COMMENT
In 1883 von Lippmann isolated hydroxycitric acid, a minor constituent of sugar beets.27 More than half a century later, in 1941, Martius and Maue28 dis´ covered that the (+) isomer of a racemic hydroxycitric acid mixture is attacked by the enzyme isocitrate dehydrogenase. The (−) hydroxycitric acid isomer of hydroxycitric acid was first isolated by Lewis and Neelakantan in 1964,29 and by 1969 Watson and colleagues5 reported the powerful inhibition by (−) hydroxycitric acid of citrate cleavage enzyme. Evidently, the additional hydroxyl group’s steric position, compared with citric acid, enhances its binding affinity
and competitively inhibits catalytic action by the enzyme. Citrate, entering the cytoplasm from mitochondria, cannot be cleaved to release acetyl coenzyme A, the substrate for de novo fatty acid synthesis. Despite these century-old, wellgrounded observations, there has been little effort to critically test the basic assumption underlying therapeutic use of
hydroxycitric acid in overweight humans: that hydroxycitric acid inhibition of lipid synthesis will significantly reduce body fat mass beyond that observed with a placebo capsule.
The present study, carried out during a 12-week evaluation period and using
accepted experimental design and in vivo analytic methods, failed to support the hypothesis that hydroxycitric acid as prescribed promotes either additional weight or fat mass loss beyond that observed with placebo. Specifically, body weight and fat mass change during the 12-week study period did not differ significantly between placebo and treatment groups. These results apply to both the primary and secondary statistical analyses. Additionally, there were no observed selective fat-mobilizing effects specifically attributable to the active
agent, hydroxycitric acid.
Seven earlier G cambogia trials have appeared in peer-reviewed literature,11,14 as abstracts,12,13 and in industrial publications as an open-label study10 and randomized controlled trials.11-14 We chose to collectively review these studies even though G cambogia typically was used in combination with other ingredients for the claimed purpose of enhancing weight loss.
Of the 7 studies reviewed, 5 reported significant (P>.05) effects of G cambogia alone or in combination with other ingredients on body weight or fat mass loss in overweight humans (Table 2). These earlier studies all have limitations when specifically considering G cambogia as a weight loss agent, including lack of placebo control or double-blinding in 1 study,10 coadministration of G cambogia in combination with other potentially ac- tive ingredients in 5 studies,10,11,13,14 use of an inaccurate body composition method (near-infrared interactance)12 in 1 study, and failure as of yet to publish study results in peer-reviewed literature in all but 213,14 of the 7 studies. However, our present investigation, carried out using accepted clinical trial design procedures and applying accurate body composition methods, failed to support a specific weight loss effect of G cambogia administeredasrecommended.Thepresent 12-week study period also exceeded
in duration all previous study treatment periods, which ranged from 4 to 8 weeks.
In our present investigation we failed to detect a weight loss or fat-mobilizing effect of active herb. The question therefore arises whether there exist conditions differing from those used in the present study that might support hydroxycitric acid efficacy. The 5040-kJ/d
low-fat diet recommended in our current study was intended to mimic diets commonly prescribed as a component of weight control programs. The possibility exists that the lipid synthesis–inhibiting properties of hydroxycitric acid may be more evident in subjects relapsing following a failed diet attempt, particularly if high-carbohydrate foods are ingested.30
Another concern is related to the timing and dosage considerations of hydroxycitric acid. Sullivan and colleagues31 showed that the effects of hydroxycitric acid in animals depend on time of administration in relation to a meal, with hydroxycitric acid maximally effective when administered 30 to 60 minutes prior to feeding. The approach used in our study and the others we reviewed suggested hydroxycitric acid ingestion about 30 minutes prior to meal intake, the lower end of the maximally effective range. A related concern is that
hydroxycitric acid provided in divided doses also was found to be more effective than the same amount given as a single dose.8 Although divided doses typically are used in weight loss protocols, human doses ranging between 750 and 1500 mg/d of hydroxycitric acid are at the extreme low end of the in vivo dose-response range established by Sullivan and colleagues.32 Thus, in light of the many requirements for its effective use, it seems unlikely that the maximal effects of hydroxycitric acid will be realized in human weight loss studies unless treatment conditions are well defined rent use of G cambogia as a weight loss
product, our conclusions should not be interpreted as a failure to support the validity of the biochemical effects of hydroxycitric acid identified by earlier investigators. In conclusion, our study evaluated the hypothesis that the active ingredient of G cambogia, hydroxycitric acid, has beneficial weight and fat mass loss effects. Our findings, obtained in a prospective, randomized, double-blind study, failed to detect either weight loss or fat-mobilizing effects of hydroxycitric acid beyond those of placebo. These observations, the first, to our knowledge, to appear in a peer-reviewed article using currently accepted experimental and statistical methods, do not support a role as currently prescribed for the widely used herb G cambogia as a facilitator of weight loss. and patient diet and medication compliance are tightly monitored.
Our study explored product safety only in the form of clinical evaluations and reported adverse events. No significant differences were observed between placebo and treatment groups in number of reported adverse events and no subjects were removed from the study
for a treatment-related adverse event. Additional studies, potentially with larger subject groups, are needed to gather specific information on the longterm safety of G cambogia.
An important concern in all pharmacological trials, particularly those in which herbal products are evaluated, is the amount and bioavailability of the active agent. As standard procedure, we confirmed the presence and quantity of hydroxycitric acid in the supplied capsules using an independent testing laboratory. However, we did not measure hydroxycitric acid blood levels or evaluate tissue or cytosolic citrate-cleavage enzyme activity. Although the format of our experiment closely resembles current use of G cambogia as a weight loss product, our conclusions should not be interpreted as a failure to support the validity of the biochemical effects of hydroxycitric acid identified by earlier in vestigators.
In conclusion,our study evaluated the hypothesis that the active ingredient of G cambogia, hydroxycitric acid, has beneficial weight and fat mass loss effects. Our findings, obtained in a prospective, randomized, double-blind study , failed to detect either weight loss or fat-mobilizing effects of hydroxycitric acid beyond those of placebo. These observations, the first, to our knowledge, to appear in a peer-reviewed article using currently accepted experimental and statistical medthods, do not support a role as currently prescribed for the widely used herb G cambogia as a facilitator of weight loss.
This study was supported by National Institutes of Health grants RR00645 and P30DK26687 and a contract with Thompson Medical Company, West Palm Beach, Fla, manufacturer of products that include G cambogia.
COMMENT In 1883 von Lippmann isolated hydroxycitric acid, a minor constituent of sugar beets.27 More than half a century later, in 1941, Martius and Maue28 dis´ covered that the (+) isomer of a racemic hydroxycitric acid mixture is attacked by the enzyme isocitrate dehydrogenase. The (−) hydroxycitric acid isomer of hydroxycitric acid was first isolated by Lewis and Neelakantan in 1964,29 and by 1969 Watson and colleagues5 reported the powerful inhibition by (−) hydroxycitric acid of citrate cleavage enzyme. Evidently, the additional hydroxyl group’s steric position, compared with citric acid, enhances its binding affinityand competitively inhibits catalytic action by the enzyme. Citrate, entering the cytoplasm from mitochondria, cannot be cleaved to release acetyl coenzyme A, the substrate for de novo fatty acid synthesis. Despite these century-old, wellgrounded observations, there has been little effort to critically test the basic assumption underlying therapeutic use ofhydroxycitric acid in overweight humans: that hydroxycitric acid inhibition of lipid synthesis will significantly reduce body fat mass beyond that observed with a placebo capsule. The present study, carried out during a 12-week evaluation period and usingaccepted experimental design and in vivo analytic methods, failed to support the hypothesis that hydroxycitric acid as prescribed promotes either additional weight or fat mass loss beyond that observed with placebo. Specifically, body weight and fat mass change during the 12-week study period did not differ significantly between placebo and treatment groups. These results apply to both the primary and secondary statistical analyses. Additionally, there were no observed selective fat-mobilizing effects specifically attributable to the activeagent, hydroxycitric acid. Seven earlier G cambogia trials have appeared in peer-reviewed literature,11,14 as abstracts,12,13 and in industrial publications as an open-label study10 and randomized controlled trials.11-14 We chose to collectively review these studies even though G cambogia typically was used in combination with other ingredients for the claimed purpose of enhancing weight loss. Of the 7 studies reviewed, 5 reported significant (P>.05) effects of G cambogia alone or in combination with other ingredients on body weight or fat mass loss in overweight humans (Table 2). These earlier studies all have limitations when specifically considering G cambogia as a weight loss agent, including lack of placebo control or double-blinding in 1 study,10 coadministration of G cambogia in combination with other potentially ac- tive ingredients in 5 studies,10,11,13,14 use of an inaccurate body composition method (near-infrared interactance)12 in 1 study, and failure as of yet to publish study results in peer-reviewed literature in all but 213,14 of the 7 studies. However, our present investigation, carried out using accepted clinical trial design procedures and applying accurate body composition methods, failed to support a specific weight loss effect of G cambogia administeredasrecommended.Thepresent 12-week study period also exceededin duration all previous study treatment periods, which ranged from 4 to 8 weeks. In our present investigation we failed to detect a weight loss or fat-mobilizing effect of active herb. The question therefore arises whether there exist conditions differing from those used in the present study that might support hydroxycitric acid efficacy. The 5040-kJ/dlow-fat diet recommended in our current study was intended to mimic diets commonly prescribed as a component of weight control programs. The possibility exists that the lipid synthesis–inhibiting properties of hydroxycitric acid may be more evident in subjects relapsing following a failed diet attempt, particularly if high-carbohydrate foods are ingested.30 Another concern is related to the timing and dosage considerations of hydroxycitric acid. Sullivan and colleagues31 showed that the effects of hydroxycitric acid in animals depend on time of administration in relation to a meal, with hydroxycitric acid maximally effective when administered 30 to 60 minutes prior to feeding. The approach used in our study and the others we reviewed suggested hydroxycitric acid ingestion about 30 minutes prior to meal intake, the lower end of the maximally effective range. A related concern is thathydroxycitric acid provided in divided doses also was found to be more effective than the same amount given as a single dose.8 Although divided doses typically are used in weight loss protocols, human doses ranging between 750 and 1500 mg/d of hydroxycitric acid are at the extreme low end of the in vivo dose-response range established by Sullivan and colleagues.32 Thus, in light of the many requirements for its effective use, it seems unlikely that the maximal effects of hydroxycitric acid will be realized in human weight loss studies unless treatment conditions are well defined rent use of G cambogia as a weight lossproduct, our conclusions should not be interpreted as a failure to support the validity of the biochemical effects of hydroxycitric acid identified by earlier investigators. In conclusion, our study evaluated the hypothesis that the active ingredient of G cambogia, hydroxycitric acid, has beneficial weight and fat mass loss effects. Our findings, obtained in a prospective, randomized, double-blind study, failed to detect either weight loss or fat-mobilizing effects of hydroxycitric acid beyond those of placebo. These observations, the first, to our knowledge, to appear in a peer-reviewed article using currently accepted experimental and statistical methods, do not support a role as currently prescribed for the widely used herb G cambogia as a facilitator of weight loss. and patient diet and medication compliance are tightly monitored. Our study explored product safety only in the form of clinical evaluations and reported adverse events. No significant differences were observed between placebo and treatment groups in number of reported adverse events and no subjects were removed from the studyfor a treatment-related adverse event. Additional studies, potentially with larger subject groups, are needed to gather specific information on the longterm safety of G cambogia. An important concern in all pharmacological trials, particularly those in which herbal products are evaluated, is the amount and bioavailability of the active agent. As standard procedure, we confirmed the presence and quantity of hydroxycitric acid in the supplied capsules using an independent testing laboratory. However, we did not measure hydroxycitric acid blood levels or evaluate tissue or cytosolic citrate-cleavage enzyme activity. Although the format of our experiment closely resembles current use of G cambogia as a weight loss product, our conclusions should not be interpreted as a failure to support the validity of the biochemical effects of hydroxycitric acid identified by earlier in vestigators. In conclusion,our study evaluated the hypothesis that the active ingredient of G cambogia, hydroxycitric acid, has beneficial weight and fat mass loss effects. Our findings, obtained in a prospective, randomized, double-blind study , failed to detect either weight loss or fat-mobilizing effects of hydroxycitric acid beyond those of placebo. These observations, the first, to our knowledge, to appear in a peer-reviewed article using currently accepted experimental and statistical medthods, do not support a role as currently prescribed for the widely used herb G cambogia as a facilitator of weight loss.
This study was supported by National Institutes of Health grants RR00645 and P30DK26687 and a contract with Thompson Medical Company, West Palm Beach, Fla, manufacturer of products that include G cambogia.
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