Obr_169.fm

Blackwell Science, LtdOxford, UKOBRobesity reviews1467-78812004 The International Association for the Study of Obesity. 693111Review ArticleAdverse events of herbal food supplements M. H. Pit- obesity reviews
Adverse events of herbal food supplements for body
weight reduction: systematic review*
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, Herbal weight-loss supplements are marketed with claims of effectiveness. Our earlier systematic review identified data from double-blind, randomized controlledtrials for a number of herbal supplements. The aim of this systematic review was Received 25 May 2004; revised 1 October to assess all clinical evidence of adverse events of herbal food supplements for body weight reduction for which effectiveness data from rigorous clinical trialsexist. We assessed Ephedra sinica, Garcinia cambogia, Paullinia cupana, guar Address reprint requests to: MH Pittler, gum, Plantago psyllium, Ilex paraguariensis and Pausinystalia yohimbe. Litera- Complementary Medicine, Peninsula Medical ture searches were conducted on Medline, Embase, Amed and The Cochrane School, Universities of Exeter and Plymouth, 25 Library. Data were also requested from the spontaneous reporting scheme of the Victoria Park Road, Exeter, EX2 4NT, UK. E- World Health Organization. We hand-searched relevant medical journals and our own files. There were no restrictions regarding the language of publication. The *See editorial, this issue pp. 89–92.
results show that adverse events including hepatic injury and death have beenreported with the use of some herbal food supplements. For herbal ephedra andephedrine-containing food supplements an increased risk of psychiatric, auto-nomic or gastrointestinal adverse events and heart palpitations has been reported.
In conclusion, adverse events are reported for a number of herbal food supple-ments, which are used for reducing body weight. Although the quality of the datadoes not justify definitive attribution of causality in most cases, the reported risksare sufficient to shift the risk–benefit balance against the use of most of thereviewed herbal weight-loss supplements. Exceptions are Garcinia cambogia andyerba maté, which merit further investigation.
Keywords: Adverse event, herbal supplement, safety, systematic review
obesity reviews (2005) 6, 93–111
22.9% of the US adult population was considered obese, Introduction
which increased to 30.5% in NHANES 1999–2000; 64.5% The prevalence of overweight and obesity is increasing at were classified as overweight (6). In the UK, the National an alarming rate and obesity has become one of the most Audit Office extrapolating prevalence data to the year 2005 important avoidable risk factors for morbidity and mortal- suggests that levels of obesity in England could reach those ity (1). The risk of developing, for instance, cancer, diabetes now experienced in the USA. In 1980, 8% of women and or heart disease increases with the degree of overweight in 6% of men were classified as obese; in 1998 the prevalence both men and women (2–5). Based on a body mass index had nearly trebled to 21% of women and 17% of men (7).
(BMI) in the healthy range – 18.5–24.9 kg m-2 – almost The increase in obesity rates occurred more rapidly in one-third of the US adult population must now be consid- England than in other European countries (8). One of the ered obese (BMI ≥ 30) and an additional third is over- major factors responsible for the increase in prevalence rates is a decrease in energy expenditure from physical Nutrition Examination Survey (NHANES) III(1988–94), 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
These considerations and the notoriously poor compli- herbal food supplements. Reports detailing adverse events ance with conventional weight management programmes after intake of single constituents of herbal extracts, cases emphasize the importance of effective, safe and acceptable of accidental poisoning, adverse events linked to occupa- therapeutic options. It is therefore not surprising to see the tional handling and studies assessing unconscious patients plethora of herbal over-the-counter slimming aids on offer, were excluded. Articles published in other languages than which are marketed with claims of effectiveness. Our ear- lier systematic review identified data from double-blind,randomized controlled trials (RCTs) for a number of herbal food supplements (10). The weight of the evidence, how-ever, seems small for most supplements and therefore even The searches identified largely anecdotal evidence. The moderate adverse events may shift the risk–benefit balance evidence relates to Ephedra sinica, Garcinia cambogia, against their use. The aim of this systematic review was to Paullinia cupana, guar gum, Plantago psyllium, Ilex assess all clinical evidence of adverse events reported with paraguariensis and Pausinystalia yohimbe. Herbal mono- the use of herbal food supplements for reducing body preparations and combination preparations were impli- weight for which effectiveness data from rigorous clinical cated. In many instances, the documentation of case reports and clinical trials is insufficient. Little information existsfor a number of important issues such as main toxic con-stituents, mechanisms that caused the adverse events and We conducted systematic literature searches on Medline,Embase, Amed and The Cochrane Library. Based on the findings of our earlier review (10), we conducted searcheson the herbal food supplements for which data from ran- Ephedra sinica or ma-huang is an evergreen shrub, which domized, double-blind trials are available. Thus, the search is native to central Asia and contains ephedrine as its pri- terms were ephedra, Ephedra sinica, Garcinia cambogia, mary active constituent (11). Food supplements containing guar gum, Cyamopsis tetragonolobus, psyllium, Plantago ephedra alkaloids have been linked to adverse central ner- ovata, yerba maté, Ilex paraguariensis, guarana, Paullinia vous system events and adverse cardiovascular events cupana, yohimbe, Pausinystalia yohimbe, adverse event, (12,13). Based on 50 randomized and non-randomized tri- adverse effect, adverse drug reaction and side effect. Each als, the most rigorous safety assessment to date concludes database was searched from 1995 to January 2004. Data that herbal ephedra and ephedrine-containing food supple- were also requested from the spontaneous reporting ments are associated with an increased risk of heart palpi- scheme of the World Health Organization (WHO, Collab- tation, psychiatric, autonomic and gastrointestinal adverse orating Centre for International Drug Monitoring, Upp- events (14). Since this assessment, additional reports of adverse events have been published, which are listed in accessed 14 January 2004). To identify additional pub- lished or unpublished material, we conducted hand-searches in our own files and in a sample of relevant medical journals (Erfahrungsheilkunde 1996–2004, For-schende Komplementärmedizin Klassische Naturheilkunde Garcinia cambogia, contains hydroxycitric acid, which has 1995–2004, Phytomedicine 1995–2004, Alternative and been shown to inhibit citrate cleavage enzyme, suppresses Complementary Therapies 1995–2004) and conference de novo fatty acid synthesis and food intake, and conse- proceedings (FACT – Focus on Alternative and Comple- quently decreases body weight gain (52). Garcinia cambo- mentary Therapies 1996–2004). The bibliographies of all gia extract has been tested in a number of trials. These trials located papers were searched for further information.
and case reports detail few and mild adverse events for both There were no restrictions regarding the language of pub- Garcinia cambogia and hydroxycitric acid (Tables 1 and 2).
lication. The screening and selection of articles and theextraction of data were performed independently by two reviewers (M.H.P., K.S.) and verified by a third (E.E.).
Disagreements during this process were largely due to read- Guarana is prepared from the seeds of Paullinia cupana ing errors and were resolved through discussion between and is indigenous to the Amazon basin (96). Guarana has the coauthors. All data (e.g. clinical trials, post-marketing been tested in a combination preparation with Ilex para- surveillance studies, case reports) were considered for guariensis (yerba maté, see below). It contains relatively inclusion. To be included articles were required to report large amounts of caffeine and is reported to prolong the data on adverse events reported with the therapeutic use of speed of gastric emptying (12). A number of adverse events 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
obesity reviews
Adverse events of herbal food supplements ts of adverse events associated with herbal weight-loss supplements 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
obesity reviews
Adverse events of herbal food supplements 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
obesity reviews
Adverse events of herbal food supplements ting adverse events associated with herbal weight-loss supplements 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
obesity reviews
Adverse events of herbal food supplements 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
obesity reviews
Adverse events of herbal food supplements 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
obesity reviews
Adverse events of herbal food supplements pain, constipation, bloating (83 patients 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
obesity reviews
Adverse events of herbal food supplements are reported with the use of guarana and include irritability, Discussion
heart palpitations, anxiety and other central nervous sys-tem events (Table 1).
The reviewed evidence indicates that a range of adverseevents has been reported with the use of herbal weight-losssupplements (Tables 1 and 2). Although the number of cases and clinical trials may collectively look impressive, Guar gum is a dietary fibre derived from the Indian cluster the quality of the data does not. Frequently, the provided bean (Cyamopsis tetragonolobus). An earlier review sug- information is incomplete and important documentation is gested predominately gastrointestinal adverse events (97).
lacking. In some instances the herbal ingredients are not Most frequently, flatulence, diarrhoea and nausea were sufficiently characterized and, in most, the mechanism of reported by patients receiving guar gum. In 3% of the action is not fully understood. Often, the information pro- patients these were severe enough to necessitate the with- vided is insufficient for making inferences about causality.
drawal from the trials. These findings are corroborated by In fact, in many of the above reports and clinical trials, an our present analysis of case reports and clinical trials assumption of a causal relationship was made only because other plausible reasons could not be identified. Therefore,in these cases, it may be unnecessarily alarmist to accept acause–effect relationship. On the other hand, the reported risks imply the potential for harm and there is a possibility Psyllium is a water-soluble fibre derived from the husks of that they do signify causality even though they do not prove ripe seeds of Plantago psyllium (12,96). Clinical trials and it. In addition, the absence of convincing data of a cause– case reports suggest adverse events for this food supple- effect relationship cannot be taken as an indication of ment. Particularly gastrointestinal complaints such as flat- safety. Thus, considering firstly that the evidence of effec- ulence, bloating, indigestion and nausea were reported. In tiveness seems small for most herbal supplements (10), and addition, a number of patients reported, vomiting and ret- secondly considering the principle of ‘first do no harm’, the rosternal pain after the use of psyllium. In many trials, reported adverse events seem sufficient to shift the risk– however, these adverse events are reported to have also benefit balance against the use of most herbal weight-loss occurred in the placebo group (Tables 1 and 2).
supplements. Exceptions are Garcinia cambogia and yerbamaté which, in our view, merit further investigation.
Patients frequently use food supplements in combination with conventional medication. Therefore, a potential for Yerba maté is prepared from Ilex paraguariensis, an ever- herb–drug interactions exists. Perhaps ironically, for many green tree native to South America. Few data are available patients the motivation for using food supplements is that on this herbal preparation. The only double-blind RCT they are perceived as risk-free, a notion that – at least in on the subject did not report on adverse events (98).
the UK – is heavily promoted by the media, which tend to Epidemiological data suggest that the habit of ingesting hot be biased in favour of alternative therapies (103). There is maté drinks over long periods of time is linked to oesoph- also evidence to suggest that adverse events experienced ageal cancer (99). However, this seems to be related to with the use of herbal food supplements are less likely to chronic thermal injury rather than to a pharmacological be reported to a healthcare professional than similar adverse events experienced with conventional medicines(104). Collectively, these factors are likely to increase therisks of food supplements in clinical practice. In addition, issues concerning the quality of herbal food supplements Yohimbe (Pausinystalia yohimbe) is a tall evergreen tree, such as adulteration with prescription drugs or other con- which is native to Central Africa. Yohimbine, an alpha-2 taminants increase risks. Herbal medicines are marketed as receptor antagonist, is the main active constituent of the food supplements in many countries and therefore are sub- ground bark of Pausinystalia yohimbe. Most clinical stud- ject to less stringent controls. In the USA, for instance, ies relate to the effects of this isolated constituent of producers of food supplements do not have to demonstrate yohimbe bark. It is often promoted for erectile dysfunction efficacy, safety and quality similar to conventional drugs and as a weight-loss supplement. The adverse events (105). The effectiveness of any regulation that may exist in reported with the use of yohimbine are well documented this area is further diminished by the advent of internet and include hypertension, anxiety and agitation (100–102).
For a herbal preparation of yohimbe, one case report of Considering the present popularity of herbal food sup- severe acute headache and hypertension is reported plements (106–108), the number of identified adverse events may seem small and their nature benign. This may 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Adverse events of herbal food supplements obesity reviews
indicate that herbal food supplements are relatively (i.e.
3. Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz compared with prescription drugs) safe. However, it could WH, Rimm E, Colditz GA. Impact of overweight on the risk of also suggest that adverse events are under-reported.
developing common chronic diseases during a 10-year period.
Arch Intern Med 2001; 161: 1581–1586.
Regardless of this unresolved issue, the most relevant ques- 4. Key TJ, Allen NE, Spencer EA, Travis RC. The effect of diet tions for clinical decision-making do not merely relate to on risk of cancer. Lancet 2002; 360: 861–868.
the adverse events reported for any given herbal food sup- 5. Kenchaiah S, Evans JC, Levy D, Wilson PWF, Benjamin EJ, plements but to the risk–benefit ratio. Some herbal weight- Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart loss supplements have been tested for effectiveness in failure. N Engl J Med 2002; 347: 305–313.
6. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence
clinical trials, but for most supplements which are on the and trends in obesity among US adults 1999–2000. JAMA 2002; market such data are not available (10,109). Research 288: 1723–1727.
efforts to answer this question should be intensified. Mean- 7. National Audit Office. Tackling Obesity in England. Stationery while, vigilance of healthcare professionals could be a valu- able first step to enhance consumer safety. It should be 8. Seidell JC, Flegal KM. Assessing obesity: classification and
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paired with more adequate education of all parties 9. Heini AF, Weinsier RL. Divergent trends in obesity and fat involved. Patients could be informed to demystify herbal intake patterns: the American paradox. Am J Med 1997; 102:
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11. Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine.
Limitations of our review pertain to the potential incom- Expanded commission E monographs. American Botanical Coun- pleteness of the reviewed evidence. Literature searches were limited to the period between 1995 and January 2004.
12. Haller CA, Benowitz NL. Adverse cardiovascular and cen- Although this may have limited the scope of the review, tral nervous system events associated with dietary supplements events that occurred before 1995 may no longer be of containing ephedra alkaloids. N Engl J Med 2000; 343: 1833–
1838.
interest and supplements may already have been discontin- 13. Morgenstern LB, Viscoli CM, Kernan WN, Brass LM, Brod- ued or banned. Other limitations pertain to the fact that erick JP, Feldmann E, Wilterdink JL, Brott T, Horwitz RI. Use of case reports are often published as short reports or letters ephedra-containing products and risk for hemorrhagic stroke.
and may appear in journals that are not indexed in elec- Neurology 2003; 60: 132–135.
tronic databases. Therefore, we cannot be sure that all 14. Shekelle PG, Hardy ML, Morton SC, Maglione M, MojicaWA, Suttorp MJ, Rhodes SL, Jungvig L, Gagné J. Efficacy and reports were located. Moreover, the number of published safety of ephedra and ephedrine for weight loss and athletic per- adverse events will be affected by a larger than usual level formance. JAMA 2003; 289: 1537–1545.
of under-reporting. In this area of healthcare, patients often 15. Krome CN, Tucker AM. Cardiac arrhythmia in a professional do not tell their physician about the use of herbal medicines football player. Physician Sportsmed 2003; 31: 21–25, 29.
and the likelihood of an adverse event being reported or 16. Schweinfurth J, Pribitkin E. Sudden hearing loss associated
with ephedra use. Am J Health Syst Pharm 2003; 60: 375–377.
published is slim. In many countries a formal post-market- 17. Rezkalla SH, Mesa J, Sharma P, Kloner RA. Myocardial ing surveillance system for herbal medicines is not in place.
infarction temporally related to ephedra – a possible role for the Thus, the cases summarized above may well represent only coronary microcirculation. WMJ 2002; 101: 64–66.
a fraction of the true number of adverse events linked to 18. Matsumoto K, Mikoshiba H, Saida T. Nonpigmenting soli- tary fixed drug eruption caused by a Chinese traditional herbalmedicine ma huang (Ephedra Hebra), mainly containing pseu- In conclusion, adverse events are reported for a number doephedrine and ephedrine. J Am Acad Dermatol 2003; 48: 628–
of herbal food supplements, which are used for reducing body weight. Although the quality of the data does not 19. Chu Hwan R, Henning JS. Exertional heatstroke in an infan- justify definitive attribution of causality in most cases, the try soldier taking ephedra-containing dietary supplements. Mil reported risks are sufficient to shift the risk–benefit balance Med 2003; 168: 429–430.
20. Foxford RJ, Sahlas DJ, Wingfield KA. Vasospasm-induced
against the use of most of the reviewed herbal weight-loss stroke in a varsity athlete secondary to ephedrine ingestion. Clin supplements. Exceptions are Garcinia cambogia and yerba J Sport Med 2003; 13: 183–185.
maté, which merit further investigation.
21. Chu WW. Acute respiratory failure in a young woman taking
herbal medications. J Crit Ill 2001; June. [WWW document] URL

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