Safety issues of herbal weight loss dietary supplements: hepatotoxicity and adulteration
Abstract
Herbal weight loss supplements are widely used in the management of obesity, but consistent data to support long-term weight loss efficacy and safety are missing. Besides, legal framework for food supplements is less restrictive than regulation of medications. The objective of this review is to give weight to the fact that many weight loss supplements contain herbal compounds with unknown mechanism of action, increasing the risk for adverse effects, even toxicity, especially in co-administration with prescribed drugs. Hepatotoxicity ranging from elevated transaminases and autoimmune-like hepatitis to acute liver failure appears to be underrecognized, but is not uncommonly encountered. Another and even more serious concern is adulteration of weight loss supplements by illegal addition of unauthorized substances or medications to provide quick effects and to increase sales. Here are some significant data regarding the possible hepatotoxicity of frequently used herbal extracts, as well as the health risks related to some common adulterants. Towards safer use of supplements, a comprehensive and critical discussion of current regulatory principles is essential to address the existing gap between the increased use of food supplements and the lack of knowledge about their benefits, providing better protection for consumers.
References
Stone TW, McPherson M, Gail Darlington L. Obesity and cancer: existing and new hypotheses for a causal connection. EBioMedicine. 2018;30:14-28.
Tang N, Ma J, Tao R, Chen Z, Yang Y, He Q, et al. The effects of the interaction between BMI and dyslipidemia on hypertension in adults. Sci Rep. 2022;12(1):927.
Elmaleh-Sachs A, Schwartz JL, Bramante CT, Nicklas JM, Gudzune KA, Jay M. Obesity management in adults: a review. JAMA. 2023;330(20):2000-15.
Khazan M, Hedayati M, Kobarfard F, Askari S, Azizi F. Identification and determination of synthetic pharmaceuticals as adulterants in eight common herbal weight loss supplements. Iran Red Crescent Med. J. 2014;16(3):e15344.
Abdel-Tawab M. Do we need plant food supplements? A critical examination of quality, safety, efficacy, and necessity for a new regulatory framework. Planta Med. 2018;84(6-07):372-93.
Kazemipoor M, Cordell GA, Sarker MR, Jasimah C, Radzi WM, Hajifaraji M, et al. Alternative treatments for weight loss: safety/risks and effectiveness of anti-obesity medicinal plants. Int J Dietary Prop. 2015;18:1942-63.
Andrew R, Izzo AA. Principles of pharmacological research of nutraceuticals. Br J Pharmacol. 2017;174:1177-94.
Oga EF, Sekine S, Shitara Y, Horie T. Pharmacokinetic herb-drug interactions: Insight into mechanisms and consequences. Eur J Drug Metab Pharmacokinet. 2016;41(2):93-108.
Scheife RT, Hines LE, Boyce RD, Chung SP, Momper JD, Sommer CD, et al. Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support. Drug Saf. 2015;38(2):197-206.
Wanwimolruk S, Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (Part 1). EXCLI J. 2014;13:347-91.
Brewer CT, Chen T. Hepatotoxicity of herbal supplements mediated by modulation of cytochrome P450. Int J Mol Sci. 2017;18:2353.
Crescioli G, Lombardi N, Bettiol A, Marconi E, Risaliti F, Bertoni M, et al. Acute liver injury following Garcinia cambogia weight-loss supplementation: Case series and literature review. Intern Emerg Med. 2018;13(6):857-72.
Zhivikj Z, Petreska Ivanovska, T, Karapandjova M, Kulevanova S, Lonchar Velkova M, Petrushevska-Tozi L. Consumer perception of risk-benefit of weight loss supplements and building safety. Mac Pharm Bull. 2020;66(Suppl 1):45-46.
Staynova R, Yanachkova V. Weight management strategies and food supplement intake among Bulgarian adults: results of a national survey. Pharmacia. 2023;70(4):1119-26.
da JustaNeves DB, Caldas ED. Determination of caffeine and identification of undeclared substances in dietary supplements and caffeine dietary exposure assessment. Dietary Chem Toxicol. 2017;105:194-202.
Geller AI, Shehab N, Weidle NJ, Lovegrove MC, Wolpert BJ, Timbo BB, et al. Emergency Department Visits for Adverse Events Related to Dietary Supplements. N Engl J Med. 2015;373(16):1531-40.
Di Lorenzo C, Ceschi A, Kupferschmidt H, Lüde S, De Souza Nascimento E, Dos Santos A, et al. Adverse effects of plant food supplements and botanical preparations: A systematic review with critical evaluation of causality. Br J Clin Pharmacol. 2015;79(4);578-92.
Lugg ST, Braganza Menezes D, Gompertz S. Chinese green tea and acute hepatitis: a rare yet recurring theme. BMJ Case Rep. doi: 10.1136/bcr-2014-208534.
Mazzanti G, Di Sotto A, Vitalone A. Hepatotoxicity of green tea: An update. Arch Toxicol. 2015;89(8):1175-91.
Smith RJ, Bertilone C, Robertson AG. Fulminant liver failure and transplantation after use of dietary supplements. Med J Aust. 2016;204(1):30-2.
Vuppalanchi R, Bonkovsky HL, Ahmad J, Barnhart H, Durazo F, Fontana RJ, et al. Garcinia cambogia, either alone or in combination with green tea, causes moderate to severe liver injury. Clin Gastroenterol Hepatol. 2022;20(6):e1416-25.
Woo SM, Davis WD, Aggarwal S, Clinton JW, Kiparizoska S, Lewis JH. Herbal and dietary supplement induced liver injury: Highlights from the recent literature. World J Hepatol. 2021;13(9):1019-41.
Galati G, Lin A, Sultan AM, O’Brien PJ. Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic Biol Med. 2006;40:570-80.
Yang CS, Pan E. The effects of green tea polyphenols on drug metabolism. Expert Opin Drug Metab Toxicol. 2012;8(6):677-89.
Emoto Y, Yoshizawa K, Kinoshita Y, Yuki M, Yuri T, Yoshikawa Y, et al. Green tea extract-induced acute hepatotoxicity in rats. J Toxicol Pathol. 2014;27:163-74.
Ramachandran B, Jayavelu S, Murhekar K, Rajkumar T. Repeated dose studies with pure epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia. Toxicol Reports. 2016;3:336-45.
Cho T, Wang X, Yeung K, Cao Y, Uetrecht J. Liver injury caused by green tea extract in PD-1-/- mice: An impaired immune tolerance model for idiosyncratic drug-induced liver injury. Chem Res Toxicol. 2021;34(3):849-56.
Hoofnagle JH, Bonkovsky HL, Phillips EJ, Li YJ, Ahmad J, Barnhart H, et al. HLA-B*35:01 and Green Tea-Induced Liver Injury. Hepatology. 2021;73(6):2484-93.
Albassam AA, Markowitz JS. An appraisal of drug-drug interactions with green tea (Camellia sinensis). Planta Med. 2017;83(6):496-508.
Werba JP, Misaka S, Giroli MG, Shimomura K, Amato M, Simonelli N, et al. Update of green tea interactions with cardiovascular drugs and putative mechanisms. J Food Drug Anal. 2018;26(2S):S72-7.
Teschke R, Zhang L, Melzer L, Schulze J, Eickhoff A. Green tea extract and the risk of drug-induced liver injury. Expert Opin Drug Metab Toxicol. 2014;10(12):1663-76.
Marquez F, Babio N, Bullo M, Salas-Salvado J. Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia extracts in humans. Crit Rev Food Sci Nutr. 2012;52(7):85-9.
Mas Ordeig A, Bordón García N. Hepatotoxicity caused by Garcinia cambogia. Gastroenterol Hepatol. 2020;43:134-35.
Kim YJ, Choi MS, Park YB, Kim SR, Lee MK, Jung UJ. Garcinia cambogia attenuates diet-induced adiposity but exacerbates hepatic collagen accumulation and inflammation. World J Gastroenterol. 2019;19:4689-4701.
Jordan AM. Interactions with drugs and dietary supplements used for weight loss. In: El-Shemy H. editor. Drug Discovery. InTech; 2013; p. 107-55. doi:10.5772/51145.
Di Giacomo S, Di Sotto A, Percaccio E, Scuotto E, Battistelli C, Mazzanti G, et al. Interaction of Garcinia cambogia (Gaertn.) Desr. and drugs as a possible mechanism of liver injury: The case of Montelukast. Antioxidants (Basel). 2023;12(9):1771.
Ekiert H, Świątkowska J, Knut E, Klin P, Rzepiela A, Tomczyk M, et al. Artemisia dracunculus (Tarragon): A review of its traditional uses, phytochemistry and pharmacology. Front Pharmacol. 2021;12:653993.
Obolskiy D, Pischel I, Feistel B, Glotov N, Heinrich M. Artemisia dracunculus L. (tarragon): A critical review of its traditional use, chemical composition, pharmacology, and safety. J Agric Food Chem. 2011;59(21):11367-84.
Yu Y, Mendoza TM, Ribnicky DM, Poulev A, Noland RC, Mynatt RL, et al. An extract of Russian tarragon prevents obesity-related ectopic lipid accumulation. Mol Nutr Food Res. 2018;62(8):e1700856.
Zarezade V, Moludi J, Mostafazadeh M, Mohammadi M, Veisi A. Antioxidant and hepatoprotective effects of Artemisia dracunculus against CCl4-induced hepatotoxicity in rats. Avicenna J Phytomed. 2018;8(1):51-62.
Johnson JD, Ryan MJ, Toft JD II, Graves SW, Hejtmancik MR, Cunningham ML, et al. Two-year toxicity and carcinogenicity study of methyleugenol in F344/N rats and B6C3F(1) mice. J Agric Food Chem. 2000;48(8):3620-32.
Herbal medicinal products [Internet]. Amsterdam: European Medical Agency; c2024 [cited 2024 Mar 5]. Available from: https://health.ec.europa.eu/medicinal-products/herbal-medicinal-products_en.
Jensen GS, Wu X, Patterson KM, Barnes J, Carter SG, Scherwitz L, et al. In vitro and in vivo antioxidant and anti-inflammatory capacities of an antioxidant-rich fruit and berry juice blend. Results of a pilot and randomized, double-blinded, placebo-controlled, crossover study. J Agric Food Chem. 2008;56(18):8326-33.
Laurindo LF, Barbalho SM, Araújo AC, Guiguer EL, Mondal A, Bachtel G, et al. Açaí (Euterpe oleracea Mart.) in Health and Disease: A Critical Review. Nutrients. 2023;15(4):989.
Stratton L. Acai berry induced cholestatic jaundice. J Med Cases, 2014;5(6):373-5.
Heinrich M, Dhanji T, Casselman I. Acai (Euterpe oleracea Mart.) - A phytochemical and pharmacological assessment of the species' health claims. Phytochem Lett. 2011;4:10-21.
Rabe C, Musch A, Schirmacher P, Kruis W, Hoffmann R. Acute hepatitis induced by an Aloe vera preparation: A case report. World J Gastroenterol. 2005;11(2):303-4.
Yang HN, Kim DJ, Kim YM, Kim BH, Sohn KM, Choi MJ, Choi, et al. Aloe-induced toxic hepatitis. J Korean Med Sci. 2010;25(3):492-5.
Lee J, Lee MS, Nam KW. Acute Toxic Hepatitis Caused by an Aloe Vera Preparation in a Young Patient: A Case Report with a Literature Review. Korean J Gastroenterol. 2014;64(1):54-8.
Parlati L, Voican CS, Perlemuter K, Perlemuter G. Aloe vera-induced acute liver injury: A case report and literature review. Clin Res Hepatol Gastroenterol. 2017;41(4):e39-e42.
de Boer YS, Sherker AH. Herbal and dietary supplement-induced liver injury. Clin Liver Dis. 2017;2:135–49.
Muschietti L, Redko F, Ulloa J. Adulterants in selected dietary supplements and their detection methods. Drug Test Anal. 2020;12:861-86.
Rocha T, Amaral JS, Oliveira MBPP. Adulteration of dietary supplements by the illegal addition of synthetic drugs: a review. Compr Rev Dietary Sci Dietary Saf. 2016;15:43-62.
Velasquez K, Ivie A, Fegely SR, Raffoul A, Vitagliano JA, Roberto CA, et al. Dietary supplements for weight loss: Legal basis for excise tax and other government action to protect consumers from a public health menace. Am J. Law Med. 2022;48(1):38-53.
Koncz D, Tóth B, Roza O, Csupor D. A systematic review of the European rapid alert system for food and feed: Tendencies in illegal food supplements for weight loss. Front Pharmacol. 2021;11:611361.
De Carvalho LM, Martini M, Moreira AP, de Lima AP, Correia D, Falcão T, et al. Presence of synthetic pharmaceuticals as adulterants in slimming phytotherapeutic formulations and their analytical determination. Forensic Sci Int. 2011;204(1-3):6-12.
Tucker J, Fischer T, Upjohn L, Mazzera D, Kumar M. Unapproved pharmaceutical ingredients included in dietary supplements associated with US food and drug administration warnings. JAMA Netw. Open. 2018;1(6):e183337.
Santarsieri D, Schwartz TL. Antidepressant efficacy and side-effect burden: a quick guide for clinicians. Drugs Context. 2015;8(4):212290.
Garlow SJ, Kinkead B, Thase ME, Judd LL, Rush AJ, Yonkers, KA, et al. Fluoxetine increases suicide ideation less than placebo during treatment of adults with minor depressive disorder. J Psychiatr Res. 2013;47(9):1199-1203.
Patel DD, Galarneau D. Serotonin syndrome with fluoxetine: Two case reports. Ochsner J. 2016;16(4):554-57.
Siddiqui R, Gawande S, Shende T, Tadke R, Bhave S, Kirpekar V. SSRI-induced coagulopathy: Is it reality? Ther Adv Psychopharmacol. 2011;1(6):169-74.
Shakibaei F, Gholamrezaei A, Alikhani M, Talaeizadeh K. Serum sodium changes in fluoxetine users at different age groups. Iran J Psychiatry. 2010;5(3):113-16.
Khazaie H, Rezaie L, Payam NR, Najafi F. Antidepressant-induced sexual dysfunction during treatment with fluoxetine, sertraline and trazodone; A randomized controlled trial. Gen Hosp Psychiatry. 2015; 37:40-5.
Zlatković J, Todorović N, Tomanović N, Bošković M, Djordjević S, Lazarević-Pašti T, et al. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study. Eur J Pharm Sci. 2014;59:20-30.
Wooltorton E. Obesity drug sibutramine (Meridia): hypertension and cardiac arrhythmias. CMAJ. 2002;166(10):1307-8.
Perrio MJ, Wilton LV, Shakir SAW. The safety profiles of orlistat and sibutramine: results of prescription-event monitoring studies in England. Obesity. 2007;15:2712-22.
Sibutramine – referral [Internet]. Amsterdam: European Medicines Agency; c2024 [cited 2024 Feb 26]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/sibutramine.
Morikawa Y, Shibata A, Sasajima Y, Suenami K, Sato K, Takekoshi Y, et al. Sibutramine facilitates apoptosis and contraction of aortic smooth muscle cells through elevating production of reactive oxygen species. Eur J Pharmacol. 2018;841:113-21.
Waszkiewicz N, Zalewska-Szajda B, Szajda SD, Simonienko K, Zalewska A, Szulc A, Ładny JR, et al. Sibutramine-induced mania as the first manifestation of bipolar disorder. BMC Psychiatry. 2012;18(12):43.
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 Chem Anal Control Expo Risk Assess. 2012;29(2):161-71.
Firozian F, Nili-Ahmadabadi A, Moradkhani S, Moulaei M, Fasihi Z, Ahmadimoghaddam D. Adulteration of the herbal weight loss products by the illegal addition of synthetic antiobesity medications: A pilot study. J Obes. 2021;2021:9968730.
EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies). Scientific opinion on the safety of caffeine. EFSA J. 2015;13(5):4102.
Cannon ME, Cooke CT, McCarthy JS. Caffeine-induced cardiac arrhythmia: An unrecognised danger of healthfood products. Med J Aust. 2001;174:520-1.
Lieberman HR, Tharion WJ, Shukitt-Hale B, Speckman KL, Tulley R. Effects of caffeine, sleep loss, and stress on cognitive performance and mood during U.S. Navy SEAL training. Psychopharmacology (Berl). 2002;164:250-61.
Pure and highly concentrated caffeine [Internet]. Maryland: Food and Drug Administration; c2024 [cited 2024 Mar 11]. Available from: https://www.fda.gov/food/information-select-dietary-supplement-ingredients-and-other-substances/pure-and-highly-concentrated-caffeine.
Baggott MJ, Childs E, Hart AB, de Bruin E, Palmer AA, Wilkinson JE, et al. Psychopharmacology of theobromine in healthy volunteers. Psychopharmacology (Berl). 2013;228(1):109-18.
Adeyina AO, Oguntoye SO, Olatunde OA, Apata DF. Comparative effects of theobromine and cocoa bean shell (CBS) extract on the performance, serum constituent profile and physiological parameters in rabbits. Glob J Pure Appl Sci. 2008;14(3):253-5.
Dunnick JK, Hailey JR. Phenolphthalein exposure causes multiple carcinogenic effects in experimental model systems. Cancer Res. 1996;56:4922-6.
Food and Drug Administration. Laxative drug products for over-the-counter human use; proposed amendment to the tentative final monograph. Maryland: Federal Register; 1997, 62(169): 46223-27.
Coogan PF, Rosenberg L, Palmer JR, Strom BL, Zauber AG, Stolley PD, et al. Phenolphthalein laxatives and risk of cancer. JNCI. 2000;92(23):1943-4.
Venhuis BJ, Zwaagstra ME, Van de Berg JDJ, Wagenaar HWG, Van Riel AJH, Barends DM. Trends in drug substances detected in illegal weight-loss medicines and dietary supplements. A 2002-2007 survey and health risk analysis. RIVM Report 370030002, 2009.
Ancuceanu R, Dinu M, Corina-Cristina A. Weight loss food supplements: Adulteration and multiple quality issues in two products of Chinese origin. Farmacia. 2013;61:28-44.
Marcus DM. Dietary supplements: what’s in a name? What’s in a bottle? Drug Test Anal. 2016;8:410-12.
Directive 2002/46/EC. Official Journal of the European Communities L 183/51.
Vettorazzi A, López de Cerain A, Sanz-Serrano J, Gil AG, Azqueta A. European regulatory framework and safety assessment of food-related bioactive compounds. Nutrients. 2020;12(3):613.
Wharton S, Bonder R, Jeffery A, Christensen RAG. The safety and effectiveness of commonly-marketed natural supplements for weight loss in populations with obesity: A critical review of the literature from 2006 to 2016. Crit Rev Food Sci Nutr. 2020;60(10):1614-30.
Sarma N, Giancaspro G, Venema J. Dietary supplements quality analysis tools from the United States Pharmacopeia. Drug Test Anal. 2016;8(3-4):418-23.
Pomeranz JL, Barbosa G, Killian C, Austin SB. The Dangerous mix of adolescents and dietary supplements for weight loss and muscle building: Legal strategies for state action. J Public Health Manag Pract. 2015;21(5):496-503.
Petkova-Gueorguieva ES, Getov IN, Ivanov KV, Ivanova SD, Gueorguiev SR, Getova VI, et al. Regulatory requirements for food supplements in the European Union and Bulgaria. Folia Med (Plovdiv). 2019;61(1):41-8.
Vo Van Regnault G, Costa MC, Adanić Pajić A, Bico AP, Bischofova S, Blaznik U, et al. The need for European harmonization of Nutrivigilance in a public health perspective: a comprehensive review. Crit Rev Food Sci Nutr. 2022;62(29):8230-46.
Anadón A, Ares I, Martínez-Larrañaga MR, Martínez MA. Evaluation and regulation of food supplements: European perspective. In: Gupta RC, Lall R, Srivastava A, E 2nd, editors. Nutraceuticals. Academic Press; 2021; p. 1241-71.
Morgovan C, Ghibu S, Juncan AM, Rus LL, Butucă A, Vonica L, et al. 2019. Nutrivigilance: a new activity in the field of dietary supplements. Farmacia. 2019;67(3):537-44.
Palet DM, Low WL, Tan LL, Zhang Q, Low MY, Chan CL, et al. Adverse events associated with the use of complementary medicine and health supplements: an analysis of reports in the Singapore Pharmacovigilance database from 1998 to 2009. Clin. Toxicol (Phila). 2012;50(6):481-9.
Schmitz SM, Lopez HL, MacKay D. Nutravigilance: principles and practices to enhance adverse event reporting in the dietary supplement and natural products industry. Int J Food Sci Nutr. 2014;65(2):129-34.
LeDoux MA, Appelhans KR, Braun LA, Dziedziczak D, Jennings S, Liu L, et al. A quality dietary supplement: before you start and after it's marketed-a conference report. Eur J Nutr. 2015;54(1):S1-8.
Cohen PA, Bass S. Injecting safety into supplements - modernizing the dietary supplement law. N Engl J Med. 2019;381(25):2387-89.