Journal of Ethnopharmacology 155 (2014) 987–991
Contents lists available at ScienceDirect
Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep
Review
Hoodia gordonii: To eat, or not to eat Carine Smith n, Annadie Krygsman Department Physiological Sciences, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland 7602, South Africa
art ic l e i nf o
a b s t r a c t
Article history: Received 21 February 2014 Received in revised form 3 June 2014 Accepted 14 June 2014 Available online 21 June 2014
Ethnopharmacological relevance: Hoodia gordonii (family Apocynaceae) has become known globally for its claimed effect of appetite suppression. Despite a relatively large body of evidence of the plant's chemical make-up, peer-reviewed studies to provide scientific information on physiological effects of Hoodia gordonii are relatively sparse. The role of the pregnane glycoside P57—commonly accepted to be responsible for appetite suppression—has been questioned recently. Furthermore, a variety of physiological side-effects associated with consumption of the plant in extracted form questions its suitability for consumption. Although adverse effects have been described before, the relative abundance of nonpeer-reviewed data originating from patent documents and lay publication for advertising, which specifically only focus on beneficial outcomes, skews the view of the risk-benefit-balance. Here we provide a review of peer-reviewed studies on the plant's physiological effects. Novel data from an in vivo rodent study further elucidate the benefit-to-risk ratio associated with consumption. Conclusions: we conclude that although Hoodia gordonii seems to have a desired effect on appetite and weight loss, this effect may at least in part be a secondary symptom of the serious adverse effects that are associated with consumption of the high doses required to achieve therapeutic clinical effect. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Appetite Gastric emptying Sympathomimetic Ventricular hypertrophy Weight loss
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. P57: the star in the line-up, or not there at all? 3. Results from in vivo studies . . . . . . . . . . . . . . . . 4. Toxicity: how much is too much? . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Traditionally, the stapeliad Hoodia gordonii (one of 4 Hoodia species) is used by the Khoi and San communities of South Africa and Namibia to suppress both hunger and thirst, which enables hunters to undertake long hunting trips (van Wyk, 2008). Hoodia gordonii has become a global commercial commodity over the past decade, mostly for its claimed appetite suppressing properties. Due to confusion caused by vernacular names, Hoodia gordonii has in the past also been named as treatment for hypertension,
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Corresponding author. Tel.: þ 27 21 808 4388; fax: þ27 21 808 3145. E-mail address: [email protected] (C. Smith).
http://dx.doi.org/10.1016/j.jep.2014.06.033 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
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gastrointestinal problems and diabetes, but these effects seem to pertain to a different Hoodia species (Vermaak et al., 2011a). Despite the world-wide consumption of Hoodia gordonii in various forms, such as powder supplements, tea and energy bars, surprising little scientific data are available on its physiological effects. Given the ever-increasing population turning to natural products for health related purposes, it is important to understand what these consumers are actually being physically exposed to, whether a product actually exerts the effect(s) claimed and importantly, what undesired effects they may experience. At the moment, unlike for pharmaceuticals, the manufacturing and commercialisation of supplements in many countries are either not sufficiently regulated, or existing regulations not sufficiently enforced. Although some plant-derived substances are prepared
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following pharmaceutical guidelines, many plant extracts available as supplements today can at best be described as a cocktail of unknowns, which sometimes does not even contain the specified plant at all (Rader et al., 2007; Avula et al., 2008). Hoodia gordonii has been characterised rather thoroughly by the scientific community in the disciplines of botany and plant chemistry, yet studies to evaluate its physiological effects are relatively sparse. Furthermore, the fact that several prominent pharmaceutical companies that were initially involved in the commercial development of Hoodia gordonii have subsequently withdrawn their interest (Vermaak et al., 2011a), raises the question of whether this plant may have as yet unreported sideeffects. We therefore reviewed the available physiologically relevant investigations on Hoodia gordonii, in order to assess whether the claimed desired effects (such as appetite-suppression) of Hoodia gordonii sufficiently outweigh side-effects associated with its use. As mentioned, the phytochemical properties of Hoodia gordonii have been comprehensively described by others and do not fall within the scope of this review. Rather, we provide a critical review of reported physiological effects of Hoodia gordonii, including elucidation of some potential active components that have been identified and their proposed mechanisms of action. In order to retain objectivity, we did not include in this review findings mentioned in patent applications. Instead, only data from peer-reviewed publications were included.
2. P57: the star in the line-up, or not there at all? Comprehensive assessment methods for composition and quality (e.g. by NMR structural elucidation) of plant extracts are available and commonly used by researchers in the relevant research arenas (Avula et al., 2008). Although numerous steroidal glycosides have been isolated from Hoodia gordonii, a discussion on the phytochemistry of Hoodia gordonii falls outside of the scope of this review. We will focus only on those constituents in Hoodia gordonii that have been a focus of physiological testing. In this context, the main constituent generally thought and advertised to be the main active ingredient that is responsible for the appetite suppression, is the pregnane glycoside called P57AS3 (commonly referred to as P57, but also known as H.g.12)(van Heerden et al., 2007). Incidentally, P57 is also commonly used in these studies to verify quality and a measure of the “dosage” of the Hoodia product being investigated. In terms of scientific support for the claims of an appetitesuppressant function of P57, a couple of studies with very promising results have been published in this context. For example, P57 was reported to act centrally, since central injection of 0.4–40 nmol l 1 of P57 resulted in significantly decreased food intake in rats, associated with increased hypothalamic ATP production, leading to the conclusion that P57 may activate some energy-sensor in the hypothalamus to alter metabolism and thus appetite (MacLean and Luo, 2004). Also, a study including both ex vivo rat and in vitro experiments using human cells (Le Neve et al., 2010) illustrated the ability of H.g.12 purified from Hoodia gordonii extract to induce cholecystokinin
(CCK) secretion in the gut, possibly though activation of bitter sensors in the gut. CCK from the gut can facilitate central appetite suppression via the vagus nerve, supporting the notion of P57 as anorectic compound in Hoodia gordonii. To date, the clinical relevance of this result remains to be evaluated in vivo. When considering results obtained in potentially non-physiological models such as the ones mentioned above, it is necessary to consider these in conjunction with the pharmacokinetics and bioavailability of the proposed active agents within the plant, in order to judge validity and applicability of results. One physiologically relevant aspect of Hoodia gordonii that has been thoroughly investigated, is the pharmacokinetics and bioavailability of specifically P57 and its metabolites. Bioavailability of intravenously administered P57 was shown in mice to be highest in the kidney, followed by the liver and brain. However, P57 was both rapidly distributed and eliminated from tissue within 4 h, suggesting the effect to be fast-acting, but short in duration (Madgula et al., 2010a). Furthermore, in the same study, after oral administration of an identical dose (25 mg P57 kg 1), only very low levels of P57 were seen in the liver, kidney and intestine, with no detectable P57 in the brain. Of interest is the fact that pure P57 was infused intravenously, while the oral administration of P57 was in a more complex extract prepared from Hoodia gordonii. The purity of P57, and even the vehicle in which it is delivered, has been reported to affect its intestinal transport significantly (Vermaak et al., 2011b). This confounding factor may at least in part explain the differences between bioavailability via the respective administration routes, as reported by Madgula and colleagues. Nevertheless, tissue:plasma ratios suggested very low tissue uptake and the half-life of the absorption phase was less than 8 min. This data supports findings in another study by the same group, which showed that simulated gastric fluid degrades P57 very quickly (45% degradation within 30 min), with a similar but less pronounced result in simulated intestinal fluid (Madgula et al., 2010b). The extensive gastric breakdown of P57 was associated with increases in its aglycone hoodigogenin A (also referred to as hoodigenin A or Gordonoside A by some groups, Fig. 1), which was resistant to gastric as well as intestinal digestion. Interestingly, breakdown of P57 in the intestinal fluid was not associated with Hoodigogenin A formation. In contrast, while P57 was shown to be metabolically stable in in vitro human liver microsomes (Madgula et al., 2008), Hoodigogenin A was unstable in the same environment (Madgula et al., 2010b). Although P57 and Hoodigogenin A thus seem to be metabolised via different organs and mechanisms, taken together, these results suggest that a fairly high dose of Hoodia gordonii extract would have to be consumed in order to obtain significant levels of P57 or Hoodigogenin A at peripheral tissue level. In the context of central bioavailability, Hoodigogenin A was illustrated to efficiently cross in vitro simulations of the blood brainbarrier (Madgula et al., 2010b), but this property has not been verified in vivo. In addition, the potential for a central effect of Hoodigogenin A is also limited, given its quick elimination, low tissue uptake and the fact that it is usually highly bound to proteins (Madgula et al., 2010b), leaving very low pharmacologically active concentrations available for crossing the blood brain-barrier. The reports by Madgula et al., showing that P57 is completely degraded in the stomach within 60 min and not present in brain
Fig. 1. Chemical structure of P57 and Hoodigogenin A.
C. Smith, A. Krygsman / Journal of Ethnopharmacology 155 (2014) 987–991
tissue at all, puts a question mark after results from mechanistic studies on this glycoside using non-physiological models, as reviewed earlier in this section, so that the interpretation from these studies, as well as other similar ones, should now probably be revisited. From the literature, the overwhelming focus on P57 and Hoodigogenin A in in vitro studies clearly suggests that researchers accept them to be responsible for the physiological effects reported after Hoodia gordonii consumption. Therefore, given the seemingly conflicting results reported in this section, it is essential to turn to results from physiologically relevant in vivo (animal and human clinical) studies that have used traditional routes of administration, in order to put together a more complete picture.
3. Results from in vivo studies Although many claims and non-reviewed data are available in various patent applications, very few in vivo studies are available in peer-reviewed article format. Furthermore, due to either the protected status of the endangered Hoodia, or secrecy of researchers working in the commercial arena, almost no clinical data is available on the effect of Hoodia gordonii in humans. We were able to find only one published human clinical trial, conducted in overweight females over a 15-day supplementation period (Blom et al., 2011). The supplement used contained predominantly the glycoside H.g.-12 (P57) and was orally administered at a dose of 1110 mg purified Hoodia gordonii extract twice daily, which reportedly achieved a plasma concentration of 100 ng ml 1 P57 (although maximum concentrations achieved in serum actually ranged from 15 to 355 ng ml 1). The majority of Hoodia gordoniisupplemented individuals complained of mild clinical adverse effects, such as nausea, emesis and disturbances of skin sensation. A variety of additional physiological effects were also reported. First, in comparison to placebo, Hoodia gordonii consumption was associated with higher systolic and diastolic blood pressure. A shortcoming of the study however is that many subjects seemed to have low blood pressure at baseline (averaging E110/65 at baseline) and the supplement-associated increases did not increase blood pressure to abnormally high levels, so that the increase in blood pressures may actually constitute a desired effect, that of correcting hypotension. This would have to be further investigated in normotensive subjects before final recommendations can be made. Second, no difference in energy intake between placebo and supplement groups was reported. However, both groups showed a trend for lower daily energy intake throughout the progression of the protocol, which may have masked an appetite suppressant effect of the Hoodia extract, given the fact that the percentage decrease in energy intake in the Hoodia group was greater than that of the placebo group (18% vs. 24% less in placebo and Hoodia groups respectively). In our opinion, the fact that a standardised menu with limited meal choices was used for a relatively long duration (15 days), as well as the fact that subjects did not have access to food or snacks apart from meals supplied as part of the protocol, probably contributed to the overall decrease in food intake. Third, and perhaps of most concern, were the increases reported for plasma bilirubin (both direct and indirect) and alkaline phosphatase levels, as well as a decreased BUN (blood urea nitrogen). Although other kidney- and liver function-related parameters were not significantly affected, these data suggest that the dose administered (2220 mg purified extract daily) was probably approaching intolerable or even toxic concentration. Unfortunately, although a comprehensive haematology profile was assessed, no results in this regard were provided, so that it is not clear whether the abnormal blood
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chemistry may have been the result of other pathology, such as increased erythrocyte breakdown. Given the somewhat inconclusive data from the above study in humans, it is necessary to consider results from in vivo studies in animals, in order to gain more insight. One of the most quoted in vivo studies on Hoodia gordonii 's appetite suppressing properties (van Heerden et al., 2007), reports decreased food intake in rats after 3 days of supplementation with Hoodia gordonii glycosides (dose range of 6.25–50 mg kg body mass 1 day 1). Unfortunately, although average data were also presented for changes in body mass, no statistical analysis was performed (or at least not reported) on the small sample (n ¼3 rats per group) and no indication of variability of results (e.g. standard deviations) were presented. This was probably because the in vivo experiment was a small component of a larger study that was actually focused on plant chemistry. It is therefore difficult to interpret these results objectively and since such a small number of animals were tested, this study cannot be considered definitive scientific proof of efficacy. We recently performed an in vivo supplementation study in rats—to our knowledge, the only one reporting in vivo effects of Hoodia gordonii in both lean and obese animals (Smith and Krygsman, manuscript submitted). In this study, supplementation with both 80 and 160 mg Hoodia gordonii extract twice daily for 14 days, resulted in striking weight loss. However, several undesired effects were recorded at these dosages, which correspond to that used in the human study mentioned earlier. Some of these will be discussed more comprehensively in the section on toxicity below. However, an important novel finding was that the Hoodia gordonii-related weight loss in these animals could be ascribed to not only decreased fat mass, but also decreases in skeletal muscle (gastrocnemius) fibre size. This suggested that the weight loss of Hoodia gordonii may be as result of a starvation response. However, insufficient data is available to conclude the exact reasons or mechanisms responsible for this “starvation profile”. Studies in rodents differ substantially in terms of intervention duration, doses of Hoodia gordonii extract administered, as well parameters assessed and side-effects reported. We present a summary of these protocols and main findings in terms of appetite suppression in Table 1. Taken together, the conclusion made from these studies is that, as suggested by the work of Madgula et al., large doses of Hoodia gordonii is required for a significant suppression of appetite. Unfortunately, these high doses seem to be associated with rather severe sideeffects, which will be discussed in detail in the next section. Apart from the many studies testing effects of Hoodia consumption on appetite, data suggesting other potentially beneficial effects are available, such as the report of significantly lower interleukin-6 (but not IL-1β or TNF-α) levels after treatment with relatively low doses of Hoodia (12.5–18 mg kg 1) in rats (Figlewicz et al., 2009). More studies are required to investigate potential anti-inflammatory properties of Hoodia as proposed, and to establish possible cause-effect relationships between the altered cytokine and steroid levels, in the context of inflammation. In the same study, circulating levels of leptin and protein YY were unchanged and fat mass was not affected, but these non-effects may have been as a result of the relatively low dose of Hoodia administered. The authors speculated that Hoodia treatment may enhance the effect of leptin, since Hoodia-treated rats consumed less self-administered sweetened solution in the active lever press model when compared to controls. Two subsequent studies by Jain and Singh have reported on these appetite regulating peptides and related biochemical parameters. The first study was performed in a small number of rats and results were inconclusive (Jain and Singh, 2013). In their most recent publication(Jain and Singh, 2014), 100 mg/kg (orally for 5 days) Hoodia gordonii indeed seemed to modulate the CCK responses to 25% calorie restriction, although other data was more difficult to interpret, given the
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Table 1 Summary of in vivo studies on rodents to illustrate main findings related to appetite, weight loss and gastrointestinal effects after oral administration of Hoodia gordonii extract. Reference
Species
Dosage (mg kg 1) Treatment duration
van Heerden et al. (2007)
Rats
6.25–50
Figlewicz et al. (2009)
Rats
12.5–18
Jain and Singh (2013)
Rats
50–150
Smith and Krygsman, (in preparation) Rats, lean and obese 80 and 160
Dent et al. (2012b)
Pregnant mice
0.5–50
Scott et al. (2012)
Mice
100–2000
Dent et al. (2012a)
Pregnant rabbits
3.6–12
study design. Unfortunately, due to the omission of a Hoodiatreated group without caloric restriction, this result cannot be directly extrapolated to inform on the degree of effectiveness, or mechanism(s) by which Hoodia gordonii may have a primary appetite-suppressive effect when a normal diet is consumed. Nevertheless, these results contribute to the elucidation of biological targets of Hoodia gordonii.
4. Toxicity: how much is too much? Given the low bioavailability demonstrated for P57, and the relatively high doses of Hoodia gordonii to be consumed for the desired appetite suppressant effect, it is essential to consider potential side-effects associated with these large doses. In a prenatal developmental toxicity study in rabbits, up to 12 mg Hoodia gordonii extract kg 1 day 1 for 25 days did not have adverse effects on foetal development (Dent et al., 2012b). Although litters were not compromised, important data regarding clinical toxicity in the adult animals was gained: while a dose of 3 mg kg 1 day 1 did not have any effects on feed intake by pregnant mothers in this study, the 6 and 12 mg kg 1 day 1 dosages resulted in a dose-dependent decrease in both food intake and weight gain. A dosage of 12 mg kg 1 day 1 proved intolerable and was associated with sharp decreases in both food and water intake, as well as thickened stomach contents in 50% of animals. A similar study by the same group in mice yielded more similar data (Dent et al., 2012a). Mice were supplemented for 12 days with Hoodia gordonii extract at doses of 0, 5, 15 and 50 mg kg 1 day 1. Only the highest dose consistently decreased maternal food intake and weight gain, but was also associated with delayed foetal development (low foetal body mass). Another rodent toxicity study reported no genotoxicity of Hoodia gordonii doses of up to 400 mg kg 1 in mice (Scott et al., 2012). Important to note is that in this study, the highest dose for supplementation (400 mg kg 1) was determined in a “dosefinding” tolerance study in 4 rats per dosage category. In this experiment, doses up to 2000 mg kg 1 were tested, and those above 350 mg kg 1 were reported to yield clinical signs of toxicity, which included swollen abdomens, body mass loss and increased mortality within 48 h. In the recent study by our group already mentioned (Smith and Krygsman, manuscript submitted), both
Outcomes
↓ food intake (all doses) No change in body mass 10 weeks, 3 days/week No change in body mass No change in leptin levels No change in Protein YY levels 5 days, daily ↓ food intake (100 and 150 mg) No effect on body mass ↑ Increased hepatic glycogen (100 mg) ↓ Corticosterone and Neuropeptide Y (100 mg) ↑Thyroid hormones (T3 and T4) (100 mg) 14 days, twice daily ↓ weight Enlarged stomach with thickened content (80 and 160 mg) ↓ in muscle fibre and adipocyte size 12 days, daily ↓ food intake (50 mg) ↓ weight gain during gestation (50 mg) Delayed foetal development (low foetal mass)(50 mg) 2 days, daily Mortality ( 4500 mg) Swollen abdomen (400 mg) 25 days, daily ↓ food intake (6 and 12 mg) ↓weight gain during gestation (6 and 12 mg) Thickened stomach content (12 mg) 3 days, daily
lean and obese rats also illustrated the adverse effect on stomach emptying at relatively low doses (80 mg kg. 1 twice daily). These results from in vivo studies in rodents illustrate large differences intolerable concentrations of Hoodia gordonii extracts in the hands of different research groups. These are most probably as a result of different extraction protocols as well as variations in plant source material, collection methods and timing and locality of harvests, so that the same differences likely occur between different supplement manufacturers. (These differences make it near impossible to establish broadly applicable tolerance levels for any plant-derived extract, highlighting the importance of pharmacokinetic and biological safety studies for individual products.) Furthermore, in the human study, huge variations were reported in maximal concentration (Cmax) values for P57 in circulation, suggesting large inter-individual variation in the uptake and metabolism of the extract. Therefore, at this point it is nearly impossible to suggest a safe, effective reference dose to use across board in any particular species. Nevertheless, the common observation remains that as soon as therapeutic concentration is reached in terms of appetite suppression, animals consistently exhibit extreme gastrointestinal signs of intolerance, posing the question of whether it should be consumed at all. It would seem from the available data that, although there is some evidence that appetite controlling peptides may be influenced, the appetitesuppressant effect of Hoodia gordonii may at least in part be ascribed to a type of “sickness behaviour” secondary to the delayed stomach emptying that would be associated with subsequent distended stomachs, bloating, abdominal pain and nausea. Apart from the side-effects mentioned above, other very disconcerting side-effects have been suggested. For example very recently, after reports of adverse cardiovascular effects (increased pulse rate and blood pressure) of Hoodia gordonii by Hungarian consumers, the effect of this plant on β-adrenergic receptors was assessed in an ex vivo study using rat uteri (Roza et al., 2013). The rationale behind this study was that other β-adrenergic agonists are known to also exhibit anorectic properties through decreased food intake (Fernandez-Lopez et al., 2002). Hoodia gordonii extract treatment was shown to have sympathomemitic effects in the study by Roza et al., which supports the adverse cardiovascular symptoms reported in the only human clinical trial published after peer-review (Blom et al., 2011), as well as the left ventricular hypertrophy reported by our group (Smith and Krygsman,
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manuscript submitted). Interestingly, these effects correspond to those reported for similar weight loss agents such as amphetamine derivatives, which were withdrawn from the market due to their adverse effects on β-adrenergic function (Roza et al., 2013).
5. Conclusions Taken together, the review of the literature presented here, illustrates the requirement for more physiological studies to elucidate in more detail the mechanisms of action, as well as side-effects and appropriate doses, of Hoodia gordonii. While there can be no doubt that Hoodia gordonii decreases energy intake resulting in weight loss, available data seem to suggest that this highly sought-after benefit may come at a huge premium, such as potentially lethal hypertension, loss of skeletal muscle mass and general feelings of gastrointestinal discomfort. Several authors of published papers have suggested that P57 and Hoodigogenin A might not be the active agents responsible for the weight loss associated with consumption of Hoodia gordonii extract. These extracts are fairly complex in nature (see representative profile in Fig. 1), so that further isolation and testing of more of its constituents may shed more light on specific agents responsible for the positive and/or negative effects reported both anecdotally and by researchers. At this stage, it cannot be excluded that Hoodia gordonii may contain the key to safe weight loss, but more studies are required to better our understanding of the plant's biological action. Identification and subsequent isolation of the truly beneficial active components may enhance the desired effect(s) and improve tolerance to such a supplement drastically. Furthermore, the literature consulted for this review revealed that many in vivo studies investigating biological efficacy of the plant in terms of appetite suppression, was conducted by chemists who isolated specific compounds from the plant. Although these groups made valiant efforts, their in vivo studies would have benefited hugely from collaboration to integrate physiological investigations. Similarly, most studies performed in the context of physiological effects fail to incorporate sufficient botanical or phytochemical information on the plants or extracts studied. From the literature, there is clearly a need for multidisciplinary studies, spanning the fields of chemistry, ethnopharmacology, nutrition and physiology, in order to comprehensively evaluate how Hoodia gordonii may be optimally used for desired outcomes with minimal side-effects. In conclusion, given the severity of the adverse effects reported, and the relative absence of comprehensive data on the mechanisms responsible for these side-effects, we conclude that at this stage, the most sensible advice is for individuals to refrain from consuming Hoodia gordonii.
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References Avula, B., Wang, Y.H., Pawar, R.S., Shukla, Y.J., Smillie, T.J., Khan, I.A., 2008. Identification and structural characterization of steroidal glycosides in Hoodia gordonii by ion-trap tandem mass spectrometry and liquid chromatography coupled with electrospray ionization time-of-flight mass spectrometry. Rapid Communications in Mass Spectrometry 22, 2587–2596. Blom, W.A., Abrahamse, S.L., Bradford, R., Duchateau, G.S., Theis, W., Orsi, A., Ward, C.L., Mela, D.J., 2011. Effects of 15-d repeated consumption of Hoodia gordonii purified extract on safety, ad libitum energy intake, and body weight in healthy, overweight women: a randomized controlled trial. The American Journal of Clinical Nutrition 94, 1171–1181. Dent, M.P., Wolterbeek, A.P., Russell, P.J., Bradford, R., 2012a. Safety profile of Hoodia gordonii extract: mouse prenatal developmental toxicity study. Food Chemical Toxicology 50 (1), S20–S25. Dent, M.P., Wolterbeek, A.P., Russell, P.J., Bradford, R., 2012b. Safety profile of Hoodia gordonii extract: rabbit prenatal developmental toxicity study. Food Chemical Toxicology 50 (1), S26–S33. Fernandez-Lopez, J.A., Remesar, X., Foz, M., Alemany, M., 2002. Pharmacological approaches for the treatment of obesity. Drugs 62, 915–944. Figlewicz, D.P., Ioannou, G., Bennett Jay, J., Kittleson, S., Savard, C., Roth, C.L., 2009. Effect of moderate intake of sweeteners on metabolic health in the rat. Physiology and Behavior 98, 618–624. Jain, S., Singh, S.N., 2013. Metabolic effect of short term administration of Hoodia gordonii, an herbal appetite suppressant. South African Journal of Botany 86, 51–55. Jain, S., Singh, S.N., 2014. Metabolic response of short term calorie restriction and supplementation with Hoodia gordonii. South African Journal of Botany 92, 73–77. Le Neve, B., Foltz, M., Daniel, H., Gouka, R., 2010. The steroid glycoside H.g.-12 from Hoodia gordonii activates the human bitter receptor TAS2R14 and induces CCK release from HuTu-80 cells. American Journal of Physiology Gastrointestinal Liver Physiology 299, G1368–G1375. MacLean, D.B., Luo, L.G., 2004. Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: studies of the anorectic mechanism of a plant steroidal glycoside. Brain Research 1020, 1–11. Madgula, V.L., Ashfaq, M.K., Wang, Y.H., Avula, B., Khan, I.A., Walker, L.A., Khan, S.I., 2010a. Bioavailability, pharmacokinetics, and tissue distribution of the oxypregnane steroidal glycoside P57AS3 (P57) from Hoodia gordonii in mouse model. Planta Medica 76, 1582–1586. Madgula, V.L., Avula, B., Pawar, R.S., Shukla, Y.J., Khan, I.A., Walker, L.A., Khan, S.I., 2008. in vitro metabolic stability and intestinal transport of P57AS3 (P57) from Hoodia gordonii and its interaction with drug metabolizing enzymes. Planta Medica 74, 1269–1275. Madgula, V.L., Avula, B., Pawar, R.S., Shukla, Y.J., Khan, I.A., Walker, L.A., Khan, S.I., 2010b. Characterization of in vitro pharmacokinetic properties of hoodigogenin A from Hoodia gordonii. Planta Medica 76, 62–69. Rader, J.I., Delmonte, P., Trucksess, M.W., 2007. Recent studies on selected botanical dietary supplement ingredients. Analytical Bioanalytical Chemistry 389, 27–35. Roza, O., Lovasz, N., Zupko, I., Hohmann, J., Csupor, D., 2013. Sympathomimetic activity of a Hoodia gordonii product: a possible mechanism of cardiovascular side effects. Biomed Research International 2013, 171059. Smith and Krygsman. Hoodia gordonii extract targets both adipose and muscle tissue to achieve weight loss in rats. Journal of Ethnopharmacology, (in preparation). Scott, A.D., Orsi, A., Ward, C., Bradford, R., 2012. Genotoxicity testing of a Hoodia gordonii extract. Food Chemical Toxicology 50 (1), S34–S40. van Heerden, F.R., Marthinus Horak, R., Maharaj, V.J., Vleggaar, R., Senabe, J.V., Gunning, P.J., 2007. An appetite suppressant from Hoodia species. Phytochemistry 68, 2545–2553. van Wyk, B.E., 2008. A review of Khoi-San and Cape Dutch medical ethnobotany. Journal of Ethnopharmacology 119, 331–341. Vermaak, I., Hamman, J.H., Viljoen, A.M., 2011a. Hoodia gordonii: an up-to-date review of a commercially important anti-obesity plant. Planta Medica 77, 1149–1160. Vermaak, I., Viljoen, A.M., Chen, W., Hamman, J.H., 2011b. in vitro transport of the steroidal glycoside P57 from Hoodia gordonii across excised porcine intestinal and buccal tissue. Phytomedicine 18, 783–787.
Contents lists available at ScienceDirect
Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep
Review
Hoodia gordonii: To eat, or not to eat Carine Smith n, Annadie Krygsman Department Physiological Sciences, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland 7602, South Africa
art ic l e i nf o
a b s t r a c t
Article history: Received 21 February 2014 Received in revised form 3 June 2014 Accepted 14 June 2014 Available online 21 June 2014
Ethnopharmacological relevance: Hoodia gordonii (family Apocynaceae) has become known globally for its claimed effect of appetite suppression. Despite a relatively large body of evidence of the plant's chemical make-up, peer-reviewed studies to provide scientific information on physiological effects of Hoodia gordonii are relatively sparse. The role of the pregnane glycoside P57—commonly accepted to be responsible for appetite suppression—has been questioned recently. Furthermore, a variety of physiological side-effects associated with consumption of the plant in extracted form questions its suitability for consumption. Although adverse effects have been described before, the relative abundance of nonpeer-reviewed data originating from patent documents and lay publication for advertising, which specifically only focus on beneficial outcomes, skews the view of the risk-benefit-balance. Here we provide a review of peer-reviewed studies on the plant's physiological effects. Novel data from an in vivo rodent study further elucidate the benefit-to-risk ratio associated with consumption. Conclusions: we conclude that although Hoodia gordonii seems to have a desired effect on appetite and weight loss, this effect may at least in part be a secondary symptom of the serious adverse effects that are associated with consumption of the high doses required to achieve therapeutic clinical effect. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Appetite Gastric emptying Sympathomimetic Ventricular hypertrophy Weight loss
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. P57: the star in the line-up, or not there at all? 3. Results from in vivo studies . . . . . . . . . . . . . . . . 4. Toxicity: how much is too much? . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Traditionally, the stapeliad Hoodia gordonii (one of 4 Hoodia species) is used by the Khoi and San communities of South Africa and Namibia to suppress both hunger and thirst, which enables hunters to undertake long hunting trips (van Wyk, 2008). Hoodia gordonii has become a global commercial commodity over the past decade, mostly for its claimed appetite suppressing properties. Due to confusion caused by vernacular names, Hoodia gordonii has in the past also been named as treatment for hypertension,
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Corresponding author. Tel.: þ 27 21 808 4388; fax: þ27 21 808 3145. E-mail address: [email protected] (C. Smith).
http://dx.doi.org/10.1016/j.jep.2014.06.033 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
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gastrointestinal problems and diabetes, but these effects seem to pertain to a different Hoodia species (Vermaak et al., 2011a). Despite the world-wide consumption of Hoodia gordonii in various forms, such as powder supplements, tea and energy bars, surprising little scientific data are available on its physiological effects. Given the ever-increasing population turning to natural products for health related purposes, it is important to understand what these consumers are actually being physically exposed to, whether a product actually exerts the effect(s) claimed and importantly, what undesired effects they may experience. At the moment, unlike for pharmaceuticals, the manufacturing and commercialisation of supplements in many countries are either not sufficiently regulated, or existing regulations not sufficiently enforced. Although some plant-derived substances are prepared
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following pharmaceutical guidelines, many plant extracts available as supplements today can at best be described as a cocktail of unknowns, which sometimes does not even contain the specified plant at all (Rader et al., 2007; Avula et al., 2008). Hoodia gordonii has been characterised rather thoroughly by the scientific community in the disciplines of botany and plant chemistry, yet studies to evaluate its physiological effects are relatively sparse. Furthermore, the fact that several prominent pharmaceutical companies that were initially involved in the commercial development of Hoodia gordonii have subsequently withdrawn their interest (Vermaak et al., 2011a), raises the question of whether this plant may have as yet unreported sideeffects. We therefore reviewed the available physiologically relevant investigations on Hoodia gordonii, in order to assess whether the claimed desired effects (such as appetite-suppression) of Hoodia gordonii sufficiently outweigh side-effects associated with its use. As mentioned, the phytochemical properties of Hoodia gordonii have been comprehensively described by others and do not fall within the scope of this review. Rather, we provide a critical review of reported physiological effects of Hoodia gordonii, including elucidation of some potential active components that have been identified and their proposed mechanisms of action. In order to retain objectivity, we did not include in this review findings mentioned in patent applications. Instead, only data from peer-reviewed publications were included.
2. P57: the star in the line-up, or not there at all? Comprehensive assessment methods for composition and quality (e.g. by NMR structural elucidation) of plant extracts are available and commonly used by researchers in the relevant research arenas (Avula et al., 2008). Although numerous steroidal glycosides have been isolated from Hoodia gordonii, a discussion on the phytochemistry of Hoodia gordonii falls outside of the scope of this review. We will focus only on those constituents in Hoodia gordonii that have been a focus of physiological testing. In this context, the main constituent generally thought and advertised to be the main active ingredient that is responsible for the appetite suppression, is the pregnane glycoside called P57AS3 (commonly referred to as P57, but also known as H.g.12)(van Heerden et al., 2007). Incidentally, P57 is also commonly used in these studies to verify quality and a measure of the “dosage” of the Hoodia product being investigated. In terms of scientific support for the claims of an appetitesuppressant function of P57, a couple of studies with very promising results have been published in this context. For example, P57 was reported to act centrally, since central injection of 0.4–40 nmol l 1 of P57 resulted in significantly decreased food intake in rats, associated with increased hypothalamic ATP production, leading to the conclusion that P57 may activate some energy-sensor in the hypothalamus to alter metabolism and thus appetite (MacLean and Luo, 2004). Also, a study including both ex vivo rat and in vitro experiments using human cells (Le Neve et al., 2010) illustrated the ability of H.g.12 purified from Hoodia gordonii extract to induce cholecystokinin
(CCK) secretion in the gut, possibly though activation of bitter sensors in the gut. CCK from the gut can facilitate central appetite suppression via the vagus nerve, supporting the notion of P57 as anorectic compound in Hoodia gordonii. To date, the clinical relevance of this result remains to be evaluated in vivo. When considering results obtained in potentially non-physiological models such as the ones mentioned above, it is necessary to consider these in conjunction with the pharmacokinetics and bioavailability of the proposed active agents within the plant, in order to judge validity and applicability of results. One physiologically relevant aspect of Hoodia gordonii that has been thoroughly investigated, is the pharmacokinetics and bioavailability of specifically P57 and its metabolites. Bioavailability of intravenously administered P57 was shown in mice to be highest in the kidney, followed by the liver and brain. However, P57 was both rapidly distributed and eliminated from tissue within 4 h, suggesting the effect to be fast-acting, but short in duration (Madgula et al., 2010a). Furthermore, in the same study, after oral administration of an identical dose (25 mg P57 kg 1), only very low levels of P57 were seen in the liver, kidney and intestine, with no detectable P57 in the brain. Of interest is the fact that pure P57 was infused intravenously, while the oral administration of P57 was in a more complex extract prepared from Hoodia gordonii. The purity of P57, and even the vehicle in which it is delivered, has been reported to affect its intestinal transport significantly (Vermaak et al., 2011b). This confounding factor may at least in part explain the differences between bioavailability via the respective administration routes, as reported by Madgula and colleagues. Nevertheless, tissue:plasma ratios suggested very low tissue uptake and the half-life of the absorption phase was less than 8 min. This data supports findings in another study by the same group, which showed that simulated gastric fluid degrades P57 very quickly (45% degradation within 30 min), with a similar but less pronounced result in simulated intestinal fluid (Madgula et al., 2010b). The extensive gastric breakdown of P57 was associated with increases in its aglycone hoodigogenin A (also referred to as hoodigenin A or Gordonoside A by some groups, Fig. 1), which was resistant to gastric as well as intestinal digestion. Interestingly, breakdown of P57 in the intestinal fluid was not associated with Hoodigogenin A formation. In contrast, while P57 was shown to be metabolically stable in in vitro human liver microsomes (Madgula et al., 2008), Hoodigogenin A was unstable in the same environment (Madgula et al., 2010b). Although P57 and Hoodigogenin A thus seem to be metabolised via different organs and mechanisms, taken together, these results suggest that a fairly high dose of Hoodia gordonii extract would have to be consumed in order to obtain significant levels of P57 or Hoodigogenin A at peripheral tissue level. In the context of central bioavailability, Hoodigogenin A was illustrated to efficiently cross in vitro simulations of the blood brainbarrier (Madgula et al., 2010b), but this property has not been verified in vivo. In addition, the potential for a central effect of Hoodigogenin A is also limited, given its quick elimination, low tissue uptake and the fact that it is usually highly bound to proteins (Madgula et al., 2010b), leaving very low pharmacologically active concentrations available for crossing the blood brain-barrier. The reports by Madgula et al., showing that P57 is completely degraded in the stomach within 60 min and not present in brain
Fig. 1. Chemical structure of P57 and Hoodigogenin A.
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tissue at all, puts a question mark after results from mechanistic studies on this glycoside using non-physiological models, as reviewed earlier in this section, so that the interpretation from these studies, as well as other similar ones, should now probably be revisited. From the literature, the overwhelming focus on P57 and Hoodigogenin A in in vitro studies clearly suggests that researchers accept them to be responsible for the physiological effects reported after Hoodia gordonii consumption. Therefore, given the seemingly conflicting results reported in this section, it is essential to turn to results from physiologically relevant in vivo (animal and human clinical) studies that have used traditional routes of administration, in order to put together a more complete picture.
3. Results from in vivo studies Although many claims and non-reviewed data are available in various patent applications, very few in vivo studies are available in peer-reviewed article format. Furthermore, due to either the protected status of the endangered Hoodia, or secrecy of researchers working in the commercial arena, almost no clinical data is available on the effect of Hoodia gordonii in humans. We were able to find only one published human clinical trial, conducted in overweight females over a 15-day supplementation period (Blom et al., 2011). The supplement used contained predominantly the glycoside H.g.-12 (P57) and was orally administered at a dose of 1110 mg purified Hoodia gordonii extract twice daily, which reportedly achieved a plasma concentration of 100 ng ml 1 P57 (although maximum concentrations achieved in serum actually ranged from 15 to 355 ng ml 1). The majority of Hoodia gordoniisupplemented individuals complained of mild clinical adverse effects, such as nausea, emesis and disturbances of skin sensation. A variety of additional physiological effects were also reported. First, in comparison to placebo, Hoodia gordonii consumption was associated with higher systolic and diastolic blood pressure. A shortcoming of the study however is that many subjects seemed to have low blood pressure at baseline (averaging E110/65 at baseline) and the supplement-associated increases did not increase blood pressure to abnormally high levels, so that the increase in blood pressures may actually constitute a desired effect, that of correcting hypotension. This would have to be further investigated in normotensive subjects before final recommendations can be made. Second, no difference in energy intake between placebo and supplement groups was reported. However, both groups showed a trend for lower daily energy intake throughout the progression of the protocol, which may have masked an appetite suppressant effect of the Hoodia extract, given the fact that the percentage decrease in energy intake in the Hoodia group was greater than that of the placebo group (18% vs. 24% less in placebo and Hoodia groups respectively). In our opinion, the fact that a standardised menu with limited meal choices was used for a relatively long duration (15 days), as well as the fact that subjects did not have access to food or snacks apart from meals supplied as part of the protocol, probably contributed to the overall decrease in food intake. Third, and perhaps of most concern, were the increases reported for plasma bilirubin (both direct and indirect) and alkaline phosphatase levels, as well as a decreased BUN (blood urea nitrogen). Although other kidney- and liver function-related parameters were not significantly affected, these data suggest that the dose administered (2220 mg purified extract daily) was probably approaching intolerable or even toxic concentration. Unfortunately, although a comprehensive haematology profile was assessed, no results in this regard were provided, so that it is not clear whether the abnormal blood
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chemistry may have been the result of other pathology, such as increased erythrocyte breakdown. Given the somewhat inconclusive data from the above study in humans, it is necessary to consider results from in vivo studies in animals, in order to gain more insight. One of the most quoted in vivo studies on Hoodia gordonii 's appetite suppressing properties (van Heerden et al., 2007), reports decreased food intake in rats after 3 days of supplementation with Hoodia gordonii glycosides (dose range of 6.25–50 mg kg body mass 1 day 1). Unfortunately, although average data were also presented for changes in body mass, no statistical analysis was performed (or at least not reported) on the small sample (n ¼3 rats per group) and no indication of variability of results (e.g. standard deviations) were presented. This was probably because the in vivo experiment was a small component of a larger study that was actually focused on plant chemistry. It is therefore difficult to interpret these results objectively and since such a small number of animals were tested, this study cannot be considered definitive scientific proof of efficacy. We recently performed an in vivo supplementation study in rats—to our knowledge, the only one reporting in vivo effects of Hoodia gordonii in both lean and obese animals (Smith and Krygsman, manuscript submitted). In this study, supplementation with both 80 and 160 mg Hoodia gordonii extract twice daily for 14 days, resulted in striking weight loss. However, several undesired effects were recorded at these dosages, which correspond to that used in the human study mentioned earlier. Some of these will be discussed more comprehensively in the section on toxicity below. However, an important novel finding was that the Hoodia gordonii-related weight loss in these animals could be ascribed to not only decreased fat mass, but also decreases in skeletal muscle (gastrocnemius) fibre size. This suggested that the weight loss of Hoodia gordonii may be as result of a starvation response. However, insufficient data is available to conclude the exact reasons or mechanisms responsible for this “starvation profile”. Studies in rodents differ substantially in terms of intervention duration, doses of Hoodia gordonii extract administered, as well parameters assessed and side-effects reported. We present a summary of these protocols and main findings in terms of appetite suppression in Table 1. Taken together, the conclusion made from these studies is that, as suggested by the work of Madgula et al., large doses of Hoodia gordonii is required for a significant suppression of appetite. Unfortunately, these high doses seem to be associated with rather severe sideeffects, which will be discussed in detail in the next section. Apart from the many studies testing effects of Hoodia consumption on appetite, data suggesting other potentially beneficial effects are available, such as the report of significantly lower interleukin-6 (but not IL-1β or TNF-α) levels after treatment with relatively low doses of Hoodia (12.5–18 mg kg 1) in rats (Figlewicz et al., 2009). More studies are required to investigate potential anti-inflammatory properties of Hoodia as proposed, and to establish possible cause-effect relationships between the altered cytokine and steroid levels, in the context of inflammation. In the same study, circulating levels of leptin and protein YY were unchanged and fat mass was not affected, but these non-effects may have been as a result of the relatively low dose of Hoodia administered. The authors speculated that Hoodia treatment may enhance the effect of leptin, since Hoodia-treated rats consumed less self-administered sweetened solution in the active lever press model when compared to controls. Two subsequent studies by Jain and Singh have reported on these appetite regulating peptides and related biochemical parameters. The first study was performed in a small number of rats and results were inconclusive (Jain and Singh, 2013). In their most recent publication(Jain and Singh, 2014), 100 mg/kg (orally for 5 days) Hoodia gordonii indeed seemed to modulate the CCK responses to 25% calorie restriction, although other data was more difficult to interpret, given the
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Table 1 Summary of in vivo studies on rodents to illustrate main findings related to appetite, weight loss and gastrointestinal effects after oral administration of Hoodia gordonii extract. Reference
Species
Dosage (mg kg 1) Treatment duration
van Heerden et al. (2007)
Rats
6.25–50
Figlewicz et al. (2009)
Rats
12.5–18
Jain and Singh (2013)
Rats
50–150
Smith and Krygsman, (in preparation) Rats, lean and obese 80 and 160
Dent et al. (2012b)
Pregnant mice
0.5–50
Scott et al. (2012)
Mice
100–2000
Dent et al. (2012a)
Pregnant rabbits
3.6–12
study design. Unfortunately, due to the omission of a Hoodiatreated group without caloric restriction, this result cannot be directly extrapolated to inform on the degree of effectiveness, or mechanism(s) by which Hoodia gordonii may have a primary appetite-suppressive effect when a normal diet is consumed. Nevertheless, these results contribute to the elucidation of biological targets of Hoodia gordonii.
4. Toxicity: how much is too much? Given the low bioavailability demonstrated for P57, and the relatively high doses of Hoodia gordonii to be consumed for the desired appetite suppressant effect, it is essential to consider potential side-effects associated with these large doses. In a prenatal developmental toxicity study in rabbits, up to 12 mg Hoodia gordonii extract kg 1 day 1 for 25 days did not have adverse effects on foetal development (Dent et al., 2012b). Although litters were not compromised, important data regarding clinical toxicity in the adult animals was gained: while a dose of 3 mg kg 1 day 1 did not have any effects on feed intake by pregnant mothers in this study, the 6 and 12 mg kg 1 day 1 dosages resulted in a dose-dependent decrease in both food intake and weight gain. A dosage of 12 mg kg 1 day 1 proved intolerable and was associated with sharp decreases in both food and water intake, as well as thickened stomach contents in 50% of animals. A similar study by the same group in mice yielded more similar data (Dent et al., 2012a). Mice were supplemented for 12 days with Hoodia gordonii extract at doses of 0, 5, 15 and 50 mg kg 1 day 1. Only the highest dose consistently decreased maternal food intake and weight gain, but was also associated with delayed foetal development (low foetal body mass). Another rodent toxicity study reported no genotoxicity of Hoodia gordonii doses of up to 400 mg kg 1 in mice (Scott et al., 2012). Important to note is that in this study, the highest dose for supplementation (400 mg kg 1) was determined in a “dosefinding” tolerance study in 4 rats per dosage category. In this experiment, doses up to 2000 mg kg 1 were tested, and those above 350 mg kg 1 were reported to yield clinical signs of toxicity, which included swollen abdomens, body mass loss and increased mortality within 48 h. In the recent study by our group already mentioned (Smith and Krygsman, manuscript submitted), both
Outcomes
↓ food intake (all doses) No change in body mass 10 weeks, 3 days/week No change in body mass No change in leptin levels No change in Protein YY levels 5 days, daily ↓ food intake (100 and 150 mg) No effect on body mass ↑ Increased hepatic glycogen (100 mg) ↓ Corticosterone and Neuropeptide Y (100 mg) ↑Thyroid hormones (T3 and T4) (100 mg) 14 days, twice daily ↓ weight Enlarged stomach with thickened content (80 and 160 mg) ↓ in muscle fibre and adipocyte size 12 days, daily ↓ food intake (50 mg) ↓ weight gain during gestation (50 mg) Delayed foetal development (low foetal mass)(50 mg) 2 days, daily Mortality ( 4500 mg) Swollen abdomen (400 mg) 25 days, daily ↓ food intake (6 and 12 mg) ↓weight gain during gestation (6 and 12 mg) Thickened stomach content (12 mg) 3 days, daily
lean and obese rats also illustrated the adverse effect on stomach emptying at relatively low doses (80 mg kg. 1 twice daily). These results from in vivo studies in rodents illustrate large differences intolerable concentrations of Hoodia gordonii extracts in the hands of different research groups. These are most probably as a result of different extraction protocols as well as variations in plant source material, collection methods and timing and locality of harvests, so that the same differences likely occur between different supplement manufacturers. (These differences make it near impossible to establish broadly applicable tolerance levels for any plant-derived extract, highlighting the importance of pharmacokinetic and biological safety studies for individual products.) Furthermore, in the human study, huge variations were reported in maximal concentration (Cmax) values for P57 in circulation, suggesting large inter-individual variation in the uptake and metabolism of the extract. Therefore, at this point it is nearly impossible to suggest a safe, effective reference dose to use across board in any particular species. Nevertheless, the common observation remains that as soon as therapeutic concentration is reached in terms of appetite suppression, animals consistently exhibit extreme gastrointestinal signs of intolerance, posing the question of whether it should be consumed at all. It would seem from the available data that, although there is some evidence that appetite controlling peptides may be influenced, the appetitesuppressant effect of Hoodia gordonii may at least in part be ascribed to a type of “sickness behaviour” secondary to the delayed stomach emptying that would be associated with subsequent distended stomachs, bloating, abdominal pain and nausea. Apart from the side-effects mentioned above, other very disconcerting side-effects have been suggested. For example very recently, after reports of adverse cardiovascular effects (increased pulse rate and blood pressure) of Hoodia gordonii by Hungarian consumers, the effect of this plant on β-adrenergic receptors was assessed in an ex vivo study using rat uteri (Roza et al., 2013). The rationale behind this study was that other β-adrenergic agonists are known to also exhibit anorectic properties through decreased food intake (Fernandez-Lopez et al., 2002). Hoodia gordonii extract treatment was shown to have sympathomemitic effects in the study by Roza et al., which supports the adverse cardiovascular symptoms reported in the only human clinical trial published after peer-review (Blom et al., 2011), as well as the left ventricular hypertrophy reported by our group (Smith and Krygsman,
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manuscript submitted). Interestingly, these effects correspond to those reported for similar weight loss agents such as amphetamine derivatives, which were withdrawn from the market due to their adverse effects on β-adrenergic function (Roza et al., 2013).
5. Conclusions Taken together, the review of the literature presented here, illustrates the requirement for more physiological studies to elucidate in more detail the mechanisms of action, as well as side-effects and appropriate doses, of Hoodia gordonii. While there can be no doubt that Hoodia gordonii decreases energy intake resulting in weight loss, available data seem to suggest that this highly sought-after benefit may come at a huge premium, such as potentially lethal hypertension, loss of skeletal muscle mass and general feelings of gastrointestinal discomfort. Several authors of published papers have suggested that P57 and Hoodigogenin A might not be the active agents responsible for the weight loss associated with consumption of Hoodia gordonii extract. These extracts are fairly complex in nature (see representative profile in Fig. 1), so that further isolation and testing of more of its constituents may shed more light on specific agents responsible for the positive and/or negative effects reported both anecdotally and by researchers. At this stage, it cannot be excluded that Hoodia gordonii may contain the key to safe weight loss, but more studies are required to better our understanding of the plant's biological action. Identification and subsequent isolation of the truly beneficial active components may enhance the desired effect(s) and improve tolerance to such a supplement drastically. Furthermore, the literature consulted for this review revealed that many in vivo studies investigating biological efficacy of the plant in terms of appetite suppression, was conducted by chemists who isolated specific compounds from the plant. Although these groups made valiant efforts, their in vivo studies would have benefited hugely from collaboration to integrate physiological investigations. Similarly, most studies performed in the context of physiological effects fail to incorporate sufficient botanical or phytochemical information on the plants or extracts studied. From the literature, there is clearly a need for multidisciplinary studies, spanning the fields of chemistry, ethnopharmacology, nutrition and physiology, in order to comprehensively evaluate how Hoodia gordonii may be optimally used for desired outcomes with minimal side-effects. In conclusion, given the severity of the adverse effects reported, and the relative absence of comprehensive data on the mechanisms responsible for these side-effects, we conclude that at this stage, the most sensible advice is for individuals to refrain from consuming Hoodia gordonii.
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