Adulteration of Slimming Products and its
Hasan S Aldewachi*, Yasser F Mustafa, Rahma Najm and Farah Ammar
Department of Pharmaceutical Chemistry, University of Mosul, Iraq
Submission: July 07, 2019; Published: November 21, 2019
*Corresponding author: Hasan Aldewachi, Lecturer of Advanced Pharmaceutical Techniques, PhD Pharmaceutical Analysis, Sheffield Hallam University, Sheffield, UK
How to cite this article: Hasan S A, Yasser F M, Rahma N, Farah A. Adulteration of Slimming Products and its Detection Methods. Glob J Pharmaceu Sci.
2019; 7(5): 555723. DOI: 10.19080/GJPPS.2019.07.555723.
Obesity is a chronic disease associated with serious health problem such as metabolic syndrome, diabetes, hypertension, and cardiovascular disease. Due to the growing trend of returning to nature and the fear of adverse reactions from conventional medicines, people are increasingly resorting to the use of herbal preparations.
Adulterated herbal weight loss products with containing undeclared synthetic drugs are common and responsible for many serious health damages. Because of long-term use and natural origin these preparations give a sense of security. But herbal weight loss formulations also possess undesirable effects and, among other dangers, present a risk connected with deliberate addition of synthetic compounds, deliberate or unintentional replacement of the plant species or simply a risk of mislabeling.
The most undeclared ingredients, which were illegally added include sibutramine, phenolphthalein, bumetanide, and phenytoin in the herbal called products, weight reducing and fat loss supplements. Caffeine, pseudoephedrine, theobromine and amfepramone were also found in the supplements. In the world of Internet ordering, these are the dangers that everyone should be aware of. In this article, we reviewed the safety issues related to adulterated or mislabeled herbal products.
Adulterated synthetic substances were detected in the herbal weight loss products. Health care professionals should make people aware of the risks of taking herbal weight-loss supplements.
Obesity, defined as abnormal or excessive fat accumulation and a Body Mass Index (BMI) above 30 kg/m. The prevalence of obesity, as a major risk for public health, has caused increasingly demand for anti-obesity supplements worldwide. Obesity can be a leading cause of many serious health problems, such as high blood pressure , cancer , type 2 diabetes , gallstones , heart diseases , stroke , erectile dysfunction , nonalcoholic fatty liver  and other health complications.
Management strategies for weight reduction in obese individuals include physical interventions such as exercise, diet, and surgery, behavioural therapies, and medicinal treatments. These strategies may be used alone or in combination for greater efficacy. Most randomized controlled trials (RCTs) evaluating pharmacotherapies include a calorie-controlled diet, and some also encourage participants to increase their physical activity.
Drugs used to induce weight loss may reduce appetite or increase satiety, reduce the absorption of nutrients, or increase energy expenditure. In the past drug therapies, available have included thyroid hormone, dinitrophenol and amphetamines, followed by amphetamine analogues, aminorex, and the fenfluramines . More recently a number of newer agents have been trialled, though only orlistat was approved for long term use (≥24 weeks . In fact, amphetamine, rimonabant and sibutramine licenses have been withdrawn due to an increased risk of psychiatric disorders and non-fatal myocardial infarction or stroke (Table1).
On the other hand, there is an increased tendency to alternative treatments that are mainly based on natural products or formulations for this problem. The increasing demand for natural slimming products can be easily understood mainly because of the false impression that, considering they are natural products, that do not cause either side effects or health damage.
However, recent studies have demonstrated the presence of
non-declared synthetic substances (i.e., adulterants) in the
formulations of these so-called “natural products‟ worldwide
The presence of synthetic substances, such as anorexics,
in natural slimming formulations gives these products higher
efficacy in the treatment of obesity. while the presence of
these ingredients could not be discriminated due to misleading
packaging. Unfortunately, continuous consumption of chemical
slimming products, which are illegally adulterated with synthetic
materials, may cause severe troubles to patients and could be
considered as a threat to individual’s health and even a reason
for mortality [12-14]
Most weigh loss adulterants are compounds that have been
removed from the market by regulatory agencies or were never
approved for use because the formulations are registered in
compositions, or it is adulteration practice violates the laws of
many countries. Adulteration caused a variety of adverse effects
from mild (allergic reactions, fatigue, gastrointestinal upset,
mood disturbances or muscle weakness, nausea, pain, and
respiratory complaints) to moderate (confusion, convulsions,
dermatitis, lethargy or seizures, leucopoenia, sensory
disturbances, vomiting) to severe (carcinomas, cerebral oedema,
coma, intracerebral haemorrhage, poisoning, metabolic acidosis,
multi-organ failure, nephrotoxicity, perinatal stroke, renal or
liver failure or death) life threatening effects see (Figure 1)  .
One notable example is the adulteration of a slimming
product known as Slim 10 by N-nitroso fenfluramine, a
hepatotoxic agent, possibly leading to a fatal case of hepatic
failure in Singapore . N-Nitroso fenfluramine was structurally
modified from fenfluramine, a previously used anti-obesity drug.
The authors concluded that in the absence of a more plausible
cause of liver damage, and with nitrosoamines being known to
be hepatotoxic, the likely cause of hepatocellular necrosis was
the nitrosofenfluramine present. From 2001 to 2002, more than
800 cases of liver damage in Japan were reported among people
taking Chinese weight loss aids containing nitrosofenfluramine
. In the subsequent year, three cases of severe hepatotoxicity
associated with a N-nitrosofenfluramine-containing weight loss
supplement were reported .
Amphetamines and amphetamine-like analogues
(phentermine, diethylpropion, phenylpropanolamine) are
indirect-acting sympathomimetic agents that act by releasing
noradrenaline (NA) from presynaptic vesicles in the lateral
hypothalamus . Mazindol, a related but discontinued drug,
blocks the reuptake of NA by presynaptic neurons. The increase
in NA concentration within the synaptic cleft results in the
stimulation of β2-adrenergic receptors and a resultant inhibition
of appetite. Likewise, amphetamine and its derivatives had been
used to treat obesity since 1937, though their addictive potential soon became obvious and they were removed from the market
for this purpose. Amphetamine- like substances derived from
the β-phenyl ethylamine core structure have been detected in
dietary supplements .
Phentermine has been available since the late 1950s and is
approved for short-term use in the US and Australia. It has been
evaluated as both monotherapy and as combination therapy
though not in large-scale studies . Phentermine has been
used in combination with fenfluramine and with fluoxetine
Combination therapy with phentermine (15mg) fenfluramine
(60mg), demonstrated significantly more weight loss than
placebo in a 28-week RCT .
Another amphetamine-like analogue has been available for
weight loss since the early 1960s; however, there are few if any
RCTs of its long term use especially with large sample sizes .
Diethylpropion (75mg daily) demonstrated significantly greater
weight loss in a small 24-week study of 20 patients than placebo
. Diethylpropion (50mg twice a day) was shown to be more
effective than placebo in a small 6-month RCT with 69 obese
adult patients (9.3kg [95% CI 7-11.5kg] versus 3.1kg [95% CI
1.8-4.3kg] . Greater than 5% weight loss was achieved in
67.6% of diethylpropion patients and 25.0% of those receiving
placebo. The most common side effects were dry mouth and
insomnia These were experienced in the first 3 months but
become less apparent with continuing treatment .
Fenfluramine and dexfenfluramine elevate serum levels of
serotonin (5HT) in the central nervous system by stimulating
5HT release and inhibiting its reuptake. Increased levels of 5HT
appear to stimulate the hypothalamus, which controls satiation
as well as mood, sleep, body temperature and other vital
functions. These agents also activate melanocortin 4 receptors
that in turn stimulate activation of 5-HT2C receptors, producing
an increased release of 5HT within the hypothalamic-pituitaryadrenal
axis which is claimed to lead to hypophagia and anorexia
A meta-analysis of RCTs with fenfluramine and
dexfenfluramine demonstrated higher weight loss than placebo
following up to 12 months of treatment. The greatest efficacy was
shown following 3 months treatment, 3.7kg weight loss, Although
RCTs with fenfluramines (fenfluramine and dexfenfluramine),
either alone  or with phentermine , demonstrated
significant weight-loss, they were withdrawn from the market
due to increased reports of valvular heart disease and primary
pulmonary hypertension . The prevalence rates of both
valvular heart disease and primary pulmonary hypertension
were higher following longer exposure to the fenfluramines .
Fluoxetine, a selective serotonin reuptake inhibitor (SSRI)
that augments 5HT within the central nervous system has
been prescribed off-label for weight loss. Although significant
weight loss was reported with 60mg of this agent in shortterm
studies of 6-8 weeks, with maximum weight loss achieved
at 12-20-weeks, this is followed by a regain in bodyweight
. Most RCTs have not shown a significant difference when
fluoxetine was compared to placebo at 52 weeks . Fluoxetine
generally has a tolerable safety profile with reported adverse
events of headache, asthenia, nausea, diarrhoea, somnolence,
insomnia, nervousness, sweating, and tremor .
Is another antidepressant which inhibits reuptake of
dopamine (DA) and NA resulting in a loss of appetite and
decreased food intake and modest weight loss in obese people
. The efficacy of bupropion as a sustained release formulation
was demonstrated at 48 weeks in obese patients. Weight loss
was dose dependent with 7.5% initial weight loss for subjects
Although bupropion is not approved for weight loss, it has been
used off-label and is currently under evaluation as combination
therapy with naltrexone, a μ-opioid receptor antagonist and
zonisamide, a GABA receptor activator
Orlistat (a gastrointestinal lipase inhibitor) is a synthetic
drug derived from a naturally occurring lipase inhibitor. It does
not directly act on appetite as other obesity pharmacotherapies,
rather it decreases fat absorption by binding to pancreatic lipase,
the principle enzyme that hydrolyses triglyceride.
The long-term efficacy of orlistat (120mg three times daily)
for weight loss has been demonstrated in several RCTs of 2- to 4-
year therapy compared to placebo , as well as improvements
in blood pressure, insulin resistance, and serum lipid levels .
Several systematic reviews in adults and a systematic
review with 2 short-term studies in adolescents demonstrated
significantly more weight loss with orlistat than placebo, 6.2kg
. The most commonly experienced side effects of orlistat
are gastrointestinal and include diarrhea, flatulence, bloating,
abdominal pain, and dyspepsia) .
Sibutramine, a 5HT and NA uptake inhibitor, was originally
developed as an antidepressant and subsequently found to
reduce appetite) . It has 2 active metabolites, which inhibit
NA and 5HT uptake (and to a lesser extent DA) without any
direct effect on neuronal NA, DA and 5HT release. It has been
suggested that sibutramine has a dual action to facilitate weight
loss, an anorectic effect suggested to be mediated through the central α1 and β1 adrenergic receptors and thermogenic effects
through β3 adrenergic receptors peripherally) . Maximal
weight loss occurs by 6 months with sibutramine treatment and
was dose related) .
Apart from increases in BP and heart rate the most
common side-effects reported with sibutramine are dry mouth,
constipation, and headache  associated with a higher
rate of CV events than placebo whilst data from a FDA early
communication indicated that there was an increased rate of
CV events (heart attacks, strokes, resuscitated cardiac arrest,
CV death) in patients with cardiovascular disease and diabetes.
The EMEA concluded that the benefits of sibutramine did
not outweigh the risks and recommended that all marketing
authorisations for medicines containing sibutramine should
be suspended throughout Europe. In 2010, however, the use of
sibutramine was banned because of an increase in the relative
risk for major adverse cardiac events in elderly overweight and
Rimonabant, an endocannabinoid receptor (subtype 1)
blocker, was developed as a result of observations on the appetite
stimulation associated with recreational cannabis use. The drug
has a range of both central and metabolic peripheral effects and
had also been investigated for smoking cessation .
Attrition rates in a pooled study of 5,580 patients without
diabetes and 1,047 patients with diabetes taking rimonabant
20mg daily for one year and a hypocaloric diet were
approximately 40% .
Phenolphthalein had been used as an over-the-counter
laxative and has often been detected together with sibutramine in
adulterated weight-loss supplements products. After finding the
potential carcinogenicity of phenolphthalein, it was reclassified
in 1997 as unsafe and ineffective .
The development of analytical methodologies to selectively
identify synthetic substances as adulterants in phytotherapeutic
formulations is of great relevance from either a clinical or
toxicological point of view.
Toward this end, research involving the development of new
methodologies for this purpose should first select the compound
classes that would probably appear as synthetic pharmaceuticals
in slimming formulations.
After identifying these possible adulterant classes, the most
frequently used pharmaceuticals in each selected class (e.g.,
anorexics) should then be followed through individual studies,
including their possible pharmaceutical associations (e.g.,
anorexics plus anxiolytics).
Figure 2 described below shows most common adulteration
methods involving different pharmaceutical classes. The
classification described in this scheme is based on the
adulteration cases already reported in the literature, involving
the most probable adulterant classes used in slimming
formulations. It is apparent that a systematic study regarding
possible adulterant classes can restrict analytes of interest by
analytical method. The main requirements that must be fulfilled
by the chosen analytical method are selectivity and sensitivity, as the possibility for adulteration is very wide among the
probable classes. Once the adulterant class has been selected,
all other probable adulterants become possible interferents
in the analytical measurement using the selected method.
Furthermore, these interferents should be systematically
investigated to assure the applicability of the method to real
samples, where there is a certain unpredictability regarding the
type and class of adulterant to be found.
Most studies reporting on the adulteration of
phytotherapeutic formulations apply chromatographic methods
to determine and identify the adulterants.
These methods can be applied to complex mixtures, as they
have a high separation capacity. This is an important feature for
the analysis of phytotherapeutic formulations, which may not
only have natural constituents but also synthetic adulterants.
Additionally, HPLC is a well-established and widespread
technique for routine analysis all over the world. Here, the
detection by coupled mass spectrometry (LC-MS or LC-MS/MS)
and nuclear magnetic resonance (LC-NMR) is very advantageous
due to the possibility of adulterant confirmation based on
structural information .
Among the chromatographic methods, gas chromatography
(GC) has been also frequently used for the determination of
adulterants in phytotherapeutics, where GC-MS is the most used
technique, mainly for the determination of benzodiazepines,
anorexics and stimulants .
Furthermore, GC-MS has been the method of choice for the
analytical screening of these adulterant classes. Most of the
described methods are developed for the screening and the
confirmation of the adulterants based on their specific retention
times and some additional spectral information  as well.
The adulterant analysis involves often the quantification and
confirmation of the pharmaceuticals by using the addition of
high purity reference standards .
Capillary electrophoresis (CE) is an analytical technique that
is becoming important among the separation techniques available
for the determination of adulterants in phytotherapeutics. Some
advantages of CE, such as high-resolution power, short analysis
time, and low consumption of chemicals and samples, make it an
attractive method for this kind of investigation .
Among the electrochemical methods, voltammetry is the
most often utilized technique for the analysis of phytotherapeutic
Voltammetric methods enable the sensitive and selective
measurement of organic compounds based on their specific
electrochemical behavior at the working electrode surface .
Electrochemical methods are advantageous in comparison with
separation methods (HPLC and CE). This is because they allow
the measurement of a sample without the total solubilization and
exhaustive filtration steps that are necessary for the separation
of insoluble excipients, as for HPLC and CE .
Furthermore, voltammetric methods are advantageous with
respect to the low cost of instrumentation and the short analysis
time . De Carvalho et al.  used electrochemical methods
to determine amfepramone, the most consumed anorexic all
over the world, in synthetic mixtures containing other anorexics,
benzodiazepines, and antidepressants .
Other relevant pharmaceuticals as adulterants of
phytotherapeutics were systematically investigated by Correia
 using the stripping voltammetry. The selective determination
of seven benzodiazepines (clonazepam, flurazepam, alprazolam,
midazolam, diazepam, medazepam, chlordiazepoxide) was
shown to be possible in the presence of other adulterant classes
(anorexics, antidepressants and hypoglicemics) in different
phytotherapeutic formulations. This methodology permitted
the rapid screening of the samples concerning the presence of
benzodiazepines as adulterants. A simultaneous determination
of benzodiazepines (clonazepam, bromazepam, midazolam,
diaze- pam, medazepam, and flurazepam) was also investigated
by dos Santos et al.  by stripping voltammetry, which also
permitted the selective determination of these pharmaceuticals
in phy- totherapeutic samples. Among the methods applied for
the analysis of adulterants in phytotherapeutics, spectroscopybased
techniques are used less frequently .
Despite their simplicity and low cost in routine analysis,
these methods suffer serious interferences from complex
matrices, such as the herbal formulations. Thus, time-consuming
pre-treatment steps are normally necessary to eliminate the
matrix interferents . The pre-treatment of phytotherapeutic
samples prior to the electrochemical and spectroscopic analysis
involves normally the extraction of the adulterants by using
methanol, ethanol, and chloroformas organic solvents .
The aforementioned electrochemical and spectroscopic
methods permit the rapid screening of adulterants in
phytotherapeutic formulations. The selective determination
of pharmaceuticals based on their specific electrochemical
behavior at electrode surfaces can be also useful as an additional
confirmation method for adulterants. However, the spectroscopic
methods (IR and UV/ vis) work mostly as a screening method for
adulterants, since various organic components of the sample can
absorb the electromagnetic radiation in the same wavelength
regions than the most common adulterants.
The consumption of weight-loss formulations has increased
markedly in the past few years. Both synthetic and natural
products represent these formulations. The identification
of controlled substances, which have been illegally added to phytotherapeutics, is a concern to regulatory bodies, as well as
The adulteration cases already reported in the literature
refer mainly to the use of anorexics, benzodiazepines, and
antidepressants. The increasing interest into the identification
of these frauds, mainly due to the risks of adulterant interactions
in the human body, leads us to predict that many cases will be
uncovered in the future.
In this context, sensitive and selective analytical methods
have been developed. The main adulteration cases have
been reported in Asia and Africa due to low quality control
measures. There are still no officially established regulations by
governmental organizations for the control of phytotherapeutics,
and the adulteration of these formulations are a recurrent
practice all over the world.
The adulterant classes reported on here are the most
frequently cited in adulteration cases related to formulations
that are commercialized for slimming purposes.