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Background: Weight loss and sports supplements containing deterenol have been associated with serious adverse events including cardiac arrest., Objective: To determine the presence and quantity of experimental stimulants in dietary supplements labeled as containing deterenol sold in the United States., Methods: Dietary supplements available for sale in the US and labeled as containing deterenol or one of its synonyms (e.g., isopropylnorsynephrine and isopropyloctopamine) were purchased online. For each brand, one container or subsample was analyzed by NSF International (Ann Arbor, MI) and one container or subsample by the Netherland's National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands). When differences existed between the two containers or subsamples of the same brand, both products were reanalyzed by Sciensano (Brussels, Belgium). NSF International carried out qualitative and quantitative analyses using ultra-high-performance liquid chromatography (UHPLC) quadrupole-Orbitrap mass spectrometry. RIVM performed qualitative and quantitative analysis using UHPLC quadrupole time-of-flight mass spectrometry. Sciensano carried out qualitative analysis using UHPLC quadrupole-Orbitrap mass spectrometry., Results: Seventeen brands of supplements were analyzed. Many brands included more than one prohibited stimulant in the same product: 4 brands (24%, 4/17) included 2 stimulants, 2 (12%, 2/17) combined 3 stimulants, and 2 (12%, 2/17) combined 4 stimulants. The range of quantities per recommended serving size of the 9 stimulants detected were 2.7 mg to 17 mg of deterenol; 1.3 mg to 20 mg of phenpromethamine (Vonedrine); 5.7 mg to 92 mg of beta-methylphenylethylamine (BMPEA); 18 mg to 73 mg of octodrine; 18 mg to 55 mg of oxilofrine; 48 mg of higenamine; 17 mg of 1,3-dimethylamylamine (1,3-DMAA); 1.8 mg to 6.6 mg of 1,3-dimethylbutylamine (1,3-DMBA); and 5.3 mg of 1,4-dimethylamylamine (1,4-DMAA)., Conclusion: Weight loss and sports supplements listing deterenol as an ingredient contained 9 prohibited stimulants and 8 different mixtures of stimulants, with as many as 4 experimental stimulants per product. These cocktails of stimulants have never been tested in humans and their safety is unknown.

Background: Higenamine is a stimulant with cardiovascular properties recently prohibited in sport by the World Anti-Doping Agency (WADA). Higenamine is also a natural constituent of several traditional botanical remedies and is listed as an ingredient in weight loss and sports supplements sold over-the-counter in the United States., Objectives: We analyzed dietary supplements available for sale in the United States prior to WADA's prohibition of higenamine in sport for the presence and quantity of higenamine., Methods: All supplements labeled as containing higenamine or a synonym (i.e., norcoclaurine or demethylcoclaurine) available for sale in the United States were identified. For each brand, one sample was analyzed by NSF International (Ann Arbor, MI) and one sample by the Netherland's National Institute for Public Health and the Environment (RIVM). NSF International carried out qualitative and quantitative analyses using ultra high performance liquid chromatography (UHPLC) with tandem mass spectrometry. RIVM carried out qualitative analysis using UHPLC quadrupole time of flight mass spectrometry for an independent confirmation of identity., Results: Twenty-four products were analyzed. The majority of supplements were marketed as either weight loss (11/24; 46%) or sports/energy supplements (11/24; 46%); two brands did not list a labeled indication. The quantity of higenamine (±95% CI) ranged from trace amounts to 62 ± 6.0 mg per serving. Consumers could be exposed to up to 110 ± 11 mg of higenamine per day when following recommended serving sizes provided on the label. Five products (5/24; 21%) listed an amount of higenamine, but none were accurately labeled; the quantity in these supplements ranged from <0.01% to 200% of the quantity listed on the label., Conclusion: Dosages of up to 62 ± 6.0 mg per serving of the stimulant higenamine were found in dietary supplements sold in the United States.

Background: The United States Food and Drug Administration banned the stimulant 1,3-dimethylamylamine (1,3-DMAA) from dietary supplements and warned consumers that the stimulant can pose cardiovascular risks ranging from high blood pressure to heart attacks., Objectives: We designed our study to determine if a new stimulant similar in structure to 1,3-DMAA has been introduced as an ingredient in supplements sold in the United States (US)., Methods: We analyzed six brands of supplements that listed an ingredient on the label (e.g., Aconitum kusnezoffii, DMHA or 2-amino-isoheptane) that might refer to an analog of 1,3-DMAA. Supplements were analyzed by two separate laboratories using ultra-high-performance liquid chromatography mass spectrometry and reference standards., Results: Two previously unidentified 1,3-DMAA analogs (2-amino-6-methylheptane [octodrine] and 1,4-dimethylamylamine [1,4-DMAA]) and two banned stimulants (1,3-DMAA and 1,3-dimethylbutylamine [1,3-DMBA]) were identified. Octodrine was found at a dose (±95% CI) of 72 ± 7.5 mg per serving. In Europe, octodrine was previously sold as a pharmaceutical in multi-ingredient medications at dosages from 8 to 33 mg. The quantity of octodrine found in our study was more than twice the largest pharmaceutical dose. The other new stimulant, 1,4-DMAA, has not previously been approved for human consumption, and its safety in humans is unknown. 1,4-DMAA was found at dosages between 21 ± 11 mg to 94 ± 48 mg per serving. In addition, two banned stimulants - 1,3-DMAA and 1,3-DMBA - were also identified: 24 ± 7.6 mg to 35 ± 11 mg of 1,3-DMAA and 51 ± 16 mg of 1,3-DMBA. In one product, 24 ± 7.6 mg of 1,3-DMAA was combined with 21 ± 11 mg of 1,4-DMAA. 1,3-DMAA has been investigated as potentially contributing to hemorrhagic strokes and sudden death, whereas the safety of 1,3-DMBA in humans is unknown., Conclusion: Two banned stimulants (1,3-DMAA and 1,3-DMBA) and two previously unidentified stimulants (1,4-DMAA and octodrine) were identified in supplements sold in the United States.

The United States Food and Drug Administration (FDA) has introduced manufacturing standards for dietary supplements, including red yeast rice, to assure their identity, purity, strength, and composition. One supplement commonly used to self-treat high cholesterol, red yeast rice, may contain monacolin K, an ingredient identical to prescription lovastatin. We examined whether FDA's manufacturing standards led to standard concentrations of the statin monacolin K in red yeast rice supplements. We analyzed 28 brands of red yeast rice supplements by ultra-high performance liquid chromatography-diode array detector-quadrupole time-of-flight mass spectrometry for monacolin K content. Monacolin K was not detected in two brands. In the 26 brands that contained monacolin K, the quantity ranged more than 60-fold from 0.09 to 5.48 mg per 1200 mg of red yeast rice. Following the manufacturers' recommendations for daily servings, the quantity of monacolin K consumed per day would range more than 120-fold from 0.09 to 10.94 mg. Despite FDA manufacturing standards, strength and composition of red yeast rice supplements sold at mainstream retail stores in the United States remains unpredictable.

Oxilofrine (4-[1-hydroxy-2-(methylamino)propyl]phenol) is a pharmaceutical stimulant prescribed in dosages of 16 to 40 mg to stimulate the heart and increase blood pressure. It has never been approved for use in the USA as a prescription drug or as a dietary supplement. Several athletes, however, have been banned from sport for testing positive for oxilofrine and have claimed that they inadvertently consumed oxilofrine in sports supplements. Consumption of supplements containing oxilofrine may also pose serious health risks. For example, one brand of supplements containing oxilofrine has been linked to serious adverse events including vomiting, agitation, and cardiac arrest. We designed our study to determine the presence and quantity of oxilofrine in dietary supplements sold in the USA. A validated ultra-high performance liquid chromatography-quadrupole time of flight-mass spectrometry method was developed for the identification and quantification of oxilofrine. The separation was achieved using a reversed phase column, mass spectrometry detection, and a water/acetonitrile gradient as the mobile phase. The presence of oxilofrine was confirmed using a reference standard. We analyzed 27 brands of supplements labelled as containing a synonym of oxilofrine ('methylsynephrine') and found that oxilofrine was present in 14 different brands (52%) at dosages ranging from 0.0003 to 75 mg per individual serving. Of the supplements containing oxilofrine, 43% (6/14) contained pharmaceutical or greater dosages of oxilofrine. Following instructions on the label, consumers could ingest as much as 250 mg of oxilofrine per day. The drug oxilofrine was found in pharmacological and greater dosages in supplements labelled as containing methylsynephrine. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Many studies have found that some dietary supplement product labels do not accurately reflect the actual ingredients. However, studies have not been performed to determine if ingredients in the same dietary supplement product vary over time. The objective of this study was to assess the consistency of stimulant ingredients in popular sports supplements sold in the United States over a 9-month period. Three samples of nine popular sports supplements were purchased over the 9-month period. The 27 samples were analyzed for caffeine and several other stimulants (including adulterants). The identity and quantity of stimulants were compared with stimulants listed on the label and stimulants found at earlier time points to determine the variability in individual products over the 9-month period. The primary outcome measure was the variability of stimulant amounts in the products examined. Many supplements did not contain the same number and quantity of stimulants at all time points over the 9-month period. Caffeine content varied widely in five of the six caffeinated supplements compared with the initial measurement (-7% to +266%). In addition, the stimulants-synephrine, octopamine, cathine, ephedrine, pseudoephedrine, strychnine, and methylephedrine-occurred in variable amounts in eight of the nine products. The significance of these findings is uncertain: the sample size was insufficient to support statistical analysis. In our sample of nine popular sports supplements, the presence and quantity of stimulants varied over a 9-month period. However, future studies are warranted to determine if the variability found is significant and generalizable to other supplements.

The amphetamine isomer β-methylphenylethylamine (BMPEA) was first synthesized in the early 1930s, but its efficacy and safety in humans has not been studied. Recently, the United States Food and Drug Administration (FDA) detected BMPEA in dietary supplements labelled as containing Acacia rigidula. Over a year after the FDA reported its findings, we analyzed Acacia rigidula dietary supplements to determine if BMPEA had been removed. Supplements were analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry. Diluted methanolic extract from each supplement was run three times and each data set obtained was analyzed using Agilent MassHunter Qualitative Analysis. The presence of BMPEA was confirmed by accurate mass, retention time and mass spectra match against a reference standard. Quantification of BMPEA was determined using an eight-point calibration curve of spiked standard to a matrix blank. Twenty-one brands of Acacia rigidula supplements were analyzed. More than half (11/21; 52.4%) of the Acacia rigidula supplement brands contained BMPEA. The stimulant was present at quantities such that consumers following recommended maximum daily servings would consume a maximum of 93.7 mg of BMPEA per day. Consumers of Acacia rigidula supplements may be exposed to pharmacological dosages of an amphetamine isomer that lacks evidence of safety in humans. The FDA should immediately warn consumers about BMPEA and take aggressive enforcement action to eliminate BMPEA in dietary supplements. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

In the USA, botanical dietary supplements are presumed to be safe, but this is not necessarily always the case. Extracts of the evergreen tree yohimbe, Pausinystalia johimbe, though banned in many countries, are sold in hundreds of dietary supplements in the USA. We analyzed 49 brands of supplements labelled as containing yohimbe or yohimbine available for sale from seven major retailers in the USA. Supplements were analyzed using ultra high-performance liquid chromatography coupled to photodiode and quadrupole time-of-flight mass spectrometry detectors for quantity of three alkaloids found in P. johimbe (yohimbine, rauwolscine, and corynanthine). The alkaloids were confirmed on the basis of retention time, ultraviolet spectra, and mass spectra against reference standards. The quantity of the most active alkaloid, yohimbine, per recommended serving ranged from none detected to 12.1 mg. Thirty-nine percent of the supplements (19/49) did not contain rauwolscine and corynanthine suggesting that the yohimbine was either from highly processed plant extract or synthetic in origin. Only 11 supplement brands (22%, 11/49) listed a specific quantity of yohimbine on the label. Most of these were inaccurately labelled (actual content ranged from 23% to 147% of the content on the label). Eighteen percent (9/49) of the supplements' labels did not provide any information about yohimbine's adverse effects. Of the 49 yohimbine supplement brands sold at seven major retail chains in the USA, only 4.1% (2/49) provided consumers with both accurate information about the quantity of yohimbine as well as information about yohimbine's known adverse effects. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Vinpocetine and picamilon are drugs prescribed in many countries to treat a variety of cerebrovascular disorders. In the United States, vinpocetine and picamilon have never been approved by the US Food and Drug Administration, but they are both available for sale directly to consumers as dietary supplements. We designed our study to determine the accuracy of supplement labels with regard to the presence and quantity of vinpocetine and picamilon. A validated ultra-high performance liquid chromatography-photodiode-array method was developed for the quantification of vinpocetine and picamilon. The separation was achieved using a reversed phase (C-18) column, photodiode array detection, and water/acetonitrile as the mobile phase. Vinpocetine and picamilon were detected at concentrations as low as 10 and 50 ng/mL, respectively. The presence of vinpocetine and picamilon was confirmed using reference standards. Twenty-three supplements labelled as containing vinpocetine were available for sale at two large supplement retail chains; 17 contained vinpocetine with quantities ranging from 0.3 to 32 mg per recommended daily serving. No vinpocetine was detected in six of the sampled supplements. The supplement label implied that vinpocetine was a constituent of lesser periwinkle in three of the supplements. Of the 31 picamilon supplements available for sale from a variety of retailers: 30 contained picamilon in quantities ranging from 2.7 to 721.5 mg per recommended daily serving. We found that consumers cannot obtain accurate information from supplement labels regarding the presence or quantity of vinpocetine and picamilon. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

1,3-dimethylbutylamine (DMBA), is a CNS stimulant, which has recently been identified in multiple dietary supplements and sometimes labeled as a natural constituent of Pouchung tea. DMBA is an homologue of 1,3-dimethylamylamine (DMAA) which the US Food and Drug Administration has attempted to remove from all dietary supplements after DMAA consumption was linked to strokes, heart disease, and sudden death. To address questions concerning the natural origin of DMBA, three independent analytical methods were developed for analyzing authentic tea samples and dietary supplements. A high performance thin layer chromatography (HPTLC) method was developed for the fast screening and chemical fingerprint analysis. Chiral Gas Chromatography-Mass Spectrometry (GC-MS) was used to determine the enantiopurity and a validated Ultra-High Performance Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry (UHPLC-QToF-MS) method was developed for the quantification of DMBA. Using these techniques the presence of DMBA was confirmed using a reference standard and was not detected in any of 25 authentic or commercial samples of Camellia sinensis tea leaves (green tea, black tea, Oolong tea, and Pouchung tea). Of 13 dietary supplements tested, 11 contained DMBA in racemic form and ranged from 0.1 to 214mg per daily dose., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A synthetic stimulant never before studied in humans, 1,3-dimethylbutylamine (DMBA), was suspected of being present in dietary supplements. DMBA is an analogue of the pharmaceutical stimulant, 1,3-dimethylamylamine (DMAA), which was recently banned by the US Food and Drug Administration. We obtained all dietary supplements sold by US distributors that listed an ingredient on the label, such as AMP Citrate, that might be a marketing name for DMBA. Supplements were analyzed for the presence and quantity of DMBA. Fourteen supplements met our inclusion criteria and were analyzed by two separate laboratories using ultra high performance liquid chromatography (UHPLC) - mass spectrometry and a reference standard. The identity of DMBA was confirmed in 12 supplements in the range of 13 to 120 mg DMBA per serving. Following recommendations on the supplement label for maximum daily intake, customers would consume from 26 to 320 mg of DMBA per day. Supplements containing DMBA were marketed to improve athletic performance, increase weight loss and enhance brain function. DMBA has never before been detected in supplements. The stimulant has never been studied in humans; its efficacy and safety are entirely unknown. Regulatory agencies should act expeditiously to warn consumers and remove DMBA from all dietary supplements., (Copyright © 2014 John Wiley & Sons, Ltd.)

Red yeast rice (RYR) is prepared by fermenting rice with various strains of the yeast Monascus spp of the Aspergillaceae family. Depending on the Monascus strains and the fermentation conditions, the products may contain monacolins, pigments and citrinin as secondary metabolites. Authentic and commercial RYR samples were analyzed using UHPLC-DAD-QToF-MS for monacolins, pigments and citrinin. A separation by UHPLC was achieved using a reversed-phase column and a gradient of water/acetonitrile each containing formic acid as the mobile phase. Accurate mass QToF spectrometry was used to distinguish isobaric monacolins. Principle component analysis (PCA), a chemometric technique was used to discriminate between authentic RYR, commercial RYR raw materials and dietary supplements. Three authentic RYR samples, 31 commercial RYR raw materials and 14 RYR dietary supplements were analyzed. Monacolin K content in 600mg of authentic RYR samples ranged from 1.2mg to 1.38mg. Amounts of monacolin K in dietary supplements labeled as containing 600mg of RYR varied more than 40-fold from 0.03mg to 2.18mg. Monacolin K content of dietary supplements labeled as containing 1200mg RYR varied more than 20-fold from 0.22mg to 5.23mg. In addition to large variations in quantity of monacolin K found in dietary supplements, RYR dietary supplements contained ratios of monacolins that differed significantly from authentic samples. The results indicated that RYR commercial products are of variable quality and the analytical method is suitable for quality control testing of a variety of RYR products., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Pharmaceuticals and banned substances have been detected in hundreds of purportedly natural supplements. Recently, several athletes have been disqualified from competition after testing positive for the methamphetamine analog N,α-diethyl-phenylethylamine (N,α-DEPEA). Athletes have claimed they unknowingly consumed the banned stimulant in workout supplements. Three samples from different lot numbers of Craze, a workout supplement, were analyzed to detect the presence and concentration of N,α-DEPEA. Two labs independently identified N,α-DEPEA in the supplement using ultra high performance liquid chromatography (UHPLC) coupled to an LTQ Orbitrap XL mass spectrometer and UHPLC-quadruple-time-of-flight mass (Q-TOF) spectrometer, respectively. The identity of N,α-DEPEA was confirmed using nuclear magnetic resonance and reference standards. Manufacturer recommended servings were estimated to provide 21 to 35 mg of N,α-DEPEA. N,α-DEPEA has never been studied in humans. N,α-DEPEA is a methamphetamine analog; however, its stimulant, addictive and other adverse effects in humans are entirely unknown. Regulatory agencies should act expeditiously to warn consumers and remove N,α-DEPEA from all dietary supplements., (Copyright © 2013 John Wiley & Sons, Ltd.)

The US Food and Drug Administration (FDA) has recently warned consumers about the risks of weight loss supplements adulterated with multiple pharmaceutical agents. Some of these supplements combine potent anorectics, such as amphetamines derivatives, with benzodiazepines, beta-blockers, and other medications to suppress the anorectics' adverse effects. These weight loss supplements represent the most recent generation of rainbow diet pills, named for their bright and varied colors, which date back more than 70 years. Beginning in the 1940s, several US pharmaceutical firms aggressively promoted rainbow pills to physicians and patients. By the 1960s the pills had caused dozens of deaths before the FDA began removing them from the US market. We used a variety of original resources to trace these deadly pills from their origins in the United States to their popularity in Spain and Brazil to their reintroduction to the United States as weight loss dietary supplements.

The evidence sufficient to establish the expectation of safety for new ingredients in dietary supplements is an area of considerable controversy. Recently, the U.S. Food and Drug Administration (FDA) proposed a sound scientific framework for evaluating the safety of new ingredients. The level of evidence the FDA requires (i.e., in vitro, animal or human testing) hinges on three key factors: (1) documented history of use; (2) the dose and formulation of the new ingredient compared with the historically used ingredient; and (3) the supplement's recommended use (i.e., daily or as needed). Despite its strengths, the framework requires four key modifications to ensure the expectation of safety: (1) historical use should rarely, if ever, be sufficient to replace experimental data; (2) entirely novel ingredients should undergo, at a minimum, a 90-day human testing; (3) manufacturers should be required to submit to the FDA all available data regarding new ingredients, both favorable and unfavorable; and (4) before assuming that consumers follow instructions on supplement labels, this assumption should be empirically confirmed. In the absence of significant modifications, the FDA's guidance may have the effect of providing a false sense of security to consumers seeking safe dietary supplements.

Pharmaceutical adulterants are commonly found in herbal weight loss products, and analytical techniques for detecting these adulterants have become increasingly important to the public health community. Previously we reported a novel analytical method for the determination of adulterants in herbal formulations by capillary electrophoresis with contactless conductivity detection. The current study refines this previously described technique by testing if anxiolytics, diuretics, and laxatives interfered with the detection of anorectics and antidepressants. A survey of herbal weight loss products sold by compounding pharmacies in Brazil were analysed to determine the presence of pharmaceutical adulterants. A total of 106 herbal products, collected from 73 pharmacies in nine Brazilian states, were analysed for amfepramone, sibutramine, fenproporex, fluoxetine, paroxetine, sertraline and bupropion using the new analytical method. The method permitted the rapid and selective screening for the seven adulterants. Of the 106 weight loss products sampled, four (3.8%) were found to be adulterated by fenproporex or sibutramine. The adulterated samples were compounded by four different pharmacies located in three different Brazilian states. The novel capillary electrophoresis method we developed may be a useful tool for public health organisations tasked with analysing herbal weight loss products.

Background: Pai You Guo is a weight loss supplement manufactured in China and adulterated with the banned pharmaceutical products sibutramine and phenolphthalein. The US Food and Drug Administration (FDA) announced a voluntary recall of Pai You Guo in 2009, yet clinicians have noted its continued use among Brazilian-born women in Massachusetts., Objective: To assess prevalence of Pai You Guo use, associated side effects, modes of acquisition, and impact of FDA regulatory action on these outcomes., Design: Cross-sectional study using an anonymous questionnaire., Participants: Women ≤60 years of age, born in Brazil who attended one primary care clinic or one of six churches in Massachusetts., Main Measures: Prevalence of use, how users first heard about the product, location of purchase, associated side effects, patterns of use before and after the FDA recall., Key Results: Twenty-three percent (130/565) of respondents reported using Pai You Guo. In multivariate analysis, obesity (adj OR 3.7, p-value <0.001) and lack of insurance (adj OR 2.6, p-value 0.005) were associated with use. The majority of users (85%) reported at least one side effect. Dry mouth (59%), anxiety (29%), and insomnia (26%) were most commonly reported adverse effects. Nearly thirty-percent of users (38/130) purchased Pai You Guo from local stores and 9% (11/130) purchased it over the Internet. The majority of respondents (79/130; 61%) purchased Pai You Guo after the FDA recall. No respondent was aware of the FDA recall., Conclusions: Use of this pharmaceutically adulterated supplement is common among Brazilian-born women in Massachusetts. The FDA alerts and recall did not appear to decrease its use.

Many patients use herbal supplements to treat chronic cardiovascular conditions and often combine herbal ingredients with cardiovascular medications. However, physicians do not reliably elicit a history of herbal use from their patients and may overlook herbal supplements' adverse effects. Although often considered harmless by patients, herbal supplements may cause adverse cardiovascular effects from an herbal ingredient, a contaminant, or an herb-drug interaction. Herbal stimulants, including bitter orange, ephedra, caffeine, guarana, maté, kola, areca, lobelia, khat, and others are the most common category of herbal therapies to cause cardiovascular effects. However, dozens of other herbal ingredients have also been linked to adverse cardiovascular events. In addition to listed ingredients, herbal supplements may become contaminated at a number of stages during production. Pesticides, heavy metals, bacteria, and pharmaceutical agents have been detected in herbal supplements. Supposedly "herbal" products that are adulterated with prescription anorectics, antidepressants, diuretics, phosphodiesterase-5 inhibitors along with other medications have been identified throughout Europe, North America, and Asia. All of these adulterants have potential cardiovascular effects. Herbal interactions with a variety of cardiovascular medications may also lead to adverse events. Herbal ingredients may cause pharmacokinetic as well as pharmacodynamic herb-drug interactions. We review clinically relevant patterns of adverse cardiovascular reactions to herbal supplements, and we provide resources and recommendations for practicing cardiologists evaluating patients with suspected herbal adverse effects.