a drug is
approved, it is up to its manufacturer to in-
vestigate and report potential adverse effects.
Doctors and pharmacists, in turn, have to rely
upon the pharmaceutical companies for notifi-
cation if there are studies have reveal adverse
and harmful interactions regarding specific
drugs. This system may be unreliable in pre-
venting coprescribing or codispensing of inter-
acting drugs (Lyle et al., 1998). The authors
concluded that we can only avoid exposing pa-
tients to known drug therapy problems if there
is complete, current medical information for
checking potential complications.
A recent report (Kohn et al., 1999) stated that
current estimates of the incidence of medica-
tion errors are undoubtedly lower than the re-
ality because many medication errors go un-
documented and unreported. In addition, it
seems that the problem is getting worse as doc-
tors prescribe an increasing number of drugs.
Between 1983 and 1993, hospital patient deaths
caused by medication errors increased 2.4-fold,
while deaths from medication errors among
outpatients increased an astonishing eightfold,
reaching almost epidemic proportions (Kohn et
al., 1999). However, the authors also reported
that doctors do not often consider possible in-
teractions among drugs that they prescribe to
patients, even in cases when medication history
information is readily available. Children and
older people are particularly prone to medica-
tion errors, which are mainly related to incor-
rect doses. A 1987 study found that physicians
prescribed inappropriate medications for
nearly 25% of all older people (cited in Kohn
et al., 1999). For every dollar spent on pre-
scription drugs, $1.3 is spent to treat iatrogenic
illness and to pay administration costs for
296
deaths resulting from administration of those
prescribed drugs (Kohn et al., 1999). The report
described two studies that found that death
rates caused by medical mistakes far exceeded
1 in 500. One study of 815 patients at a uni-
versity hospital showed that 36% of these pa-
tients had an iatrogenic disease and, in 9% of
the cases, the condition produced considerable
disability or was life-threatening. A second
study examined 1047 patients admitted to two
intensive care units and one surgical unit in a
large hospital. Of the 1047 people studied, 480
(46%) had an adverse event. For 185 patients
(18%), this adverse event was serious, produc-
ing disability or death (Kohn et al., 1999). Thus,
rates of death come near to the 1:50–100 mark.
Cohen (1999) raised the question of pre-
scriptions with sufficient regard for individual
variation. He stated that recommended dosages
are often universal, without regard for indi-
vidual responses. He noted that compliance is-
sues caused by adverse side-effects are a com-
mon problem with many kinds of medications,
resulting in patients quitting treatment within
the first year. This is especially true in the cases
of antihypertensive and cholesterol-lowering
drugs. When these ADRs compromise treat-
ment, they have serious ramifications, because
hypertension and hypercholesterolemia are
major factors in the etiology of heart disease
and strokes, the numbers 1 and 3 causes of
death in the United States respectively. Cohen
(1999) emphasized the need to adjust doses ac-
cording to individual responses in order to
achieve maximum effects and minimize side-
effects that might prompt patients to discon-
tinue medication. Besides identifying a pa-
tient’s individual size, weight, and age, he
emphasised the need to inquire about individ-
ual responses to drugs as well as habitual pat-
terns of patients. His proposal is that patients,
upon their first visits to physicians should fill
out a detailed questionnaire. He summarized
his review by stating that ADRs are leading
causes of disability, morbidity, and mortality
and that most ADRs are dose-related phenom-
ena occurring at the standard, manufacturer-
recommended doses, which might be excessive
for some patients. Identifying at-risk patients
and starting with lowest possible doses can
prevent many ADRs (Cohen, 1999).
SØRENSEN
CYTOCHROME p450 ENZYMES
Drug metabolism occurs mainly in the liver,
with additional contributions by the kidneys,
the gastrointestinal tract, lung, blood, and other
tissues. Over the last few years, a group of en-
zymes, called collectively the cytochrome p450
system (CYP 450, also individually as cy-
tochrome P and a number, e.g., CYP 1A2), were
found to be responsible for many metabolic
processes. Currently, more than 30 different
human isozymes have been identified (Limon,
2000). These enzymes are responsible for ox-
idative reactions, which result in the conver-
sion of numerous compounds, including many
medications, into more polar metabolites, fa-
cilitating renal excretion. CYP enzymes are ac-
tive in the so-called phase I of metabolism,
when metabolite substrates are broken down.
In phase II metabolism, these metabolized sub-
strate products are coupled to endogenous sub-
stances that usually, but not always, yield in-
active metabolites. In recent years, interest in
these enzymes has exploded as the result of a
greater understanding of their role in drug me-
tabolism, drug interactions, drug toxicity, and
the creation of carcinogenic byproducts (Guen-
gerich, 1997; Holland and Degruy, 1997; Prior,
et al. 1999). The isozymes most commonly in-
volved in drug metabolism are CYP 3A4, CYP
2D6, and CYP 1A2 (Limon, 2000).
A relatively new technique which has been
utilized since the middle of the 1990s enables
researchers to conduct metabolism studies in-
volving the CYP enzymes and isolated hepa-
tocytes. Human liver tissue and recombinant
human CYPs are now readily available, and in
vitro systems have been used as screening tools
to predict in vivo actions and drug interactions.
In the late 1990s, assays were developed, using
cryopreserved human hepatocytes and these
were useful experimental tools for evaluating
drug metabolism, toxicity, and drug–drug in-
teractions (Li et al., 1999). Since then, a large
amount of data concerning metabolism and in-
teraction potentials of drugs has become avail-
able. Of special interest, is the ability of other
coadministered drugs to either inhibit or in-
duce the activity of the CYP enzymes, being
that these are the key mechanisms in drug–
drug interactions (Li et al., 1997a).
ADVERSE DRUG REACTIONS
Competitive binding at an enzyme’s binding
site usually causes enzyme inhibition (Limon,
2000). This produces delayed drug metabolism,
which can result in drug accumulation to po-
tentially toxic levels in the human body. In-
duction of metabolism would, on the contrary,
mean that drugs are metabolized much more
quickly, thereby not being able to perform their
specific activities to necessary extents. Inhibit-
ing activity on the P450 system is regarded as
a more serious complication in terms of known
clinical problems and is responsible for a large
number of documented adverse drug interac-
tions and toxic reactions (Guengerich, 1997; Lin
and Lu, 1998).
In addition, the individual metabolizing ca-
pability of patients has to be taken into
consideration. Some of these enzymes can be
present in different forms, varying with in-
terindividual and interracial factors. As a result
of this genetic polymorphism, some individu-
als are categorized as “poor,” “effective,” or
“ultrarapid” metabolizers (PM, EM, and UM
respectively). For example, it has been well-
established that 3%–5% of Caucasians and
15%–20% of Asians are CYP 2C19 PMs, 1%–3%
of Caucasians are CYP 2C9 PMs, and 5%–10%
Caucasians are 2D6 PMs (Flockhart, 2000).
However, racial and interindividual variations
have recently been reported for additional
isozymes as well. Examples are CYP 2A6 (Free-
man et al., 2000), CYP 1A2 (Johnson et al., 2000;
Prior et al., 1999), CYP 1A1, CYP 1B1 (Inoue et
al., 2000), CYP 3A4 (Hirth et al., 2000), and CYP
3A (Dresser et al., 2000; Wandel et al., 2000a).
Genetic variation in the expression of these
enzymes is potentially dangerous, especially in
the metabolism of drugs with narrow thera-
peutic indices, such as warfarin (anticoagu-
lant), a substrate for CYP 2C9, CYP 2A6 (Free-
man et al. 2000), and CYP 2C19 (Flockhart,
2000). Polymorphism that impairs warfarin
metabolism is common, occurring in 34% of pa-
tients (Freeman et al., 2000).
A recent study offered an example of the im-
pact of genetic variability. The influence of ge-
netic variability in CYP 2D6 expression (UM,
EM, and PM) was investigated among one
hundred psychiatric inpatients by evaluating
ADRs, hospital stays, and total costs involved
during a 1-year period. A trend toward greater
297
numbers of ADRs was observed as one moved
from a group of patients with ultrarapid CYP
2D6 activity (UM) to a group of patients with
poor CYP 2D6 activity (PM). The cost of treat-
ing patients with extremes in enzyme activity
(UM and PM) was significantly elevated and
hospital stays were more prolonged for pa-
tients in the CYP 2D6 PM group (Chou et al.,
2000).
There are also gender-specific differences.
Cigarette smoking is known to induce CYP 1A2
activity. However, a study of the interaction of
clozapine and smoking revealed that serum
levels of the drug were lower only in male
smokers whereas female smokers and non-
smokers had unchanged serum levels of the
drug. (Prior et al., 1999). Ou-Yang et al. (2000)
reported polymorphism in CYP 1A2 activity
and that the activity of this isozyme seems to
be higher in men than in women. Smoking
habits also seem to influence CYP 2D6 metab-
olism. The prevalence of UMs of CYP 2D6 in
heavy smokers was found in a study to be four-
fold compared to nonsmokers. The researchers
suggested that increased CYP 2D6 activity
seems to be associated with addiction to smok-
ing (Saarikoski et al., 2000). However, it could
also be argued that smoking strongly induces
CYP 2D6 activity. Diseases can also have an in-
fluence on CYP enzyme activity. Matzke et al.
(2000) noted increased CYP 1A2 activity in pa-
tients with type 1 diabetes. Liver disease and
thyroid dysfunction are well-documented as
factors that affect warfarin response (Demirkan
et al., 2000).
Another factor to take into account, apart
from genetic, racial, or gender-specific varia-
tions, is that the P450 system has a remarkable
ability to respond metabolically to chemical
challenges and xenobiotic inputs. CYP 3A4 is
especially versatile, CYP 3A4 metabolizes a
wide range of lipophilic substrates, including
endogenous steroids and prescription drugs
(Xie et al., 2000). Xie et al. reported that a di-
verse array of chemicals, including many CYP
3A4 substrates can upregulate this isozyme’s
expression. This upregulated expression re-
sults in varying CYP 3A/4 levels between
individuals, according to their exposure to
chemicals. An up-regulation of CYP 3A/4 ex-
pression causes enhanced protection against
298
toxic xenobiotic compounds. However, Xie et
al. (2000) also reported that such upregulation
also caused growth retardation, hepatomegaly,
and hepatopathology in vivo (rats), suggesting
that continuous overexpression might disturb
the function of CYP 3A/4 to keep homeostasis
of some endogenous substances.
With the available knowledge of P450 and its
substrates, it is possible to do in vitro experi-
ments and make useful preclinical predictions.
A wide range of medications have been
classified as inducers or inhibitors of CYP
enzymes—and this ever-expanding knowledge
is of considerable clinical interest with regard
to issues concerning comedication and iatro-
genic diseases. Because a large number of com-
monly prescribed medications undergo metab-
olism via one or more CYP enzymes, the rate
of metabolism of these medications is prone to
alteration by other substances acting as enzyme
inhibitors or inducers (Flockhart 2000; Li et al.
1997a). However, a study that evaluated in-
hibitors of the CYP 450 system via in vitro and
in vivo methods concluded that in vitro evalu-
ations might not always reflect in vivo obser-
vations (Chang et al., 1999). Controlled in vivo
studies are still limited. Information on in vivo
metabolism via CYP enzymes is mainly de-
rived from case reports in which patients had
received several medications. Often, these case
studies consisted of single observations with-
out any appropriate controls or evaluations of
other possible contributing factors (Prior et al.,
1999). Other mechanism besides the P 450 sys-
tem might also be involved. In particular, in-
hibition of CYP 3A4 may involve inhibition of
the transporter protein P-glycoprotein (Dresser
et al., 2000; Wandel et al., 2000b). Scientists
have proposed a set of data acceptance criteria
for future research (Li et al., 1997a). One of
these criteria is that reproducible observation
should be based on multiple human hepatocyte
donors, taking interindividual variations into
account. Another criterion is that doses used
should be realistic not cytotoxic. In addition,
replicate treatment and/or multiple dose treat-
ment should be performed and possible indi-
vidual variations and potential genetic poly-
morphism should be evaluated (Li et al., 1997a).
As early as 1992, Murray and Field (1992)
suggested the need for definitive in vivo stud-
SØRENSEN
ies of phenotyped patients and for studies to
assess the utility of phenotyping in clinical
practice. Considering the substantial interindi-
vidual variations observed, it was suggested
that individual liver-enzyme status should be
assessed prior to any treatment. Because ex-
pression of CYP enzymes is genetically coded,
and the genetic basis for many of the alleles is
now well-defined, research is increasingly con-
cerned with developing methods to assess in-
dividual metabolizing capacities (Chang et al.,
1999). Mizugaki et al. (2000) have developed a
polymerase chain reaction (PCR) test that al-
lows rapid, simple, and cost-effective assess-
ment of liver enzyme function. The test uses
patients’ blood or saliva. Roberts et al. (2000)
reported a method for rapid and economical
determination of CYP2D6 poor metabolizers
via PCR using DNA prepared by a range of
methods, including dried-blood spots on a
card.
As we have seen, drug–drug interactions and
adverse effects that result in drug-related dis-
orders are a serious medical problem resulting
in considerable mortality, significant morbid-
ity, and increased cost (Bates et al., 1995; Kohn
et al., 1999; Lazarou et al., 1998). It is regret-
table that medical practitioners are often not
sufficiently informed about drug–drug interac-
tions. CYP inhibition may affect the metabo-
lism of numerous drugs, with potentially seri-
ous consequences. Several studies emphasize
that practitioners should educate themselves
to be aware of drug–drug interactions (Guen-
gerich, 1997; Richelson, 1997). Physicians should
understand the relevance of genetic poly-
morphism, environmental factors, and the in-
fluence of other substrates on the enzymatic
biotransformation of drugs. Information re-
garding potential drug interactions determined
by genetic polymorphism and based on stud-
ies with enzymes should be increasingly con-
tained in drug compendia (Meyer et al., 1996).
Because it is impossible to remember all
drug–drug interactions, it is important to be
aware of the classes of drugs involved in more
significant interactions. “Red flag” drugs in-
clude rifamycin agents, protease inhibitors,
macrolides, antifungals, antiretrovirals, trans-
plantation medications, cancer chemotherapy
agents, and anticonvulsants. Cisapride (a peri-
ADVERSE DRUG REACTIONS
staltic-stimulating drug) is involved in many
interactions and poses a potential risk of car-
diac toxicity. All drugs with narrow therapeu-
tic indices, such as warfarin, theophylline, and
digoxin should be carefully evaluated (Limon,
2000).
Because new information about CYP isozymes
and their substrates, inducers, and inhibitors
becomes increasingly and constantly available,
it is useful for accessing current data. Flexner
and Piscitelli (2000) established an interactive
tool on the Internet to check drug–drug inter-
actions and to generate a daily schedule for
multidrug regimens that take dietary require-
ments and lifestyles into account. The site is
freely available and is frequently updated.
Flexner (2000) also reports new interaction
findings periodically. Flockhart (2000) keeps a
well-updated, freely available listing of CYP-
based drug interactions and provides CYP-sub-
strate, -inducer, and -inhibitor charts on the In-
ternet. The U.S. Food and Drug Administration
(FDA, Food and Drug Administration, 1999)
provides information about in vivo drug me-
tabolism and drug interaction studies on the In-
ternet. These sources are valuable tools and
worth bookmarking.
In addition, the recent emphasis on individ-
ual and polymorphic responses to medications
should provide a reason to reevaluate medical
practice. In future, mainstream health practi-
tioners may have to determine individual
detoxification capabilities and to take each pa-
tient’s diet and habits into account before pre-
scribing medications. Dietary habits do influ-
ence the activity of drugs to a certain extent. It
is discouraging that, although medical treat-
ment and pharmacologic advances during
the last decades have been beneficial to hu-
mankind, these agents have been responsible
for iatrogenic diseases, with often fatal out-
comes. It is time to revise prescribing practices
based on the recent scientific findings with re-
gard to drug metabolism and individual re-
sponses to medications.
In addition to the abovementioned need to
assess individual enzyme activity, recent re-
ports on foodstuffs and beverages of natural
origin note their ability to interfere with me-
tabolism of prescribed drugs. This phenome-
non alters the picture of individual responses
299
to drugs. Several natural foods, herbs, and bev-
erages have been shown to either induce or in-
hibit the metabolism of pharmaceuticals; this is
another reason to include information regard-
ing dietary habits and the use of nutritional
supplements while obtaining a patient’s his-
tory. This is already a routine procedure for
medical herbalists.
DRUG–FOOD INTERACTIONS
Seasonal changes of diet, changes in diet as
a result of war and starvation periods, or ac-
cording to whatever the environment could of-
fer presented an ever-changing challenge to hu-
man metabolizing enzymes. Induction and
inhibition of these enzymes have undergone
dynamic change with regard to nutritional
availability. This ensures that toxic substances
can be eliminated from the body and beneficial
metabolites retained.
The CYP enzyme family has always been
able to metabolize biotic inputs in a well-bal-
anced way. However, these enzymes now must
work with the simultaneous input of xenobi-
otics in the form of medicines. In recent times,
food–drug interactions have received much at-
tention. Some foods, minerals, vitamins, herbs,
and beverages have shown inducing and in-
hibiting activity on the CYP system, possibly
interacting with several medications. Yet, it
could be argued that the medications are the
source of interference being that the P450 en-
zyme system was originally conditioned to
work with human foodstuffs.
The various pharmacokinetic processes via
which foods may interact with coadministered
drugs are prior to and during gastrointestinal
absorption, and during distribution, metabo-
lism, and elimination. Absorption and metab-
olism mediated by enzymes are the phases dur-
ing when food has the most influence. An
understanding of these effects may serve as a
key to pharmacokinetic optimization in drug
therapy (Singh, 1999).
Research has focused mainly on the effects
of food on drug absorption in the small in-
testines and these drug–food interactions can
be divided into three effect categories: (1) in-
creased; (2) decreased, or (3) unaffected drug
300
absorption (Garey and Rodvold 1998). A few
studies have established drug–food interac-
tions as responsible for certain adverse reac-
tions in general, without specifying the mech-
anisms or single factors involved. These studies
emphasize that dietary consideration should be
assessed further in order to develop strategies
for improvement of patient outcomes. For ex-
ample, one study attempted to identify the dif-
ferent dietary, environmental, and genetic fac-
tors that prevent maintenance of adequate
anticoagulation control in Puerto Rican pa-
tients (Feliu and Mendez 1998).
Drug–food interactions are a commonly
overlooked aspect in physicians’ prescribing
practices. As more pharmaceutical agents be-
come available, attention should be focused
how drugs interact with food and nutrients
(Trovato et al., 1991). The number of potential
food–drug interactions is almost limitless and
interactions most often occur with the use of
diuretics, antibiotics, anticoagulants, antihy-
pertensive agents, thyroid and sodium com-
pounds, and alcohol (Bobroff, 1988). Other im-
portant drug classes involved in drug–food
interactions are antiretroviral drugs (Garey and
Rodvold, 1998) and antidepressants (Jefferson,
1998). Heck et al. (2000) reported that more
food–drug interactions have been reported for
warfarin than for any other prescription med-
ication.
In the late 1990s, researchers accidentally dis-
covered that grapefruit juice increased blood
levels of a calcium-channel antagonist (felodip-
ine) dramatically, and over the last decade sci-
entists discovered that an ever-expanding list
of medications are affected by grapefruits. It
was found that grapefruit was a potent in-
hibitor of several CYP enzymes, namely CYP
3A4 and CYP 1A2, increasing plasma concen-
trations of several drugs that are substances for
these enzymes, including cyclosporin, estro-
gens, several benzodiazepines, and protease in-
hibitors such as saquinavir and buspirone (Lilja
et al., 1998; Rodvold and Meyer, 1996). At least
20 other drugs have been assessed for interac-
tions with grapefruit juice. The duration of this
inhibitory effect can last up to 24 hours (Bailey
et al. 1998). In the case of simvastatin, a cho-
lesterol-lowering drug, grapefruit juice in-
creased mean peak serum concentrations ap-
SØRENSEN
proximately ninefold and researchers con-
cluded that concomitant use should be avoided
and also mentioned the possibility of greatly
reducing simvastatin in therapy (Lilja and Neu-
vonen, 1997).
These findings have spurred scientists to ex-
amine other food–drug interactions. Foods that
are rich in vitamin K—such as cabbage, Brus-
sel’s sprouts, asparagus, lettuce, spinach, avo-
cado, and liver—can counteract the activity of
warfarin and should be avoided by patients
who take this agent (Vistisen et al., 1991).
Canola and soy oils are also rich in vitamin K.
Even brewed green tea (Camellia sinensis),
which reportedly contains only 0.03 mg of vi-
tamin K per 100 g reduced the therapeutic ac-
tivity of warfarin critically (News, Nurses Drug
Alert, 1999). However, the mechanism in these
cases does not involve the CYP450 system, but
rather involves the role of vitamin K in acti-
vating coagulation factors.
Soybeans, peanuts, and vegetables of the
cabbage family (such as broccoli and cauli-
flower) contain goitrogens that interfere with
thyroid function and can lead to goiter (Bo-
broff, 1988).
However, cruciferous vegetables (such as
broccoli, cabbage, and Brussels’ sprouts) have
also increased CYP 1A2 activity, wheres apia-
ceous vegetables (such as carrots and celery)
decreased this enzyme’s activity (Lampe et al.,
2000). CYP 1A2 is involved in the transforma-
tion of procarcinogens and the induction of this
enzyme by cruciferous vegetables may prevent
chemically induced carcinogenesis (Kall et al.,
1996). However, with regard to food–drug in-
teractions, induction of CYP 1A2 might de-
crease efficacy of drugs that are substrates for
this enzyme, such as warfarin, theophylline,
and clozapine (Flockhart, 2000).
Cigarette smoking has induced CYP 1A2 ac-
tivity, and it has been reported that this inter-
action can have clinical significance. In this
case, a patient taking clozapine who quit smok-
ing subsequently had a seizure that was at-
tributed to elevated levels of clozapine (Prior
et al., 1999).
Fluvoxamine (an antidepressant) is a very
potent inhibitor of CYP 1A2 and caffeine is a
substrate for this enzyme. It has been reported
that caffeine intake during fluvoxamine ther-
ADVERSE DRUG REACTIONS
apy can lead to caffeine intoxication (Jeppesen
et al., 1996). Other inhibitors of CYP 1A2 are
cimetidine and mibefradil (Flockhart, 2000).
Potentially fatal food–drug interactions can
occur between monoamine oxidase inhibitors
(MAOIs), which are used to treat depressive
disorders, tuberculosis, and high blood pres-
sure, and foods that are rich in tyramine. When
MAOIs and tyramine-rich foods are combined,
they can cause palpitations, sweating, severe
headaches, or hypertensive crises that result in
fatal cerebral hemorrhages and comas (Janicak
et al., 1997). Tyramine is indirectly sympath-
omimetic and suppressing its metabolism by
MAOIs results in markedly increased blood
pressure, cardiac arrhythmia, and cerebral he-
morrhage (Bland, 1998). The list of foods con-
taining tyramine is long. The classes of foods
that should strictly be avoided are broad bean
pods; yeast concentrates (such as marmite,
brewers yeast, or yeast supplements); salted,
smoked, or pickled fish; and aged cheeses, in-
cluding blue types, Camembert types, and hard
types such as cheddar, Swiss cheese, or parme-
san cheese (Graedon and Graedon, 1998). Over-
ripe foods, fermented beverages, and chocolate
contain tyramine (Bland, 1998). Soy products,
tofu, and soy sauces can contain significant
amounts of tyramine and should also be
avoided with MAOI therapy (Shulman and
Walker, 1999). As a result of tyramine-content
analyses in draught beer and the occurrence of
several cases of hypertensive crises following
the consumption of modest amounts of draught
beer by patients on MAOIs, Shulman et al. (1997)
concluded that all draught beer should be
avoided by patients who take MAOIs.
Several flavonoids extracted from hops (Hu-
mulus lupulus) and present in beer are potent
inhibitors of CYP 1A1, –1B1, and –1A2, and the
chemoprotective activity of these flavonoids
might be the result of the inhibition of these en-
zymes, which play a role in activating carcino-
gens (Henderson et al., 2000).
Watercress is a potent inhibitor of CYP 2E1
and has been reported to lead to 56% increased
plasma levels of the muscle relaxant chlorzox-
azone (Leclerq et al., 1998) Garlic inhibits the
same enzyme and might have similar actions.
Other substrates of CYP 2E1 are the anasthetic
drugs halothane and methoxyflurane (Flock-
301
hart, 2000). Increased plasma levels of these
anaesthetic drugs are hepatotoxic.
Anesthesiologists in the department of anes-
thesia and critical care, University of Chicago, IL,
reported in 1997 that foods that are rich in solana-
ceous glycoalkaloids (SGAs) such as tomatoes,
potatoes, and eggplants, delay recovery from
anesthesia and recommended restricting these
foods a few days before surgery. The SGAs are
reported to inhibit cholinesterases, which are en-
zymes important for metabolizing anesthetic
drugs (Krasowski et al., 1997). It was reported
that two particular SGAs present in solanaceous
vegetables alter the effects of anesthetics and
neuromuscular blocking drugs in vivo (rabbits).
The Cholinesterases were inhibited by amounts
of SGAs similar to those found in a standard
serving of potatoes consumed by human beings.
The researchers concluded that dietary factors
influence the metabolism of anaesthetic drugs
strongly and that diet may, therefore, contribute
to the wide variation in recovery time from neu-
romuscular blockade seen in normal healthy in-
dividuals (McGehee et al., 2000).
The German Pharmacists Association (Apothe-
kerverband) lists 315 pharmaceuticals that in-
teract with foods. An important group is the
tetracycline antibiotics that interact with cal-
cium in dairy products resulting in lower, sub-
therapeutic plasma levels of these antibiotics.
This does not only involve such calcium-rich
dairy products as milk, yoghurt, and cheeses,
but also calcium-containing nutritional supple-
ments and calcium-fortified soymilk or juices
(Manhardt and Forum Ernährung Heute, 2000).
Laxatives that contain bisacodyl should not
be swallowed with milk. It can dissolve their
protective coating too early and result in
stomach pain and gastritis. Guar gum, a thick-
ener in many prepared foods such as low-fat
sauces and salad dressings can interfere with
absorption of glucophage, a diabetic medica-
tion (Graedon and Graedon, 1998). Graedon
and Graedon (1998) emphasized that even
aware doctors will have a difficult time find-
ing specific, clear information on how the
drugs they prescribe interact with beverages
and foods. These researchers have developed
a well-researched list of medications accord-
ing to their administration with food or on an
empty stomach. Charcoal-grilled meats, whether
302
these be chicken, beef or fish, contain compo-
nents that induce CYP 1A and speed up the me-
tabolism of antiasthmatic drugs, such as theo-
phylline, and warfarin. Fontana et al. (1999)
reported that char grilled meat induced CYP
1A both in the liver and the small intestines of
all the healthy humans in their study.
A fiber rich diet can reduce the absorption of
drugs such as antidepressants and digoxin (a
life-saving cardiac drug). Meals that were rich
in fat caused a reduction in the maximum serum
concentration of indinavir by an astonishing
84% compared to low-fat meals that included
toast, coffee, cornflakes, jelly, and low-fat milk.
However, administration of saquinavir with a
high-fat diet increased bioavailability by 30%
(Garey and Rodvold, 1998). Garey and Rod-
vold, in their paper on antiretroviral-food in-
teractions, concluded that knowledge of these
interactions will aid in optimizing the phar-
macokinetics of the medical agents and the clin-
ical outcomes of patients with human immuno-
deficiency virus.
It can be concluded that diet and nutritional
state, along with individual CYP enzyme ex-
pression, are important factors that influence
drug efficacy or toxicity, especially because
complexity of drug therapy regimens has in-
creased the potential for interactions to occur.
Although the recent explosion of information
about drug–diet interactions has greatly com-
plicated and confused the use of drugs, even-
tually, such information, if it is clearly under-
stood, will enhance the safety and efficacy of
these medications (Jefferson, 1998). Thus, Gau-
thier and Malone (1998) reported that an ideal
program for preventing food–drug interactions
would include patient counseling and a label-
ing system for selecting the most appropriate
drug administration times for each drug. Fur-
thermore, awareness of potential interactions
by physicians and nurses should be increased
to prevent drug–food interactions in hospital-
ized patients and to prevent decreased drug ef-
ficacy or increased drug toxicity.
With regard to increased awareness of some
medications’ adverse effects, perhaps there is a
phenomenon in health care. Alternative/com-
plementary medicine is no longer considered
to be so “alternative.” A recent survey showed
that 49% of Americans used herbal remedies
SØRENSEN
sporadically during a 12-month period, and
24% used an herbal remedy regularly (John-
ston, 2000). Common reasons for using herbal
remedies were to ensure good health (75%), to
improve energy (61%), to prevent or treat colds
and “flu” (58%), to improve memory (43%), to
reduce anxiety (41%), to ease depression (35%),
and to prevent or treat serious illness (29%)
(Johnston, 2000). To avoid possible interac-
tions, medical herbalists and conventional
physicians need to take a patient’s diet into ac-
count and consider a patient’s use of conven-
tional and alternative/complementary reme-
dies. Whereas patients will easily report use of
conventional medications alternative practi-
tioner, the use of herbal medications or dietary
supplements is seldom reported to the con-
ventional physician (Heck et al., 2000).
DRUG–NUTRIENT INTERACTIONS
In the last decade readily available supple-
ments have been put on the market. These min-
erals and vitamins interact with prescription
medicine and their use is seldom reported to
conventional physicians. For example, vitamin
B6 induces metabolism of anticonvulsant med-
ication (phenytoin) up to 50%, affecting the ef-
ficacy of the drug. Because patients who are on
phenytoin may become deficient in folic acid
and vitamin B6, supplementation of these
substances is problemmatic (Graedon and
Graedon, 1993). Lewis et al. (1995) propose
therefore, to commence folic-acid (folate) sup-
plementation and phenytoin therapy concomi-
tantly because serum folate decreases when
phenytoin therapy is commenced without fo-
late supplementation and subsequent addition
of folate supplements after starting phenytoin
therapy would decrease phenytoin efficacy.
Treasure (2000a) summarises several nutri-
ent and vitamin depletions by common med-
ications. Thus vitamin C is depleted by corti-
costeroids, the bowel flora disrupting activity
of antibiotics results in vitamin B and K defi-
ciency, and anticonvulsants reduce vitamin E
levels, interfere with vitamin K metabolism and
inhibit hepatic vitamin D metabolism. Salicy-
lates and vitmain C compete for common bind-
ing sites, resulting in vitamin C depletion,
while vitamin C diminishes antibiotic activity.
ADVERSE DRUG REACTIONS
Treasure’s compilation of data can be down-
loaded from the Internet.
DRUG–HERB INTERACTIONS
Certain herbs have also been reported to in-
fluence medication metabolism. The most re-
cent (and overextensively reported) interaction
involved Hypericum perforatum (St. John’s wort),
a popular herbal remedy for depression and
mood disorders.
One study showed decreased plasma con-
centrations of digoxin following the use of H.
perforatum (Johne et al., 1999). Ruschitzka et
al. (2000) reported two cases of decreased cy-
closporin plasma concentrations in patients
that underwent heart transplantation. One of
the patients presented with acute heart trans-
plant rejection. Both of these patients had
started taking H. perforatum during their ther-
apy. When the herbal remedy was discontin-
ued, the patients’ cyclosporin levels returned
to a stable state. In a letter to The Lancet (Yue
et al., 2000) reported a reduced anticoagulant
effect of warfarin in association with H. perfo-
ratum.
Media coverage of the interaction studies in-
volving St. John’s wort has been extensive
throughout Europe and the United States dur-
ing the last few months. This media reaction is
astonishing in light of the abovementioned
drug–drug interaction complications. With all
the attention medical mistakes have received
during the last months, it must have come as a
relief to many readers that the focus was now
shifted away from this issue.
DeSmet and Touw (2000) note that, being
that these reports were bound to receive atten-
tion from the lay press, more attention should
have been paid to the potential risk that such
sensational reports might incite in the lay pop-
ulation. St. John’s wort is a very popular sup-
plement and patients should not be advised to
injudiciously discontinue its use because this
could lead to toxic reactions in patients who
have been stabilized on the herb. It was re-
ported that the mechanism involved is hepatic
CYP induction and induction of the drug-
transporter P-glycoprotein mediating intestinal
absorption, distribution, and renal excretion
303
(Johne et al., 1999). Recent studies suggest that
H. perforatum extracts increase the activity of
CYP3A4, which is involved metabolizing more
than 50% of all drugs and, thus, possibly low-
ers the activity of these drugs when adminis-
tered simultaneously (Moore et al., 2000; Roby
et al., 2000). However, controversially, it has
also been reported that H. perforatum should
inhibit P450 enzymes, especially CYP 2D6, CYP
2C9, and CYP 3A4 (Obach, 2000). Markowitz et
al. (2000) reported on a human study and con-
cluded that H. perforatum, when taken at rec-
ommended doses is unlikely to interfere with
CYP 2D6 or CYP 3A4. H. perforatum has also
been reported to increase serotonin levels in pa-
tients who take selective serotonin reuptake in-
hibitors.
However, most reports on herb–drug inter-
actions need more critical evaluation. Many
“interactions” between herbs and drugs do not
necessarily indicate interaction problems but
rather pharmacologic activities of the herbs
themselves. When it is reported for example,
that diuretics may be potentiated by coadmin-
istration of herbal diuretics such as Taraxacum
officinale (dandelion), that hypnotics and anxi-
olytics may react with sedative herbs as Valeri-
ana officinale or Passiflora incarnata, or that car-
diovascular-active herbs such as Crataegus spp.
(hawthorn) may potentiate antiarrhythmic
drugs (Newall and Phillipson, 1999), the term
“interaction” might be inaccurate.
In a 5-year toxicologic study of herbal reme-
dies, relatively few cases involving interactions
between herbal remedies and pharmaceutical
medications have been reported. In addition, of
those reported, none of them were proved con-
clusively. Four possible interactions reported
were; papaya extract (Carica papaya)/warfarin
(increased plasma level of warfarin), Harpago-
phytum procumbens (devil’s claw)/warfarin,
Ginkgo biloba/thiazide diuretics (produced
hypertension), and Oenothera biennis (even-
ing primrose)/anesthetics (produced seizures)
(Shaw et al. 1997). There are documented re-
ports of warfarin–herb interactions for danshen
(Salvia miltiorrhiza), devils’ claw, and dong quai
(Angelica sinensis). These herbs increased war-
farin effects (Heck et al., 2000).
Miller has summarized many drug–herb in-
teractions (Miller, 1998). Ginseng (Panax spp.)
304
may lead to adverse effects such as manic
episodes in patients who are treated with
phenelzine sulfate. These are obvious results,
which could be termed synergistic, or mutually
potentiating, effects rather than interactions.
Thus, valerian (Valeriana officinale), an herbal
sedative, enhances the sedative effect of barbi-
turates. Immune-stimulants (Echinacea spp.)
should not be given with immune-suppressive
medications (corticosteroids and cyclosporin).
Hawthorn (which is known to have cardiac ac-
tivity) may potentiate digoxin. H. perforatum
should not be mixed with MAOIs and SSRIs.
And kelp (Fucus vesiculosus), as a source of io-
dine, might interfere with thyroid hormone-
replacement therapy. Feverfew (Tanacetum
parthenum), ginger (Zingiber officinale), ginkgo,
garlic (Allium sativum), and ginseng (Panax gin-
seng) potentiate anticoagulant therapy and may
alter bleeding times and should, therefore, not
be used concomitantly with warfarin (Miller,
1998).
In a recent review including sources from
MEDLINE® , 1966–98, one author remarks that
many reports lack crucial documentation on
temporal relations and concomitant drug use.
She also notes that there is a consistent absence
of any effort to establish positive identification
of the herb involved and to exclude the effect
of contaminants or adulterants (Fugh-Berman,
2000). She mentions some of the above-men-
tioned interactions. In addition, she noted that
licorice (Glycyrrhiza glabra) increases plasma
concentrations of prednisolone, potentiates hy-
drocortisone activity, and reacts with oral
contraceptives resulting in adverse effects.
Yohimbine (Pausinystalia yohimbe) can cause
hypertension on its own, but lower doses cause
hypertension when combined with tricyclic an-
tidepressants.
It is well known to medical herbalists that
licorice raises blood pressure and is con-
traindicated in such cases. Although the herb
is efficient for healing gastric ulcers (Schambe-
lan, 1994), all health care practitioners need to
be aware of the blood pressure–raising activity
of licorice. Because licorice is not just a herbal
remedy but also is widely available as a con-
fection, heath care professionals need to be
fully aware of G. glabra–induced hypertension
that might be more common than is appreci-
SØRENSEN
ated (Olukoga and Donaldson, 2000, Schambe-
lan, 1994).
Cayenne (Capsicum spp.) increases the bio-
availability of many drugs by enhancing gut
absorption; however, this herb also lowers the
activity of angiotensin-converting enzyme in-
hibitors. Ma huang (Ephedra spp.) reduces the
efficacy of beta-blockers and contributes to el-
evated blood pressure when used with MAOIs
as well as producing this effect on its own
(Treasure, 2000b). Several herbs that contain
coumarins and salicylates or that have an-
tiplatelet properties have the potential to inter-
fere with warfarin therapy, and a theoretical
risk for potentiation of the anticoagulant effect
exists when these herbs are taken with war-
farin. However, there have been no docu-
mented case reports of an interaction of war-
farin with any of those herbs (Heck et al., 2000).
It is, however, essential to evaluate literature
critically on herb interactions. In many cases,
the correct identity of herbal ingredients has
not been established and adverse effects may
be the result of substitution or contamination
of the remedy with a more toxic botanical, a
poisonous metal, or a potent nonherbal drug
substance. Likewise, one needs to be critical in
distinguishing between the likelihood of phar-
macologically suspected interactions and well-
documented clinical studies (DeSmet and
D’Arcy, 1996; Heck et al., 2000). Treasure (2000b)
provides a frequently updated and critically
evaluated herb–drug interaction chart that can
be downloaded from the Internet. In addition,
Herr (2000) frequently reports herb-drug inter-
action research updates that are freely available
on the Internet. The latter author provides a list
of references on this Web site.
DISCUSSION AND CONCLUSION
Instead of blaming foodstuffs, beverages,
and other natural nutrients, medical scien-
tists—practitioners as well as members of the
pharmacological industry—will have to accept
the responsibility of reevaluating the concept
of dosage administration and coadministration
of drugs and adopt a much more differentiated
and individualized system of prescription. Not
only drug–drug interactions have to be con-
ADVERSE DRUG REACTIONS
sidered, but also the phenotype of a patient, the
kind of “metaboliser” he or she is. And, the pa-
tients’ daily diet, intake of supplements, and
lifestyle should also be taken into considera-
tion. Although it is easier to administer a fixed
drug, or a combination of fixed drug dosages,
to patients, a consideration for the future of
medical care is the more work-intensive indi-
vidual treatment of patients. It seems to be the
only way out of the current situation, being that
medications account for 20% of deaths in hos-
pitals and millions of partially severe ADRs
that patients suffer.
Recent advances in understanding drug me-
tabolism and interactions and development of
technical equipment to screen such interactions
promise an eventually wider understanding
of pharmacokinetics. Adverse effects of drug
therapies will be studied in more depth and
will help to contribute to their avoidance. With
the ever-evolving understanding of the subtle
mechanisms of the human body, scientists still
often choose to focus and report on the effects
of isolated substances on isolated cells. Cher-
ishing the newly found equipment and biotech-
nical, analytical methods, many scientists still
fail to see the obvious: any action, reaction, and
activity of a single substance is subject to the
polydifferentiated and multipotent system of
life. This is a system that exposes every single
substance—single as it might be—to a complex
mechanism of adaptation and survival that has
been actively maintaining human existence for
millennia.
Regarding food–drug, nutrient–drug, and
herb–drug interactions, it is obvious that these
involve human existence—one cannot merely
tell patients to refrain from nutrition during
treatment with medications. Yet, the knowl-
edge of how dietary factors can improve or de-
crease drug efficacy can help to design an op-
timal individual regimen. Knowledge of all the
factors involved can help to design drug, nu-
trition, and herbal remedy programs for indi-
vidual patients, avoiding adverse reactions and
promoting healing and health.
It might be interesting, in that context, to re-
search the synergistic effect of certain herbs
with certain medications in order to reduce
xenobiotic inputs. Herbs that increase a pre-
scription drug’s efficacy, when taken concomi-
305
tantly, could allow for lower drug doses—a
possible beneficial interaction that could prob-
ably be researched further. Considering the
many hazardous results of drug–drug interac-
tions and taking patients’ dietary patterns into
account could enable medical practitioners,
herbalists, and the pharmaceutical industry to
evaluate drug administration more critically.
It is fortunate that science is constantly con-
tributing to human knowledge and it is advis-
able that practitioners keep themselves up to
date about new findings. Qualitative and quan-
titative drug administration should be evalu-
ated according to the latest knowledge of
interactions and adjusted to each patient’s in-
dividual response and enzymatic function, as
well as to his or her dietary regime. In light of
the almost-epidemic increase of mortality
caused by the conventional drug administra-
tion system, a new approach should be strongly
encouraged, an approach that could save lives
and improve quality of life for a large percent-
age of the population. Allopathic medical prac-
titioners will have to educate themselves about
supplements and herbal products; whereas
herbal medical practitioners will have to keep
themselves up to date on pharmaceutical de-
velopments.
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