Dietary supplements containing prohibited substances: A review (Part 1)

Abstract

Dietary supplements and chemical agents have been used for a number of decades among athletes striving to achieve increased strength and performance. This has led to a huge, growing market for the food supplement industry. The latter’s products are classified as ‘foods’ rather than drugs and are therefore free of the stringent requirements for registration of pharmaceuticals, i.e. no safety and efficacy data are required prior to registration. During the past decade, some dietary supplements have been shown to contain pharmaceutically active components not adequately identified on their package labels. These pharmaceuticals may have unintentionally entered the product or may have been intentionally added. Although the concentrations of these substances may be low and devoid of health or performance-enhancing effects, they may lead to positive doping tests. In Part 1 of this two-part review, a selection of the World Anti-Doping Agency-prohibited illegal stimulants, i.e. ephedrine, pseudoephedrine, sibutramine and methylhexaneamine, are discussed. Certain food supplement labels do mention the presence of natural sources of illegal stimulants, e.g. Ephedra sinica (ephedrine), but do not refer to the chemical entities of ephedrine and its analogues as such. The pharmacological adverse effects of stimulants, in particular those on the cardiovascular system, are briefly reviewed. Suggestions for avoiding these pitfalls are made.

Full text

ORIGINAL RESEARCH
SAJS M VOL. 26 NO. 2 2014 59
REVIEW
Dietary supplements and chemical agents have been used for a number of decades among athletes striving to achieve increased strength
and performance. is has led to a huge, growing market for the food supplement industry. e latter’s products are classied as ‘foods’
rather than drugs and are therefore free of the stringent requirements for registration of pharmaceuticals, i.e. no safety and ecacy data
are required prior to registration. During the past decade, some dietary supplements have been shown to contain pharmaceutically active
components not adequately identied on their package labels. ese pharmaceuticals may have unintentionally entered the product or may
have been intentionally added. Although the concentrations of these substances may be low and devoid of health or performance-enhancing
eects, they may lead to positive doping tests. In Part 1 of this two-part review, a selection of the World Anti-Doping Agency-prohibited
illegal stimulants, i.e. ephedrine, pseudoephedrine, sibutramine and methylhexaneamine, are discussed. Certain food supplement labels
do mention the presence of natural sources of illegal stimulants, e.g. Ephedra sinica (ephedrine), but do not refer to the chemical entities of
ephedrine and its analogues as such. e pharmacological adverse eects of stimulants, in particular those on the cardiovascular system,
are briey reviewed. Suggestions for avoiding these pitfalls are made.
S Afr J SM 2014;26(2):59-61. DOI:10.7196/SAJSM.552
Dietary supplements containing prohibited substances:
A review (Part 1)
P van der Bijl, BSc Hons (Chem), BSc Hons (Pharmacol), BChD, PhD, DSc
Emeritus Professor and Former Head, Department of Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town,
South Africa; and Invited Foreign Professor, Department of Pharmacology, Pirigov’s Russian National Research Medical University, Moscow, Russia
Corresponding author: P van der Bijl (pietervanderbijlcpt@gmail.com)
While it is well recognised that a balanced diet is
the foundation for developing optimal training and
performance, competitive sport and strenuous phys-
ical activity make demands on the human body
beyond its normal physiological range.[1] Some ath-
letes may therefore benefit from additional supplements to help
maintain homeostasis with adequate nutrients and energy in specic
circumstances, especially where food intake or choice is restricted.
For this reason, dietary supplements have been used by athletes for
many years to boost, even by small margins, their strength and per-
formance.
[2-4] Pressure to perform and the potential rewards coupled
with success are powerful driving forces for many top athletes to
continue striving for that chemical competitive edge. For this pur-
pose, they use these dietary supplements as part of their regular
training or competition routine, even if the rationale for using these
products is not always underpinned by solid evidence-based res-
earch.[1] Supplements commonly used include vitamins, minerals,
protein, creatine and various ergogenic compounds. While some
supplements indeed enhance athletic performance, many have no
proven benets, are of uncertain content and purity, and may have
serious systemic adverse eects, including death.
e practice of using dietary supplements among the population
at large and athletes at all levels of competition has led to a huge,
continuously growing, multibillion dollar industry with a worldwide
market estimated at more than $142 billion in 2011 and expected to
rise to $205 billion by 2017.[5] Coupled with aggressive marketing
techniques in which bold as well as unsubstantiated claims are
frequently made, this explosive growth has been further fuelled in
many countries worldwide which have acts similar to the Dietary
Supplement Health and Education Act (DSHEA), which was passed by
the US Congress in 1994. In essence, these acts allow substances that
are marketed as dietary supplements to be regulated as foods rather
than as pharmaceuticals. A dietary supplement is a product taken
orally that contains a ‘dietary ingredient’ intended to supplement the
diet. e ‘dietary ingredients’ in these products may include vitamins,
minerals, herbs or other botanicals, amino acids, and substances
such as enzymes, organ tissues, glandulars and metabolites.[6] Dietary
supplements can be extracts or concentrates, and may be found in
many forms such as tablets, capsules, sogels, gelcaps, liquids or
powders. ey can also be in other forms, such as a bar, but if they
are, information on the label must not represent the product as a
conventional food or a sole item of a meal or diet.[6] Whatever their
form may be, the DSHEA places dietary supplements in a special
category under the general umbrella of ‘foods’, not drugs, and requires
that every supplement be labelled a dietary supplement.[6] Other than
for pharmaceuticals, in which regulatory authorities scrutinise data
on safety and ecacy before giving marketing approval, supplement
manufacturers do not have to prove efficacy for their products,
providing that they do not claim that their preparations can be used
to diagnose, cure, mitigate, treat or prevent diseases. Furthermore,
manufacturers of dietary supplements do not have to demonstrate
their safety, and the burden rests on regulatory authorities to show
that a particular product is harmful before steps can be taken to
ensure its removal from the market.

60 SAJSM VOL. 26 NO. 2 2014
These dietary supplement regulations have facilitated their avail-
ability not only to the population at large and noncompeting ama-
teurs, but especially to professional athletes in whom their use, oen
in
megadoses, is widespread.[7,8] Estimated use in the latter group
varies between 44% and 100%; however, this very much depends
not only on the type of sport but also on the level of competition
and age and gender of the athletes.[8-11] Large quantities of nutrients,
commonly found in normal human diets, are consumed without there
being much knowledge of possible health risks and the maximum
daily safe doses involved. Over the past decade, a new hazard related
to dietary supplement use has been identied in that some products,
marketed under the aegis of the regulatory requirements for foods,
have been shown to contain unapproved pharmaceutically active
ingredients. ese dietary regulations have allowed manufacturers
to bypass the necessity of providing safety and ecacy data for their
products. It is of great concern that a wide variety of dietary supp-
lements contain ingredients not adequately chemically identied on
their packaging labels. ese ingredients, which are sometimes listed
as ‘natural’, ‘herbal’ or otherwise, may constitute prohibited substances.
ey may have inadvertently entered the product, possibly as a result
of accidental cross-contamination in manufacturing plants, or may
have been intentionally added to the supplement, posing a potential
health hazard to all consumers.[4,12] While concentrations of these
non-approved substances may be too small to achieve any health or
performance-enhancing eects, they may be large enough for athletes
to fail a doping test, and scandals appear to be more fre quent.[4]
In recent years, there has been an increase in the number of dietary
supplements containing unapproved pharmaceutical ingredients,
recalled by the Food and Drug Administration.[13] With as many as
150 million citizens in the USA consuming dietary supplements in
some form or another, the challenges that are posed by this growing
and unregulated industry are enormous.
Ephedrine and pseudoephedrine
Although stimulants can easily be detected in laboratories, they
are still popular among athletes. Because the list of legal and illegal
stimulants is extensive, only a selection will be discussed here.
Studies have shown that certain dietary supplements have con -
tained prohibited substances such as ephedrine and its analogues
(pseudoephedrine, methylephedrine, etc.), caffeine, 3,4-methylene-
dioxy-N-methylamphetamine (MDMA, or ‘ecstasy’) and other
amphetamine-related compounds, which may or may not be de-
clared on packaging labels.[12] Ephedrine and its congeners are used
as nasal decongestants and as pressor agents for hypotension. While
caeine is no longer considered a prohibited substance by the World
Anti-doping Agency (WADA) since 2004, the use of ephedrine and
its analogues and MDMA is banned during competition by this
organisation.[14] On certain food supplement labels, natural sources
of ephedrine, e.g. Ephedra sinica – a species of ephedra (ma huang),
which contains the alkaloids ephedrine and pseudoephedrine – are
mentioned instead of the chemical entities of ephedrine and its ana-
logues. Similarly, synephrine is obtained from Citrus aurantium.
Both plant products have been found in dietary supplements that
were labelled as ‘ephedrine free’. Apart from the doping infringement
aspects of supplements containing prohibited stimulants, there are
potential health risks involved that should not be ignored. Ephedrine
has structural similarities with amphetamine and therefore has
similar modes of action and a comparable side-eect prole. Both
ephedrine and pseudoephedrine are stimulants, but they affect
physical achievement dierently. Ephedrine adversely aects running
time over 10 km, but anaerobic performance of athletes increases.[15,16]
Supporting evidence found in a meta-analysis of eight studies was,
however, insucient to demonstrate clear benets in performance
with ephedrine.[17] Similarly, improvements in fatigue and cycling
performance with pseudoephedrine ingestion could not be found,
but in a limited study an improvement in running times over 1.5 km
following the use of this pharmaceutical agent was shown.[18-20]
Adverse effects of ephedrine may be serious. A two- to three-
fold risk of anxiety, increased irritability and agitation (psychiatric
symptoms), insomnia, tremors (autonomic system symptoms) and
heart palpitations (cardiac symptoms) were found on analysis of
71 case reports and 50 clinical trials.[17] In the foregoing analysis of
cases of death, myocardial infarctions, cerebrovascular accidents,
seizures and psychoses were found in some reports. Regarding
pseudoephedrine anxiety, gastrointestinal disturbances and tremors
have been reported.[21] Both ephedrine and pseudoephedrine have
been declared prohibited substances by the WADA.[14]
Sibutramine
Dietary supplements adulterated with sibutramine, an anti-obesity
agent, which do not mention the presence of this compound on the
packaging label, have also appeared on the market. Sibutramine has
been found in products advertised as ‘pure herbal’ slimming capsules
and ‘natural’ tea.[22-24] Urinary metabolites of sibutramine were found
in detectable quantities 50 hours aer administration of a single ‘dose’
of tea to a volunteer.[24] is synthetic anorectic drug, which only has
market approval as a prescription anti-obesity agent, has been on the
WADA prohibited list since 2006. Furthermore, market withdrawal of
sibutramine was recommended by the European Medicines Agency
at the beginning of 2010. is agent produces severe systemic adverse
eects, blood pressure elevation and cardiac eects (tachycardia),
and patients using sibutramine are required to be monitored by a
physician experienced in the treatment of obesity and familiar with
this agent, on a regular basis.
Methylhexaneamine
Methylhexaneamine, a stimulant originally intended to be market-
ed as a nasal decongestant, has been detected as an ingredient of
dietary supplements and was declared a prohibited compound by
the WADA in 2009.[25] e serious adverse eects of this stimulant
have recently been highlighted by a case report on the death of
two US soldiers who were taking commercially available dietary
supplements that contained methylhexaneamine. Both soldiers
collapsed from cardiac arrest during physical exertion and ulti-
mately died.[26] The issues surrounding this stimulant have been
complicated by the fact that methylhexaneamine is found on package
labels under a very wide variety of chemical and non-chemical
names, e.g. 1,3-dimethylamylamine, 1,3-dimethylpentylamine,
2-amino-4-methylhexane, 2-hexanamine, 4-methyl-2-hexanamine,
4-methyl-2-hexylamine, 4-methylhexan-2-amine, dimethylamyl -
amine, methyl hexaneamine, dimethylpentylamine, oradrene, forthan,
forthane, fouramin, geranamine, geranium extract, geranium ower

SAJS M VOL. 26 NO. 2 2014 61
extract, geranium oil, geranium stems and leaves, metexaminum,
methexaminum, etc. Only the names methylhexaneamine and di-
methy lpentylamine appear on the WADA 2011 list of prohibited
agents, creating even further confusion among consumers and
complicating identication. While geranium root extract or geranium
oil are mentioned as natural sources of methylhexaneamine, the
presence of this compound in these plant products could not be
demonstrated on analysis, strengthening the suspicion that it was
added during or aer the manufacturing process.[27]
Conclusion
While food supplements and pharmaceutical agents may enhance
strength and performance of athletes, there is insucient scientic
data to support this theory. Although stimulants have been widely
used among athletes for performance enhancement, these substances
are prohibited by the WADA. In addition, ingestion of stimulants
via accidentally or intentionally contaminated dietary supplements
may lead to failed doping tests and its consequences. e presence
of stimulants in nutritional supplements may also lead to serious
systemic adverse eects; athletes, coaches and sports doctors should
be aware of these pitfalls when using or advising on the intake of these
products. e risk of accidental ingestion of forbidden substances
from dietary supplements can be diminished by using ‘safe’ products
listed on databases such as those available in the Netherlands and
Ge r many.[12]
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