Garcinia cambogia extract side effects gas
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Garcinia cambogia extract side effects gas
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Garcinia Cambogia is a fruit that is known to enhance the culinary experience of food, and enhances satiety from a meal (possibly by enhancing the flavor experience). Its usage as a fat burner does not appear to extend to humans.
This page features 48 unique references to scientific papers.
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Summary of Garcinia cambogia
Primary Information, Benefits, Effects, and Important Facts
Garcinia Cambogia (Malabar Tamarind) is a small fruit that has some traditional usage to enhance the culinary experience of a meal, but beyond that has limited medicinal usage. It is a very good source of hydroxycitric acids (structurally related to citric acid, a sour flavorant) and one of the isomers, known as (-)-Hydroxycitric acid, is thought to help in weight control.
The mechanism of action is inhibiting an enzyme called Citric acid lysase which is required in the synthesis of fatty acids, known as de novo lipogenesis. At least in rats, evidence of suppressed de novo lipogenesis has been noted and oral consumption of (-)-Hydroxycitric acid appears to reliably reduce food intake and body weight (the latter to a degree where food intake cannot explain all the observed effects)
Studies in humans, for the most part, fail to replicate this; this may be related to less actual activity of de novo lipogenesis in humans and a much higher level in rats. Some isolated studies do note weight loss, but it appears to be quite variable and unreliable. Many studies also do report subjective appetite decrease, but tend to record dropout rates (how often people leave the study due to being unable to maintain the diet protocol) rather than food intake; even then the benefits are still unreliable and sometimes not present.
Although there is some limited potential for (-)-Hydroxycitric acid as a weight loss aid, the magnitude of effect is quite low (up to 2kg over 3 months) and the benefit is unreliable; making it hard to recommend this compound as a fat burner or anti-obesity agent.
The ONLY Guide You Need for Garcinia Cambogia
Things to Know
Also Known As
Gambooge, Pazham Puzhi, Bitter Kola, Malabar tamarind, (-)-Hydroxycitric acid, HCA, Hydroxycitric acid
Do Not Confuse With
Hoodia gordonii (another ineffective appetite suppressant)
Is a Form Of
How to Take
Recommended dosage, active amounts, other details
Standard dosing of Garcinia Cambogia and its bioactive, (-)-Hydroxycitric acid, is 500mg of (-)-Hydroxycitric acid taken 30-60 minutes prior to a meal and usually taken at up to three different meals daily.
It is unsure if this is the ideal dose since human studies usually fail to find a benefit with any dosage.
Confused about supplements?
Human Effect Matrix
The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects garcinia cambogia has on your body, and how strong these effects are.
Studies Excluded from Consideration
Excluded due to being confounded with White Kidney Bean Extract and Inulin 
Confounded with a lot of things 
Table of Contents:
- 1 Sources and Composition
- 1.1 Sources
- 1.2 Composition
- 2 Pharmacology
- 2.1 Serum
- 3 Neurology
- 3.1 Appetite
- 3.2 Neuroprotection
- 4 Cardiovascular Health
- 4.1 Lipoproteins and Cholesterol
- 4.2 Blood
- 5 Interactions with Fat Mass
- 5.1 Mechanisms
- 5.2 Adipokines
- 5.3 Weight Regain
- 5.4 Weight Gain
- 5.5 Weight Loss
- 6 Interactions with Glucose Metabolism
- 6.1 Glycogen
- 7 Interactions with Hormones
- 7.1 Testosterone
- 7.2 Estrogen
- 8 Interactions with Organ Systems
- 8.1 Kidney and Bladder
- 8.2 Testes
- 9 Safety and Toxicology
- 9.1 General
- 9.2 Mutagenicity
- 9.3 Case Studies
The ONLY Guide You Need for Garcinia Cambogia
1 Sources and Composition
A Brief Information on Garcinia Cambogia Garcinia cambogia is a fruit native to the regions of Indonesia, as well as in India and several parts of Southeast Asia.
Garcinia Cambogia (of the family Guttiferae), sometimes also referred to as Pazham Puzhi  , Malabar tamarind,  or Bitter Kola  is a plant that bears small fruits (5cm diameter) and has traditionally been used as a food additive to both enhance the flavor of food products and to enhance satiety following consumption.  Very limited traditional medicine usage extends to gastrointestinal complications. 
The fruits of Garcinia Cambogia tend to contain:
Citric Acids (causative of taste and flavor) at 10-30% dry weight, of which a large segment consists of hydroxycitric acids (HCAs);  HCAs come in four isomers, (-)-Hydroxycitric acid, (+)-Hydroxycitric acid, (-)-Allo-HCA, and (+)-Allo-HCA 
Guttiferone I-K   and M-N 
The polyisoprenylated benzophenones Garcinol  and Isogarcinol 
Xanthochymol (highly variable between 113.66+/-0.75ng/mL fruit and undetectable) and Isoxamthochymol (23.26ng/mL or lower); about 2.52-2.56ng/mL of both in the leaves  
Cambogin, an isomer of isoxanthochymol  and Camboginol  (88.2mg/g of the fruit methanolic extract; undetectable in aqueous extracts, seeds, or stems) 
Isoxanthochymol (16.6mg/g methanolic extract; none in aqueous extract of the stems/seeds) 
It should be noted that currently marketed (-)-Hydroxycitric Acid supplements tend to be calcium/potassium salts of (-)-HCA containing about 60% (-)-HCA by weight. 
2g of (-)-HCA salts given to 4 human participants on an empty stomach resulting in plasma levels of 0.8μg/mL within 30 minutes leading up to plasma levels of 8.4μg/mL at two hours with a variable peak between 4.7 and 8.4μg/mL.  The authors hypothesized that if absorption was complete and evenly distributed, it would have resulted in a serum peak of 46μg/mL (based on the participant's body weight and 25% body fat), a preliminary guess at the bioavailbility of (-)-Hydroxycitric acid following oral administration would be 10-18%. 
The bioactive has been demonstrated to appear in the blood following oral administration, and may have bioactivity
In freshly prepare rat brain slices, (-)-Hydroxycitric acid (salt form; 60% HCA by weight) was able to inhibit serotonin reuptake into rat corticol slices by 20% (300uM concentration), which was outperformed by fluoxetine (100uM) plus clomipramine (10uM) which inhibited 30% of uptake; oddly, no inhibition was noted with 1000uM (1mM) of (-)-Hydroxycitric acid.  The increased bioavailability of serotonin is thought to be related to appetite suppressing effects of supplemental (-)-Hydroxycitric acid. 
Another possible mechanism is the thought to be leptin related. One rat study (that failed to find reductions in food intake or weight after 4 weeks of 3.3% (-)-Hydroxycitric acid) noted that serum levels of insulin and leptin decreased, which was thought to be in response to leptin-mimetic actions (not established). 
May inhibit the reuptake of serotonin (not yet confirmed in a living model)
In rats who have had the reductions in feed intake quantified, it has been reported to be reduce by 13.7% (0.2% feed intake), 26.7% (2% feed intake) and 25.6% (5% feed intake) in male rats with similar reductions in female rats, with significant reductions of feed intake in this study only occurring 46 days after consumption (earliest) or 74 days (all tested doses). 
In rats, appears to suppress food intake
Garcinia Cambogia has once been associated with reduced brain oxidation and pathology of neurodegeneration, but was said to be working vicariously through reduced food intake and body weight (with the study concluding that the state of obesity and a high fat diet impairs neural function). 
4 Cardiovascular Health
4.1. Lipoproteins and Cholesterol
A study in rates using 200-400mg/kg Garcinia Cambogia seeds (ethanolic extract) noted slight but statistically significant increases in LDL-C (the 'bad' cholesterol) with decreases in HDL-C, vLDL-C, and triglycerides. 
In obese humans given 2g of Garcinia Cambogia (60% Hydroxycitric acid) for 10 weeks, there were no significant alterations in ApoA1, ApoB, Phospholipids, Free Fatty acids, or the Artherogenic Index. 
One study on blood lipids also noted a small but significant increase in red blood cell count, indicative of erythropoeisis.  One review  suggests this may be due to the iron content of the seeds, or perhaps an increase in testosterone from the polyphenolic component.
5 Interactions with Fat Mass
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(-)-Hydroxycitric acid appears to be a competitive inhibitor of the enzyme adenosine triphosphate-citrate (pro-3S)-lyase (a shorter designation is ATP Citrate Lysase),  which is an enzyme in the biosynthetic pathway of fatty acids (de novo lipogenesis) and its inhibition results in suppressed formation of Acetyl-CoA from Citrate and less substrate for fatty acid synthesis in vitro.  The (+)- isomer of Hydroxycitric acid does not have this same inhibitory potential, and is instead a substrate of the enzyme.
Can inhibit an enzyme in the de novo lipogenesis pathway that mediates fatty acid synthesis from non-fat sources, thought to inhibit the synthesis and deposition of fatty acids via this mechanism
The relevance of this pathway to humans may be in question, as human capacity for de novo lipogenesis does exist but tends to be less than that of rodents that are commonly used in research. 
In regards to this mechanism of action, there may be species-related differences
2g of Garcinia Carmbogia for 10 weeks was associated with a reduction in the adipokine Adipsin (19%) without significantly influencing Adiponectin or Leptin. 
5.3. Weight Regain
There have been a few studies assessing weight regain. One in rats who were semi-starved (less than 10g of food daily for 10 days) who were subsequently randomized to receive normal diets of standard chow, sucrose loaded chow, glucose loaded chow or a high glucose fat diet with half of each group recieving 3% (-)-Hydroxycitric acid (85mmol/kg) and then followed for 10 days (so overall, 8 groups of which 4 had HCA supplementation).  This study noted that the inevitable weight regain in these rats was attenuated with HCA supplementation in all groups except normal chow, and only reached significance with glucose and glucose+fat diet groups; this was in part due to less food intake, and appeared to decrease the food efficiency ratio with all groups except standard chow.  This trial style was replicated with the glucose group, and it was noted that food intake was suppressed for a short time, and although there was indication that de novo lipogenesis may have been inhibited there was no significant suppressive effect on body weight regain. 
Two rat studies suggesting that Garcinia can reduce the amount of weight regained during a period of overfeeding after a period of low caloric intake
5.4. Weight Gain
A rat trial in which rats were fed an obesogenic diet for 15 days with 2% added (-)-Hydroxycitric acid (as trisodium conjugate) noted that the food efficiency ratio decreased to 60% of control, and that body weight gain was suppressed to approximately half (49%) of control; food intake also decreased 17%, which would have contributed to the observed reduction in weight. 
One rat study suggesting that Garcinia can attenuate the rate of weight gain
5.5. Weight Loss
A study in human subjects using 2g Garcinia cambogia (60% Hydroxycitric acid) for 10 weeks in 86 overweight adults failed to find significant differences in weight loss or food intake.  One study using 2400mg of Garcinia cambogia daily divided before meals noted that while active treatment lost more weight from a low calorie diet than placebo over a period of 12 weeks (3.7+/-3.1kg weight loss rather than 2.4+/-2.9kg) that there were no reported differences in appetite. 
One of the larger and better controlled studies on the matter noted that, 1000mg of Garcinia Camboga (50% HCA by weight) taken before the three main meals of a low calorie diet given to overweight but otherwise healthy adults (of which placebo was also placed on) and then followed for 12 weeks failed to find any significant differences in dropout rates, weight loss, or adverse effects relative to placebo. 
Studies done in humans using isolated Garcinia Cambogia have mixed results on fat loss, with the one study reporting benefit showing relatively low magnitude of benefit (1.3kg more than placebo over 3 months, with very high variability)
In 40 persons with a BMI between 27.5-39 (mostly obese) given 100mg Garcinia Cambogia (confounded with inclusion of 400mg Inulin and 200mg White Kidney bean extract) before each of the three major meals for a period of 12 weeks, with both placebo and supplemental group being advised to diet (1200kcal), noted that weight loss in the diet and supplement group was greater (4% body weight over 12 weeks) than the diet and placebo group (not statistically significance).  Dropouts from the study were also greater in placebo (6) than supplement (1) groups.
To discover the effectiveness of Super Citrimax – it might be useful to examine how effective Garcinia cambogia is – particularly studies done on the performance of HCA as a supplement.
 One other study that uses Garcinia Cambogia but is highly confounded with other nutrients also noted beneficial effects on weight loss. 
The studies that are associated with both weight loss and Garcinia Camboga are confounded with many ingredients, and the observed effects on fat loss cannot be attributed to Garcinia itself
Several reviews on the efficacy of Garcinia Cambogia suggest no significant benefit for weight loss in human interventions.      The rather frequent inclusion of Garcinia Cambogia in review articles relative to the lack of interventions may be related to the popularity of the supplement.
Numerous review articles assessing the evidence of Garcinia Cambogia conclude that there is no significant benefit of this compound in humans
6 Interactions with Glucose Metabolism
When 500mg (-)-Hydroxycitric acid is consumed alongside 2g/kg carbohydrate post exercise in humans, a slight increase in the rate of glycogen resynthesis occurs. 
7 Interactions with Hormones
1667.3mg of Garcinia Cambogia for 12 weeks (1000mg (-)-Hydroxycitric acid) failed to find significant influences on serum testosterone. 
1667.3mg of Garcinia Cambogia for 12 weeks (1000mg (-)-Hydroxycitric acid) failed to find significant influences on serum estrogens (estrone and estradiol). 
8 Interactions with Organ Systems
8.1. Kidney and Bladder
While ingestion of a high-fat or high-sucrose diet is able to increase serum levels of urea and creatinine (thought to be indicative of kidney impairment), coingestion of Garcinia Cambogia at 50mg/kg is able to effectively normalize the increases in creatinine and urea. 
Oral ingestion of the leaves from Garcinia Cambogia at 100-200mg/kg of either the water extract or ethanolic extract was able to increase urine output in the range of 36-72% (ethanolic) or 17-39% (aqueous), both of which underperformed to 20mg/kg injections of the reference drug furosemide. 
The leaves of Garcinia may have weak diuretic properties
One study noted that oral consumption of 778-1244mg/kg bodyweight of (-)-Hydroxycitric acid to rats for up to 93 days was associated with testicular toxiciy with lower doses not associated with testicular toxicity.  This study has been critiqued,  where the lack of assurance on the salt form was questioned and the fact that the No Obervable Adverse Effect Limit (NOAEL) of 389mg/kg in rats is still 10-16 fold higher than the typical recommended serving for humans. 
A lone report on testicular toxicity with high dose (-)-Hydroxycitric acid consumption; may not be relevant to human supplementation doses
9 Safety and Toxicology
Acute (14 day) administration of 5000mg/kg bodyweight (-)-Hydroxycitric Acid to albino rats of both genders (small sample size of 10) was not associated with any mortality or clinical signs of toxicology. 
Studies that do not inhernetly design themselves to assess toxicology but nevertheless use (-)-Hydroxycitric acid supplementation have also failed to find any toxicity associated with 3% of the rat diet for 5 days  or 10 days,  or up to 5% of the feed for 90 days. 
Currently, the human trials cited in Examine do not report any adverse effects that occur in the treatment groups (using Garcinia Camboga) to a greater degree than placebo.
No observable toxicity in rats or humans following oral ingestion at this moment in time
A preliminary study assessing the mutagenicity of (-)-Hydroxycitric acid on five strains of Salmonella typhimurium (TA98, TA100, TA102, TA1535, and TA1537) up to 5000mcg/plate failed to find evidence of DNA damage or mutagenicity associated with (-)-Hydroxycitric Acid  and a lack of genotoxicity was repeatedly demonstrated elsewhere with the Ames test;   this latter study noted that (-)-HCA increased the amount of micronucleated polychromatic erythrocytes (MNPCEs) after intravenous administration, which is though to be genotoxic.  The conclusion of this has been criticized for being suggestive of genotoxicity while the study had some design flaws (used DSMO alongside (-)-HCA while control got water, DMSO not being recommended for this test  ) and no LD50 test of the method of administration prior to genotoxicity testing. 
In rats given up to 5% (-)-Hydroxycitric acid in feed intake for a period of 90 days, there does not appear to be any significant DNA fragmentation in the liver or testicles. 
There does not appear to be any influence of the bioactive (-)-Hydroxycitric acid on DNA fragmentation or genomic damage; unlikely to be carcinogenic
Garcinia cambogia extract is derived from the plant also called garcinia cambogia, but also known as malabar tamarind or brindle berry in other countries.
There are numerous case reports of hepatoxicity associated with a supplement known as 'Hydroxycut' which touts Garcinia Cambogia as the main active ingredient,   although it has been argued that there is no evidence to suggest a link to (-)-Hydroxycitric acid due to inclusion of many ingredients. 
In a patient on chronic Monteluskat treatment who then consumed two supplements, fatality occurred; it was thought that Montelukast interacted advesely with one of the many compounds consumed but causative could not be linked. 
One reported case of Rhabdoyolysis associated with a dietary supplement of which contained Garcinia Cambogia has been noted, although Ma Huang (plant source of ephedrine) is a large confound alongside chromium and Guarana. 
Due to the usage of Garcinia in fat burners, there has been reported connections between Garcinia and adverse effects; there is currently no evidence to assume a direct link between the compounds
Scientific Support & Reference Citations
- A randomized, double-blind, placebo-controlled trial of a new weight-reducing agent of natural origin .
- Effects on the Human Body of a Dietary Supplement Containing L-Carnitine and Garcinia cambogia Extract: A Study using Double-blind Tests .
- Efficacy of 12 weeks supplementation of a botanical extract-based weight loss formula on body weight, body composition and blood chemistry in healthy, overweight subjects--a randomised double-blind placebo-controlled clinical trial .
- Vasudeva N, Yadav N, Sharma SK. Natural products: a safest approach for obesity . Chin J Integr Med . (2012)
- Márquez F, et al. Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia extracts in humans . Crit Rev Food Sci Nutr . (2012)
- Oluyemi KA, et al. Erythropoietic and anti-obesity effects of Garcinia cambogia (bitter kola) in Wistar rats . Biotechnol Appl Biochem . (2007)
- (−)-Hydroxycitric acid—the principal acid in the fruits of Garcinia cambogia desr .
- Masullo M, et al. Polyisoprenylated benzophenones and an unusual polyisoprenylated tetracyclic xanthone from the fruits of Garcinia cambogia . J Agric Food Chem . (2008)
- Kolodziejczyk J, et al. Effects of garcinol and guttiferone K isolated from Garcinia cambogia on oxidative/nitrative modifications in blood platelets and plasma . Platelets . (2009)
- On the structures of garcinol, isogarcinol and camboginol .
- Chattopadhyay SK, Kumar S. Identification and quantification of two biologically active polyisoprenylated benzophenones xanthochymol and isoxanthochymol in Garcinia species using liquid chromatography-tandem mass spectrometry . J Chromatogr B Analyt Technol Biomed Life Sci . (2006)
- Chattopadhyay SK, Kumar S. Liquid chromatography-tandem mass spectrometry method for identification and quantification of two biologically active polyisoprenylated benzophenones, isoxanthochymol and camboginol, in Garcinia species . Biomed Chromatogr . (2007)
- Chattopadhyay SK, Kumar S. A rapid liquid chromatography-tandem mass spectrometry method for quantification of a biologically active molecule camboginol in the extract of Garcinia cambogia . Biomed Chromatogr . (2007)
- Loe YC, et al. Gas chromatography/mass spectrometry method to quantify blood hydroxycitrate concentration . Anal Biochem . (2001)
- Ohia SE, et al. Safety and mechanism of appetite suppression by a novel hydroxycitric acid extract (HCA-SX) . Mol Cell Biochem . (2002)
- Hayamizu K, et al. Effect of Garcinia cambogia extract on serum leptin and insulin in mice . Fitoterapia . (2003)
- Shara M, et al. Dose- and time-dependent effects of a novel (-)-hydroxycitric acid extract on body weight, hepatic and testicular lipid peroxidation, DNA fragmentation and histopathological data over a period of 90 days . Mol Cell Biochem . (2003)
- Amin KA, Kamel HH, Abd Eltawab MA. The relation of high fat diet, metabolic disturbances and brain oxidative dysfunction: modulation by hydroxy citric acid . Lipids Health Dis . (2011)
- Kim JE, et al. Does Glycine max leaves or Garcinia Cambogia promote weight-loss or lower plasma cholesterol in overweight individuals: a randomized control trial . Nutr J . (2011)
- Watson JA, Lowenstein JM. Citrate and the conversion of carbohydrate into fat. Fatty acid synthesis by a combination of cytoplasm and mitochondria . J Biol Chem . (1970)
- Lowenstein JM. Effect of (-)-hydroxycitrate on fatty acid synthesis by rat liver in vivo .
We also observed a unique tactic that some of these companies were doing.
J Biol Chem . (1971)
- Hellerstein MK. De novo lipogenesis in humans: metabolic and regulatory aspects . Eur J Clin Nutr . (1999)
- Leonhardt M, Hrupka B, Langhans W. Effect of hydroxycitrate on food intake and body weight regain after a period of restrictive feeding in male rats . Physiol Behav . (2001)
- Leonhardt M, Balkan B, Langhans W. Effect of hydroxycitrate on respiratory quotient, energy expenditure, and glucose tolerance in male rats after a period of restrictive feeding . Nutrition . (2004)
- Lipid-lowering and antiobesity effect of (−)hydroxycitric acid .
- Mattes RD, Bormann L. Effects of (-)-hydroxycitric acid on appetitive variables . Physiol Behav . (2000)
- Heymsfield SB, et al. Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial . JAMA . (1998)
- Egras AM, et al. An evidence-based review of fat modifying supplemental weight loss products . J Obes . (2011)
- Cherniack EP. Potential applications for alternative medicine to treat obesity in an aging population . Altern Med Rev . (2008)
- Lenz TL, Hamilton WR. Supplemental products used for weight loss . J Am Pharm Assoc (2003) . (2004)
- Pittler MH, Ernst E. Dietary supplements for body-weight reduction: a systematic review . Am J Clin Nutr . (2004)
- Heber D. Herbal preparations for obesity: are they useful . Prim Care . (2003)
- Cheng IS, et al. Oral hydroxycitrate supplementation enhances glycogen synthesis in exercised human skeletal muscle . Br J Nutr . (2012)
- Hayamizu K, et al. Effects of Garcinia cambogia extract on serum sex hormones in overweight subjects . Fitoterapia . (2008)
- Amin KA, Kamel HH, Abd Eltawab MA. Protective effect of Garcinia against renal oxidative stress and biomarkers induced by high fat and sucrose diet . Lipids Health Dis . (2011)
- Mathew GE, et al. Diuretic activity of leaves of garcinia cambogia in rats . Indian J Pharm Sci . (2011)
- Saito M, et al. High dose of Garcinia cambogia is effective in suppressing fat accumulation in developing male Zucker obese rats, but highly toxic to the testis . Food Chem Toxicol . (2005)
- Burdock G, et al. Garcinia cambogia toxicity is misleading . Food Chem Toxicol . (2005)
- Shara M, et al. Physico-chemical properties of a novel (-)-hydroxycitric acid extract and its effect on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry, and histopathological changes over a period of 90 days . Mol Cell Biochem . (2004)
- Soni MG, et al. Safety assessment of (-)-hydroxycitric acid and Super CitriMax, a novel calcium/potassium salt . Food Chem Toxicol . (2004)
- Lee KH, Lee BM. Evaluation of the genotoxicity of (-)-hydroxycitric acid (HCA-SX) isolated from Garcinia cambogia . J Toxicol Environ Health A . (2007)
- Hayashi M, et al. In vivo rodent erythrocyte micronucleus assay . Mutat Res . (1994)
- Lau FC, Bagchi M, Bagchi D. Refuting "Evaluation of the genotoxitocity of (-)-hydroxycitric acid (HCA-SX) isolated from Garcinia Cambogia" by Lee and Lee, Journal of Toxicology and Environmental Health, 70:388-392, 2007 . J Toxicol Environ Health A . (2008)
- Stevens T, Qadri A, Zein NN. Two patients with acute liver injury associated with use of the herbal weight-loss supplement hydroxycut . Ann Intern Med . (2005)
- Lobb A. Hepatoxicity associated with weight-loss supplements: a case for better post-marketing surveillance . World J Gastroenterol . (2009)
- Stohs SJ, et al. No evidence demonstrating hepatotoxicity associated with hydroxycitric acid . World J Gastroenterol . (2009)
- Actis GC, et al. Fatal liver failure following food supplements during chronic treatment with montelukast . Dig Liver Dis . (2007)
- Mansi IA, Huang J. Rhabdomyolysis in response to weight-loss herbal medicine . Am J Med Sci . (2004)
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