ArticlePDF AvailableLiterature Review

Heart Toxicity Related to Herbs and Dietary Supplements: Online Table of Case Reports. Part 4 of 5

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Background: The purpose of this review was to create an online research summary table of heart toxicity case reports related to dietary supplements (DS; includes herbs). Methods: Documented PubMed case reports of DS appearing to contribute to heart-related problems were used to create a "Toxic Table" that summarized the research (1966 to April, 2016, and cross-referencing). Keywords included "herb," "dietary supplement," and cardiac terms. Case reports were excluded if they were herb combinations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, mushrooms, poisonous plants, self-harm (e.g. suicide), excess dose (except vitamins/minerals), drugs or illegal drugs, drug-herbal interactions, and confounders of drugs or diseases. The spectrum of heart toxicities included hypertension, hypotension, hypokalemia, bradycardia, tachycardia, arrhythmia, ventricular fibrillation, heart attack, cardiac arrest, heart failure, and death. Results: Heart related problems were associated with approximately seven herbs: Four traditional Chinese medicine herbs - Don quai (Angelica sinensis), Jin bu huan (Lycopodium serratum), Thundergod vine or lei gong teng (Tripterygium wilfordii Hook F), and Ting kung teng (Erycibe henryi prain); one an Ayruvedic herb - Aswagandha, (Withania somnifera); and two North American herbs - blue cohosh (Caulophyllum thalictroides), and Yohimbe (Pausinystalia johimbe). Aconitum and Ephedra species are no longer sold in the United States. The DS included, but are not limited to five DS - bitter orange, caffeine, certain energy drinks, nitric oxide products, and a calming product. Six additional DS are no longer sold. Licorice was the food related to heart problems. Conclusion: The online "Toxic Table" forewarns clinicians, consumers and the DS industry by listing DS with case reports related to heart toxicity. It may also contribute to Phase IV post marketing surveillance to diminish adverse events that Government officials use to regulate DS.
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JOURNAL OF DIETARY SUPPLEMENTS
https://doi.org/./..
REVIEW
Heart Toxicity Related to Herbs and Dietary Supplements:
Online Table of Case Reports. Part  of .
AmyC.Brown,PhD,RDN
Complementary and Alternative Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa,
Honolulu, HI, USA
KEYWORDS
Cardiac; heart; toxicity;
dietary supplement; herb;
transplant; plant extract
ABSTRACT
Background: The purpose of this review was to create an online research
summary table of heart toxicity case reports related to dietary sup-
plements (DS; includes herbs). Methods: Documented PubMed case
reports of DS appearing to contribute to heart-related problems were
used to create a “Toxic Table” that summarized the research (1966 to
April, 2016, and cross-referencing). Keywords included “herb,” “dietary
supplement,” and cardiac terms. Case reports were excluded if they
were herb combinations (some exceptions), Chinese herb mixtures,
teas of mixed herb contents, mushrooms, poisonous plants, self-harm
(e.g. suicide), excess dose (except vitamins/minerals), drugs or illegal
drugs, drug-herbal interactions, and confounders of drugs or diseases.
The spectrum of heart toxicities included hypertension, hypotension,
hypokalemia, bradycardia, tachycardia, arrhythmia, ventricular brilla-
tion, heart attack, cardiac arrest, heart failure, and death. Results: Heart
related problems were associated with approximately seven herbs: Four
traditional Chinese medicine herbs – Don quai (Angelica sinensis), Jin
bu huan (Lycopodium serratum), Thundergod vine or lei gong teng
(Tripterygium wilfordii Hook F), and Ting kung teng (Erycibe henryi prain);
one an Ayruvedic herb – Aswagandha, (Withania somnifera); and two
North American herbs – blue cohosh (Caulophyllum thalictroides), and
Yohimbe (Pausinystalia johimbe). Aconitum and Ephedra species are no
longer sold in the United States. The DS included, but are not limited
to ve DS – bitter orange, caeine, certain energy drinks, nitric oxide
products, and a calming product. Six additional DS are no longer sold.
Licorice was the food related to heart problems. Conclusion: The online
“Toxic Table”forewarns clinicians, consumers and the DS industry by list-
ing DS with case reports related to heart toxicity. It may also contribute
to Phase IV post marketing surveillance to diminish adverse events that
Government ocials use to regulate DS.
Introduction
This is the fourth of ve review articles investigating dietary supplements (DSs; includes
herbs). Article one covers DS denitions, usage, ecacy, safety, and an overview of DS
regulation in the United States; articles two through ve cover case reports in tabular form
related to liver toxicity, kidney toxicity, heart toxicity, and cancer (Brown, 2017a–c,inpress;
CONTACT Amy C. Brown amybrown@hawaii.edu University of Hawaii at Manoa, Complementary and Alternative
Medicine, John A. Burns School of Medicine,  Ilalo Street, MEB , Honolulu , HI, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ijds.
©  Taylor & FrancisGroup, LLC
2A. C. BROWN
Tab le  . Potential heart-related problems researched for dietary supplement associations.
Type of heart problem Definition
Hypertension / mm Hg
Hypotension / mm Hg
Hypokalemia Low blood potassium (K) levels
Hypernatremia High blood sodium (Na) levels
Bradycardia Slow heart rate (< beats/minute)
Tachycardia Rapid hear tbeat (+beats/minute) interfering with heart’s ability to pump blood
normally
Arrhythmia Abnormal heart rhythm
Ventricular fibrillation The most serious cardiac rhythm disturbance. The lower chambers quiver so the heart
cannot pump any blood, leading to cardiac arrest.
Myocardial infarction Partial or full blockage of oxygen to the heart; , annual heart attacks in the United
States.
Cardiac arrest Heart stops due to malfunction of heart’s electrical system.
Heart failure Heart is not pumping efficiently.
Death (from heart
disease)
Risk factors are high blood cholesterol and triglyceride levels, diabetes and prediabetes,
overweight and obesity, smoking, lack of exercise, unhealthy diet, stress, age, gender,
and family history (NIH, ).
The term cardiac toxicity was not used in this series of table toxicities as it specifically defines damage to the heart due to
harmful chemicals such as drugs, especially chemotherapy drugs.
©  Amy Brown
this article). Interest in complementary and alternative medicine (CAM), also known as func-
tional, integrative, traditional, or holistic medicine, continues to grow. These terms, often
synonymous with each other, describe health care methods complementing conventional
medicine with modalities such as acupuncture, diet (does not include conventional diets),
dietary supplements, herbs, yoga, tai-chi, chiropractic, massage, meditation (mindfulness-
based stress reduction), prayer, healing touch, biofeedback, and others. Combinations of
these practices include Ayurvedic medicine (India), traditional Chinese medicine (TCM),
Kanpo or Kampo (Japanese), all native traditions, naturopathy, and homeopathy.
Although natural is not always safe, the majority of botanical products appear inherently
safe (Marcus & Grollman, 2002),andsomehavedemonstratedecacy.Thisreviewfocuses
on the potentially life-threatening DSs that increase heart toxicity risk, as detected through
PubMed case reports. Case reports do not always demonstrate causation or association, but
reoccurrences raise concerns (Haaz et al., 2006). In this review, the selected heart toxicities
are dened, the literature search methods employed are described, and a summary table of
theresultsalongwithabriefdiscussionofselectedDSsarepresented.
Methods
The potential heart-related problems researched for this review are listed in Tab l e 1.
Documented PubMed case reports (1966 to April 2016, and cross-referencing) of
DSs appearing to contribute to heart toxicity are listed in “DS Toxic Tables” found at
http://mscr.hawaii.edu/faculty/amybrown/. The broad search included the keywords “plant
extracts” or “plant preparations” with “heart” and “toxicity” (“human” species lter always
selected). The narrowed search included the keywords “herb” or “dietary supplement”
(combined with “heart” to generate an overview list, and possibly “toxicity” to narrow the
selection). Specic herb “names” found through this process were combined with “heart”
and “toxicity.” “Cardiotoxic” “herbs” or “supplement” or “dietary supplement” were searched
for more precise articles. Keywords also included “cardiac,” “cardiovascular,” “arrhythmia,
“tachycardia,” “hypertension,” “hypotension,” “hypokalemia,” “hypernatremia,” “ventricular
JOURNAL OF DIETARY SUPPLEMENTS 3
Tab le  . Breakdown of herb Pubmed case reports related to heart toxicity.
 no longer allowed for sale in the United States
Aconitum spp. etc.
Ephedra (Ephedra sinica)
 herbs remained, but with only – published case reports each
 of these were of Traditional Chinese Medicine origin and not frequently consumed in the United States.
Don quai (Angelica sinensis)
Jinbuhuan(Lycopodiumserratum)
Thundergod vine or lei gong teng (Tripterygium wilfordiiHook F)
Ting kung teng (Erycibe henryi prain)
 originated from India
Aswagandha (Withania somnifera)
 were reported from North America
Blue cohosh (Caulophyllum thalictroides)
Yoh im be ( Pausinystalia johimbe)
 others were from accidental plant poisonings and not dietary supplements
Foxglove (Digitalis Ianata and purpurea)
Henbane (Hyoscyamus niger)
Jimsonweed (Datura st ramonium)
Jin bu huan (Lycopodium serratum)
Lily of the Valley (Convallaria majalis)
Oduvan (Clistanthus collinus)
Squill (Urginea maritima)
Yoh im be ( Pausinystalia johimbe)(repeats)
©  Amy Brown
brillation,” “myocardial infarction,” “cardiac arrest,” “heart failure,” “death,” and sometimes
“toxicity.” The letter “s” was added to or removed from “herb” or “dietary supplement” to
generate the greater abstract number. Case reports were excluded if they involved herb combi-
nations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, mushrooms,
poisonous plants, self-harm, excessive doses (except vitamins/minerals), legal or illegal drugs,
drug–herb interactions, and confounders of drugs or diseases. Since commercial DSs often
include a combination of ingredients, they were treated separately; so were foods. Lastly,
a table of case reports consisted of publications including insucient data to assess heart
toxicity. English articles were the primary focus, but some reports in other languages were
considered if the abstracts were in English.
Results
From this review, approximately seven herbs (not including two that were banned; Tables 2
and 3), ve DSs (not including six no longer sold; Table 4), and one food were related to heart-
toxicity problems (Tabl e 5 ).Theherbsincluded,butarenotlimitedto,fourtraditionalChinese
medicine herbs: Don quai (Angelica sinensis), Jin bu huan (Lycopodium serratum), Thunder-
god vine or lei gong teng (Tripterygium wilfordii Hook F), and Ting kung teng (Erycibe henryi
prain);oneAyruvedicherb:Aswagandha,(Withania somnifera); and two North American
herbs: blue cohosh (Caulophyllum thalictroides)andYohimbe(Pausinystalia johimbe). Aconi-
tum and Ephedra species are no longer sold in the United States. The DSs included, but are not
limited to, bitter orange, caeine, certain energy drinks, nitric oxide products, and a calming
product.SixadditionalDSsarenolongersold(Table 4 ). The one food related to heart prob-
lems was licorice.
Herbs
Among the herbs, seven were found to be related to heart toxicity case reports (Table 2). How-
ever, this does not include the two most problematic herbs (possible increased risk of death):
4A. C. BROWN
Tab le  . Reported cases of heart toxicity related to herb consumption.
Common name Scientific name Suggested active compounds Uses Side-effects (cardiac) References
Aconitum
Aconite
Blue rocket
Devil’s helmet
Leopard’s bane
Monkshod
Mousebane
Queen of all poisons
Wolf ’s ban e
Women’s bane
Chuanwu
Caowu
Numerous species
Root of Aconitum
carmichaeli
Root of Aconitum
kusnezoffii
Aconite alkaloids:
Aconitine
Mesaconitine
Hypaconitine
Traditional Chinese medicine acting as
analgesic and anti-inflammatory to treat
rheumatism, arthritis, bruise, fractures, and
cardiac complaints (Chan, )
Most reports are from China, Taiwan, Hong
Kong, and other Asian countries
Nausea, vomiting, hypotension, tachycardia,
fibrillation, ventricular arrhythmias, asystole,
cardiac arrest, death
But, Tai, & Young ()
( deaths)
(Chan, a)
Chan ()
Chan (a),
Chan (b)
Chan ()
Chan () 
Chan () 
Chan ()
Dickens et al. ()
Dwivedi, Aggarwal, &
Sharma ()
Fatovitch ()
Fitzpatrick et al. ()
Guha et al. ()
Kolev et al. ()
Lin et al. ()
Lin, Chan, & Deng ()
(repeat  cases w/Chan)
Lin, Chou, & Lin ()
McVann et al. ()
Sheth et al. ()
Tai e t al. ()
( deaths)
Aswagandha
Indian ginseng, poison
gooseberry, or winter
cherry
Withania somnifera Alkaloids (isopelletierine,
anaferine, cuseohygrine,
anahygrine, etc.), steroidal
lactones (withanolides,
withaferins) and saponins
(Singh et al., )
Ayurvedic medicine for prevention and
treatment of gastric ulcers and indigestion
Promotes increased lactation
Shock and ventricular tachycardia Dwivedi, Aggarwal, &
Sharma ()
(Continued on next page)
JOURNAL OF DIETARY SUPPLEMENTS 5
Tab le  . (Continued)
Common name Scientific name Suggested active compounds Uses Side-effects (cardiac) References
Blue Cohosh Caulophyllum
thalictroides
Glycosides To promote uterine contractions and induce
labor or abortion
Infant suffered severe multi-organ failure,
was not breathing, and had permanent
central nervous system damage
Gunn&Wright()
Mother of newborn ingested blue cohosh
and infant had acute myocardial infarction,
congestive heart failure, and shock
Jones & Lawson ()
-year-old female developed tachycardia,
diaphoresis, abdominal pain, vomiting,
muscle weakness, and fasciculations after
taking blue cohosh to induce an abortion.
Rao & Hoffman ()
Don Quai Angelica sinensis Z-ligustilide and ferulic acid Popular Chinese herbal medicine for irregular
menses, anemia, postpartum weakness, and
uterine hypotonia
-year-old female with hypertension
(/ mm Hg); also in her infant (/ mm
Hg possibly via breast milk)
Nambiar, Schwartz, &
Constantino ()
Ephedra
Ma Huang
Ephedra sinica Ephedrine alkaloids
The synergistic effect of caffeine
may simultaneously act as a
diuretic causing hypokalemia
and resulting ventricular
arrhythmia (Takeuchi, )
Approved by German Commission E for
cough and bronchitis. Also used for asthma,
edema, weight loss, and energy.
+adverse reports received by
FDA—rapid or irregular heartbeats, increased
blood pressure, chest pain, anxiety,
nervousness, tremor, hyperactivity,insomnia,
heart attack, stroke, psychoses,
hallucinations, seizure, and death.
Several states have banned the sale of
botanical ephedra.
Chen-Scarabelli et al.
()
Dennehy, Tsourounis, &
Horn ()
Haller & Benowitz ()
Naik & Freudenberger
) ( Deaths)
Samenuk et al. )
Jin Bu Huan Lycop odium
serratum
Levo-tetrahydropalmatine; Traditional Chinese medicine used as a
sedative, analgesic, and indigestion aid
Life-threatening bradycardia, respiratory
distress (plus acute hepatitis)
Horowitz et al. ()
Pyrrolizidine alkaloids Centers for Disease
Control and Prevention
(,)
Thunder God Vine
Lei Gong Teng
Tripterygium
wilfordii Hook F
Triptolide (a diterpenoid
epoxide)
Autoimmune suppressant for rheumatoid
arthritis (RA) and systemic lupus
erythematosus (SLE)
-year-old male with hypovolemic shock
leading to death
Chou et al. ()(Death)
 cases of acute cardiogenic shock caused by
myocardial damage
Huang, Li, & Liu ()(
Deaths)
Ting Kung Teng Erycibe henryi Prain Tropane alkaloids Used in Chinese medicine to relieve pain such
as arthritis, sciatica, and traumatic tissue
swelling (Huang et al., )
 cases of mistaken identity resulting in
bradycardia, hypotension, ventricular
tachyarrhythmias
Huang et al. ()
Lin & Chen ()
Kearney, Tu, & Haller
()
Yoh im be Pausinystalia
johimbe
Yohimbine alkaloid Erectile dysfunction and sports enhancement. California Poison Control System reported 
cases over  years (–; /year) of
which % ( cases or /year) were
tachycardia
Banned in Australia, Canada, Netherlands,
and United Kingdom but not United States
(Cohen, )
©  Amy Brown
These case reports are compiled from published articles in the scientific literature.
Gray shading indicates no longer for sale in the United States.
6A. C. BROWN
Tab le  . Reported cases of heart toxicity related to dietary supplements.
Common name Scientific name Suggested active compounds Uses Side-effects (cardiac) and confounders References
Bitter Orange “Extract”
Synephrine
Also known as:
Bigarade orange
Chisil (Korean)
Kitjitsu (Japanese)
Marmalade
orange
Seville orange
Shangzhou
Citrus aurantium
(old name =
Fructus aurantii)
Synephrine alkaloid Ephedra-free substitute for weight loss in the
West
Digestive problems in the East (Fugh-Berman,
)
Heart stimulant in the Mediterranean
(Rossato et al., )
Angina
Tac hyc ardia
Ventricular fibrillation
Myocardial infraction
-year-old female taking  mg Citrus
aurantium ( mg synephrine) had
tachycardia on first day of consumption
Treated, released from hospital, and had
repeated tachycardia when rechallenged 
month later (Firenzuoli, Gori, & Galapai, )
Firenzuoli, Gori, & Galapai
()
Gange et al. ()
Smedema & Müller ()
Stephensen & Sarlay
()
Thomas et al. ()
zhiqiao
Sour orange
Synephrine
Zhi Qiao (Chinese)
Zhi Shi (Chinese)
Caffeine (see energy
drinks)
,,-
Trimethylpurine-
,-dione
,,-Trimethylpurine-,-dione
Methylxanthine alkaloid
Energy boost, alertness, stimulant, weight
loss
-year-old female on diet pills who died
- & -year-old males with tachycardia after
ingesting energy capsules containing  mg
caffeine each, but analysis indicated +
mg/capsule (caffeine toxicity)
Garriottetal.()
Kromhout et al. ()
-year-old female taking over-the-counter
appetite suppressant who died
McGee ()
Calcium Calcium Calcium over , mg/day Osteoporisis Increased risk of ventricular arrhythmias and
cardiac arrest in the presence of
hypercalcemia in patients with chronic kidney
disease (not healthy persons)
Genovesi & Gellieni ()
(Continued on next page)
JOURNAL OF DIETARY SUPPLEMENTS 7
Tab le  . (Continued)
Common name Scientific name Suggested active compounds Uses Side-effects (cardiac) and confounders References
DexaprineDutch brand name Contained synephrine,
oxilofrine, deterenol, yohimbine,
caffeine, theophylline, and
β-methyl-β-phenylethylamines.
Weight loss and energizer for athletes Reports to the Dutch Poisons Information
Center (DPIC) showed that ingestion of as
little as half a tablet caused several cases of
nausea, agitation, tachycardia, and
palpitations and even one case of cardiac
arrest.
Venhuis et al. ()
Removed from Dutch market.
DNP,-dinitrophenol ,-dinitrophenol Weight loss  published deaths in the medical literature
due to hyperthermia, tachycardia,
diaphoresis, and tachypnea. Also causes
cataracts.
Grundlingh et al. ()
TOXBASE, the National Poisons Information
Services (NPIS) in UK was evaluated
(–) and  cases were found—%
experienced tachycardia, five fatalities (four
were acute overdose).
Kamour et al. ()
Energy drinks
(see caffeine)
Varies by
brand—caffeine,
guarana, ginseng,
glucoronolactone,
taurine, etc.
(Clauson et al.,
)
Caffeine
Niacin (liver)
Energy boost, improved aerobic and mental
performance (Alford, Cox, & Wescott, )
-year-old male motocross rider consumed
– cans of a caffeinated energy drink and
experienced ventricular fibrillation followed
by fatal cardiac arrest.
Insomnia, nervousness, headache,
tachycardia, death
Berger ()
Clauson et al. ()
- and -year-old males with palpitations,
irregular heartbeat, and chest discomfort
after excessive caffeinated drink consumption
Di Rocco et al. ()
-year-old male with palpitations, atrial
fibrillation, and syncopal episode after
drinking energy drink. Palpitations twice
before after drinking same products.
Izquierdo et al. ()
-year-old male with chest pain after
drinking – cases of Red Bull daily for one
week.
Scott, El-Hassan, & Khan
()
(Continued on next page)
8A. C. BROWN
Tab le  . (Continued)
Common name Scientific name Suggested active compounds Uses Side-effects (cardiac) and confounders References
-year-old male with myocardial infarction
after drinking – cans of energy drink daily
Solomin, Borron, & Watts
()
-year-old male with chest pain within
– hours after drinking  energy drinks.
Unal ()
-year-old male drank – Red Bull cans
( mg caffeine each) and – Monster cans
( mg each). Possible myopericarditis, but
angina and acute coronary artery vasospasms
followed drinks.
Wilson et al. ()
Herbal ecstasyVaried ingredients
that can change
Ephedra (FDA banned, ) Stimulant -year-old male with hypertension
(/ mm Hg) and ventricular arrhythmias
after taking  capsules
Zahn, Li, & Purssell ()
JackDVaried ingredients
that can change
DMAA or citrus aurantium Weight loss and sports performance -year-old male with angina chest pain and
myocardial infraction
Smith et al. ()
Metabolife Varied ingredients
that can change
Ephedra (FDA banned, ) Weight loss or general well-being -year-old female with myocardial
infarction. Switched from Metabolife  to
Metabolife  E-Z for  month ( mg
ephedrine + mg caffeine twice a day)
Enders ()
LoVecchio, Sawyers, &
Eckholdt ()
-year-old female with transient ischenic
attack associated with Metabolife  use
McBride et al. ()
-year-old female experienced  shocks on
her implantable cardioverter defibrillator
(ICD) firing over a -day period after
consuming Metabolife 
Mehendale, Bauer, & Yuan
()
Company received approximately ,
consumer complaints over about  years
(–), and , were serious adverse
events. This was before the FDA made it
mandatory for companies to report adverse
events.
(Continued on next page)
JOURNAL OF DIETARY SUPPLEMENTS 9
Tab le  . (Continued)
Common name Scientific name Suggested active compounds Uses Side-effects (cardiac) and confounders References
NO (nitric oxide) products Varied ingredients Arginine Athletic performance thought to increase
with NO concentrations by increasing
vasodilation that then increases oxygen and
nutrient delivery (Prosser et al., )
-year-old male with palpitations and
syncope after  grams of arginine
alpha-ketoglutarate.
Prosser et al. ()
-year-old male with palpitations and near
syncope after NO.
-year-old male with palpitations and
headache.
All  had no significant past medical history
and denied medication use.
Sedacalm Varied ingredients
that can change
Flavonoids in passion flower
(Passiflora incarnate)
Insomnia; sedative, hypnotic, antispasmodic -year-old female taking  tables ( mg
each) on first day with vomiting and
ventricular arrhythmias
Fisher, Purcell, & Le
Couteur ()
Xenedrine Varied ingredients
that can change
Ephedra (FDA banned, ) Weight loss Patient with hypertension after taking
Xenadrine EFX for  weeks
Moaddeb, Tofade, &
Bevins ()
Xenadrine EFX- mixture of
caffeine, guarana, and bitter
orange (standardized to
synephrine) (Moaddeb, Tofade,
&Bevins,)
Xenadrine RFA – ephedra
( mg), caffeine ( mg) (–
times/day) (Haller, Jacob, &
Benowitz, )
-year-old male body builder with dilated
cardiomyopathy, dyspnea, dizziness
-year-old male Body builder with
myocardial infarction after taking Xenadrine
RFA (no heart disease history or risk factors)
Riccioni et al. ()
Sachdeva et al. ()
©  Amy Brown
These case reports are compiled from published articles in the scientific literature. Commercial formulations may have changed.
Gray shading indicates no longer for sale in the United States.
10 A. C. BROWN
Tab le  . Reported cases of heart toxicity related to food.
Common
name Scientific name
Suggested active
compounds Uses Side-effects (cardiac) confounders References
Licorice Glycyrrhiza glabra Glycyrrhizic acid,
triterpene saponins,
hydroxycoumarins
Approved by the German Commission E for gastritis,
cough, & bronchitis. Also used for ulcers, inflammation,
& epilepsy.
Hypertension, hypokalemia, hypernatremia,
cardiac arrest, heart failure, death
Hypokalemic paresis (could not walk or hold cup
of coffee) after excess intake of licorice
( gm/day) for  weeks.
Oral contraceptives can predispose a person to
licorice toxicity (Francini-Pesenti et al., )
Achar ()
Albermann et al. ()
Arola ()
Bannister, Ginsburg, & Shneerson ()
Blachley & Knochel ()
Böcker & Breithardt ()
Campana et al. ()
Caubet-Kramar et al. ()
Celik et al. ()
Chamberlain ()
Conn, Rovner, & Cohen ()
Crean, Abdel-Rahman, & Greenwood ()
Cumming et al. ()
Eriksson, Carlberg, & Hillörn ()
Farese et al. ()
Francini-Pesenti et al. ()
Gerritsen et al. ()
Harris ()
Hasegawa et al. ()
Johns ()
Kormann et al. ()
Korri et al. ()
Machalke et al. ()
Minvielle, Cristol, & Badach ()
Miyamoto et al. ()
Montoliu ()
Morgan, Chou, & Stelfox ()
Mumoli & Cei ()
Omar et al. ()
Oztürk et al. ()
Tancevski et al. ()
Toner & Ramsey ()
Yamamoto et al. ()
Yor gu n et a l. ( )
©  Amy Brown
JOURNAL OF DIETARY SUPPLEMENTS 11
Aconitum, which is no longer allowed for sale in the United States, and DS containing ephedra
that were prohibited by the U.S. Food and Drug Administration (FDA) in 2004. Selected acci-
dental plant poisonings were not part of this review, but a few are shown in Ta ble 6 to forewarn
physicians. The remaining seven only had one-to-four publications each, of which four were
traditional Chinese medicinals, one was Ayruvedic (Table 2 ), and two were North American
herbs: blue cohosh and yohimbe. Case reports with confounding variables are summarized in
Tabl e 7 .
Traditional Chinese medicine
China served as the origin for four herbs plus the two no longer sold (Aconitum and Ephedra
species). Shaw (2010) stated that many adverse reports using Chinese herbs are “due to
misuse or abuse of Chinese medicine” (p. 2017) (not following standardized doses or tak-
inglargerdosestofeeltheheartraceorutterorincreasebodytemperaturethinkingthat
this will increase metabolism, referred to as feeling the “burn”) and that some herbs “have
narrow therapeutic ranges (e.g., Aconitum species), so toxic eects are frequently reported”
(p. 2017). Shaw mentioned that “Chinese medicine appears to be relatively safe with compar-
atively few reports of adverse reactions compared with overall drug reports” (p. 2017). The
problem appears to be when TCM herbs such as aconite and ephedra were used dierently
in Western countries (dose, usage, processing, lack of a practitioner, etc.; Zhou et al., 2015).
Nevertheless, perhaps certain Asian DSs increase the potential risk for heart toxicity and need
further investigation.
Dietary supplements–drug interactions
Another factor to consider is DS–drug interactions, but these were not part of this review,
because drug–herb interactions have been covered in 10+extensive reviews (Awang &
Fugh-Berman, 2002; Chung, 2004; Cohen & Ernst, 2010;Huetal.,2005; Izzo, 2012;
Izzo et al., 2005; Posadzki, Watson, & Ernst, 2013; Tachjian, Maria, & Jahangir, 2010;Valli&
Giardina, 2002; Villegas et al., 2001;Yangetal.,2006). The fact remains that approximately
one third (34.3%) of all U.S. adults report concomitant DS and prescription medication use
(Farina, Austin, & Lieberman, 2014). Drug–herb or herb–herb interactions can occur because
some herbs act as substrates for the liver’s drug metabolizing steps, such as cytochrome P450s
(CYPs) and/or P-glycoprotein, leading to altered drug clearance, response, and toxicity (Yang
et al., 2006). The majority of drug–herb interactions were not severe (Posadzki, Watson,
&Ernst,2013), and the most common interactions resulting in cardiovascular side eects
were due to anticoagulants (warfarin, aspirin, and phenprocoumon) and antiplatlets (aspirin
[ASA], clopidogrel [Plavix], prasugrel [Eent], etc.) (Posadzki, Watson, & Ernst, 2013). Izzo
and colleague’s (2005) review on cardiovascular pharmacotherapy noted that plasma digoxin
concentrations decrease with the use of guar gum, St. Johns wort, Siberian ginseng, and wheat
bran.However,itmightbeprudentthatpatientsoncardiovascularorimmunosuppressant
drugs, and especially transplant recipients, to avoid herbs such as St. Johns wort and others
(chamomile, Earl Grey teas, etc.) that can reduce cyclosporine levels (Rahimi & Abdollahi,
2012; Nowack and Nowak, 2005). The American Society of Anesthesiologists recommends
discontinuation of herbal medicines two or more weeks prior to surgery (Dasgupta & Bernard,
2006).
Adulterants
Article 1 in this series addressed adulterated products, dened by the FDA as “tainted prod-
ucts marketed as DS” (Brown, 2017a, p. 457), and drugs are the most common adulterant in
DSs. These drugs are added either minutely through accidental contamination of uncleaned
12 A. C. BROWN
Tab le  . Reported cases of heart toxicity related to poisonous plant consumption.
Common name Scientific name
Suggested active
compounds Uses Side effects (cardiac) References
Foxglove Digitalis lanata
Digitalis pururea
Cardiac glycosides Congestive heart failure
Comfreyleavescanbeconfusedforfoxglove
leaves when the plants are not in bloom
(Lin et al., ).
Tachycardia, bradyarrhythmia, ventricular
fibrillation, & death.
Bain ()
Brustbauer & Wenisch ()
Cardano et al. ()
Dickstein & Kunkel ()
Lacassie et al. ()
Lin et al. ()
Oerther ()
Scherer et al. ()
Henbane Hyoscyamus niger Tropa ne
alkaloids—atropine
(hyoscyamine) and
scopolamine (hyoscine)
Herbal therapy in most traditional medicines
(Alizadeh, )
Stomach complaints, toothaches, ulcers, &
tumors
Hallucinations, confusion, and, less
commonly, tachycardia, arrhythmia,
convulsion, impaired vision, constipation,
flushed skin, and coma 
Bedouin children hospitalized after plant
ingestion—restlessness and hallucinations (
went into a coma)
Aslan et al. ()
Urkin et al. ()
Jimsonweed Datura stra monium Tropane alkaloids
(hyoscyanmine)
Madness, epilepsy, depression. Gout, boils,
abscesses, & wounds (Steenkamp et al., )
Hallucinations, disorientation, tachycardia Glatstein et al. ()
Thabat et al. ()
Tiongson & Salen ()
Jin Bu Huan Lycopodium serratum Levo-
tetrahydropalmatine;
Pyrrolizidine alkaloids
Traditional Chinese medicine used as a
sedative, analgesic, and indigestion aid
Life-threatening bradycardia, respiratory
distress (plus acute hepatitis)
Horowitz et al. ()
Centers for Disease Control and
Prevention, (,)
(Continued on next page)
JOURNAL OF DIETARY SUPPLEMENTS 13
Tab le  . (Continued)
Common name Scientific name
Suggested active
compounds Uses Side effects (cardiac) References
Lily of the valley Convallaria majalis Cardiac glycosides similar
to those in foxglove
plant—convallarin
(concallamarin)
Arrhythmia, cardiac insufficiency, and
nervous heart complaints
Nausea, vomiting, arrhythmia, cardiac shock Alexandre et al. ()
Edgerton ()
Oduvan Clistanthus collinus Lignan lactones, diphyllin
and glycosides such as
Cleistanthin A and B
(Bammigatti et al., )
Remedy in India for arthritis (Dwivedi,
Aggarwal, & Sharma, )
Hypokalemia
 cases of leaf poisoning resulting in
hypokalemia and arrhythmias
Bammigatti et al. ()
Shankar et al. ()
Thomas et al. ()
Squill Urginea maritima Cardiac glycosides Sea squill (Drimia maritima L.) extracts have
been used for centuries for the medical
treatment of heart diseases (Knittel, Stintzing,
& Kammerer, ). Approved by the German
Commission E for cardiac insufficiency,
arrhythmia, nervous heart complaints, &
venous conditions. Other uses include
bronchitis, asthma, whooping cough, and
wounds.
-year-old female ingested  bulbs of squill
as a folk remedy for arthritis.
Nausea, vomiting, hyperkalemia, arrhythmias,
and atroventricular block,  case of death
Tunock et al. ()
Yoh im be Pausinystalia johimbe Yohimbine alkaloid Erectile dysfunction and sports enhancement. Hypertension, tachycardia Friesen, Palatnick, & Tenenbein
()
Banned in Australia, Canada, Europe, and
other countries, but not United States
(Cohen, ).
Linden et al. ()
Varkey ()
©  Amy Brown
These case reports are compiled from published papers in the scientific literature. Commercial formulations may have changed.
14 A. C. BROWN
Tab le  . Insufficient evidence for heart toxicity related to herbs.
Common name Scientific name
Suggested active
compounds Uses
Dietary supplement–induced cardiac injury and
confounders References
Ephedra Ephedra sinica Ephedrine alkaloids Weight loss and sports performance.
Approved by German Commission E for
cough & bronchitis. Also used for asthma,
edema, weight loss, and energy.
Death thought to be due to sudden cardiac arrhythmia in
-year-old female athlete taking ephedrine, and 
different anabolic steroids in  out of  months, with an
alcohol abuse history, and feelings of meaninglessness.
Death followed  days after winning a national fitness
competition.
Thiblin, Mobini-Far, &
Frisk ()
 yr male with hypertension taking Ma Huang
(Herbalife), – tablets twice daily for  months, but also
taking pravastatin
Zaacks et al. ()
©  Amy Brown
These case reports are compiled from published articles in the scientific literature. Commercial formulations may have changed.
Gray shading indicates no longer for sale in the United States.
JOURNAL OF DIETARY SUPPLEMENTS 15
manufacturing equipment or by a deliberate criminal act to create a therapeutic eect. For
example, bumetanide, a loop diuretic, was found in a DS marketed as a dietary aid (Hoggan
et al., 2007).
Despite the limited number of case reports suggesting cardiac side eects from certain
herbs, possible DS–drug interactions, and potential adulterants, certain researchers maintain
“the presumptive belief in some therapeutic ecacy of botanicals as evidenced by a long his-
tory of use in traditional medicine” and “the absence of serious adverse eects, also as evi-
denced by a long history of use in traditional medicine” (Schi et al., 2006, p. 465).
Some DSs may be protective of the heart (e.g., possible increased antioxidant activity and
reduced hypercholesterolemia, postoperative atrial brillation, ventricular arrhythmias, and
mortality) as summarized by several reviews (Ho, Cheung, & Yu, 2012;Ho&Jie,2007;Liu
et al., 2012;Mashour,Lin,&Frishman,1998;Miller,1998; Vogel et al., 2005;Wangetal.,2011).
Those that do not appear protective and are associated with heart toxicity are now briey
discussed, specically aconite, blue cohosh, ephedra (ma huang), foxglove, and yohimbe.
Aconite (Aconitum species)
The FDA’s Poisonous Plant Database lists 326 citations under “Aconitum” (FDA, 2008).
Aconite-containing herbs had the highest number of case report publications in the “DS Toxic
Table,” but they are no longer allowed for sale in the United States. Many reports originated
from China, Taiwan, Hong Kong, and other Asian countries.
Raw Aconitum species roots contain aconitine and other aconitum alkaloids that are well-
known cardiotoxins (Tai, 1992). Severe aconite poisoning can occur after accidental ingestion
of the wild plant or consumption of an herbal decoction made from Aconitum species roots.
Theserootvegetableshavebeenusedtopreparesoupsandmealsfortheirpurportedhealth
benets (Chan, 2014). In traditional Chinese medicine, aconite roots are used as an analgesic,
anti-inammatory, and cardiotonic (Fatovich, 1992), but only after processing to reduce the
toxic alkaloid content. Soaking and boiling during processing or decoction preparation will
hydrolyze aconite alkaloids into less toxic and nontoxic derivatives. However, using larger
doses (50–500 g instead of 3–30 g per person), and/or inadequate preparation (raw instead
of processed), increases the poisoning risk. Even prolonged boiling may not be suciently
protective, if larger than recommended amounts of raw roots are consumed.
In China, herb-induced aconite poisonings were predominantly caused by drinking herbal
medicinal wine (Chan, 2011). In Hong Kong, 17 cases of accidental herb-induced aconite
intoxication occurred among ve hospitals (1989–1991). Most developed tachyarrhythmias,
from which two patients died. This suggests that the possible problem of aconite intoxica-
tion warrants attention, especially in the Far East (1989–1991) (Tai et al., 1992). A case in
India found as little as eight drops of a homeopathic tincture caused a 40-year-old male to
experience bradycardia (Guha et al., 1999). Small amounts, as low as 0.2 mg, of aconitine can
produce severe symptoms that usually occur within seconds to two hours (Tai et al., 1992). If
death occurs, it is usually due to cardiovascular collapse, secondary to arrhythmias or respi-
ratory failure (Guha et al., 1999). Researchers suggested that the public should be warned of
severe poisoning risks related to either culinary or traditional medicinal uses of aconite roots
(Chan, 2014).
Blue cohosh (Caulophyllum thalictroides)
American Indians used “papoose root” or “squaw root” by brewing it as a tea to relieve men-
strual cramps and childbirth pains. Blue cohosh was listed in the United States Pharmacopeia
(USP) as a labor inducer between 1882 and 1905, and with indirect evidence for inducing
16 A. C. BROWN
labor (Dugoua et al., 2008). A 1999 survey reported that it is used by 64% of U.S. midwives, but
they also reported transient fetal tachycardia as one of the side eects (McFarlin et al., 1999).
Three serious case reports were found in PubMed (Dugoua et al., 2008). The rst case was
ofamotheringestingbluecohoshwhogavebirthtoaninfantwithacutemyocardialinfarc-
tion, congestive heart failure, and shock. Ruled out were congenital heart disease, abnormal
coronary arteries, and perinatal asphyxia (Jones, 2008), but possible confounders could have
been thrombus or myocarditis (from viral infections such as Coxsackie). The second patient
involved a 24-year-old woman who drank blue cohosh tea at 40 weeks gestation (gravida 2,
para 0) and the infant had seizures in the right arm; a subsequent CT scan showed an evolving
infarct (Finkel & Zarlengo, 2004). Another case was of a child born with severe multi-organ
hypoxic injury who was not breathing at the time of delivery and who suered permanent
central system damage, which may or may not have been related to the blue cohosh (Gunn &
Wrig ht, 1996).
Use of blue cohosh is often by word of mouth, so incorrect doses may be a contributing fac-
tor, because it is typically administered as a tincture (5 drops every 4 hours or 10 drops in hot
water every 2 hours; Dugoua et al., 2008). Clinicians should recognize the potential toxicity of
blue cohosh (Rao & Homan, 2002) and possibly recommend against using any herbs during
pregnancy and lactation that lack sucient ecacy or safety studies. This is of particular con-
cern since a New York City Poison Control Center case report described a 21-year-old female
developing tachycardia after using blue cohosh in an attempt to induce abortion (Rao &
Homan, 2002). Blue cohosh is one of the herbs listed at www.Natural-HomeRemedies.com
as an eective herb for abortion.
Ephedra (Ephedra sinica and other species)
Ephedra, also known as ma huang, was widely used by Chinese practitioners for 2,500 years
for respiratory symptoms before it was transformed into a popular synthesized ingredient in
Western weight-loss and energy-boosting formulations (Mehendale, Bauer, & Yuan, 2004). It
started to appear more frequently in the United States market between the 1990s and early
2000s (Zell-Kanter, Quigley, & Leikin, 2015), when approximately 2 million or more adults
consumed ephedra-containing products (Bent, Padula, & Neuhaus, 2004). Controlled clinical
trials testing ephedra supported a statistically signicant weight loss (fat burners, so named
because you can feel the “burn”) of two pounds a month over the placebo and a modest eect
on sports performance. However, there was an increased risk of nausea, vomiting, anxiety,
mood change, hyperactivity, and palpitations (U.S. Department of Health and Human Ser-
vices, 2003). The millions of people consuming ephedra resulted in case reports of adverse
events: hypertension, pulmonary arterial hypertension, cardiac dysrhythmias, myocardial
infarction, seizure, stroke, and sudden death (Ender et al., 2003; Haller & Benowitz, 2000;
Samenuk et al., 2002;Woolf,2005). Due to these signicant health problems, the FDA banned
ephedra in 2004 (FDA, 2004b).
The toxicity of ephedra is from ephedrine and pseudoephedrine alkaloids that are also syn-
thesized drugs regulated under the FDA (FDA, 2004b). This chemical substance extracted
from a plant into the pure form is a drug that is sometimes called ephedra. Ephedra is also
sometimes a DS, but the extraction concentration and usage in traditional use diered from
modern approaches, and so did the side eects. Another nontraditional use was adding caf-
feine as a common co-ingredient in ephedra-containing DSs, resulting in possible synergistic
negativeside-eectssuchasheartarrhythmias.
Haller and Benowitz’s (2000) ephedra review found 140 adverse events (July 1997 to March
1999) of which 31% were denite or probable and 31% possible. Among these, 47% involved
JOURNAL OF DIETARY SUPPLEMENTS 17
cardiac symptoms of hypertension (17 reports); palpitations, tachycardia, or both (13 reports);
stroke (10 reports); and seizures (7 reports). Ten resulted in death, and 13 produced perma-
nent disability. There were 3,308 adverse events reported to the FDA’s Center for Food Safety
and Applied Nutritions Special Nutritionals Adverse Event Monitoring System (SN/AEMS)
for all DSs between 1993 and 2001, of which 1,398 (42%) were associated with ephedra-
containing DSs. Of these, 405 (30%) were serious adverse events such as chest pain, hyper-
tension, arrhythmia, myocardial infarction, stroke, or death. Ephedra contributed to more
than 60% of the cases related to cardiovascular events (Mehendale, Bauer, & Yuan, 2004). The
FDA provides an online evidenced-based review on ephedra for health professionals (FDA,
2004a), and reviews have been published by Andraws, Chawla, and Brown (2005), Palamar
(2011), and Woolf et al. (2005).
After approximately 155 deaths, DS containing ephedra became the rst DS to be prohib-
ited by the FDA (Lobb, 2009). The 2004 FDA ban was eective, as the number of ephedra poi-
sonings decreased by more than 98% (Zell-Kanter, Quigley, & Leikin, 2015). Ephedra, one of
the major causes of cardiac adverse events due to herbs, is no longer sold in the United States.
Foxglove (DIGITALIS species)
Digitalin is the heart drug derived from Digitalis,agenusofabout20foxglovespeciesplants.
Digitalis intoxication from drug overdose can also occur from consuming these plants. Inges-
tion is often accidental and commonly caused by confusing foxglove leaves for comfrey leaves
when making tea. Certain areas of Africa have traditional healers for 60%–80% of the black
population, and in one evaluation of 41 autopsies, 44% were found to contain cardiac glyco-
sides (McVann, 1992).
Yohimbe (Pausinystalia johimbe)
Yohimbine is the most common alkaloid found in the bark extract derived from the yohimbe
(Pausinystalia johimbe) plant. Prescriptions were available for erectile dysfunction (ED)
(at dosages of 5–10 mg per day) long before Viagra. Eleven clinical studies showed modest
improvement for ED (approximately 5 mg t.i.d. or 15 mg total a day) (Tam, Worcel, & Wyllie,
2001).Infact,yohimbinehydrochloridewasapharmaceuticaldrugthatisnolongeravailable
due to Viagra’s success (Cohen, 2016).
It has been suggested that dose, and especially in the presence of underlying cardiac condi-
tions, might be a factor in whether a person reacts to yohimbine. Canadian authorities stated
that yohimbine use “may result in serious adverse reactions, particularly in people with high
blood pressure, heart, kidney or liver disease,” and that yohimbine is a prescription drug that
should only be used under the supervision of a health care practitioner. “The use of drugs con-
taining yohimbine (either as yohimbine hydrochloride or yohimbe bark extract) may result”
in side eects such as “increased blood pressure andheartrate,anxiety,dizziness,tremors,
headache, nausea and sleep disorders. It should not be used by children, pregnant or nurs-
ing women” (Health Canada, 2015). Yohimbine supplements are now banned in Australia,
Canada,Europe(e.g.,Belgium,CzechRepublic,Denmark,Ireland,Netherlands,UnitedKing-
dom), and other countries, but not in the United States (Aquilar, 2013).
Despitethesebans,veryfewcasereportsexistinthePubMedliterature,andtheyareallat
higher doses than those used for erectile dysfunction (Tam, Worcel, & Wyllie, 2001). These
three case reports were not listed in the DS table, but rather under poisonous plants because
their doses were excessive (Tab le 5).
rThe rst case is a 16-year-old girl who consumed about 250 mg of yohimbine and
after 20 minutes began to experience anxiety, headache, nausea, palpitations, chest pain,
18 A. C. BROWN
hypertension, tachycardia, tachypnea, diaphoresis, pallor, tremors, and an erythematous
rash (Linden, Vellman, & Rumack, 1985). Serum epinephrine and norepinephrine levels
became elevated.
rA 38-year-old male with diabetes ingested 350 mg of yohimbine and two hours later
experienced chest pains, atrial brillation, and a ventricular rate of 150 beats per minute
(Varkey, 1992).
rA 62-year-old diabetic male was taking yohimbine for nine days, but then ingested
100 tablets (2.0 mg each for a total of 200 mg) plus 4–5 ounces of vodka, and within
90–120 minutes he began to experience anxiety and tachycardia (Friesen, Palatnick, &
Tenenb e i n , 1993).
Using a broader reporting scale, the California Poison Control System reported 235
yohimbine-related adverse events over approximately seven years (34 cases/year during 2000–
2006). These products were taken for sexual enhancement (27.7%), weight loss (9.2%), and
stimulant eects (7.6%). Common adverse event reports in descending order included gas-
trointestinal distress (46%), tachycardia (43%), anxiety/agitation (33%), and hypertension
(25%) (Kearney, Tu, & Haller, 2010). People with panic attacks, hypertension, and post-
traumatic stress disorder (PTSD) due to combat have been reported to be more sensitive
to yohimbine (increased anxiety) (Tam, Worcel, & Wyllie, 2001). Tam, Worcel, and Wyllies
(2001) review of 25 studies revealed a signicant increase in the blood pressure measurable
outcomeinatleasthalfthestudies.Amongthe11additionalstudiesonerectiledysfunction,
there were one or two individuals in half of these studies experiencing elevated blood pressure
and one subject reporting tachycardia (Tam, Worcel, & Wyllie, 2001).
Dose appears important, but knowing the amounts in DSs is problematic because 78%
(38/49) of DSs analyzed did not list ingredient quantities, and among those that did, that
content ranged from 23% to 147% of label amounts (Cohen, 2016). It is critical that consumers
stay within safe limits. Authors of one study stated, “A reexamination of whether yohimbine
should be considered a ‘safe’ dietary supplement under the Dietary Supplement Health and
Education Act) is warranted” (Kearney, Tu, & Haller, 2010, Abstract).
Dietary supplements
Approximately ve DSs (not including the ones no longer sold) were related to heart toxicity
in PubMed case reports, specically, bitter orange, caeine, certain energy drinks, nitric oxide
products, and Sedacalm (Tab l e 4). Those no longer for sale in the formulations associated with
the case reports are dexatrim, DNP, herbal ecstasy, Jack3D, Metabolife 356, and Xendrine EFX
and RFA. Formulations and companies often change, so the original forms of these DS may
no longer available on the market, even if their brand names remain the same or similar. For
example, DS containing ephedra were prohibited in 2004 by the FDA and was no longer listed
as an ingredient in herbal ecstasy, Metabolife 356, and Xenadrine. Several DS case reports had
confounding variables (Table 8). Selected DSs are now discussed, specically, bitter orange,
energy drinks, and caeine.
Bitter orange
Weight loss dietary supplements. The FDA’s 2004 ruling prohibited DS containing ephedra
due to heart toxicity led manufacturers to formulate “ephedra-free” DSs for weight loss and
sports performance (Rossato et al., 2011). The most common substitute was Citrus aurantium,
also known as bitter orange (Bent, Padula, & Neuhaus, 2004). In traditional Chinese medicine,
bitter orange extracts were obtained from the dried fruit peels of certain Citrus plants, often
Citrus aurantium (Holmes & Tavee, 2008). Extracts can also be derived from oranges (Seville,
JOURNAL OF DIETARY SUPPLEMENTS 19
Tab le  . Insufficient evidence for heart toxicity related to dietary supplements.
Common name Scientific name Suggested active compounds Uses
Dietary supplement–induced cardiac injury and
confounders References
Bitter Orange Citrus aurantium
(old name =Fructus
aurantii)
Synephrine alkaloid Ephedra-free
substitute for
weight loss
Myocardial infarction: -year-old woman taking bitter
orange ( mg extract daily for one year); smoker with
underlying cardiovascular disease
Nykamp, Fackih, &
Compton ()
Also known as:
Bigarade orange
Chisil (Korean)
Kitjitsu (Japanese)
Palpitations in -year-old male ingesting . mg
synephrine and  mg caffeine. Preexisting palpitations
two years earlier.
Upadhyay et al. ()
Marmalade
orange
Seville orange
Shangzhou
zhiqiao
Sour orange
Synephrine
Zhi Qiao (Chinese)
Dehydroepiandrosterone
(DHEA)
Dehydroepiandrosterone Dehydroepiandrosterone Weight loss. -year-old male with palpitations after taking high
doses ( mg DHEA) with subsequent rechallenge
( mg), but also taking Redux (dexfenfluramine
hydrochloride) known for cardiovascular side effects and
removed from the market.
Sahelian&Borken
()
Energy drinks(see
caffeine)
Varies by
brand—caffeine,
guarana, ginseng,
glucoronolactone,
taurine, etc. (Clauson
et al., )
Caffeine
Niacin (liver)
Energy boost -year-old male drank  drinks of vodka with energy
drink before experiencing chest pain followed by
thrombus blocking artery that required bypass surgery.
Benjo ()
(Continued on next page)
20 A. C. BROWN
Tab le  . (Continued)
Common name Scientific name Suggested active compounds Uses
Dietary supplement–induced cardiac injury and
confounders References
-year-old female with preexisting mitral valve prolapse
with ventricular fibrillation fatality after drinking “natural
energy” guarana health drink, but patient sensitive to
caffeine
Cannon, Cooke, &
McCarthy ()
-year-old male died of cardiac arrhythmias after
drinking  cans of energy drink, but mixed with street
drug ecstasy (,-methylenedioxymethamphetamine
/MDMA).
Hanan, Strizevsky, &
Raviv ()
year-old male with myocardial infraction after just one
energy drink ( mg caffeine)
Polat ()
Hydroxycut Varies according to type
of product; formulas have
frequently changed.
Hydroxycut gummies. Alpha-quinidine in
olive leaf suggested by Hammond et al.
(); however, caffeine levels need to be
measured. Lady’s mantle “extract,” olive
“extract,” cumin “extract,”wild mine
“extract,” goji “extract,”acerola concentrate,
blueberry, pomegranate, bilberry “extract.
Ingredients listed of which some were
caffeine, Gymnema sylvestre, potassium, etc.
Epigallocatechin (EGCG) in green tea
suggested by Karth et al. ()
Weight loss -year-old female with ventricular tachycardia after
 days of use. Probable cause of arrhythmia (Naranjo
Scale).
FDA “Warning on Hydroxy Products”for liver damage
http://www.fda.gov/ForConsumers/ConsumerUpdates/
ucm.htm
-year-old female with atrial fibrillation after  weeks on
Hydroxycut ( capsules tid) (probable). However, taking
meloxicam that is associated with increased risk of
cardiovascular events (McGettigan & Henry, ).
Hammond et al.
()
Karth et al. ()
XenedrineVaried ingredients that
have changed
Ephedra (FDA banned, ) Weig ht loss -year-old male with myocardial infarction taking
ephedra, Xenadrine (RFA), Hydroxycut for two years.
Flanagan et al. ()
Xenadrine EFS—bitter orange
(synephrine) replaced ephedra -year-old woman with exercise-induced syncope
(transient loss of consciousness and postural tone). Can
precede sudden cardiac death. Taking Xenadrine EFX for 
year, stopped for  months, and restarted on day of
episode and . mile run. Contained DMEA and bitter
orange.
Nasir et al. ()
©  Amy Brown
These case reports are compiled from published articles in the scientific literature. Commercial formulations may have changed.
Gray shading indicated no longer for sale in the United States.
JOURNAL OF DIETARY SUPPLEMENTS 21
Figure . p-synephrine (synephrine) and m-synephrine (phenylephrine) chemical structures.
mandarin, Marrs sweet), clementines, Nova tangerines, and grapefruits (Stohs, Preuss, &
Shara, 2011). These extracts are now dened as bitter orange, bitter orange extract, or more
specically the pure chemical extract, an alkaloid called synephrine (p or m isomer not listed
on labels but shown in Figure 1). Bitter orange–containing DSs are often standardized to 4%–
6% synephrine, but chemical analyses of DSs range widely (Avula et al., 2005).
Synephrine, an alkaloid occurring naturally in some plants, became one of the most
popular stimulants in weight-loss products. The ephedra substitution was made because
synephrine is similar in structure to ephedrine (as shown in Figure 2), an alpha-adrenergic
agonist with some beta-adrenergic properties (Haaz et al., 2006). Synephrine’s physiologic
properties had previously led to two approved drugs:
1. p-Synephrine, referred to as synephrine [a trace amine] or Sympatol, has been sold as
an eye drop pharmaceutical since 1927 under the name oxedrine and marketed as an
intravenous drug to treat hypotension (Rossato et al., 2011).
2. m-Synephrine, known as Neo-Synephrine or phenylephrine, is one of the most widely
used over-the-counter (OTC nasal) decongestants.
Nomenclature confusion. Synephrine has six possible isomers (para, meta, ortho, and each
hasadorlform),butthespecicisomerisrarelyidentiedinstudiesaseitherp-synephrine,
m-synephrine, or both (Allison et al., 2005). The distinction is important because the
synephrine isomers (p and m) are claimed to have dierent safety and ecacy proles. Sidney
Stohs, a consultant for bitter orange extract manufacturers, stated that much of the research
does not identify which form is being used and that p-synephrine does not appear associ-
ated with cardiovascular events (Stohs, Preuss, & Shara, 2011). It is interesting to note that
one study analyzing the para- and meta-synephrine content in six DSs revealed that they only
contained para-synephrine (Santana,Sharpless,&Nelson,2008).
Figure . Ephedrine chemical structure is similar to that of synephrine.
22 A. C. BROWN
rm-synephrine (phenylephrine). It is important to know which isomer is used because
the primary known side eect of phenylephrine (m-synephrine), a sympathomimetic
drug that stimulates the sympathetic nervous system, is hypertension (Bent, Padula, &
Nehaus, 2004). Even eye drops containing a 10% concentration increase blood pressure
(Stavert et al., 2015). Researchers also recommend that Seville orange juice (which con-
tains m-synephrine or phenylephrine) should be avoided by people with severe hyper-
tension, tachyarrhythmias, or narrow-angle glaucoma and those prescribed monoamine
oxidase inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), selegiline
(Emsam), Tranylcypromine (Parnate), and so on (Penzak et al., 2001). Previous DSs con-
taining m-synephrine did not place the standard warning on their label that is found
on nasal decongestants containing this substance: “Do not use this medicine if you have
taken an MAO [monoamine oxidase] inhibitor in the past 14 days” (C.S. Mott Children’s
Hospital, 2017,p.1).
rMethylsynephrine (addition of a methyl group to the αposition in the side chain of
synephrine). In 2016, the FDA mailed seven DS companies letters stating that methyl-
synephrine (also known as oxilofrine, p-hydroxyephedrine) is a substance that does not
meet the statutory denition of a dietary ingredient (FDA, 2016). Under existing law,
the FDA can take action to remove products from the market if they are adulterated or
misbranded.
Serious adverse events. Bent and associates (2004)suggestedthatCitrus aurantium consump-
tion increases blood pressure and the risk of adverse cardiovascular events.
rSixteen serious cardiovascular adverse reports (3.2/year) were linked to bitter orange
or synephrine (isomer not mentioned) by Health Canada (January 1998 to February
2004). Side eects included tachycardia, ventricular brillation, transient collapse, car-
diac arrest, and blackout (Haaz et al., 2006).
rA case report of variant angina was reported by Gange et al. (2006), and a myocardial
infarction case report was reported in a 55-year-old woman consuming a DS (Edita’s
Skinny Pill) containing 300 mg of bitter orange for a year. Other case reports are listed
in Tabl e 4 .
rA randomized, double-blind, placebo-controlled cross-over design with 15 young,
healthy males showed that ingesting a single 900 mg dose of bitter orange standardized
to 6% synephrine resulted in increased blood pressure (systolic and diastolic) and heart
rate up to ve hours (Bui, Nguyen, & Ambrose, 2006).
rSeifert and colleagues’ (2011) review pointed out that six publications indicated blood
pressure increases while six other publications showed no eect. The time between inges-
tion and measurement is important because increased heart rates and blood pressures
occurwithinthersttwohours.Itisalsoimportanttoknowanyotheringredientsand
their dosages.
Co-ingredients. Bitter orange extract is rarely a single DS ingredient, which makes com-
parative analysis dicult. More importantly, the heart toxicity of bitter orange extract, or
synephrine, could be enhanced by other stimulants, especially caeine (Stohs, Preuss, &
Shara, 2012). However, caeine is not as attractive to consumers as “bitter orange” (Rossato
et al., 2011). Other co-ingredients have included, but are not limited to, green tea extract
(epigallocatechin gallate [EGCG]), ginseng, ginkgo biloba, guarana extract (contains caf-
feine), and previously ephedra, which is now illegal in the US (Jordan, Murty, & Pilon, 2004;
JOURNAL OF DIETARY SUPPLEMENTS 23
Rossato et al., 2011). St. John’s wort was added to one DS to enhance the eect of Citrus auran-
tium (Colker et al., 1999).Bothcaninuencetheincreasedordecreasedmetabolismofcer-
tain drugs by inhibiting the liver’s metabolizing enzyme CYP3A4 (Fugh-Berman & Myers,
2004).
Dose. An Intertek Cantox report (toxicology testing corporation) suggested that p-
synephrine is unlikely to have signicant eects on blood pressure and not likely to cause
adverse eects if taken in a dose under 60 mg of p-synephrine alone or 40 mg in combination
with 320 mg caeine (Stohs, 2013). Naturally found in food sources, p-synephrine in orange
juice averages up to 25–40 mg per eight-ounce glass (Stohs, 2013).
However, a 52-year-old female ingesting 500 mg Citrus aurantium (30 mg synephrine; iso-
mer not dened) experienced tachycardia within 24 hours. She was treated and released from
the hospital, but a second tachycardia episode followed one month later when she consumed
the supplement again (Firenzuoli, Gori, & Galapai, 2005). The potential for toxicity limits
the concentration of certain isomers of synephrine in over-the-counter products. Endal, a
nasal decongestant containing phenylephrine (m-synephrine), contains 20 mg per tablet (rec-
ommended dose is two tablets twice a day, totaling 80 mg/day). The dose for oxedrine (p-
synephrine) is approximately 300 mg/day (Haaz et al, 2006). In humans, the minimum adult
lethal dose of m-synephrine is 1,000 mg/day (Haaz et al., 2006). In rats, Citrus aurantium
extract consumption resulted in a dose-dependent mortality (10%–50%) secondary to heart
toxicity (Huang et al., 1995).
Weight loss. Very few ecacy studies have tested synephrine alone (either p or m) for weight
loss, and neither is it sold as a single ingredient in DSs. Rather, synephrine is added to other DS
ingredients. Table 9 shows that synephrine ecacy for weight loss is minimal to nonexistent.
Risk-benet ratio. Cardiovascular events related to bitter orange extract (synephrine; isomer
not dened), if any, might very well be enhanced or caused by other co-ingredient stimu-
lants in DSs such as caeine and or occur in individuals with preexisting cardiac conditions
(Fugh-Berman & Myers, 2004). It appears from existing limited research that synephrine (p or
m) alone is not ecacious for weight loss (Fugh-Berman & Myers, 2004)orenhancedsport
performance (Gutierrez-Hellín et al., 2016), and so any risk, especially cardiovascular risk
(regardless whether due to p- or m-synephrine), would not appear justied.
Energy drinks/caffeine
Caeine-containing energy drinks rst appeared in the United States in 1997 with Red
Bull,followedbybrandssuchasRockstar,FullThrottle,Monster,Amp,Vault,andothers
(Wolk, Ganetsky, & Babu, 2012). Some energy drinks are marketed as DSs (e.g., 5-Hour
Energy, Monster Energy, Rockstar), while others are marketed as conventional foods (e.g.,
Red Bull) (Generali, 2013). A DS “supplements” the diet and contains one or more “dietary
ingredients” listed under the FDA’s DS denition (see Brown, 2017a)andcannotbethesole
item in a meal or diet as a conventional food can. Common ingredients other than sugar
include guarana, ginseng, glucuronolactone, yerba mate, bitter orange, taurine, and niacin
(Tabl e 1 0).
In 2012, the FDA listed numerous adverse event reports of signicant injury or death asso-
ciated with products marketed as “energy drinks” (between January 2004 and October 2012)
(FDA, 2015a). Symptoms ranged from nonserious fatigue, nausea, vomiting, anxiety, and
24 A. C. BROWN
Tab le  . Evidence for synephrine efficacy in weight loss.
Reference Participants Duration (dose) Outcome: Heart effects Outcome: Weight loss
Stohs et al. ()  participants (/group)  hours to measure metabolic rate.
Multiple ingredient DS: Advantra Z, p-synephrine ( mg)
No significant difference in
blood pressure or heart rate.
Increased metabolic rate by  kcals from baseline (it
would take  weeks to = lb [. kg] weight loss).
Placebo resulted in  kcal decrease.
Greenway et al.
()
Pilot study #
Supplement (n=)
Placebo (n=)
 weeks
Multiple ingredient DS: pantothenic acid ( mg); green tea leaf
extract % epigallocatechin gallate/EGCG ( mg); guarana
extract ( mg of caffeine in , mg of guarana extract); bitter
orange ( mg of synephrine in  mg of bitter orange, but
referred to as phenylephrine in article); white willow bark extract
( mg of salicin in  mg); ginger root ( mg); and proprietary
blend (L-tyrosine, L carnitine, and naringin) ( mg)
 weeks
phenylephrine ( mg)
No adverse events . lb (. kg) versus . lb (. kg) weight gain
Pilot study #
Supplement (n=)
No control
. ±. lb (. ±. kg) weight loss (not
significant); resting metabolic rate increased
(p<.)
Zenk et al. ()Treatment(n=)  weeks No adverse events No significant difference in weight
Calorie-restricted diet ( kcals less than estimated energy
requirement) plus exercise, plus multiple ingredient DS: Lean
System ; -aceytl--oxo-dehydroepiandrosterone ( mg); Citrus
aurantium extract ( mg, % synephrine = mg synephrine);
Coleus forskohlii extract ( mg, % forskolin); yerba mate
(, mg); guarana extract (, mg, % caffeine); Piper nigrum
(. mg); dandelion ( mg)
Kalman et al. ()  overweight participants
(BMI >)
Treatment (n=)
Placebo (n=)
 weeks
 kcal/kg plus exercise regimen.
Multiple ingredient DS: caffeine ( mg); ephedrine ( mg);
salicin ( mg); synephrine ( mg)
No adverse events . lb (. kg) difference (p<.)
Note: ephedrine is known to result in weight loss,
but discontinued due to heart toxicity side effects
Colker et al. () Supplement (n=)
Placebo (n=)
Control group
(no pills; n=)
 weeks
, kcal diet plus exercise;
Multiple ingredient DS: C. aurantium extract ( mg; %
synephrine, or . mg); St. John’s wort ( mg); caffeine
( mg).
No adverse events . lb (. kg) weight loss within group (not
between groups as placebo group lost . lbs or
. kg) (p<.); increased metabolic rate by %–%
DS =dietary supplement; BMI =body mass index.
©  Amy Brown
JOURNAL OF DIETARY SUPPLEMENTS 25
Table . Common ingredients found in certain energy drinks.
Ingredient Notes
Bitter orange (Citrus aurantium extract) Synephrine or pure synephrine (isoform not always identified) has reports
related to heart side-effects
Guarana (Paullinia cupana) A Brazilian plant containing “guaranine,”which is nothing more than
caffeine in about twice the caffeine concentration found in coffee beans.
There is approximately %–% caffeine in guarana seeds, compared to
%–% in coffee beans (Sanchis-Gomar et al., )
Ginseng (extract of genus Panax (Panax
ginseng, P quinquefolius, and P japonicus)
Exerts its stimulating effects through a mixture of ginsenosides
Glucoronolactone A component of connective tissue and plant gums that is claimed to
improve endurance of secondary exercise events in animals
Niacin B vitamin (– mg daily recommendation). Nicotinic acid (not
nicotinamide) is used to treat high blood cholesterol at much higher doses
(, to , mg per day), but in some individuals imparts a flushing
warmth that may be perceived as “burn,” a sensation sought by
manufacturers of “fat burners.” Excess consumption of nicotinicacid has
been associated with liver toxicity (Vivekanandarajah, Ni, & Waked, ).
Taurine An amino acid purported to improve mental focus.
Yerba mate (Ilex paraguariensis) A cup of tea brewed from these leaves contains as much caffeine as a cup of
coffee.
©  Amy Brown
ushing to serious conditions such as renal failure, seizures, arrhythmias, chest pain, myocar-
dial infarction, cardiac arrest, loss of consciousness, and death. It has also been reported that
energy drinks are associated with increased platelet activity, which may increase the risk of
coagulation that may then increase the risk of a cardiac event (Pommerening et al., 2015).
Ali and colleague’s (2015) research review of energy drinks listed 43 case reports (between
January 1980 and May 2014) and suggested that some of the adverse eects (e.g., anxiety,
nausea, palpitations) are known reactions to caeine (Generali, 2013). Compared to an eight-
ounce cup of coee that contains about 95 mg of caeine, certain energy products range
widely,suchas47to80mgpereightouncestoashighas207mgpertwoounces.Wolk
et al. (2012) reported that the concentrated nature of energy drinks allows people to inadver-
tently consume toxic caeine doses, possibly leading to cardiovascular events (arrhythmia,
tachycardia), convulsions, coma, and death (Kerrigan & Lindsey, 2005;Wolketal.,2012).
Caeinesaddictivenaturecontributestotheriskofoverconsumption(Holmgren,
Nordén-Pettersson, & Ahlner, 2004),andphysicianshavesuggestedthatexcessiveintakeof
caeine-containing products such as energy drinks be considered a possible cause of coro-
nary vasospasms, particularly in teenagers and young adults (Berger & Alford, 2009;Wilson
et al., 2012). The American Academy of Pediatrics and the American Medical Association
both recommend avoiding energy drink consumption, especially in younger people (Ali
et al., 2015). Tabl e 1 1 lists physician recommendations regarding energy drink consumption
in adolescents.
Table . Recommendations regarding energy drink consumption.
Do not consume more than  can ( mL) of ED per day
Avoid ED consumption before or during sports practice
Individuals with diagnosed cardiovascular anomalies should consult cardiologists before drinking EDs
Do not combine ED consumption and alcohol or other drugs
Possibly problematic for poorly controlled or undiagnosed psychiatric conditions (Clauson et al., )
Parents should be taught potential adverse effects related to ED consumption
Provide continual advice against overconsumption/abuse of EDs
ED =energy drink.
Source: Sanchis-Gomar et al. ().
26 A. C. BROWN
Figure . Caffeine is extracted from tea leaves by steeping them in hot water. Source of tea leaves
image: https://pixabay.com/en/peppermint-garden-green-leaves-/. Source of tea cup image:
https://pixabay.com/en/lemon-tea-tea-cup-of-tea-lemon-/.
Caffeine
Plant leaves contain caeine as a natural insect repellant protecting them from animal con-
sumption.PeoplesteepdriedCamellia sinensis plant leaves in hot water to extract chemicals
and caeine through infusion (Figure 3).
Caeine concentrations. Caeine is a mild central nervous system stimulant that has a long
history of safe use when consumed at these low doses:
rTea (one cup/eight ounces) contains approximately 47 milligrams of caeine.
rCoee (one cup/eight ounces) contains about 95 milligrams of caeine (USDA, 2015).
rCola-type beverages are allowed 0.02% according to the Generally Recognized as Safe
(GRAS) List (FDA, 2015b).
Harmful caeine concentrations have been known for a long time (FDA, 2015b). The phar-
macological dose of caeine used to stimulate central nervous system activity in humans is
approximately 3 mg per kg (FDA, 2015b). Going above this level, or an oral administration of
caeine at 4 mg per kg, has been found to increase blood pressure in fasted individuals (FDA,
2015b). Symptoms include vomiting, abdominal pain, agitation, altered conscious state, rigid-
ity, seizures, ventricular tachyarrhythmia, and death often due to ventricular brillation (The-
lander et al., 2010). Higher caeine concentrations of 5 to 50 grams are linked to fatal out-
comes (Jabber & Hanly, 2013). The acute human fatal dose of caeine appears to be greater
than 170 mg per kg, and a human blood concentration over 100 ug/ml is considered lethal
(Holmgren, Nordén-Pettersson, & Ahlner, 2004).
Over-the-counter supplements used to combat fatigue typically contain 100–200 mg caf-
feine per tablet (Kerrigan & Lindsey, 2005). A teaspoon of powdered caeine is equivalent to
25 cups of coee (Bonner, 2015). A fatal case due to self-inicted excess (10–12 grams) was
reported in a 39-year-old male. Approximately 45 caeine-related fatalities were reported in
PubMed Medline between 1959 and 2010, and 20 of these occurred between 1993 and 2009
(Jabber & Hanly, 2013).
According to a 2006 FDA-sponsored, one-year prospective study, the majority of calls to
the San Francisco poison control center involving DSs represented minor problems, of which
themostcommonDSinvolvedthosecontainingcaeine(approximately47%;caeinemg
notlistedonthelabel).Yohimbeproductswerenextandrelatedto18%ofstimulantsymp-
toms (Haller et al., 2008). Only one death, due to stroke during strenuous physical exertion,
was reported as possibly attributable to caeine ingestion. A search of the National Institutes
of Health (NIH) DS label database (http://www.dsld.nlm.nih.gov/dsld/) listing over 50,000
DS products, revealed 117 products contained caeine as an ingredient, and 26 contained
yohimbe (as of May 2016).
Researchers at the FDA’s Center for Food Safety and Applied Nutrition (Division of Tox-
icology) proposed an in vitro method to test human cardiomyocyte cells for increased beats
per minute (BPM) (Calvert et al., 2015). They found that caeine increased BPM at a toxic
JOURNAL OF DIETARY SUPPLEMENTS 27
level of 250 uM and that phenylethylamine (PEA), higenamine, and ephedrine had the same
eect.
The American Academy of Pediatrics does not recommend the use of caeine in children
because of potential harmful side eects (tachycardia, blood pressure changes) and detrimen-
tal eects on development (neurologic and cardiovascular) (American Academy of Pediatrics,
2011; Generali, 2013).
Foods
By far the greatest number of case report publications, but not the number of people aected,
was for a food (excluding DSs no longer on the market). Licorice can cause cardiac problems
and even death if consumed in excessive amounts. Over 34 case reports exist of excess licorice
consumption linked to cardiac side eects, including hypertension (Tab le 5).
Licorice (Glycyrrhiza glabra)
Glycyrrhiza is derived from the ancient Greek terms “glykos,” meaning sweet, and ‘rhiza,
meaning root. Licorice can cause hypermineralocorticoidism (an uncommon form of hyper-
tension) due to its glycyrrhizic acid content. This acid inhibits 11-ß-hydroxysteroid dehy-
drogenase enzyme type 2 resulting in cortisol-induced sodium retention, potassium loss,
edema, increased blood pressure, and depression of the renin-angiotensin-aldosterone sys-
tem (Omar et al., 2012; Størmer, Reistad, & Alexander, 1993). Table 12 lists possible licorice-
related heart problems (Omar et al., 2012). Hypokalemia, dened as serum potassium levels
less than 3.5 mEq/L (3.5 mmol/L) can cause life-threatening cardiac arrhythmias. Other plants
possibly contributing to hypokalemia include aloe, buckthorn bark/berry, cascara sagrada
bark, rhubarb root, and senna leaf/pod (Myhre, 2000).
Recommended intake. Wide individual variation exists in glycyrrhizic acid susceptibility. The
most sensitive individuals react to approximately 100 mg glycyrrhizic acid (about 50 gm
Tab le  . Excessive licorice consumption–induced side effects.
Cardiovascular Hypertension
Hypertensive encephalopathy
Cardiac arrhythmias and death due to QT prolongation
Heart failure and pulmonary edema
Generalized edema
Embolic ischemia
Neurological Hypokalemic myopathy Stroke
Rhabdomyolysis
Carpal tunnel syndrome
Licorice-induced myoclonus
Occular deficits
Electrolyte and renal abnormalities Hypokalemia
Metabolic alkalosis
Elevated CPK
Acute tubular necrosis due to myoglobinuria
Allergic reactions Occupational asthma
Contact dermatitis
Drug interaction Inhibition of the P and CYPA systems
Potentiation of the effect of warfarin therapy
Digoxin toxicity due to licorice-induced hypokalemia
CPK =creatine phosphokinase; CYP =cytochrome P.
Source: Omar et al. ().
28 A. C. BROWN
Tab le  . U.S. Food and Drug Administration limitations for the use of licorice and its derivatives in foods
( CFR .c).
Food category
Maximum allowable levels in foods
as % glycyrrhizin content Functional use
Baked goods . , 
Alcoholic beverages . , , 
Nonalcoholic beverages . , , 
Chewing gum . , 
Hard candy . , 
Soft candy . , 
Herbs and seasonings . , 
Plant protein products . , 
Vitamin or mineral dietary supplements . , 
All other foods, except sugar substitutes . , 
Also found in laxatives, chewing tobacco, and pharmaceuticals
=flavor enhancer;  =flavoring agent;  =surface-active agent.
Source: Omar et al ().
licorice sweets, assuming a 0.2% glycyrrhizic acid concentration). Healthy individuals expe-
rienced increased blood pressure (systolic/diastolic by approximately 7/4 mmHg) after con-
suming 150 gm per day for two weeks (Leskinen et al., 2014). Most people will experience
adverse eects after consuming 400 mg or more of glycyrrhizic acid each day (Størmer, Reis-
tad, & Alexander, 1993). To protect individuals from excess intake, the European Scientic
Committee on Food set an upper limit of 100 mg/day in 2003 (Scientic Committee on Food,
2003).
Susceptible patients. Cardiovascular patients should be warned to avoid excess licorice, and
its overconsumption should be suspected in patients with unexplained hypokalemia and mus-
cle weakness (Omar et al., 2012). In the United States, glycyrrhizin is generally recognized as
safe(GRAS)withincertainlimitsforvariousfoods(Tabl e 1 3).Candywasthemostoftencited
licorice source in case reports, followed by beverages, laxatives, and chewing tobacco. Another
avenue of ingesting too much glycyrrhizin was reported in the Middle East, specically Egypt
during Ramadan. A thirsty patient had consumed excessive amounts of a beverage called erk
soos that is made by dissolving 2 ounces licorice root in a gallon of water.
Limitations
The“DSToxicTables”inthisreviewseriesarebasedonthePubMedindexingofpeer-
reviewed scientic journal articles, and while comprehensive, they are not entirely inclusive
of all the literature, nor should they be viewed as such. Limiting the literature review to
this resource ensures some degree of standardization. This review did not cover literature
indexing resources from other countries that may have more varied histories or usage of
DSs (including herbs) as part of their traditional treatments: India (Ayruvedic), China
(traditional Chinese medicine), Japan (Kanpo or Kampo), Polynesia, Africa, South America,
and elsewhere. Regional plant names and uses may be dierent and not identied with those
commonly recognized in the United States or reported in PubMed. In addition, this review
did not include non–peer reviewed, but possibly more plethoric, reports found in interna-
tional toxicity lists, MedWatch, NapAlert, Poison Control Centers, MedWatch, World Health
Organization (WHO), commercial entities, and other agencies. The Institute of Medicine
recommended that the FDA work with the nation’s poison control centers as a source of
adverse event reports, but a number of limitations interfere with reliable data, such as
JOURNAL OF DIETARY SUPPLEMENTS 29
inaccurate coding, co-medications, incomplete product information, lack of laboratory test-
ing, and inadequate follow-up (Haller et al., 2008). Underreporting to regulatory authorities
and publication in peer-reviewed journals is a repeating theme for case reports, especially in
developing countries (Neergheen-Bhujun, 2013). Other case report limitations are discussed
in Article 1 of this series (Brown, 2017a).
Further limiting the results were the exclusion criteria of case reports involving herb combi-
nations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, mushrooms,
poisonous plants, self-harm, excess dose (except vitamins/minerals), drugs or illegal drugs,
drug–herb interactions, and confounders of drugs or diseases.
Toxicity tables for proactive protection
The “DS Toxic Tables” are available online to create a virtual online table summary of
PubMed case reports related to DSs that can be continually updated (http://mscr.hawaii.
edu/faculty/amybrown/). Other tables on DSs related to heart problems have been published
(Ernst, 2003; Vogel et al., 2005),butoursattemptstociteallcasereports,doesnotinclude
reviews, restricts confounding variables, and can be continuously updated online.
Additional case reports
The case reports presented here do not reect all the case reports in the literature, so additional
case report submissions, preexisting or new, are welcomed online.
Alternatively,datacanbesubmittedonlinewherecoauthorsareavailabletoassistinwriting
up case reports for 530 publications, after which they will be added to the online table. This
real-time online table can now be accessed by consumers, clinicians, and corporations to nd
DSs and/or their ingredients that have been reported to be related to toxicity. If a DS is related
to toxicity cases, regardless of how small due to idiosyncratic DS reactions, then why impart
the risk to the consumer or corporation?
The safest route for consumers is to avoid potentially toxic DSs. As always, until more
information is available, it appears that DS consumption may not be prudent for people with
liver, kidney, heart, and/or cancer conditions, for organ transplant recipients, two weeks prior
to surgery, during pregnancy (except prenatal vitamins and minerals) or lactation, with con-
comitant medication, with underlying disease (except standard dietary therapies, and/or as
medical treatment) without a physicians approval.
These online “DS Toxic Tables” can contribute to continued Phase IV postmarketing
surveillance and alert government agencies responsible for upholding existing laws regulating
DSs, so that future outbreaks can be curtailed or even prevented.
Bullet summary
Herbs
rApproximately seven herbs have been related to heart toxicity case reports.
rFour of these herbs, plus the two no longer available, originated from traditional
Chinese medicine, so perhaps more research that includes Asian research indexes is
warranted.
rThe FDA no longer allows herbs containing Aconitum or Ephedra species to be sold in
the United States.
30 A. C. BROWN
rPregnant women should consider avoiding blue cohosh for stimulating delivery due to
three case reports suggesting serious cardiac problems in newborns following delivery.
rThe safety of Yohimbine (alkaloid in yohimbe) under DSHEA may need to be reconsid-
ered as it is banned in several countries.
rPatients taking cardiovascular or immunosuppressant drugs, and especially transplant
recipients, should avoid herbs such as St. Johns wort and others (chamomile, Earl Grey
teas, etc.) that can reduce cyclosporine levels.
rThe American Society of Anesthesiologists recommends discontinuation of herbal
medicines two or more weeks prior to surgery.
Dietary supplements
rApproximately ve DSs (not including six formulations no longer sold) were associated
with cardiac events, but based on limited case reports.
rDSs related to heart symptoms include, but are not limited to, bitter orange, caeine,
certain energy drinks, nitric oxide products, and Sedacalm.
rCaeine, a potential co-ingredient, is a known cardiac stimulant.
rDSs most frequently related to heart problems are those for weight loss and body build-
ing.
rIt may be prudent for people with preexisting heart conditions to avoid certain weight-
loss and/or body-building DSs and to follow physician recommendations for energy
drinks.
rPatients with chronic kidney disease and their physicians should be aware of the possi-
bility of calcium supplements contributing to hypercalcemia that may result in possible
arrhythmias and cardiac arrest.
Food
rExcessive licorice consumption resulted in more heart toxicity case reports than all
the DSs currently combined (excluding those no longer sold). Common symptoms are
hypokalemia and muscle weakness.
rPeople with hypertension and other heart conditions need to be advised not to consume
more than 100 mg (about three ounces) of licorice a day.
Declaration of interest
Amy Brown is CEO of Natural Remedy Labs, LLC, and has served as an expert witness in herb and
DS cases. The names, formulations, and corporate name and/or ownership of DSs may change, so any
identicationinthispublicationmaynolongerapply.
About the author
AmyC.Brown,PhD,RDN,receivedherdoctorateinHumanNutritionandFoodsfromVirginiaPoly-
technic Institute & State University. She works at the University of Hawaii’s John A. Burns School of
Medicine in the Department of Complementary and Alternative Medicine. Her research is in medical
nutrition therapy, specically diet, foods, and plant extracts that may hold therapeutic potential for dis-
ease.Shehasauthoredover36scienticpublications,andauthoredUnderstanding Food,thebest-selling
college textbook in its eld.
JOURNAL OF DIETARY SUPPLEMENTS 31
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... A recent review series summarised, in a tabular form, the major organ toxicities caused by herbs and herbal medicines for the liver, kidney and heart, as well as the potential of herbs and dietary supplements of causing cancer (Brown 2017b(Brown , 2017c(Brown , 2018a(Brown , 2018b. The same author published regulatory issues of herbs and dietary supplements in the United States in the fifth article from this review series (Brown 2017a). ...
... The same author published regulatory issues of herbs and dietary supplements in the United States in the fifth article from this review series (Brown 2017a). According to these articles, the largest number of publications on the adverse effects of herbs and herbal medicines on the target organs have been on germander, black cohosh, kava extract and green tea extract for hepatotoxicity; the aristolochic acid-containing herbs guang fang ji and chocolate vine or mu tong for nephrotoxicity; and Don quai Jin bu huan, Thundergod vein, lei gong teng, Ting kung teng, Aswagandha, blue cohosh and Yohimbe for cardiotoxicity (Brown 2017b(Brown , 2017c(Brown , 2018b. A comprehensive search of literature from the past 50 years, in terms of increased risk of cancer due to herb use, highlighted three herbs: guang fang ji and dietary supplements containing guang fang ji or aristolochic acid and two others used as food: bracken fern and Ilex paraguariensis (consumed as herbal infusion under the name 'hot mate' in some regions of South America). ...
... Эхинацея может также вызывать аллергические реакции, сыпь или усугублять астму [33,34]. Солодка содержит глицирризиновую кислоту, тритерпеновые сапонины, гидроксикумарины и может вызывать опасные для жизни сердечные аритмии из-за возникновения гипокалиемии (подобно алоэ и ягодам крушины), а также цирроз печени, отек легких, электролитные и почечные аномалии [35]. Гинкго двулопастное (G. ...
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In the review the historical preconditions for implementation and the state of use (for 2021) of phytogenic substances as growth and productivity stimulators of farm animals are considered. The main aspects of phytobiotics use have been analyzed in detail: 1) mechanisms of action; 2) distinction between phytobiotics and veterinary medicines; 3) species range of the plants used and their active substances; 4) productive efficiency. The following limitations and disadvantages in the use of existing phytobiotics are considered: they do not have a direct anabolic effect and are useless under severe stress, and by the combination of bad factors the negative effect cannot be overcome. In addition, there are problems with their safety. Other limitations - the composition of phytobiotics varies widely, there is no standardization for active substances, and attempts to do this reveal cytoxicity in very small dosages of these compounds (essential oils, saponins, isoquinoline alkaloids). In the prospect of further studies, unique plant sources from Russia are proposed, which are absent abroad and contain ecdysteroids as biologically active components, not available in the phytogenic substances widely used now. Distinctive properties of phytoecdysteroids and ecdysterone as their main representative are as follows: feed additives containing them relieve severe stress, conventional phytobiotics do not have such an effect; have direct anabolic effect; have pleiotropic (multiple) effect. Their use in livestock breeding does not cause fears, as they are safe substances. It is possible to combine such substances with other antimicrobial agents in order to improve bioavailability and prolong the action of the active ingredient of ecdysterone
... Not only do cardiac safety liabilities remain a major obstacle for the pharmaceutical industry, they also pose an increasing concern in the context of environmental risks [141] as they have been associated with exposure to environmental chemicals [142] such as pesticides [143,144], flame retardants [145,146], and polycyclic aromatic hydrocarbons (PAHs) [147,148]. Cardiac safety is also becoming recognized as an issue with dietary supplements and herbal products [149]. ...