Blackwell Science, LtdOxford, UKOBRobesity reviews1467-78812004 The International Association for the Study of Obesity. 693111Review ArticleAdverse events of herbal food supplements M. H. Pittler et al.
obesity reviews
Adverse events of herbal food supplements for body weight reduction: systematic review* M. H. Pittler, K. Schmidt and E. Ernst
Complementary Medicine, Peninsula Medical
Summary
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 controlled trials for a number of herbal supplements. The aim of this systematic review was to assess all clinical evidence of adverse events of herbal food supplements for body weight reduction for which effectiveness data from rigorous clinical trials exist. We assessed Ephedra sinica, Garcinia cambogia, Paullinia cupana, guar gum, Plantago psyllium, Ilex paraguariensis and Pausinystalia yohimbe. Literature searches were conducted on Medline, Embase, Amed and The Cochrane Library. Data were also requested from the spontaneous reporting scheme of the World Health Organization. We hand-searched relevant medical journals and our own files. There were no restrictions regarding the language of publication. The results show that adverse events including hepatic injury and death have been reported with the use of some herbal food supplements. For herbal ephedra and ephedrine-containing food supplements an increased risk of psychiatric, autonomic or gastrointestinal adverse events and heart palpitations has been reported. In conclusion, adverse events are reported for a number of herbal food supplements, which are used for reducing body weight. Although the quality of the data does not justify definitive attribution of causality in most cases, the reported risks are sufficient to shift the risk–benefit balance against the use of most of the reviewed herbal weight-loss supplements. Exceptions are Garcinia cambogia and yerba maté, which merit further investigation.
UK
Received 25 May 2004; revised 1 October 2004; accepted 4 October 2004
Address reprint requests to: MH Pittler, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter, EX2 4NT, UK. Email:
[email protected] *See editorial, this issue pp. 89–92.
Keywords: Adverse event, herbal supplement, safety, systematic review obesity reviews (2005) 6, 93–111
Introduction The prevalence of overweight and obesity is increasing at an alarming rate and obesity has become one of the most important avoidable risk factors for morbidity and mortality (1). The risk of developing, for instance, cancer, diabetes or heart disease increases with the degree of overweight in both men and women (2–5). Based on a body mass index (BMI) in the healthy range – 18.5–24.9 kg m-2 – almost one-third of the US adult population must now be considered obese (BMI ≥ 30) and an additional third is overweight (BMI ≥ 25) (6). In the National Health and Nutrition Examination Survey (NHANES) III(1988–94),
22.9% of the US adult population was considered obese, which increased to 30.5% in NHANES 1999–2000; 64.5% were classified as overweight (6). In the UK, the National Audit Office extrapolating prevalence data to the year 2005 suggests that levels of obesity in England could reach those now experienced in the USA. In 1980, 8% of women and 6% of men were classified as obese; in 1998 the prevalence had nearly trebled to 21% of women and 17% of men (7). The increase in obesity rates occurred more rapidly in England than in other European countries (8). One of the major factors responsible for the increase in prevalence rates is a decrease in energy expenditure from physical activity (9).
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
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These considerations and the notoriously poor compliance with conventional weight management programmes emphasize the importance of effective, safe and acceptable therapeutic options. It is therefore not surprising to see the plethora of herbal over-the-counter slimming aids on offer, which are marketed with claims of effectiveness. Our earlier systematic review identified data from double-blind, randomized controlled trials (RCTs) for a number of herbal food supplements (10). The weight of the evidence, however, seems small for most supplements and therefore even moderate adverse events may shift the risk–benefit balance against their use. The aim of this systematic review was to assess all clinical evidence of adverse events reported with the use of herbal food supplements for reducing body weight for which effectiveness data from rigorous clinical trials exist.
Methods We conducted systematic literature searches on Medline, Embase, Amed and The Cochrane Library. Based on the findings of our earlier review (10), we conducted searches on the herbal food supplements for which data from randomized, double-blind trials are available. Thus, the search terms were ephedra, Ephedra sinica, Garcinia cambogia, guar gum, Cyamopsis tetragonolobus, psyllium, Plantago ovata, yerba maté, Ilex paraguariensis, guarana, Paullinia cupana, yohimbe, Pausinystalia yohimbe, adverse event, adverse effect, adverse drug reaction and side effect. Each database was searched from 1995 to January 2004. Data were also requested from the spontaneous reporting scheme of the World Health Organization (WHO, Collaborating Centre for International Drug Monitoring, Uppsala, Sweden https://websearch.who-umc.org/login.asp; accessed 14 January 2004). To identify additional published or unpublished material, we conducted handsearches in our own files and in a sample of relevant medical journals (Erfahrungsheilkunde 1996–2004, Forschende Komplementärmedizin Klassische Naturheilkunde 1995–2004, Phytomedicine 1995–2004, Alternative and Complementary Therapies 1995–2004) and conference proceedings (FACT – Focus on Alternative and Complementary Therapies 1996–2004). The bibliographies of all located papers were searched for further information. There were no restrictions regarding the language of publication. The screening and selection of articles and the extraction 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 reading errors and were resolved through discussion between the coauthors. All data (e.g. clinical trials, post-marketing surveillance studies, case reports) were considered for inclusion. To be included articles were required to report data on adverse events reported with the therapeutic use of
herbal food supplements. Reports detailing adverse events after intake of single constituents of herbal extracts, cases of accidental poisoning, adverse events linked to occupational handling and studies assessing unconscious patients were excluded. Articles published in other languages than English were translated in-house.
Results The searches identified largely anecdotal evidence. The evidence relates to Ephedra sinica, Garcinia cambogia, Paullinia cupana, guar gum, Plantago psyllium, Ilex paraguariensis and Pausinystalia yohimbe. Herbal monopreparations and combination preparations were implicated. In many instances, the documentation of case reports and clinical trials is insufficient. Little information exists for a number of important issues such as main toxic constituents, mechanisms that caused the adverse events and incidence figures.
Ephedra sinica Ephedra sinica or ma-huang is an evergreen shrub, which is native to central Asia and contains ephedrine as its primary active constituent (11). Food supplements containing ephedra alkaloids have been linked to adverse central nervous system events and adverse cardiovascular events (12,13). Based on 50 randomized and non-randomized trials, the most rigorous safety assessment to date concludes that herbal ephedra and ephedrine-containing food supplements are associated with an increased risk of heart palpitation, psychiatric, autonomic and gastrointestinal adverse events (14). Since this assessment, additional reports of adverse events have been published, which are listed in Tables 1 and 2.
Garcinia cambogia Garcinia cambogia, contains hydroxycitric acid, which has been shown to inhibit citrate cleavage enzyme, suppresses de novo fatty acid synthesis and food intake, and consequently decreases body weight gain (52). Garcinia cambogia extract has been tested in a number of trials. These trials and case reports detail few and mild adverse events for both Garcinia cambogia and hydroxycitric acid (Tables 1 and 2).
Paullinia cupana Guarana is prepared from the seeds of Paullinia cupana and is indigenous to the Amazon basin (96). Guarana has been tested in a combination preparation with Ilex paraguariensis (yerba maté, see below). It contains relatively large amounts of caffeine and is reported to prolong the speed of gastric emptying (12). A number of adverse events
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Patients age, gender, n
27 years, m 1
38 years, f 1
25 years, m 1
31 years, f 1
20 years, m 1
24 years, m 1
29 years, f 1
23 year, f 1; 21, 51 years, m2
First author (reference
Krome (15)
Schweinfurth (16)
Rezkalla (17)
Matsumoto (18)
Chu Hwan (19)
Foxford (20)
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Chu (21)
Estes (22) Not reported
Not reported
Pseudoephedrine, methylephedrine, caffeine (Xenadrine)
Guarana, bitter orange, white willow bark, ginger, green tea, carnitine (Xenadrine RFA-1)
Not reported (Sepi Gold)
Not reported
Guarana, chromium picolinate (Ripped Fuel)
Not reported
Other main constituents (brand name)
Not reported, ‘Several days to months’
Not reported
109 mg ephedrine once, regular intake of ephedrine tablets
20 mg ephedrine, 2 d
Not reported ‘several times’
96 mg ephedra ‘a few weeks’
334 mg ephedra once
Two ‘tablets’, since the beginning of the football season’
Daily dose, duration
Disulfiram, kava
Ginger root, primrose, red raspberry, bee pollen, tobacco, amphetamines
None
None
Not reported
History of chronic cocaine and tobacco use
‘No significant medical or medication history’
Ginseng
Concomitant medication
Fulminant hepatic failure
Fever, chills, cough, dyspnoea, pleuritic chest pain
Severe right-sided headache, collapse, left-sided weakness, left facial droop
Exertional collapse disorientation, mental status change, increased blood pressure, tachycardia
Slightly tender, palm-sized erythema
Left-sided tightness in the chest, left arm numbness
Unilateral hearing loss, vertigo
Racing heart, shortness of breath, substernal chest tightness, dizziness, lightheadedness
Adverse events
‘Marked to subtotal liver necrosis consistent with toxic injury in two patients.’
‘A case of acute eosinophilic pneumonia with severe acute respiratory failure [. . .]. Suspicion for an association with herbal medication use was precipitated by the fortuitous result of a urine toxicology screen.’
‘[. . .] a case of a varsity athlete who suffered permanent disability after ingesting a combination of ephedrine-containing supplements and subsequently developed a vasospastic stroke during training.’
‘[. . .] highly trained, heatacclimatized infantry soldier who suffered from exertional heatstroke during a 12-mile road march shortly after taking an ephedra-based supplement.’
‘In our case Ephedra herba [. . .] was determined as the cause of non-pigmenting solitary fixed drug eruption.’
‘Acute myocardial infarction could be related to ephedrine present in diet pills [. . .]’
‘Given the evidence of an acute cochlear injury and the lack of associated risk factors in this patient a drug-mediated vascular injury was suspected as the cause of her hearing loss.’
‘[. . .] the cardiologist made the diagnosis of atrial arrhythmia secondary to ephedrine use.’
Authors’ evaluation/conclusion
Adverse events of herbal food supplements
E. sinica, not reported
E. sinica, not reported
E. sinica, boosting energy levels
E. sinica, boosting energy levels
E. sinica, common cold
E. sinica, weight loss
E. sinica, not reported
E. sinica, boosting energy levels
Herbal medicines, indications
Table 1 Case reports of adverse events associated with herbal weight-loss supplements
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45 years, m 1
19, 21 years, m2
Verduin (29)
Naik (30)
18, 34 years, m2
Case (26)
30 years, m 1
42 years, m 1
Wettach (25)
Warner (28)
23 years, m 1
Charatan (24)
26 years, f 1
21 years, f 1
Boerth (23)
Kola nut, white willow bark, grapefruit, chitosan (Stacker III)
Guarana, damiana, ginseng, ginger, sarsaparilla, goldenseal, nettle, gotu kola,chromium picolinate (Metabolife)
Caffeine
Guarana, bitter orange, white willow bark (Xenadrine)
Guarana, damiana, ginseng, ginger, sarsaparilla, goldenseal, nettle, gotu kola, chromium picolinate (Metabolife 356)
Guarana, damiana, ginseng, ginger, sarsaparilla, goldenseal, nettle, gotu kola, chromium picolinate (Ripped Fuel, Metabolife, Red Bull)
Guarana, bitter orange, white willow bark, ginger, green tea, carnitine (Xenadrine RFA-1)
Not reported
Other main constituents (brand name)
Not detailed
‘several pills a day’, 2 weeks
25 mg ephedrine, 4 months
Not reported, 1 month
24 mg ephedrine 3, 10 d
1000 mg mahuang, ‘many weeks’
60 mg ephedrine, not reported
Not reported, ‘Several months’
Daily dose, duration
Riboforce, ripfuel, tissue growth promoter, TheraFlu, tobacco
Molindone, tobacco
Alcohol, tobacco
None
None
Multivitamins, saw palmetto
Not reported
None
Concomitant medication
Shortness of breath, chest pain
Disorientated, confused, agitated, hallucinating
Painless, progressive, bilateral loss of vision
Bloody diarrhoea, crampy abdominal pain, lightheadedness, dizziness
Polydipsia, polyuria, confusion, weakness, nausea, vomiting
Increased blood pressure and heart rate
Heatstroke
Psychomotor agitation, delusional thinking, suicidal ideation
Adverse events
‘[. . .] we believe ephedra may have caused cardiomyopathy in these 2 patients.’ Death of one patient after re-admission with exacerbation of heart failure.
‘The temporal relationship between Mr A’s initiation of Metabolife and subsequent development of psychosis and delirium strongly suggests that this agent, ephedra in particular, was responsible for his symptoms.’
‘We propose that our patient’s use of a dietary supplement containing ephedra and caffeine contributed to the metabolic stress that may have precipitated the onset of his symptoms of optic neuropathy.’
‘This case report suggests that use of such herbal products [. . .] could be risk factors for development of ischemic colitis in an otherwise healthy person.’
‘Two cases of diabetic ketoacidosis in newly diagnosed type 1- and type 2-diabetic individuals associated with Metablife-356.’
Hypertension and tachycardia in a reservist who was taking large doses of Ephedra sinica for bodybuilding.
Heatstroke resulting in multiorgan failure and death.
At discharge a diagnosis of schizoaffective disorder of bipolar type was made.
Authors’ evaluation/conclusion
M. H. Pittler et al.
E. sinica, bodybuilding
E. sinica, weight loss
E. sinica, not reported
E. sinica, weight loss
E. sinica, not reported,
E. sinica, bodybuilding
E. sinica, weight loss
E. sinica, heightened alertness and prevent drowsiness
Herbal medicines, indications
Adverse events of herbal food supplements
Ryan (27)
Patients age, gender, n
First author (reference
Table 1 Continued
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© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Patients age, gender, n
29–39 years, f 3; 19, 45 years, m 2
44 years, m 1
20–51 years, f 3; 23–71 years, m 4
34, 48 years, f 2; 48 years, m1
29 years, m 1
51 years, f 1
25 years, f 1
First author (reference
Chen (31)
Bajaj (32)
WHO (33)
WHO (34)
Donadio (35)
Baghkhani (36)
Cannon (37)
Table 1 Continued
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Ginseng (Race 2005 Energy Blast)
(i) Gotu kola, kola nut, barley grass, ginseng (not reported); (ii) Gotu kola (not reported)
Gingko, kava (Guaranaginkgo Plus)
Not reported
Not reported (Xenadrin RFA-1 in 2 patients)
Guarana, green tea, l-carnitine, Garcinia cambogia (Hydroxycut)
Guarana, chromium picolinate damiana, ginseng, ginger, sarsaparilla, goldenseal, nettle, gotu kola, green tea, l-carnitine (Ripped Fuel, Metabolife 356, Hydroxycut)
Other main constituents (brand name)
55 mL, once
400 mg to 4 g, ‘over a month’
Not reported (1 flacon contains 500 mg), once
1.2 g, 3, 4 d
1–4 g ephedra (reported in 3 patients), once to 16 d
60 mg ephedra alkaloids, 4 months
40–72 mg ephedrine, 1–4 g ephedra, 5 weeks to 4 years
Daily dose, duration
None
Estradiol, progesterone, bupropion, zolpidem, tobacco
Not reported
Not reported
Alcohol and venlafaxine hydrochloride (reported in 1 patient)
Fluticasone inhaler, albuterol inhaler
Oral contraceptives, chiropractic treatment
Concomitant medication
Collapse, arterial fibrillation, death
Anxiety, irritability, heart palpitations
Diffuse muscle pain, dark urine
Dizziness, increased appetite, dry mouth, palpitation, hepatic enzyme increase
Myocardial infarction, ST elevated, dizziness, gastrointestinal complaints, vomiting, depression, tachycardia, death, sweating, heart murmur, dyspnoea, chest pain, pallor, tremor, anxiety, nervousness, palpitation, rash, collapse, leg cramps, impaired consciousness
Yellowish discoloration of eyes and skin, ashen stools, dark urine
Headache, left/right-sided weakness, hemianopsia, aphasia, dysarthria
Adverse events
‘In this patient’s case the Coroner found that the high level of caffeine was associated with the development of an intractable arrhythmia.’
‘Although the exact cause of tachycardia in our report is not proven a large amount of caffeine consumption is thought to be a possible causal effect.’
‘. . . we believe that the methylxanthine effects of guarana and the anti-dopaminergic and neuromuscular blocking activities of kava were pathogenetically relevant.’
n.a.
n.a.
‘[. . .] it was felt that the patient had a toxic hepatitis most likely due to the ma-huang component of the Hydroxycut dietary supplement.’
‘Five patients with ischemic infarctions associated with use of ephedra products were evaluated [. . .]. Despite extensive investigations no more likely aetiologies for these patients’ strokes were found.’
Authors’ evaluation/conclusion
Adverse events of herbal food supplements
P. cupana, not reported
P. cupana, ‘boosting energy levels’
P. cupana, bodybuilding
G. cambogia, not reported
E. sinica, not reported
E. sinica, weight loss
E. sinica, weight loss, athletic enhancement
Herbal medicines, indications
obesity reviews M. H. Pittler et al. 97
Patients age, gender, n
27–44 years, f 6; 17, 47 years, m 2; not reported, 1
43–80 years, f 8; 70–71 years, m3
26 years, f 1
69 years, f 1
54 years, m 1
41 years, f 1
64 years, f 1
First author (reference
WHO (38)
WHO (39)
Fraquelli (40)
Vaswani (41)
Germán (42)
Salguero Molpeceres (43)
Manbeck (44)
Table 1 Continued
P. psyllium, not reported
Maltodextrin, citric acid, aspartame (Metamucil)
Not reported (Cenat)
Not reported (Cenat)
None (Perdiem)
Dextrose, Emblica officinalis (Isabgol)
Not reported
‘2 tablepoonful’, not reported
10 mg, once
Not reported, ‘For several days’
‘continuous daily use’, not reported
0.1–15 g, once to 2 years
Unspecified, (10 mL in 1 patient) once to 40 d
Daily dose, duration
Cisapride, trazodone, omeprazole, nifedipine
Not reported
Not reported
Not reported
None
Not reported
Acetylsalicylate lysine, simvastin, ethanol, codeine phosphate, paracetamol, doxylamine succinate, fluoxetin hydrochloride, sertraline hydrochloride, clonazepam, vitamins
Concomitant medication
Vomiting, heartburn
Retrosternal pain, cough
Nausea, anaphylactic shock
Hoarseness, wheezing, generalized body swelling, flushing, urticaria, dyspnoea, nausea
Fatigue, anorexia, jaundice, asthenia
Flatulence, diarrhoea, dysphagia, chest pain, urticaria, pruritus, flushing, dyspepsia, malaise, hyperglycaemia, hepatitis
Paraesthesia, diarrhoea, nausea, palpitation, personality disorder, manic reaction, insomnia, rash, Quincke’s oedema, hyperkinesia, twitching, somnolence, asthenia, myalgia, fatigue, anxiety, hypertension, chest pain, impaired concentration
Adverse events
‘Analysis of the fragments (of the bezoar) was consistent with the ingredient of Metamucil.’
‘Esophageal obstruction caused by Plantago ovata [. . .].’
‘According to the evaluation [. . .] the present clinical case can be considered as a possible adverse event associated with psyllium facilitated by co-existing atopia.’
‘Physicians should be aware that psyllium sensitization may cause lifethreatening anaphylaxis.’
‘The causative role of the herbal remedy was further supported by the spontaneous and dramatic clinical, biochemical and histologic improvement observed following its withdrawal, despite the absence of any treatment.’
n.a.
n.a.
Authors’ evaluation/conclusion
M. H. Pittler et al.
P. psyllium, chronic constipation
P. psyllium, constipation
P. psyllium, constipation
P. psyllium, chronic constipation
Not reported
Not reported
Other main constituents (brand name)
Adverse events of herbal food supplements
P. cupana, not reported
P. cupana, not reported
Herbal medicines, indications
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40 years, m 1
39–55 years, f 3; 57, 52 years, m 2
63 year, m 1
Hulbert (45)
WHO (46)
Ruck (47)
P. yohimbe, erectile dysfunction
P. psyllium, not reported
P. psyllium, constipation
Herbal medicines, indications
Not reported
Not reported
Citric acid, potassium bicarbonate, sodium bicarbonate (Fybogel)
Other main constituents (brand name)
‘one tablet’, 1 month
5 g, 15 d (1 patient)
3.5 g, once
Daily dose, duration
Patients mean age, gender, n (herb/placebo or no treatment)
36–40 years, f 17, m 10 (19/8)
25–38 years, f 5, m 3 (8/n.a.)
First author (reference)
Kalman (48)
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Haller (49)
E. sinica, pharmacologic evaluation
E. sinica, weight loss
Herbal medicines, indications
Guarana, willow bark, cayenne fruit (Metabolift)
Guarana, bitter orange, willow bark, ginger, green tea, carnitine (Xenadrine RFA-1)
Other main constituents (brand name)
24 mg ephedrine alkaloids, once
40–80 mg ephedrine alkaloids, 2 weeks
Daily dose Duration
None
Shakiness (3), heart pounding (4), restlessness (4), chest pain (1), flushing (2), dizziness (1), numbness (1), sweating (1)
Dry mouth, feeling hyper, headache, increased thirst, difficulty initiating sleep (cases not reported)
n.a.
Not reported
Adverse events in placebo/notreatment group (no. of patients)
Headache, weakness, hypertension
Dermatitis, allergic reaction, rash, urticaria, pruritus, skin eruption, depression
Feeling wheezy, cardiorespiratory arrest, death
Adverse events
Adverse events in treatment group (no. of patients)
Acetylsalicylic acid, lithium, sertraline
Salbutamol, beclamethasone diproprionate
Concomitant medication
Oral contraceptives
None
Concomitant medication
Table 2 Clinical trials reporting adverse events associated with herbal weight-loss supplements
n.a., not available.
Patients age, gender, n
First author (reference
Table 1 Continued
‘[. . .] young healthy adults can have significant cardiovascular responses and central nervous system effects after a single dose of a supplement that contains relatively modest doses of ephedrine alkaloids and caffeine.’
‘Statistically, there were no differences between treatment and placebo for adverse events.’
Authors’ evaluation/conclusion
‘We recently treated a case of hypertensive crisis associated with herbal yohimbine usage.’
n.a.
‘[. . .] fatal bronchospasm following oral ingestion of a laxative containing ispaghula.’
Authors’ evaluation/conclusion
obesity reviews Adverse events of herbal food supplements M. H. Pittler et al. 99
G. cambogia, weight loss
44 years, f 20, m 24 (21/23)
Hayamizu (56)
G. cambogia, weight loss
G. cambogia, weight loss
Not reported (25/23)
Rothacker (54)
G. cambogia, weight loss
G. cambogia, weight loss
G. cambogia, lipid lowering
E. sinica, pharmacologic evaluation
Not reported
Guggul, phosphate (not reported)
Guarana, green tea, chromium picolinate (not reported)
Phaseolus vulgaris, inulin (Suco-Bloc)
Not reported
Chitosan, chrome (Colenon)
Guarana, damiana ginseng, ginger, sarsaparilla, goldenseal, nettle, gotu kola, chromium picolinate (Metabolife 356)
Other main constituents (brand name)
1.7 g, 12 weeks
4 g, 6 weeks
2.6 g, 6 weeks
3.9 g, 12 weeks
3 g, 12 weeks
1.26 g, 4 weeks
12 mg ephedra extract, once
Daily dose Duration
None
None
None
Headache (9), upper respiratory symptoms tract symptoms (16), gastrointestinal symptoms (13)
Nausea (3), headache (1)
Jitteriness, queasiness, ‘not feeling quite right’, tachycardia, palpitations, tremor (15)
Adverse events in treatment group (no. of patients)
Not specified; Common cold (1), supplements that toothache(3), may influence body diarrhoea (2) weight, body fat or serum lipids were not allowed
Not specified; anorectic medications were not allowed
Not reported
Not reported
None
Not specified; concomitant intake of drugs that could interfere with the results was not allowed
Not specified; concomitant use of potentially interacting drugs was not allowed
Concomitant medication
Common cold (10), toothache (3), diarrhoea (4), headache (4)
Not reported
None
None
Headache (12), upper respiratory tract (13), gastrointestinal symptoms (6)
Nausea and/or constipation (3)
None
Adverse events in placebo/notreatment group (no. of patients)
‘No severe adverse effect was observed at any time in the test period.’
‘No adverse effects were noted in the participants who ingested the guggulsterone phosphate compound.’
‘No serious adverse events were reported.’
‘The excellent tolerability of the product suggests that it could provide a useful alternative [. . .].’
‘No patient was removed from the study protocol for a treatment-related adverse event, and the number of reported adverse events was not significantly different between the placebo and treatment groups.’
‘Mild and transient adverse events were reported [. . .] without any statistically significant differences between the three groups.’
‘[. . .] a single dose of a dietary supplement containing ephedra and caffeine significantly prolongs the QTc interval and p-wave duration.’
Authors’ evaluation/conclusion
M. H. Pittler et al.
Antonio (55) 39–56 years, f 10, m 8 (6/6/6 no treatment)
40–46 years, f 36, m 4 (20/20)
Thom (53)
42 years, f 79, m 71 (50/50 half dose/50)
Girola (51)
39 years, f 116, m 19 (66/69)
27 years, f 6, m 9 (8/7)
McBride (50)
Herbal medicines, indications
Adverse events of herbal food supplements
Heymsfield (52)
Patients mean age, gender, n (herb/placebo or no treatment)
First author (reference)
Table 2 Continued
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Patients mean age, gender, n (herb/placebo or no treatment)
35–39 years, f 26, m 9 (18/17)
Not reported (91/91)
65 years, f 25, m 20 (15/15/15 caffeine)
(range) 40–70 years, (19/19)
44 years, m 12 (11/11)
50–54 years, f 27, m 31 (24,/27)
51–54 years, f 58, m 104 (81/81)
First author (reference)
Román Ramos (57)
Bourin (58)
Fernandes Galduróz (59)
Sesmilo (60)
Blake (61)
Jensen (62)
Knopp (63)
Table 2 Continued
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
1.5 g, 8 weeks
Daily dose Duration
Soy fibre, pea fibre, corn bran, pectin (Choltrol)
Psyllium, locust bean gum, pectin (not reported)
Wheat flower (Meyprogat 90)
Not reported
Not reported
20 g, 15 weeks
15 g, 24 weeks
16 g, 3 weeks
60 g, 3 months
1 g, 150 d
Valeriana officinalis, 90 mg, Passiflora incarnata, 28 d Crataegus oxycantha (Euphytose)
Not reported
Other main constituents (brand name)
Not specified; patients had not used hypolipidemic drugs for at least 2 months
Not specified; patients on lipid-lowering medication were not allowed.
Not reported
Not reported
None
Not reported
Not reported
Concomitant medication
Diarrhoea (10), flatulence (30), loose stools (11), decreased incidence of constipation (5)
Gastrointestinal discomfort, flatulence, bloating, loose stools (not reported)
Nausea, headache (1), flatulence (3)
Not specified (1)
‘burning in the stomach’(3), tachycardia (1)
Dry mouth (1), headache (1), constipation (1), drowsiness (1)
Nausea, headache (2)
Adverse events in treatment group (no. of patients)
Diarrhoea (1), flatulence (16), loose stools (5), decreased incidence of constipation (11)
Not reported
None
Not reported
Insomnia (1)
Dry mouth (1), constipation (2), stomach pain (3), drowsiness (2)
Nausea, headache (1)
Adverse events in placebo/notreatment group (no. of patients)
‘The majority of these side effects were of mild severity.’
‘[. . .] adverse effects were minimal according to subject diaries.’
‘[. . .] few side effects were recorded by subjects ingesting a mean daily dose of 13.9 g guar gum, except for an increase in flatulence in three of the subjects.’
‘[. . .] guar gum improves the metabolic control of obese NIDDM patients with a very low incidence of gastrointestinal side effects.’
‘[Guarana] is not totally free of side effects since our volunteers showed some discomfort with one not completing the study due to tachycardia . . .’
‘There was no difference in the number of adverse events between the two treatment groups.’
‘The absence of adverse events connected with the anorectic sympathomimetic amines . . .’
Authors’ evaluation/conclusion
Adverse events of herbal food supplements
Guar gum, hypercholesterolaemia
Guar gum, hypercholesterolaemia
Guar gum, hypercholesterolaemia
Guar gum, type 2 diabetes mellitus
P. cupana, cognition
P. cupana, anxiety
G. cambogia, weight loss
Herbal medicines, indications
obesity reviews M. H. Pittler et al. 101
56–57 years, f 23, m 91 (61/53)
63 years, f 8, m 32 (18/19)
83 years, f 12, m 4 (16/16)
55 years, f 16, m 34 (25/25)
34 years, m 10 (10/10)
Salenius (69)
Patrick (70)
Hosobuchi (71)
Alam (72)
43 years, m 28 (28/28)
Kovacs (66)
Vajifdar (68)
29–31 years, f 59 (19/20/20 no treatment)
Riikonen (65)
30 years, f 48 (24/24)
37–41 years, f 40, m 27 (35/32)
Tai (64)
Guar gum, effects on intestinal absorption
None (Benefiber)
Acacia, pectin (Bioslife II)
None (Benefiber)
None (Guarem)
Fenugreek, wheat bran (Fibernat)
Not reported
None (Meyprofin M-175)
None (Guarem)
Ispaghula husk, citric acid, betacarotene, potato starch (Minolest)
Other main constituents (brand name)
42–63 g, 7d
9 g, 12 weeks
8–12 g, 8 weeks
15 g, 25 months
20 g, 6 months
5–15 g, 4 weeks
7.5 g, 2 weeks
5–15 g, ≥10 d
16.5 g, 3 months
Daily dose Duration
None
Not reported
Laxatives
Aspirin, dipyridamole
Not specified; patients on lipid lowering drugs were excluded
Not reported
Not reported
Not specified; prometazinhydrochloride for severe pruritus
None
Concomitant medication
None
Gastrointestinal complaints (15)
Flatulence (5)
Flatulence, diarrhoea (1)
Flatulence, borborygmi, feeling of fullness
None
Nausea, flatulence (not reported)
Abdominal distress, diarrhoea, flatulence (8)
Flatulence or abdominal discomfort (4)
Adverse events in treatment group (no. of patients)
Not reported
Gastrointestinal complaints (8)
Not reported
Diarrhoea (1)
None
Not reported
Not reported
Abdominal distress, diarrhoea, flatulence (6)
Flatulence or abdominal discomfort (5)
Adverse events in placebo/notreatment group (no. of patients)
‘We conclude that Benefiber is a safe source of soluble fibre.’
‘Gastrointestinal side effects are the most common reasons for dropping out of the intervention group.’
‘The degree of flatulence was not considered clinically significant [. . .].’
‘Toleration of granulated guar gum with meals was good; only one patient interrupted treatment because of gastrointestinal complaints.’
‘Fibernat is well tolerated with no significant adverse effects.’
‘There were no side effects of the treatment either in the mothers or in the newborns.’
‘[. . .] we conclude that the semisolid meal with or without guar gum and the solid meal were well tolerated [. . .]’
‘[. . .] guar gum relieved pruritus of intrahepatic cholestasis of pregnancy without any serious side effects.’
‘Few subjects reported side effects.’
Authors’ evaluation/conclusion
M. H. Pittler et al.
Guar gum, hypercholesterolaemia
Guar gum, constipation
Guar gum, hypercholesterolaemia
Guar gum, chronic ischemic heart disease
Guar gum, intrahepatic cholestasis of pregnancy
Guar gum, weight loss
Guar gum, intrahepatic cholestasis of pregnancy
Guar gum, hypercholesterolaemia
Herbal medicines, indications
Adverse events of herbal food supplements
Gylling (67)
Patients mean age, gender, n (herb/placebo or no treatment)
First author (reference)
Table 2 Continued
102
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© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Patients mean age, gender, n (herb/placebo or no treatment)
52–54 years, f 118, m 130 (197/51)
62–64 years, m 34 (18/16)
Not reported (19/19)
59 years, f 141, m 235 (198/178)
40–46 years, f 34, m 31
First author (reference)
Anderson (73)
Anderson (74)
Chicouri (75)
BonithonKopp (76)
FernándezBañares
Table 2 Continued
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
None (Cenat)
Not reported
Paraffin, sorbitol (not reported)
Maltodextrin, citric acid, aspartame (Metamucil)
Maltodextrin, citric acid, aspartame (Metamucil)
Other main constituents (brand name)
20 g, 1 years
3.5 g, 3 years
10 g, 3 weeks
13.4 g, 8 weeks
13.4 g, 26 weeks
Daily dose Duration
Mesalamine
Not specified; patients treated with digitalis glycosides were excluded
Sulphonamide, diuretics, phlebotonics
Not specified; patients taking sulphonylurea agents were allowed
Not specified; patients taking corticosteroids, androgens, phenytoin, thyroid hormones, oral contraceptives, antibiotics, lipidlowering medications, other fibre or calcium supplements were excluded
Concomitant medication
Constipation (2), flatulence (6), nausea (1), diarrhoea (1)
Not specified (19); severe diarrhoea or abdominal pain (3), recurrence of adenoma (58)
None
Respiratory system disorders (not reported)
Flatus, bloating, indigestion, nausea, heartburn, diarrhoea, constipation (51)
Adverse events in treatment group (no. of patients)
Not reported
Not specified (12); severe diarrhoea or abdominal pain (3), recurrence of adenoma (36)
Not reported
Respiratory system disorders (not reported)
Flatus, bloating, indigestion, nausea, heartburn, diarrhoea, constipation (16)
Adverse events in placebo/notreatment group (no. of patients)
‘One patient receiving Plantago ovata and two treated with P ovata plus mesalamine withdrew because of constipation and/or flatulence.’
‘Supplementation with fibre as ispaghula husk may have adverse effects on colorectal adenoma recurrence.’
‘The authors conclude that the drug demonstrated efficacy without side effects occurrence . . .’
‘There were no significant differences between treatment groups in the incidence of adverse events or in the type of event reported. No serious adverse events related to treatment were reported by either the placebo group or psyllium group.’
‘There were no significant differences in the incidence of adverse events between groups. No serious adverse events related to treatment were reported in either group.’
Authors’ evaluation/conclusion
Adverse events of herbal food supplements
P. psyllium, ulcerative colitis
P. psyllium, colorectal carcinoma
P. psyllium, constipation
P. psyllium, hypercholesterolaemia
P. psyllium, hypercholesterolaemia
Herbal medicines, indications
obesity reviews M. H. Pittler et al. 103
45 years, f 19, m 47 (66/n.a.)
32–33 years, f 49, m 44 (93/n.a.)
Ho (81)
Oliver (82)
Not reported, f 250, m 139 (224/n.a.)
Dettmar (79)
55–56 years, f 78, m 118 (138/58)
44 years, f 7, m 16 (23/23)
Weingand (78)
P. psyllium, healthy
P. psyllium, haemorrhoids
P. psyllium, hypercholesterolaemia
P. psyllium, constipation
P. psyllium, hypercholesterolaemia
Herbal medicines, indications
3.4–10.2 g, 24 weeks
7 g, 4 weeks
13.4 g, 8 weeks
Daily dose Duration
Not reported
5.3 g, 2 weeks 10.5 g, 50 weeks
Citric acid, 7.0 g, potassium 3 months bicarbonate, sodium bicarbonate (Fybogel)
Not reported
Citric acid, potassium sodium bicarbonate, bicarbonate (Fybogel)
Maltodextrin, citric acid, aspartame (Metamucil)
Other main constituents (brand name)
Not specified; patients taking vitamins or mineral supplements were excluded
Not reported
Not reported
Lactulose, bisacodyl, docusate sodium, senna, magnesium sulphate
Not specified; patients taking lipid-lowering medications, corticosteroids, androgens, phenytoin, thyroid hormones, oestrogens, oral contraceptives, antibiotics were excluded
Concomitant medication
Headache (64), flatulence (37), rhinitis (62), diarrhoea (43), abdominal pain (38), dyspepsia (20), influenza-like symptoms (30), pharyngitis (31), nausea (20), vomiting (24), constipation (22)
None
Gastrointestinal complaints (3), recurrence of Tourette syndrome (1), exacerbation of gout (1)
Abdomimal pain (123), distension (115), diarrhoea (19), flatulence (147), indigestion (80), nausea (58)
Stomach upset (1), rubbery stool consistency (1), skin reaction (1)
Adverse events in treatment group (no. of patients) Authors’ evaluation/conclusion
n.a.
n.a.
Gastrointestinal complaints (1)
n.a.
‘A daily dose of 10.5 g [. . .] was well tolerated and the majority of adverse events recorded were minor, of short duration and either unrelated or possibly related to the study treatment.’
‘Micronized purified flavonidic fraction used with fibre supplement rapidly and safely relieved bleeding from nonprolapsed hemorrhoids.’
‘Thus a low cost, well-tolerated adjunct to the NCEP diets such as consumption of palatable foods containing psyllium seed husk may improve long-term maintenance of low LDLcholesterol concentrations [. . .].’
‘Overall, ispaghula husk was an effective treatment for simple constipation and was associated with [. . .] a lower incidence of adverse events compared with lactulose or with other laxatives.
Abdominal cramps (1) ‘This study confirms the efficacy and safety of consuming 5.1 g psyllium twice daily for serum LDL cholesterol reduction.’
Adverse events in placebo/notreatment group (no. of patients)
Adverse events of herbal food supplements
Davidson (80)
Patients mean age, gender, n (herb/placebo or no treatment)
First author (reference)
Table 2 Continued
104 M. H. Pittler et al.
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57 years, f 68, m 55 (63/60)
66–67 years, f 8, m 12 (20/n.a.)
(range) 19–23 years, not reported (8/n.a.)
60 years, f 197, m 72 (132/137)
(range) 18–75 years, f 72, m 36 (not reported)
34–35 years, f 19, m 10 (25/20)
RodríguezMorán (83)
Sierra (84)
Washington (85)
Van Beusekom (86)
Zumarraga (87)
© 2005 The International Association for the Study of Obesity. obesity reviews 6, 93–111
Barroso Aranda (88)
P. psyllium, diarrhoea
P. psyllium, healthy volunteers
P. psyllium, constipation
P. psyllium, rheumatoid arthritis
P. psyllium, healthy volunteers
P. psyllium, type 2 diabetes mellitus
P. psyllium, type 2 diabetes mellitus
Herbal medicines, indications
Maltodextrin, citric acid, aspartame (Metamucil)
Chitosan (Fat Trapper Plus)
Maltodextrin, citric acid, aspartame (Metamucil)
Saccharose, natriumchloride (Volcolon)
Citric acid, potassium bicarbonate, sodium bicarbonate (Fybogel)
None (Plantaben)
Maltodextrin, citric acid, aspartame (Metamucil)
Other main constituents (brand name)
Not reported
900 mg, 3d
6.8 g, 1 week
8 g, 6 months
10.5 g, 5d
14 g, 6 weeks
15 g, 6 weeks
Daily dose Duration
Not reported
Not reported
Not reported
Auranofin, corticosteroids, NSAIDs
Lactulose
Sulphonylurea
Not specified; patients taking lipid-lowering drugs, corticosteroids, other soluble fibre were excluded
Concomitant medication
n.a.
n.a.
None
Adverse events in placebo/notreatment group (no. of patients)
Bloating (not reported), flatus (not reported)
None
None
Constipation (3 patients from total group)
Bloating (not reported), flatus (not reported)
Diarrhoea, nausea, stomach or abdominal pain, constipation, bloating (83 patients fromtotal group)
Flatulence (not reported), constipation (2), stomach cramps (1)
None
Abdominal discomfort, flatus and colic pain (1)
Adverse events in treatment group (no. of patients)
‘Metamucil was very welltolerated by patients, none of whom complained of gastrointestinal side effects or an inability to take the Metamucil.’
‘. . . oral supplementation of this novel formulation of chitosan and psyllium husk seeds [. . .] may exhibit a significant number of health benefits.’
‘Psyllium [. . .] did not cause greater gaseous symptomatology than did placebo in subjects who believed that these preparations caused gas.’
‘Patients and investigators attributed some of these symptoms to the ’bulkforming agent. However, no differences between the groups were found.
‘[. . .] no serious side effects were reported.’
‘As indicated by other authors [. . .] in this study psyllium was well tolerated without any significant adverse effects.’
‘There was an excellent tolerance to psyllium without significant adverse effects.’
Authors’ evaluation/conclusion
Adverse events of herbal food supplements
Murphy (89) 54–67 years, f 9, m 51 (30/30)
Patients mean age, gender, n (herb/placebo or no treatment)
First author (reference)
Table 2 Continued
obesity reviews M. H. Pittler et al. 105
55 years, f 62, m 43 (24/29)
(range) 6–18 year, not reported (32/32)
Spence (94)
Davidson (95)
P. psyllium, hypercholesterolemia
P. psyllium, hypercholesterolaemia
P. psyllium, diarrhoea
P. psyllium, hypercholesterolaemia
P. psyllium, hypercholesterolaemia
P. psyllium, hypercholesterolaemia
Not reported
Maltodextrin, citric acid, aspartame (Metamucil)
Not reported 3–13 d
None Not reported
None (Kneipp Granulat Psyllium)
Not reported (Fybogel)
Other main constituents (brand name)
Not specified; patients taking lipidlowering drugs were excluded
Not reported
Thyroxine replacement therapy
Concomitant medication
6.4 g, 6 weeks
15 g, 10 weeks
Not reported
Not reported
Not reported Not reported
1.3 g, 8 weeks
19.5 g, 3 weeks
7.0/10.5 g, 12 weeks
Daily dose Duration
None
Angioderma of the face (1), abdominal pain (7), distension (9), belching (6), flatulence (21), bloating (17), nausea (4), diarrhoea (6), constipation (6)
Dislike of taste (3), difficulty swallowing (1)
None
None
Withdrawals because of adverse events: diarrhoea (8), constipation (3), bloating (1), nausea plus vomiting (2), abdominal pain (1), dyspepsia (2), haemorrhoids (1)
Adverse events in treatment group (no. of patients)
Not reported
Abdominal pain (13), distension (9), belching (18), flatulence (26), bloating (17), nausea (12), diarrhoea (9), constipation (17)
n.a.
Not reported
Chronic obstipation and epigastric symptoms (1), indisposition with nausea (1)
Withdrawals because of adverse events: diarrhoea (2), nausea (2), bloating (1), headache plus skin rash (1), dyspepsia (1), skin irritation (1)
Adverse events in placebo/notreatment group (no. of patients)
‘[. . .] psyllium was effectively incorporated into a children’s cereal without adverse effects or without significantly affecting taste or texture.’
‘It was surprising that psyllium alone [. . .] was associated with adverse effects that were as bothersome as those associated with colestipol alone, 5 g three times daily.’
‘Ispaghula husk [. . .] was significantly less effective than codeine phosphate and was unpleasant to taste and difficult to swallow.’
‘None of the subjects for any of the dietary groups complained of symptoms indicated in the discomfort questionnaire.’
‘Psyllium is an effective and safe drug for the treatment of hypercholesterolaemia.’
‘Ispaghula husk as an adjunct to diet is effective and well tolerated in the management of appropriate patients with mild to moderate primary hypercholesterolaemia.’
Authors’ evaluation/conclusion
M. H. Pittler et al.
n.a., not available.
Not reported, f 10 (5/n.a.)
Lodge (93)
55–57 years, f 88, m 73 (78/83)
Brock (91)
35–38 years, m 36 (10/14)
51 years, f 119, m 221 (224/116)
MacMahon (90)
Herbal medicines, indications
Adverse events of herbal food supplements
Romero (92)
Patients mean age, gender, n (herb/placebo or no treatment)
First author (reference)
Table 2 Continued
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are reported with the use of guarana and include irritability, heart palpitations, anxiety and other central nervous system events (Table 1).
Cyamopsis tetragonolobus Guar gum is a dietary fibre derived from the Indian cluster bean (Cyamopsis tetragonolobus). An earlier review suggested predominately gastrointestinal adverse events (97). Most frequently, flatulence, diarrhoea and nausea were reported by patients receiving guar gum. In 3% of the patients these were severe enough to necessitate the withdrawal from the trials. These findings are corroborated by our present analysis of case reports and clinical trials (Tables 1 and 2).
Plantago psyllium Psyllium is a water-soluble fibre derived from the husks of ripe seeds of Plantago psyllium (12,96). Clinical trials and case reports suggest adverse events for this food supplement. Particularly gastrointestinal complaints such as flatulence, bloating, indigestion and nausea were reported. In addition, a number of patients reported, vomiting and retrosternal pain after the use of psyllium. In many trials, however, these adverse events are reported to have also occurred in the placebo group (Tables 1 and 2).
Ilex paraguariensis Yerba maté is prepared from Ilex paraguariensis, an evergreen tree native to South America. Few data are available on this herbal preparation. The only double-blind RCT on the subject did not report on adverse events (98). Epidemiological data suggest that the habit of ingesting hot maté drinks over long periods of time is linked to oesophageal cancer (99). However, this seems to be related to chronic thermal injury rather than to a pharmacological effect.
Pausinystalia yohimbe Yohimbe (Pausinystalia yohimbe) is a tall evergreen tree, which is native to Central Africa. Yohimbine, an alpha-2 receptor antagonist, is the main active constituent of the ground bark of Pausinystalia yohimbe. Most clinical studies relate to the effects of this isolated constituent of yohimbe bark. It is often promoted for erectile dysfunction and as a weight-loss supplement. The adverse events reported with the use of yohimbine are well documented and include hypertension, anxiety and agitation (100–102). For a herbal preparation of yohimbe, one case report of severe acute headache and hypertension is reported (Table 1).
M. H. Pittler et al.
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Discussion The reviewed evidence indicates that a range of adverse events has been reported with the use of herbal weight-loss supplements (Tables 1 and 2). Although the number of cases and clinical trials may collectively look impressive, the quality of the data does not. Frequently, the provided information is incomplete and important documentation is lacking. In some instances the herbal ingredients are not sufficiently characterized and, in most, the mechanism of action is not fully understood. Often, the information provided is insufficient for making inferences about causality. In fact, in many of the above reports and clinical trials, an 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 a cause–effect relationship. On the other hand, the reported risks imply the potential for harm and there is a possibility that they do signify causality even though they do not prove it. In addition, the absence of convincing data of a cause– effect relationship cannot be taken as an indication of safety. Thus, considering firstly that the evidence of effectiveness seems small for most herbal supplements (10), and secondly considering the principle of ‘first do no harm’, the reported adverse events seem sufficient to shift the risk– benefit balance against the use of most herbal weight-loss supplements. Exceptions are Garcinia cambogia and yerba maté which, in our view, merit further investigation. Patients frequently use food supplements in combination with conventional medication. Therefore, a potential for herb–drug interactions exists. Perhaps ironically, for many patients the motivation for using food supplements is that they are perceived as risk-free, a notion that – at least in the UK – is heavily promoted by the media, which tend to be biased in favour of alternative therapies (103). There is also evidence to suggest that adverse events experienced with the use of herbal food supplements are less likely to be reported to a healthcare professional than similar adverse events experienced with conventional medicines (104). Collectively, these factors are likely to increase the risks of food supplements in clinical practice. In addition, issues concerning the quality of herbal food supplements such as adulteration with prescription drugs or other contaminants increase risks. Herbal medicines are marketed as food supplements in many countries and therefore are subject to less stringent controls. In the USA, for instance, producers of food supplements do not have to demonstrate efficacy, safety and quality similar to conventional drugs (105). The effectiveness of any regulation that may exist in this area is further diminished by the advent of internet sales. Considering the present popularity of herbal food supplements (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
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Adverse events of herbal food supplements
M. H. Pittler et al.
indicate that herbal food supplements are relatively (i.e. compared with prescription drugs) safe. However, it could also suggest that adverse events are under-reported. Regardless of this unresolved issue, the most relevant questions for clinical decision-making do not merely relate to the adverse events reported for any given herbal food supplements but to the risk–benefit ratio. Some herbal weightloss supplements have been tested for effectiveness in clinical trials, but for most supplements which are on the market such data are not available (10,109). Research efforts to answer this question should be intensified. Meanwhile, vigilance of healthcare professionals could be a valuable first step to enhance consumer safety. It should be paired with more adequate education of all parties involved. Patients could be informed to demystify herbal food supplements from the aura of being natural and therefore risk-free. Also, regulators could control herbal food supplements more adequately. Limitations of our review pertain to the potential incompleteness of the reviewed evidence. Literature searches were limited to the period between 1995 and January 2004. Although this may have limited the scope of the review, events that occurred before 1995 may no longer be of interest and supplements may already have been discontinued or banned. Other limitations pertain to the fact that case reports are often published as short reports or letters and may appear in journals that are not indexed in electronic databases. Therefore, we cannot be sure that all reports were located. Moreover, the number of published adverse events will be affected by a larger than usual level of under-reporting. In this area of healthcare, patients often do not tell their physician about the use of herbal medicines and the likelihood of an adverse event being reported or published is slim. In many countries a formal post-marketing surveillance system for herbal medicines is not in place. Thus, the cases summarized above may well represent only a fraction of the true number of adverse events linked to herbal weight-loss supplements. In conclusion, adverse events are reported for a number of herbal food supplements, which are used for reducing body weight. Although the quality of the data does not justify definitive attribution of causality in most cases, the reported risks are sufficient to shift the risk–benefit balance against the use of most of the reviewed herbal weight-loss supplements. Exceptions are Garcinia cambogia and yerba maté, which merit further investigation.
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