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ALTERNATIVE MEDICINES
UPDATE:
A FOCUS ON THE MOST COMMON
PRODUCTS YOUR PATIENTS ARE
USING

Irene Lelekis, Pharm.D. candidate


Complementary and alternative medicine
(CAM) is defined as a group of therapeutic and diag-
nostic disciplines that usually exist outside the insti-
tutions where conventional health care is taught and
provided.1 The National Center for Complementary
and Alternative Medicine (NCCAM) developed a
similar definition in 2002.2 That definition was re-
vised in 2005 to include any practices that have
greater potential for success and benefit to public
health. It divides CAM into 4 categories: mind-body
medicine, biologically based practices herbalss, bo-
tanicals, and dietary regimens), manipulative and
body-based practices, and energy medicine.
Between 1990 and 2000, alternative medicine
use and expenditures increased concurrently. In
1997, 18.4% of prescription users were also taking
an herbal and/or high-dose vitamin.3 In 2002, ap-
proximately 38.2 million adults in the United States
used herbals and supplements.4 More than half
(57.3%) of them used these products to treat specific
conditions; however, only 33.4% told a conventional
health care provider about their herbal or supplement
use. US consumers spent 27 billion in 1997 and over
34 billion in 2000 on CAM therapies, and expendi-
tures continue to rise.5 One-fourth of adults reported
use within the past year.6 Furthermore, CAM use
increases with the number of health conditions and
number of physician visits.2


Dietary supplements are not regulated by the
FDA. Instead, they are defined and marketed under
the Dietary Supplement and Health Education Act of
1994 (DSHEA). Products must include proper label-
ing of all ingredients, which would include the name
and quantity of each dietary ingredient. If the ingre-
dient is botanical in origin, the labeling must include
the part of the plant that represents the active ingredi-
ent. Even though all ingredients must be listed, this
act does not require the label to inform consumers of
potential risks. A lack of standardization in herbals
makes it difficult to understand why a product works
or the reasons for its adverse effects, resulting in a
product whose safety and efficacy is unknown.6 The
US has a goal of standardization to maintain the
same extract and amount of active ingredients in die-
tary supplements, yet the products are regulated less
compared to other countries. In Germany, physi-
cians receive formal accreditation in different spe-
cialties relating to CAM. As a result, 73% of Ger-
mans greater than 16 years old have used at least 1
form of CAM.
In 2005, NCCAM announced the release of
its new 5-year strategic plan to research and educate
physicians and patients about the benefits and disad-





INSIDE THIS ISSUE:
ALTERNATIVE MEDICINES UPDATE:
A FOCUS ON THE MOST COMMON PRODUCTS YOUR
PATIENTS ARE USING



l r" I


mm
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VOLUME 23, ISSUE 8 MAY 2008


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vantages of certain alternative medicines.2 In 2008,
the FDA's Center for Food Safety and Applied Nu-
trition (CFSAN) reported that of the six most com-
monly used dietary botanical supplements, ginseng
has the most adverse effects, followed by echinacea
and garlic.8 Alternative medicine remains a balanc-
ing act between significant benefits, side effects and
potential drug interactions.
According to a review in 2004, the ten most
commonly used herbal products are echinacea, gar-
lic, ginkgo biloba, saw palmetto, ginseng, grape seed
extract, green tea, St. John's wort, bilberry, and
aloe.6 From a 2002 NHIS CAM survey, the top 4
products in the US were echinacea (41%), ginseng
(25%), ginkgo biloba (22%), and garlic (20%).9,10
This article will review the clinical data of the top 4
commonly used products, along with St. John's wort
and alpha-lipoic acid.

Echinacea
Echinacea is the most commonly used herbal
with the least conclusive evidence. The active com-
ponent is unknown, but it may be related to the
amount of echinacosides. Its proposed mechanism of
action involves a stimulatory effect on the immune
system. Different echinacea species can have differ-
ent effects on the immune system and on inflamma-
tion. Echinacea has antioxidant activity, anti-
inflammatory effects via COX inhibition, and antivi-
ral and antifungal activity via leukocyte stimulation.
The most researched benefit of echinacea is its claim
to treat and/or prevent the common cold and general
upper respiratory tract infections (URI).
Most studies determined that echinacea is no
different from placebo. Yale, et al. determined that
Echinacea purpurea does not effectively reduce
symptoms and duration of the common cold.11 A
reason could be that herbals are not standardized due
to varying parts of plant composition, extraction
method, and formulation. Additionally, studies were
not appropriately powered. To account for power
inadequacies, a meta-analysis is currently the only
tool to assess the clinical use of echinacea. Accord-
ing to a Cochrane review of 15 randomized con-
trolled trials (RCT) by Linde, et al., Echinacea pur-
purea is the only preparation that might be effective
in early treatment of colds, but the results are not
clear.12 A meta-analysis of 14 studies by Shah, et al.
found echinacea decreased the incidence of develop-
ing a common cold by 58% and the duration of a


cold by 1.4 days.13 Early URI intervention with a
standardized formulation of echinacea is recom-
mended, and may result in a 23% decrease in symp-
tom severity (p<0.01).14 However, this study used
high doses and frequency for one week (10 doses on
the first day, followed by four doses per day for six
days). The German Commission E has approved E.
purpurea at a recommended dose of 900 mg a day
until symptoms resolve.13
Echinacea is usually well tolerated. General
side effects associated with echinacea are rash and
dyspnea. Hepatotoxicity has been reported in rare
cases. The immunostimulant property of echinacea
combined with immunosuppressants or corticoster-
oids counteract each other and should not be taken
concurrently.

Ginseng
Ginseng's (Panax ginseng) major active com-
ponents are the ginsenosides. Animal studies have
shown that ginseng can stimulate hepatic ribosomes
and protein synthesis, inhibit platelet aggregation,
possibly increase natural killer cell activity and en-
hance the production of interferons. The clinical sig-
nificance of these mechanisms may be prolonged
exercise time, prevention of stress-induced ulcers,
and increased activity of the immune system. Gin-
seng has also been used for its alleged sedative, hyp-
notic, demulcent, aphrodisiac, antidepressant, and
diuretic activity. These benefits may translate to im-
proved stamina, concentration, vigilance, and well-
being. A hypoglycemic effect is due to increased
lipogenesis and glycogen storage.15 A systematic
review of 16 trials sought to determine the efficacy
of ginseng on physical performance, psychomotor
performance and cognitive function, immunomodu-
lation, diabetes mellitus and herpes simplex type-II
infections.16 Results indicate that ginseng root ex-
tract has no compelling evidence for any of these in-
dications.
Side effects are uncommon, but in rare cases
can cause insomnia, diarrhea, vaginal bleeding, se-
vere headache, psychosis, and Stevens-Johnson syn-
drome.15 Siberian ginseng is reported to have the
most adverse effects, especially neurologic symp-
toms such as dizziness and fatigue.8 Ginseng may
inhibit CYP3A4, thereby inhibiting the metabolism
of 3A4 substrates, such as certain calcium channel
blockers and stations. Pharmacodynamic interactions
include potentiation of ethanol's and warfarin's ef-


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PharmaNote







fects, an induction of mania and psychoactive effects
when used concomitantly with phenelzine, and an
increased efficacy of influenza vaccination.17 There
is contrasting data for the pharmacokinetic interac-
tion between ginseng and warfarin. Jiang, et al. did
not show an effect on the metabolism or clearance of
warfarin18, whereas at least three separate trials did
show a decrease in warfarin's AUC.19'20,21 In either
instance, ginseng exerts antiplatelet effects;thus, it
should be used cautiously with warfarin, NSAIDs,
and other supplements with antiplatelet or anticoagu-
lant effects. Other common dietary supplements that
exhibit antiplatelet effects or anticoagulant activity
are feverfew, garlic, ginger, green tea, horse chest-
nut, willow bark, danshen, and dong quai. Adverse
effects worsen when ginseng is taken continuously at
doses greater than 400 mg daily.15

Ginkgo biloba
The flavonoids in gingko biloba increase an-
tioxidant activity, cerebral blood flow (by increasing
prostaglandins and norepinephrine release), and anti-
inflammatory effects (through inhibition of platelet
binding). As a result, it may improve memory defi-
cits and concentration in Alzheimer's patients. Off-
labeled uses of Ginkgo biloba extract (GBE) include
relief of intermittent claudication, tinnitus and ver-
tigo of vascular origin, premenstrual syndrome, and
antidepressant-induced sexual dysfunction.22
A meta-analysis of 4 RCTs before 1998 re-
vealed a small but statistically significant difference
with ginkgo use on cognitive function in patients
with Alzheimers.23 The dose of GBE used was
120-240 mg/day PO divided into 2 to 3 doses for at
least 4 6 weeks. The most recent Cochrane review
from April 2007 identified 33 RCTs that assessed
safety and efficacy of ginkgo in cognitive decline.24
Clinical global improvement (CGIC) showed benefit
when more than 200 mg ginkgo each day is used for
24 weeks (OR 1.66, 95% CI 1.12 to 2.46, P=0.01).
Cognitive function and activities of daily living,
measured by the Crichton Geriatric Scale (CRS), dis-
played benefit for ginkgo (dose less than 200 mg) at
12 weeks (MD -5.0, 95% CI -7.88, -2.12, p=0.0007)
and 24 weeks (SMD -0.16, 95% CI -0.31 to -0.01,
p=0.03). Although ginkgo has a modest effect in the
treatment of cognitive impairment and dementia, ef-
fect sizes were small and may not be clinically sig-
nificant.24 The Hawthorne effect may be responsible
for any proposed benefit if the subjects were not


properly blinded.25
Recommendations for ginkgo to improve
mild-to-moderate dementia and cognitive function
symptoms have become more contradictory within
the last year. Lovera, et al. found that ginkgo did not
statistically improve cognition in multiple sclerosis
patients.26 Dodge, et al. determined that extending
the duration of treatment to assess the safety and ef-
fectiveness of ginkgo does not delay cognitive de-
cline.27 Woelk, et al. found that 480 mg of ginkgo
extract (EGb761) daily for more than 4 weeks en-
hances cognitive function, stabilizes mood, and re-
duces anxiety (p = 0.003).28 Anxiety symptoms im-
proved more with higher doses and higher baseline
anxiety scores.
Side effects are rare, but the most common
are headache, flatulence, nausea/vomiting/diarrhea,
increased risk for bleeding, and possible infertility.
One case report found that trazodone use with
ginkgo lead to oversedation.29 Gingko increases the
effects of calcium channel blockers by possibly in-
hibiting their metabolism via CYP3A4. Ginkgo used
in dangerously high doses could lead to seizures or
loss of consciousness, especially in patients with a
history of seizures. The cause could be related to the
ginkgo nuts which contain a potent neurotoxin, and/
or CYP2C19 induction by ginkgo leading to sub-
therapeutic levels of phenytoin and valproic acid.30

Garlic
Garlic (Allium sativum L.) is converted to the
active component, allicin, when crushed. Allicin
claims to decrease cholesterol by inhibiting hepatic
cholesterol biosynthesis32, enhancing cholesterol
turnover to bile acids, and through enhanced bile
acid excretion.33 The net effect on lipids is a pro-
posed decrease in LDL and VLDL, with an increase
in HDL. S-allyl-cysteine (SAC) is one of the main
active and bioavailable components.34 SAC is the
most abundant water-soluble organosulfur compound
in aged garlic extract (AGE). B-chlorogenin contrib-
utes to antiplatelet activity.
In the most recent systematic review of 5
studies for hypercholesterolemia, garlic was esti-
mated to decrease total cholesterol levels by 4 to 6%
vs. placebo (-0.41 mmol/L, 95% CI, -0.66 to -0.15
mmol/L).5 An NIH-funded, randomized, clinical
trial reported that no form of garlic in reasonable
doses has statistically significant effects on LDL.35
Six months of using 1.8 mg AGE 6 days per week


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PharmaNote







slightly increased LDL by 0.2 mg/dL vs. placebo (CI
-5.3 to 5.7, p = 0.29). Another systematic review
stated that the effects were too small to be clinically
relevant.36 Garlic is suggested to have anti-
hypertensive, anti-diabetic, antithrombotic and anti-
hyperhomocysteinemia effects, along with biological
activities including antimicrobial, antioxidant, anti-
carcinogenic, antimutagenic, antiasthmatic, immuno-
modulatory and prebiotic.33 It has an anticoagulant
effect through inhibition of platelet adhesion.37 The
change in platelet function may contribute to the
lipid effect, as well as decrease the progression of
colorectal adenomas in humans.38 Complications of
sickle-cell anemia are decreased due to the signifi-
cant antioxidant activity on sickle RBCs.39
The most common side effects associated
with garlic are bad breath and body odor.33 It stimu-
lates CYP enzymes, thus increases metabolism of
drugs such as saquinavir. Using a standardized prod-
uct such as AGE will not stimulate P450 enzymes
nor produce severe gastrointestinal toxicity.34 AGE
showed no significant difference in major adverse
events (hemorrhage and bleeding) or minor events
(headache, fatigue, colds, and dizziness) compared to
placebo.40 Due to its extraction method, AGE has a
greater and more consistent efficacy and safety com-
pared with any other form of garlic.33 AGE may be
the only well standardized preparation, and is safe
even with high doses.

St John's Wort
St John's wort is the sixth most commonly
used product1 and the herbal with the most drug in-
teractions7. The extract Hypericum perforatum L.
contains hypericin, hyperforin, and flavonoids, all of
which may contribute toward the treatment of de-
pression. St. John's wort inhibits serotonin, norepi-
nephrine, and dopamine re-uptake, decreases inter-
leukin-6 levels, and increases corticotropin-releasing
hormone.5
Randlov, et al. confirmed that hypericum has
a clinically significant effect in minor depressed pa-
tients (HAM-D score 7 to 17).41 St. John's wort is
equivalent to TCAs (RR 1.03, 95% CI, 0.93-1.14;
seven trials) and SSRIs (RR 0.98, 95% CI, 0.85-1.12;
six trials) for treating mild to moderate depression.42
Patients given hypericum extracts were 25% less
likely to drop out of trials compared to TCAs (OR
0.25, 95% CI, 0.14-0.45) and 60% compared to
SSRIs (OR 0.60, 95% CI, 0.31-1.15). Although


there was no standardization of the extract, most
RCTs used LI-160 (hypericum perforatum) at an av-
erage dose of 900 mg daily for 8 weeks. There is no
evidence to support the benefits of hypericum in se-
vere depression.
Side effects are usually minor and uncom-
mon, slightly less than standard antidepressants, and
significantly less than older antidepressants.41 They
include gastrointestinal symptoms, dizziness, confu-
sion, tiredness and sedation. High and long-term
dosing will increase LFTs and contribute to the ad-
verse effects of other drugs. St. John's wort primar-
ily induces CYP 3A4 and P-glycoprotein (Pgp),
which will increases the metabolism of drug sub-
strates. According to Markowitz and colleagues,
3A4 substrates represent approximately 50% of all
marketed medications.43 Concomitant St. John's
wort did not affect carbamazepine, dextromethor-
phan, mycophenolic acid, and pravastatin.44 Serious
and life threatening interactions occur when cyc-
losporin, anticoagulants, digoxin, antidepressants,
and protease inhibitors are taken with St John's Wort.
The combination with SSRIs and other agents that
potentiate serotonin can cause serotonin syndrome.

Alpha-Lipoic Acid
Alpha-lipoic acid (ALA) is an endogenous,
potent antioxidant that has recently been labeled as
the only FDA approved supplement indicated for
neuropathy.45 Sola, et al. suggested that the anti-
inflammatory effects, when combined with its anti-
thrombotic effects, may improve endothelial dys-
function.46 This translates to improved neuropathic
symptoms, including stabbing pain, burning pain,
paresthesia, and sleep numbness, along with a
marked decrease in neuropathic deficits in patients
diagnosed with distal symmetric polyneuropathy
(DSP).45 Other proposed benefits include decreased
blood glucose, increased insulin sensitivity, and neu-
roprotection, but further studies are warranted.
A dose of 600 mg daily for at least 5 weeks
resulted in side effects confined to the gastrointesti-
nal tract. Other doses were studied in the Sympto-
matic Diabetic Neuropathy 2 trial (SYDNEY2), but
600 mg had a similar efficacy and favorable safety
profile to higher doses. Sixty-two percent of patients
experienced greater than 50% reduction in neuro-
pathic symptoms after 3 weeks vs 26% of patients
receiving placebo (p<0.05).45 Oral formulations are
comparable to intravenous. A meta-analysis com-


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PharmaNote







Table 1. Summary of Clinical Data
Product Citation Trials Population studied Dose Author's Conclusions

23% decrease in symp-
Echinacea Shah, et al. Patients with symptoms of the 900 mg 23 decrease in symp-
Meta-analysis toms, incidence, and
(E. purpurea) 2007 -early common cold daily incidnc nd
duration of cold


t systematic Physical/psychomotor perform- 200 600
Ginseng 19 review of 16 ance, cognitive function, immu- mg extract No indications for use
trials nity, DM, HSVII infections daily


Co -> 200 mg 66% improvement in
Cochrane re- > 200 mg
Ginkgo biloba Birks, et al. view of 33 Patients with symptoms of de- daily x 24 cognitive symptoms
(GBE, EGb761) 2007 mentia and/or cognitive decline and similar SEs vs pla-
RCTs weeks
cebo (p = 0.01)

No form of garlic sig-
Mild to moderate hypercholes- 4 g clove/ .N
Garlic Gardner, et al. Mild to moderate hypercholes- 4 g clove nificantly decreased
(AGE) 2007 RCT terolemia (LDL: 130 190 mg/ day, 6 d/wk LDL-C;up to 4-6%
(AGE) 2007 dl) x 6 months LDL-C;upto 4-6%
dl) x 6 months d
decrease

Significantly better than
St. John's wort L e Cochrane re- w s o m 240 1800 placebo, Similar effi-
(hprm Linde, et al. Patients with symptoms of mild Ls S
(hypericum, view of 37 mg daily x cacy to ADs, Less SEs
e2005 o moderate depression
LI 160) RCTs 4-12 weeks and more drug interac-
tions

600 mg po Decreased neuropathic
a-lipoic acid Ziegler, et al.
c ad et a RCT DM type 1 or 2 with neuropathy daily x 5 pain symptoms and
(ALA) weeks deficits (p<0.05)

RCT = randomized controlled trial; DM = diabetes mellitus; HSVII = herpes simplex virus II; SEs = side effects; ADs = antidepressants (TCAs and SSRIs); PO = by
mouth

bined data from the four major studies (ALADINI, for using CAM. Although there is some evidence
ALADIN III, SYDNEY, and NATHAN II) that sup- that echinacea decreases the severity and/or duration
plemented 600mg of parenteral ALA over a period of the common cold, more well-designed trials are
of three weeks. The authors suggested that this regi- needed. Alpha-lipoic acid is the only FDA proven
men of ALA is safe and superior to placebo in clini- supplement indicated for neuropathy.
cal treatment of neuropathic symptoms and deficits.47 Use all herbal supplements with extreme cau-
A rare side effect of ALA is insulin autoimmune syn- tion in children less than two years of age and in
drome, which causes hypoglycemia when autoanti- pregnancy or lactation. Since there is no standardi-
bodies are produced to insulin.48 Dose dependent zation of extracts, and no warning labels to address
effects such as nausea, vomiting, and vertigo are also potential adverse effects, treat herbals as medicinal
uncommon. Drug interactions appear minimal, if products with side effect profiles and potential for
any.45 drug interactions. In the future, highlighting the po-
tential side effects and drug interactions on the prod-
Summary uct packaging may help prevent inadvertent use in
More than 25% of Americans use herbal vulnerable individuals.
products, yet patients (and health-care professionals)
often lack accurate information about their safety and References
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PharmaNote Volume 23, Issue 8 May 2008







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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

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Shawn Anderson Assistant Editor
Pharm.D.


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Phamaot Vlue 3, sse My 00


Volume 23, Issue 8 May 2008


PharmaNote




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