Getting More Than You Paid For: Unauthorized “Natural” Substances in Herbal Food Supplements on EU Market

Abstract

As the population in the industrialized world develops preference for what is perceived as a natural and holistic way of disease treatment, the popularity and the number of food supplements on the market, including herbal ones, is experiencing an unprecedented rise. However, unlike herbal medicinal products, intended for treating or preventing disease, current legislation classifies food supplements as products intended for achieving nutritional or physiological effect and to supplement the normal diet. Accordingly, most food supplements are not to be associated with specific health claims. However, either due to the subtle suggestions by the producers or the wishful thinking of the consumers, certain pharmacological effects from food supplements are often expected. Medicinal plants included in food supplements usually do not produce dramatic and instant pharmacological effects. Therefore, in order to meet the expectation of their customers, some producers have turned to the illicit and dangerous practice of adulterating their products with synthetic adulterants, including naturally occurring molecules, having the desired activity. Such practice is prevalent in, although not limited to, food supplements intended for use as weight-loss aids, as well as for sport performance and libido enhancement. The review is focusing on naturally occurring alkaloids, phenylethanolamines, and their semi-synthetic derivatives in food supplements in the European Union as reported by the Rapid Alert System for Food and Feed. Their desired and undesired pharmacological effects, as well as the methods for their detection and quantification in food supplements, will be reviewed.

Key words

adulterant - alkaloid - food supplement - herbal - phenylethanolamine

• References

• 1 Cabut S, Marie C, Vendittelli F, Sauvant-Rochat MP. Intended and actual use of self-medication and alternative products during pregnancy by French women. J Gynecol Obstet Hum Reprod 2017; 46: 167-173
• 2 Egan B, Hodgkins C, Shepherd R, Timotijevic L, Raats M. An overview of consumer attitudes and beliefs about plant food supplements. Food Funct 2011; 2: 747-752
• 3 Samojlik I, Mijatović V, Gavarić N, Krstin S, Božin B. Consumersʼ attitude towards the use and safety of herbal medicines and herbal dietary supplements in Serbia. Int J Clin Pharm 2013; 35: 835-840
• 4 Coppens P, Delmulle L, Gulati O, Richardson D, Ruthsatz M, Sievers H, Sidani S. Use of botanicals in food supplements. Ann Nutr Metab 2007; 50: 538-554
• 5 European Commission. Herbal Medicinal Products. Available at. https://ec.europa.eu/health/human-use/herbal-medicines_en Accessed June 15, 2017
• 6 European Commission. Nutrition and Health Claims. Available at. http://ec.europa.eu/food/safety/labelling_nutrition/claims_en Accessed June 15, 2017
• 7 Barnes J, McLachlan AJ, Sherwin CM, Enioutina EY. Herbal medicines: challenges in the modern world. Part 1. Australia and New Zealand. Expert Rev Clin Pharmacol 2016; 9: 905-915
• 8 Sammons HM, Gubarev MI, Krepkova LV, Bortnikova VV, Corrick F, Job KM, Sherwin CM, Enioutina EY. Herbal medicines: challenges in the modern world. Part 2. European Union and Russia. Expert Rev Clin Pharmacol 2016; 9: 1117-1127
• 9 Teng L, Zu Q, Li G, Yu T, Job KM, Yang X, Di L, Sherwin CM, Enioutina EY. Herbal medicines: challenges in the modern world. Part 3. China and Japan. Expert Rev Clin Pharmacol 2016; 9: 1225-1233
• 10 Job KM, Kiang TKL, Constance JE, Sherwin CMT, Enioutina EY. Herbal medicines: challenges in the modern world. Part 4. Canada and United States. Expert Rev Clin Pharmacol 2016; 9: 1597-1609
• 11 Campbell N, Clark JP, Stecher VJ, Thomas JW, Callanan AC, Donnelly BF, Goldstein I, Kaminetsky JC. Adulteration of purported herbal and natural sexual performance enhancement dietary supplements with synthetic phosphodiesterase type 5 inhibitors. J Sex Med 2013; 10: 1842-1849
• 12 Skalicka-Woźniak K, Georgiev MI, Orhan IE. Adulteration of herbal sexual enhancers and slimmers: the wish for better sexual well-being and perfect body can be risky. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc 2017; 108: 355-364
• 13 Calahan J, Howard D, Almalki AJ, Gupta MP, Calderón AI. Chemical adulterants in herbal medicinal products: a review. Planta Med 2016; 82: 505-515
• 14 Karioti A, Giocaliere E, Guccione C, Pieraccini G, Gallo E, Vannacci A, Bilia AR. Combined HPLC-DAD-MS, HPLC-MS(n) and NMR spectroscopy for quality control of plant extracts: the case of a commercial blend sold as dietary supplement. J Pharm Biomed Anal 2014; 88: 7-15
• 15 Petroczi A, Taylor G, Naughton DP. Mission impossible? Regulatory and enforcement issues to ensure safety of dietary supplements. Food Chem Toxicol 2011; 49: 393-402
• 16 Parcher JF, Khan IA. Establishment of a “natural” origin for phytochemicals. J Chromatogr A 2015; 1406: 347
• 17 Palamar J. How ephedrine escaped regulation in the United States: a historical review of misuse and associated policy. Health Policy Amst Neth 2011; 99: 1-9
• 18 Stohs SJ, Badmaev V. A review of natural stimulant and non-stimulant thermogenic agents. Phytother Res 2016; 30: 732-740
• 19 Bohn AM, Khodaee M, Schwenk TL. Ephedrine and other stimulants as ergogenic aids. Curr Sports Med Rep 2003; 2: 220-225
• 20 Gurley BJ, Steelman SC, Thomas SL. Multi-ingredient, caffeine-containing dietary supplements: history, safety, and efficacy. Clin Ther 2015; 37: 275-301
• 21 Miller SC. Safety concerns regarding ephedrine-type alkaloid-containing dietary supplements. Mil Med 2004; 169: 87-93
• 22 European Commission RASFF. Food and Feed Safety Alerts. Available at. https://ec.europa.eu/food/safety/rasff_en Accessed May 29, 2017
• 23 Pourmand A, Li A, Yiu A, Mazer-Amirshahi M, Shokoohi H. Survival after profound acidosis and rhabdomyolysis due to dietary supplement use. Am J Emerg Med 2016; 34: 2259.e1-2259.e3
• 24 Van Wyk BE. A review of commercially important African medicinal plants. J Ethnopharmacol 2015; 176: 118-134
• 25 Corazza O, Martinotti G, Santacroce R, Chillemi E, Di Giannantonio M, Schifano F, Cellek S. Sexual enhancement products for sale online: raising awareness of the psychoactive effects of yohimbine, maca, horny goat weed, and Ginkgo biloba . Biomed Res Int 2014; 2014: 841798
• 26 Abdel-Hamid IA, Elsaied MA, Mostafa T. The drug treatment of delayed ejaculation. Transl Androl Urol 2016; 5: 576-591
• 27 Keller Ashton A, Hamer R, Rosen RC. Serotonin reuptake inhibitor-induced sexual dysfunction and its treatment: a large-scale retrospective study of 596 psychiatric outpatients. J Sex Marital Ther 1997; 23: 165-175
• 28 Smits JAJ, Rosenfield D, Davis ML, Julian K, Handelsman PR, Otto MW, Tuerk P, Shiekh M, Rosenfield B, Hofmann SG, Powers MB. Yohimbine enhancement of exposure therapy for social anxiety disorder: a randomized controlled trial. Biol Psychiatry 2014; 75: 840-846
• 29 Cimolai N, Cimolai T. Yohimbine use for physical enhancement and its potential toxicity. J Diet Suppl 2011; 8: 346-354
• 30 Johnson S, Iazzetta J, Dewar C. Severe Raynaudʼs phenomenon with yohimbine therapy for erectile dysfunction. J Rheumatol 2003; 30: 2503-2505
• 31 Myers A, Barrueto F. Refractory priapism associated with ingestion of yohimbe extract. J Med Toxicol Off J Am Coll Med Toxicol 2009; 5: 223-225
• 32 Giampreti A, Lonati D, Locatelli C, Rocchi L, Campailla MT. Acute neurotoxicity after yohimbine ingestion by a body builder. Clin Toxicol Phila Pa 2009; 47: 827-829
• 33 [Anonymous] “Dietary supplement” warning. FDA Consum 2002; 36: 4
• 34 Anderson C, Anderson D, Harre N, Wade N. Case study: two fatal case reports of acute yohimbine intoxication. J Anal Toxicol 2013; 37: 611-614
• 35 Venhuis B, Keizers P, van Riel A, de Kaste D. A cocktail of synthetic stimulants found in a dietary supplement associated with serious adverse events. Drug Test Anal 2014; 6: 578-581
• 36 Vas A, Gulyás B. Eburnamine derivatives and the brain. Med Res Rev 2005; 25: 737-757
• 37 Cohen PA. Vinpocetine: An unapproved drug sold as a dietary supplement. Mayo Clin Proc 2015; 90: 1455
• 38 Patyar S, Prakash A, Modi M, Medhi B. Role of vinpocetine in cerebrovascular diseases. Pharmacol Rep PR 2011; 63: 618-628
• 39 Bereczki D, Fekete I. Vinpocetine for acute ischaemic stroke. Cochrane Database Syst Rev 2008; (01) CD000480
• 40 Szatmari SZ, Whitehouse PJ. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev 2003; (01) CD003119
• 41 Heckman PRA, Wouters C, Prickaerts J. Phosphodiesterase inhibitors as a target for cognition enhancement in aging and Alzheimerʼs disease: a translational overview. Curr Pharm Des 2015; 21: 317-331
• 42 Spagnoli A, Tognoni G. “Cerebroactive” drugs. Clinical pharmacology and therapeutic role in cerebrovascular disorders. Drugs 1983; 26: 44-69
• 43 [Anonymous] Vinpocetine. Monograph. Altern Med Rev J Clin Ther 2002; 7: 240-243
• 44 Avula B, Chittiboyina AG, Sagi S, Wang YH, Wang M, Khan IA, Cohen PA. Identification and quantification of vinpocetine and picamilon in dietary supplements sold in the United States: quantification of vinpocetine and picamilon from dietary supplements using UHPLC-PDA. Drug Test Anal 2016; 8: 334-343
• 45 Yu H, Jin H, Gong W, Wang Z, Liang H. Pharmacological actions of multi-target-directed evodiamine. Mol Basel Switz 2013; 18: 1826-1843
• 46 Hu Y, Fahmy H, Zjawiony JK, Davies GE. Inhibitory effect and transcriptional impact of berberine and evodiamine on human white preadipocyte differentiation. Fitoterapia 2010; 81: 259-268
• 47 Kobayashi Y, Nakano Y, Kizaki M, Hoshikuma K, Yokoo Y, Kamiya T. Capsaicin-like anti-obese activities of evodiamine from fruits of Evodia rutaecarpa, a vanilloid receptor agonist. Planta Med 2001; 67: 628-633
• 48 Schwarz NA, Spillane M, La Bounty P, Grandjean PW, Leutholtz B, Willoughby DS. Capsaicin and evodiamine ingestion does not augment energy expenditure and fat oxidation at rest or after moderately-intense exercise. Nutr Res N Y N 2013; 33: 1034-1042
• 49 Kim HJ, Park JM, Kim JA, Ko BP. Effect of herbal Ephedra sinica and Evodia rutaecarpa on body composition and resting metabolic rate: a randomized, double-blind clinical trial in Korean premenopausal women. J Acupunct Meridian Stud 2008; 1: 128-138
• 50 Wang ZY, Liu JG, Li H, Yang HM. Pharmacological effects of active components of Chinese herbal medicine in the treatment of Alzheimerʼs disease: a review. Am J Chin Med 2016; 44: 1525-1541
• 51 Wang R, Yan H, Tang X. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 2006; 27: 1-26
• 52 Zhang H. New insights into huperzine A for the treatment of Alzheimerʼs disease. Acta Pharmacol Sin 2012; 33: 1170-1175
• 53 Yang G, Wang Y, Tian J, Liu JP. Huperzine A for Alzheimerʼs disease: a systematic review and meta-analysis of randomized clinical trials. PLoS One 2013; 8: e74916
• 54 Zheng W, Xiang YQ, Ungvari GS, Chiu FKH, Ng CH, Wang Y, Xiang YT. Huperzine A for treatment of cognitive impairment in major depressive disorder: a systematic review of randomized controlled trials. Shanghai Arch Psychiatry 2016; 28: 64-71
• 55 Laver K, Dyer S, Whitehead C, Clemson L, Crotty M. Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews. BMJ Open 2016; 6: e010767
• 56 Xing S, Zhu C, Zhang R, An L. Huperzine A in the treatment of Alzheimerʼs disease and vascular dementia: a meta-analysis. Evid Based Complement Alternat Med 2014; 2014: 363985
• 57 Felgenhauer N, Zilker T, Worek F, Eyer P. Intoxication with huperzine A, a potent anticholinesterase found in the fir club moss. J Toxicol Clin Toxicol 2000; 38: 803-808
• 58 Zhang N, Lian Z, Peng X, Li Z, Zhu H. Applications of higenamine in pharmacology and medicine. J Ethnopharmacol 2017; 196: 242-252
• 59 Deldicque L, Francaux M. Potential harmful effects of dietary supplements in sports medicine. Curr Opin Clin Nutr Metab Care 2016; 19: 439-445
• 60 Lee SR, Schriefer JM, Gunnels TA, Harvey IC, Bloomer RJ. Acute oral intake of a higenamine-based dietary supplement increases circulating free fatty acids and energy expenditure in human subjects. Lipids Health Dis 2013; 12: 148
• 61 Bloomer RJ, Schriefer JM, Gunnels TA. Clinical safety assessment of oral higenamine supplementation in healthy, young men. Hum Exp Toxicol 2015; 34: 935-945
• 62 Feng S, Jiang J, Hu P, Zhang J, Liu T, Zhao Q, Li B. A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects. Acta Pharmacol Sin 2012; 33: 1353-1358
• 63 Jeter J, DeZee KJ, Kennedy L. A case of paraspinal muscle rhabdomyolysis in a 22-year-old male after ingesting a supplement containing higenamine. Mil Med 2015; 180: e847-e849
• 64 Chu NS. Neurological aspects of areca and betel chewing. Addict Biol 2002; 7: 111-114
• 65 Garg A, Chaturvedi P, Gupta PC. A review of the systemic adverse effects of areca nut or betel nut. Indian J Med Paediatr Oncol 2014; 35: 3-9
• 66 Liu YJ, Peng W, Hu MB, Xu M, Wu CJ. The pharmacology, toxicology and potential applications of arecoline: a review. Pharm Biol 2016; 54: 2753-2760
• 67 Aronson JK. ed. Meylerʼs Side Effects of Drugs, 16th ed. Oxford: Elsevier; 2016: 65-75
• 68 Rossato LG, Costa VM, Limberger RP, Bastos Mde L, Remiao F. Synephrine: from trace concentrations to massive consumption in weight-loss. Food Chem Toxicol 2011; 49: 8-16
• 69 Guccione C, Bergonzi M, Piazzini V, Bilia A. A simple and rapid HPLC-PDA MS method for the profiling of citrus peels and traditional Italian liquors. Planta Med 2016; 82: 1039-1045
• 70 Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DB. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update. Obes Rev 2006; 7: 79-88
• 71 Bakhiya N, Ziegenhagen R, Hirsch-Ernst KI, Dusemund B, Richter K, Schultrich K, Pevny S, Schäfer B, Lampen A. Phytochemical compounds in sport nutrition: synephrine and hydroxycitric acid (HCA) as examples for evaluation of possible health risks. Mol Nutr Food Res 2017; DOI: 10.1002/mnfr.201601020.
• 72 Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Longev 2011; 2011: 482973
• 73 Koncic MZ, Tomczyk M. New insights into dietary supplements used in sport: active substances, pharmacological and side effects. Curr Drug Targets 2013; 14: 1079-1092
• 74 Gutiérrez-Hellín J, Del Coso J. Acute p-synephrine ingestion increases fat oxidation rate during exercise. Br J Clin Pharmacol 2016; 82: 362-368
• 75 Gougeon R, Harrigan K, Tremblay JF, Hedrei P, Lamarche M, Morais JA. Increase in the thermic effect of food in women by adrenergic amines extracted from Citrus aurantium . Obes Res 2005; 13: 1187-1194
• 76 Preuss HG, DiFerdinando D, Bagchi M, Bagchi D. Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview. J Med 2002; 33: 247-264
• 77 Bakhyia N, Dusemund B, Richter K, Lindtner O, Hirsch-Ernst KI, Schäfer B, Lampen A. Gesundheitliche Risiken von Synephrin in Nahrungsergänzungsmitteln. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2017; 60: 323-331
• 78 Smedema JP, Müller GJ. Coronary spasm and thrombosis in a bodybuilder using a nutritional supplement containing synephrine, octopamine, tyramine and caffeine. S Afr Med J 2008; 98: 372-373
• 79 Chung H, Kwon SW, Kim TH, Yoon JH, Ma DW, Park YM, Hong BK. Synephrine-containing dietary supplement precipitating apical ballooning syndrome in a young female. Korean J Intern Med 2013; 28: 356-360
• 80 Stephensen TA, Sarlay R. Ventricular fibrillation associated with use of synephrine containing dietary supplement. Mil Med 2009; 174: 1313-1319
• 81 Thomas JE, Munir JA, McIntyre PZ, Ferguson MA. STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature. Tex Heart Inst J 2009; 36: 586-590
• 82 Sandhu RS, Como JJ, Scalea TS, Betts JM. Renal failure and exercise-induced rhabdomyolysis in patients taking performance-enhancing compounds. J Trauma 2002; 53: 761-763
• 83 Burke J, Seda G, Allen D, Knee TS. A case of severe exercise-induced rhabdomyolysis associated with a weight-loss dietary supplement. Mil Med 2007; 172: 656-658
• 84 Cohen PA, Avula B, Venhuis B, Travis JC, Wang YH, Khan IA. Pharmaceutical doses of the banned stimulant oxilofrine found in dietary supplements sold in the USA. Drug Test Anal 2017; 9: 135-142
• 85 Kauert G, Angermann C, Lex H, Spes C. Clinical pharmacokinetics after a single oral dose of oxilofrine. Int J Clin Pharmacol Res 1988; 8: 307-314
• 86 Pawar RS, Grundel E. Overview of regulation of dietary supplements in the USA and issues of adulteration with phenethylamines (PEAs). Drug Test Anal 2017; 9: 500-517
• 87 Stohs SJ. Physiological functions and pharmacological and toxicological effects of p-octopamine. Drug Chem Toxicol 2015; 38: 106-112
• 88 Chizzali E, Nischang I, Ganzera M. Separation of adrenergic amines in Citrus aurantium L. var. amara by capillary electrochromatography using a novel monolithic stationary phase. J Sep Sci 2011; 34: 2301-2304
• 89 Shawky E. Determination of synephrine and octopamine in bitter orange peel by HPTLC with densitometry. J Chromatogr Sci 2014; 52: 899-904
• 90 Stewart I, Wheaton TA. I-octopamine in citrus: isolation and identification. Science 1964; 145: 60-61
• 91 Anderson WG. The sympathomimetic activity of N-isopropyloctopamine in vitro . J Pharmacol Exp Ther 1983; 225: 553-558
• 92 Mercader J, Wanecq E, Chen J, Carpéné C. Isopropylnorsynephrine is a stronger lipolytic agent in human adipocytes than synephrine and other amines present in Citrus aurantium . J Physiol Biochem 2011; 67: 443-452
• 93 Bovee TFH, Mol HGJ, Bienenmann-Ploum ME, Heskamp HH, Van Bruchem GD, Van Ginkel LA, Kooijman M, Lasaroms JJP, Van Dam R, Hoogenboom RLAP. Dietary supplement for energy and reduced appetite containing the β-agonist isopropyloctopamine leads to heart problems and hospitalisations. Food Addit Contam Part Chem Anal Control Expo Risk Assess 2016; 33: 749-759
• 94 Upadhyay RK. Bel plant: a source of pharmaceuticals and ethno medicines. Int J Green Pharm 2015; 9: 204-222
• 95 Kesari AN, Gupta RK, Singh SK, Diwakar S, Watal G. Hypoglycemic and antihyperglycemic activity of Aegle marmelos seed extract in normal and diabetic rats. J Ethnopharmacol 2006; 107: 374-379
• 96 Singh SP, Sashidhara KV. Lipid lowering agents of natural origin: an account of some promising chemotypes. Eur J Med Chem 2017; 140: 331-348
• 97 Johnston DI, Chang A, Viray M, Chatham-Stephens K, He H, Taylor E, Wong LL, Schier J, Martin C, Fabricant D, Salter M, Lewis L, Park SY. Hepatotoxicity associated with the dietary supplement OxyELITE Pro^™ – Hawaii, 2013. Drug Test Anal 2016; 8: 319-327
• 98 Heidemann LA, Navarro VJ, Ahmad J, Hayashi PH, Stolz A, Kleiner DE, Fontana RJ. Severe acute hepatocellular injury attributed to OxyELITE Pro: a case series. Dig Dis Sci 2016; 61: 2741-2748
• 99 Gibbons RD. OxyELITE Pro and liver disease: statistical assessment of an apparent association. J Stat Theory Pract 2017; DOI: 10.1080/15598608.2017.1305923.
• 100 Lundström J. β-Phenethylamines and Ephedrines of Plant Origin. In: Cordell GA. ed. The Alkaloids: Chemistry and Pharmacology, vol. 35. Oxford: Elsevier; 1989: 77-154
• 101 Liapakis G, Chan WC, Papadokostaki M, Javitch JA. Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the beta2 adrenergic receptor. Mol Pharmacol 2004; 65: 1181-1190
• 102 Malik AK, Blasco C, Picó Y. Liquid chromatography-mass spectrometry in food safety. J Chromatogr A 2010; 1217: 4018-4040
• 103 Cohen PA, Wang YH, Maller G, DeSouza R, Khan IA. Pharmaceutical quantities of yohimbine found in dietary supplements in the USA. Drug Test Anal 2016; 8: 357-369
• 104 Sun J, Chen P. Chromatographic fingerprint analysis of yohimbe bark and related dietary supplements using UHPLC/UV/MS. J Pharm Biomed Anal 2012; 61: 142-149
• 105 Santana J, Sharpless KE, Nelson BC. Determination of para-synephrine and meta-synephrine positional isomers in bitter orange-containing dietary supplements by LC/UV and LC/MS/MS. Food Chem 2008; 109: 675-682
• 106 Nelson BC, Putzbach K, Sharpless KE, Sander LC. Mass spectrometric determination of the predominant adrenergic protoalkaloids in bitter orange (Citrus aurantium). J Agric Food Chem 2007; 55: 9769-9775
• 107 Paiga P, Rodrigues MJE, Correia M, Amaral JS, Oliveira MBPP, Delerue-Matos C. Analysis of pharmaceutical adulterants in plant food supplements by UHPLC-MS/MS. Eur J Pharm Sci 2017; 99: 219-227
• 108 Attipoe S, Cohen PA, Eichner A, Deuster PA. Variability of stimulant levels in nine sports supplements over a 9-month period. Int J Sport Nutr Exerc Metab 2016; 26: 413-420
• 109 Chen P, Bryden N. Determination of yohimbine in yohimbe bark and related dietary supplements using UHPLC-UV/MS: single-laboratory validation. J AOAC Int 2015; 98: 896-901
• 110 Mol HGJ, Van Dam RCJ, Zomer P, Mulder PPJ. Screening of plant toxins in food, feed and botanicals using full-scan high-resolution (Orbitrap) mass spectrometry. Food Addit Contam Part A 2011; 28: 1405-1423
• 111 Tero-Vescan A, Vari CE, Imre S, Ősz BE, Filip C, Hancu G. Comparative analysis by HPLC-UV and capillary electrophoresis of dietary supplements for weight loss. Farmacia 2016; 64: 699-705
• 112 Obreshkova D, Tsvetkova D. Validation of HPLC method with UV-detection for determination of yohimbine containing products. Pharmacia 2016; 63: 3-9
• 113 French JMT, King MD, McDougal OM. Quantitative determination of vinpocetine in dietary supplements. Nat Prod Commun 2016; 11: 607-609
• 114 Gao X, Yang XW, Marriott PJ. Simultaneous analysis of seven alkaloids in Coptis-Evodia herb couple and Zuojin pill by UPLC with accelerated solvent extraction. J Sep Sci 2010; 33: 2714-2722
• 115 Chen J, Sun JN, Song XY, Shi YP. Holistic analysis of seven constituents from three medicinal herbs composing Wuji pills in a single run by ultra performance liquid chromatography: application to quality control study. Anal Methods 2012; 4: 2989
• 116 Gao X, Yang XW, Marriott PJ. Evaluation of Coptidis Rhizoma Euodiae Fructus couple and Zuojin products based on HPLC fingerprint chromatogram and simultaneous determination of main bioactive constituents. Pharm Biol 2013; 51: 1384-1392
• 117 Viana C, Zemolin GM, Lima FO, de Carvalho LM, Bottoli CBG, Limberger RP. High-performance liquid chromatographic analysis of biogenic amines in pharmaceutical products containing Citrus aurantium . Food Addit Contam Part A 2013; 30: 634-642
• 118 Viana C, Zemolin GM, Müller LS, Dal Molin TR, Seiffert H, de Carvalho LM. Liquid chromatographic determination of caffeine and adrenergic stimulants in food supplements sold in Brazilian e-commerce for weight loss and physical fitness. Food Addit Contam Part A 2015; 33: 1-9
• 119 Rebiere H, Guinot P, Civade C, Bonnet PA, Nicolas A. Detection of hazardous weight-loss substances in adulterated slimming formulations using ultra-high-pressure liquid chromatography with diode-array detection. Food Addit Contam Part A 2012; 29: 161-171
• 120 Arbo MD, Braun P, Leal MB, Larentis ER, Aboy AL, Bulcao RP, Garcia SC, Limberger RP. Presence of p-synephrine in teas commercialized in Porto Alegre (RS/Brazil). Braz J Pharm Sci 2009; 45: 273-278
• 121 Putzbach K, Rimmer CA, Sharpless KE, Sander LC. Determination of bitter orange alkaloids in dietary supplements standard reference materials by liquid chromatography with ultraviolet absorbance and fluorescence detection. J Chromatogr A 2007; 1156: 304-311
• 122 Mercolini L, Mandrioli R, Trere T, Bugamelli F, Ferranti A, Raggi MA. Fast CE analysis of adrenergic amines in different parts of Citrus aurantium fruit and dietary supplements. J Sep Sci 2010; 33: 2520-2527
• 123 Gatti R, Lotti C, Morigi R, Andreani A. Determination of octopamine and tyramine traces in dietary supplements and phytoextracts by high performance liquid chromatography after derivatization with 2, 5-dimethyl-1H-pyrrole-3, 4-dicarbaldehyde. J Chromatogr A 2012; 1220: 92-100
• 124 Percy DW, Adcock JL, Conlan XA, Barnett NW, Gange ME, Noonan LK, Henderson LC, Francis PS. Determination of Citrus aurantium protoalkaloids using HPLC with acidic potassium permanganate chemiluminescence detection. Talanta 2010; 80: 2191-2195
• 125 Slezak T, Francis PS, Anastos N, Barnett NW. Determination of synephrine in weight-loss products using high performance liquid chromatography with acidic potassium permanganate chemiluminescence detection. Anal Chim Acta 2007; 593: 98-102
• 126 Gatti R, Lotti C. Development and validation of a pre-column reversed phase liquid chromatographic method with fluorescence detection for the determination of primary phenethylamines in dietary supplements and phytoextracts. J Chromatogr A 2011; 1218: 4468-4473
• 127 Monakhova YB, Kuballa T, Lobell-Behrends S, Maixner S, Kohl-Himmelseher M, Ruge W, Lachenmeier DW. Standardless 1H NMR determination of pharmacologically active substances in dietary supplements and medicines that have been illegally traded over the Internet. Drug Test Anal 2013; 5: 400-411
• 128 Adel-Kader MS, Alwahebi NWH, Alam P. Estimation of yohimbine base in complex mixtures by quantitative HPTLC application. Pak J Pharm Sci 2017; 30: 149-154
• 129 Putzbach K, Rimmer CA, Sharpless KE, Wise SA, Sander LC. Determination of bitter orange alkaloids in dietary supplement standard reference materials by liquid chromatography with atmospheric-pressure ionization mass spectrometry. Anal Bioanal Chem 2007; 389: 197-205
• 130 Di Lorenzo C, Dos Santos A, Colombo F, Moro E, DellʼAgli M, Restani P. Development and validation of HPLC method to measure active amines in plant food supplements containing Citrus aurantium L. Food Control 2014; 46: 136-142
• 131 Andrade AS, Schmitt GC, Rossato LG, Russowsky D, Limberger RP. Gas chromatographic method for analysis of p-synephrine in Citrus aurantium L. products. Chromatographia 2009; 69: 225-229
• 132 Vaysse J, Balayssac S, Gilard V, Desoubdzanne D, Malet-Martino M, Martino R. Analysis of adulterated herbal medicines and dietary supplements marketed for weight loss by DOSY 1H-NMR. Food Addit Contam Part A 2010; 27: 903-916
• 133 Avula B, Chittiboyina A, Wang YH, Sagi S, Raman V, Wang M, Khan I. Simultaneous determination of aegeline and six coumarins from different parts of the plant Aegle marmelos using UHPLC-PDA-MS and chiral separation of aegeline enantiomers using HPLC-ToF-MS. Planta Med 2016; 82: 580-588