Pregnane

Pregnane

1. Identity and Chemical Classification

Pregnane (systematic IUPAC name: pregnane) is a saturated C₂₁ steroid hydrocarbon that serves as the parent skeleton from which a large and pharmacologically diverse class of natural steroids — the pregnane steroids — are defined and named. Pregnane steroids are secondary metabolites with a significant role in various biological systems; these compounds possess 21 carbons arranged in the characteristic pregnane skeleton. The pregnane framework consists of the fundamental four-ring cyclopentaperhydrophenanthrene (gonane) nucleus — three six-membered rings (A, B, C) fused to one five-membered ring (D) — with a two-carbon side chain at C-17 that distinguishes C₂₁ steroids from shorter or longer steroid series.

Removal of part of the cholesterol side chain gives rise to C₂₁ compounds of the pregnane series, which include progestins and corticosteroids. Total removal of the side chain produces C₁₉ steroids of the androstane series, including the androgens, whereas further loss of the 19-methyl group by aromatization yields the estrane series, to which estrogens belong. Within the pregnane series, two key stereochemical sub-types are recognised: the 5α-pregnane configuration (A/B-ring trans fusion) and the 5β-pregnane configuration (A/B-ring cis fusion), which differ in their three-dimensional conformations and biological activities.

The term "pregnane" in everyday dietary supplement and natural products contexts almost always refers specifically to pregnane glycosides — plant-derived secondary metabolites in which one or more sugar (deoxysugar) chains are attached, typically at the C-3 position, to an oxygenated pregnane aglycone core. Over 500 unique pregnane steroids have been isolated, showing the extraordinary chemical diversity found in plants.

1.1 Systematic Names and Synonyms of Key Members

• Pregnane (the parent hydrocarbon): 5α-pregnane or 5β-pregnane (depending on A/B-ring stereochemistry)
• Pregnenolone: pregn-5-en-3β-ol-20-one; a direct biosynthetic precursor to all other pregnane hormones
• Progesterone: pregn-4-ene-3,20-dione; the principal endogenous pregnane hormone in humans
• P57AS3 (P57): the oxypregnane steroidal glycoside found in Hoodia gordonii and the most studied plant-derived pregnane glycoside in the dietary supplement context
• Hoodigogenin A: the aglycone (sugar-free core) shared by many Hoodia pregnane glycosides, bearing a characteristic 12β-tigloyl group

2. Natural Sources

Pregnane steroids are typically derived from higher plants and often show a wide range of biological activities due to their diverse structures. Their syntheses from cholesterol are carried out through complex biosynthetic pathways, and these compounds are known for structural complexity, including multiple rings as well as functional groups and substituents.

The plant families most abundantly characterised as sources of pregnane glycosides include the Apocynaceae (formerly split into Apocynaceae and Asclepiadaceae), the Buxaceae, the Meliaceae, and others. Notable genera and species documented in peer-reviewed literature include:

• Hoodia gordonii (Apocynaceae / Asclepiadaceae): a spiny succulent plant with rows of small thorns, visible along fairly hard and fleshy, glabrous, grey-brown to grey-green stems, with a narrow geographical distribution widely spread throughout the dry, desert areas of South Africa and Namibia. This species is the principal commercial and scientific focus for pregnane glycosides in the dietary supplement industry.
• Caralluma spp. (Apocynaceae): A genus of succulent plants distributed widely across Africa, Arabia, India, and southern Europe. Phytochemical investigation of Caralluma quadrangula aerial parts alone yielded six new pregnane glycosides, in addition to nine known pregnane glycosides. Multiple species — including C. fimbriata, C. dalzielii, C. tuberculata, C. russeliana, C. hexagona, and others — have been systematically studied.
• Marsdenia spp. (Apocynaceae): Systematic investigation of several important plant species from the Dai ethnological medicine has led to the discovery of bioactive chemicals from natural sources; the roots of M. tenacissima have yielded four pregnane steroids and 16 pregnane glycosides. Marsdenia cundurango and M. tomentosa have also been studied.
• Asclepias spp. (Apocynaceae), including A. incarnata (swamp milkweed), documented as a fast-growing temperate source of pregnane glycoside-enriched extracts.
• Pachysandra terminalis (Buxaceae): Four new pregnane steroids, terminalones A–D, have been obtained from the whole herb of Pachysandra terminalis Sieb. et Zucc.
• Toona ciliata var. pubescens (Meliaceae): Five new pregnane steroids, toonasterones A and B, (Z)-aglawone, and two forms of toonasterone C, were isolated from the stem bark of Toona ciliata var. pubescens; their structures were elucidated by detailed spectroscopic analysis, and the stereochemistry was confirmed by X-ray diffraction.
• Gymnema sylvestre (Apocynaceae): Known primarily for its anti-diabetic saponins, the plant also yields C21 steroidal glycosides of the pregnane class.
• Strophanthus divaricatus (Apocynaceae): This species, widely distributed in the southern and southwestern regions of China, has been used in traditional Chinese medicine to treat vascular sclerosis, rheumatoid arthritis, snakebites, and heart failure; previous chemical investigations have demonstrated that the plants are rich sources of steroid glycosides.

The majority of secondary metabolites isolated from the subfamily Asclepiadoideae of the Apocynaceae have been characterised as pregnane glycosides containing 6-deoxy- and 2,6-dideoxy sugars; phytochemical investigations of Hoodia gordonii have shown that this class of compounds is present in this plant.

2.1 Endogenous Occurrence in Humans and Animals

Pregnane steroids are not exclusively phytochemicals; they form the backbone of major endogenous human hormones. Steroid hormones are derived from cholesterol and thus have closely related structures based on the common steroid skeleton. In humans, progesterone, cortisol, corticosterone, aldosterone, and their metabolites are all members of the pregnane series. The steroid hormones progestagens, estrogens, androgens, and glucocorticoids, as well as their precursor cholesterol, are required for successful establishment and maintenance of pregnancy and proper development of the fetus.

3. Common Forms and Preparations

In the dietary supplement market, pregnane-containing materials are sold primarily as whole-plant or concentrated extract preparations of Hoodia gordonii or Caralluma fimbriata. Analytical methods have been applied to identify pregnane glycosides across a wide variety of commercial formats including gels, capsules, tablets, sprays, teas, snack bars, powders, and juices.

Standardised extracts enriched for the oxypregnane steroidal glycoside P57 have been developed for research and commercial use. Hoodia species are slow-growing, succulent desert plants and the pregnane glycosides cannot be obtained synthetically at scale; the commercial goal has been the development of an enriched extract for use as a medicine or food supplement.

Isolated or purified individual pregnane glycosides (e.g., P57AS3, hoodigosides, gordonosides) are used in preclinical research contexts but are not commercially available to consumers as isolated compounds. Pregnane steroids used therapeutically in medicine — such as progesterone, allopregnanolone (brexanolone), and synthetic corticosteroids — exist as pharmaceutical preparations distinct from the botanical dietary supplement category.

4. Traditional and Historical Use

4.1 Southern African Indigenous Use (Hoodia gordonii)

The most extensively documented traditional use of pregnane glycoside-containing plants centers on Hoodia gordonii among the Khoisan peoples of southern Africa. Traditionally, the Khoisan people in southern Africa sucked on Hoodia stems while on long hunting trips to quench hunger and thirst. It is also said that the stems were used traditionally in the treatment of tuberculosis.

African cactiform Hoodia gordonii (Asclepiadaceae) has been used for thousands of years by Xhomani Bushmen as an anorexant during hunting trips and has been proposed as a new agent for the management of body weight. Ethnobotanical reports date to 1796, but Hoodia received little attention until a South African scientific project evaluated its appetite suppressant effects in 1963. In the 1980s, modern techniques in plant structure analysis revealed the bioactive oxypregnane steroidal glycoside P57AS3 (or P57).

Many books and articles documented the use of stapeliad species as food plants and earlier references refer to the use of Hoodia species as a thirst quencher; however, prior to the publication of the patent application, only a single reference referring to the use of Hoodia pilifera as an appetite suppressant was found. This distinction is important: traditional use appears to have been primarily as a general food-plant in conditions of scarcity, and the specific characterisation as an "appetite suppressant" is at least partly a modern, commercialised interpretation layered over ethnobotanical practice.

H. gordonii is a traditional food and medicinal plant of the Khoisan but had been patented without their prior consent. Consequently, these groups and other stakeholders challenged this lack of intellectual and financial recognition, resulting in 2004 in a belated benefit-sharing agreement — one of the first such agreements — which gave the Khoisan a share of royalties derived from the sale of products containing the patented extract.

4.2 Indian Subcontinent and Middle East Use (Caralluma spp.)

Traditional uses attributed to Caralluma quadrangula include treatment of liver diseases, diabetes, hypertension, snake venom, scorpion bite, cancer, tuberculosis, skin disorders, fever, inflammation, rheumatic arthritis, ulcers, leprosy, and as antiseptics and disinfectants, as well as to fulfill hunger and thirst. Caralluma hexagona, endemic to Yemen and Saudi Arabia, has been traditionally used to treat diabetes, abdominal pain, and stomach ulcers.

4.3 Traditional Chinese Medicine (Marsdenia tenacissima)

Systematic investigation of several important plant species from Dai ethnological medicine has led to the discovery of an array of interesting small molecules with diverse bioactivities. Strophanthus divaricatus, belonging to the Apocynaceae family, has been used in traditional Chinese medicine to treat vascular sclerosis, rheumatoid arthritis, snakebites, and heart failure.

5. Key Constituents and Active Compounds

5.1 Structural Features of Plant Pregnane Glycosides

Pregnane glycosides share a common steroid core, C-12 side chain moieties, deoxysugar moieties forming polysaccharide glycosylation patterns at the C-3 carbon, and an optional double bond between C-5 and C-6 carbons. The aglycone core in the best-studied dietary supplement species is typically a 14β-hydroxypregnanone, and the attached sugars are predominantly 2,6-dideoxysugars (such as cymarose, thevetose, and oleandrose), which are rarely found in plant sterols outside the Apocynaceae.

P57AS3 (P57), an oxypregnane steroidal glycoside, is the only reported active constituent from Hoodia gordonii as an appetite suppressant. Among the known Hoodia glycosides, 11 new oxypregnane glycosides (hoodigosides A–K) share a common aglycone moiety 12-O-β-tigloyl-3β,14β-dihydroxypregn-5-en-20-one (hoodigogenin); another study reported isolation of 10 C21-steroidal glycosides (gordonosides A–L) from a chloroform extract.

5.2 Diversity Across Genera

Plants of the Asclepiadaceae and Apocynaceae family are a rich source of pregnane and pregnane glycosides; they are found in nature either in free state or as their glycosides. They have shown antitumor, anticancer, hypoglycaemic, antioxidant, and antimicrobial activities.

The acylating group at C-12 of the aglycone strongly influences biological activity. The conversion of progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to either androstenedione or 11-deoxycortisol was most strongly affected by pregnane glycosides, with 12-cinnamoyl-, benzoyl-, and tigloyl-containing pregnanes showing the highest activity in adrenocortical cell assays — a finding with significant safety implications.

6. Biosynthesis and Mechanisms of Action

6.1 Biosynthesis in Animals

In animals, the pregnane skeleton originates from cholesterol through a tightly regulated enzymatic cascade. In animal steroidogenesis, the biosynthesis of pregnane derivatives begins with the conversion of cholesterol to pregnenolone, a C21 Δ5-pregnene steroid, catalyzed by the mitochondrial enzyme cytochrome P450 side-chain cleavage (CYP11A1, also known as P450scc). This rate-limiting reaction occurs on the inner mitochondrial membrane and involves a three-step, six-electron oxidation process: first, hydroxylation at the C-22 position to form 22R-hydroxycholesterol; second, hydroxylation at the C-20 position to yield 20R,22R-dihydroxycholesterol; and third, cleavage of the C20–C22 bond, producing pregnenolone and isocaproaldehyde as a byproduct.

Pregnenolone can be converted either to progesterone, which branches to the glucocorticoid and androgen/estrogen pathways, or to 17α-hydroxypregnenolone, which is another route for the formation of androgens and estrogens. CYP11A1 converts cholesterol to pregnenolone, followed by the HSD3B2-catalyzed conversion of pregnenolone to the Δ4 steroid, progesterone.

6.2 Proposed Mechanisms of Plant Pregnane Glycosides

Appetite Suppression — Hypothalamic ATP Pathway

P57AS3 pregnane glycoside is the only reported active constituent from H. gordonii that acts as an appetite suppressant in rodents, possibly by increasing ATP content of hypothalamic neurons. The proposed mechanism is that elevated ATP in hypothalamic neurons signals satiety, mimicking the post-prandial state. The use of the oxypregnane steroidal glycoside P57 as an appetite suppressant has been suggested as a marker of this species; P57AS3 is claimed to induce increased ATP synthesis in the hypothalamic neurons, thereby reducing appetite by giving out false satiety signals to the appetite center.

Melanocortin Pathway and BDNF

In a study using Asclepias incarnata pregnane glycoside extract in rats, the food-intake suppressive effects were found to depend on stimulation of the melanocortin signaling pathway and brain-derived neurotrophic factor (BDNF). Consumption of the pregnane glycoside-enriched extract from the fast-growing swamp milkweed Asclepias incarnata produced melanocortin receptor-mediated suppression of food intake in rats in the absence of adverse outcomes during a 90-day subchronic toxicity study.

Leptin Sensitisation

Members of the family Apocynaceae, including Caralluma spp. and Hoodia spp., contain pregnane glycosides that have been shown to restore sensitivity to the appetite suppressant hormone leptin in obese mice. This leptin-sensitising effect represents a mechanistically distinct pathway from the ATP hypothesis.

Interference with Adrenal Steroidogenesis

A critical mechanistic finding concerns the ability of plant pregnane glycosides to interfere with steroidogenic enzymes. Investigation of the effects, structure-activity relationships, and mechanism of action of pregnane glycosides on steroidogenesis in human adrenocortical H295R cells showed that administration of pregnane glycosides for 24 hours suppressed the basal and forskolin-stimulated release of androstenedione, corticosterone, and cortisone from H295R cells. Incubation of pregnane glycosides for 24 hours had no effect on mRNA transcripts of CYP11A1, CYP21A1, CYP11B1 cytochrome enzymes and steroidogenic acute regulatory protein (StAR) protein, yet resulted in a twofold decrease in HSD3B1 mRNA. This suggests that the suppression of corticosteroid production occurs post-transcriptionally, likely through enzymatic inhibition of HSD3B (3β-hydroxysteroid dehydrogenase).

Multidrug Resistance Reversal

The MDR reversal activity of newly isolated molecules, along with previously reported analogues, was screened for chemo-reversal ability against P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MCF-7/ADR cell line. This P-gp inhibitory activity suggests potential utility as adjuncts to cancer chemotherapy to overcome drug efflux-mediated resistance, though this remains preclinical only.

Antidiabetic Mechanisms

Different extracts, fractions, and main constituents of Caralluma hexagona were evaluated for their inhibitory activity against key enzymes in diabetes and hyperlipidemia — specifically α-glucosidase and pancreatic lipase — and the antioxidative effect and inhibition of advanced glycation end products (AGEs) were also assayed. Inhibition of α-glucosidase slows post-prandial glucose absorption, and inhibition of pancreatic lipase reduces dietary fat absorption — both recognised mechanisms for glycemic and weight management.

7. Scientific Evidence by Area of Use

7.1 Appetite Suppression and Weight Management

Animal Evidence

Multiple in vivo animal studies have reported anorectic effects of pregnane glycoside-enriched extracts. Controversial appetite-suppressant effects have been demonstrated in some in vivo experiments conducted on rats and chickens. The leptin-sensitising effects in obese mice noted above represent additional supporting animal-model evidence. These animal findings provided the biological rationale that drove commercial development of Hoodia products.

Human Clinical Evidence — The Key RCT

The only fully published, peer-reviewed randomised controlled trial (RCT) of Hoodia gordonii purified extract (HgPE) — the principal commercial pregnane glycoside supplement — is the 2011 Blom et al. study published in the American Journal of Clinical Nutrition. Healthy, overweight women, stratified by percentage body fat, received either HgPE (n = 25) or placebo (n = 24) for 15 days; subjects received 2 servings per day of 1,110 mg HgPE or placebo formulated in a yogurt drink 1 hour before breakfast and dinner.

There were no serious adverse events, but HgPE was less well tolerated than placebo because of episodes of nausea, emesis, and disturbances of skin sensation. Blood pressure, pulse, heart rate, bilirubin, and alkaline phosphatase showed significant (P < 0.05) increases in the HgPE group. Mean effects on ad libitum energy intakes and body weights did not differ significantly between the HgPE- and placebo-treatment groups (P > 0.05). HgPE was less well tolerated than placebo and did not show any significant effects on energy intakes or body weights relative to the placebo.

Published, peer-reviewed, randomised controlled clinical trials evaluating the efficacy of Hoodia gordonii are lacking beyond this single 15-day study. Evidence strength: weak. The sole available human RCT showed no efficacy for weight loss or energy intake reduction, and was associated with clinically significant adverse changes in cardiovascular and hepatic parameters.

Caralluma fimbriata Clinical Evidence

In a single, double-blind, placebo-controlled trial with 50 healthy volunteers receiving 1 g of Caralluma extract per day for 60 days, waist circumference and hunger showed a significant decline in the experimental group compared to the placebo after 2 months of treatment. This small trial showed some benefit for C. fimbriata, though it is a single study with limited sample size and duration. Evidence strength: preliminary; larger and longer trials are needed.

7.2 Anticancer and Antiproliferative Activity

Pregnane glycosides have been extensively tested in cancer cell-line (in vitro) models. Twenty-seven new pregnane glycosides were isolated from the whole plant of Caralluma dalzielii; all isolated compounds were tested for their antiproliferative activity on J774.A1, HEK-293, and WEHI-164 cell lines, and moderate to high potency of cytotoxicities were found in almost all tested compounds, confirming the significant cytotoxic activity of pregnane glycosides.

Seven new pregnane glycosides were isolated from the bark of Marsdenia cundurango (Asclepiadaceae); the isolated compounds were evaluated for their cytotoxic activity against HL-60 human leukemia cells, A549 human lung adenocarcinoma cells, and TIG-3 normal human lung cells, including apoptosis-inducing activity of a representative pregnane glycoside in HL-60 cells.

The structural variations of pregnane steroids contribute to diverse biological activities, including anti-inflammatory, antibacterial, antifungal, antiviral, and anticancer properties. Evidence strength: entirely preclinical (in vitro / cell line). No human clinical trials for cancer treatment exist for plant pregnane glycosides as dietary supplements. These findings cannot be extrapolated to human therapeutic efficacy.

7.3 Anti-Inflammatory Activity

Chemophenetic analysis highlighted the occurrence of seco and diseco pregnane types; both scaffolds exhibited intriguing structural features, and their derivatives have demonstrated anti-inflammatory and cytotoxic activities. Various Caralluma species have been studied for anti-inflammatory effects in animal and cell models. Evidence strength: preclinical only; no adequate human RCTs specifically targeting inflammation with isolated pregnane glycosides.

7.4 Antidiabetic and Antihyperlipidaemic Activity

In vitro inhibition of α-glucosidase and pancreatic lipase has been demonstrated for Caralluma hexagona pregnane glycosides. The genus Caralluma has been attributed significant therapeutic activities, including antioxidant, antidiabetic, anticancer, antimicrobial, anti-malarial, anti-inflammatory, and antieczema properties. Evidence strength: preclinical (in vitro enzyme assays); limited animal model data; no adequate human trials specific to pregnane glycosides in diabetes management.

7.5 Multidrug Resistance Reversal in Cancer Chemotherapy

From the roots of Marsdenia tenacissima, four pregnane steroids and 16 pregnane glycosides were separated and identified. All the isolates, along with an array of previously reported analogues in a compound library, were screened for their chemo-reversal ability against P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MCF-7/ADR cell line. Six compounds showed notable MDR reversal activity. Evidence strength: preclinical cell-line data only. No human clinical trials have validated pregnane glycosides from supplements as MDR reversal agents.

8. Body Systems and Health Areas Associated with Pregnane

• Endocrine system: Pregnane steroids are central to the hypothalamic–pituitary–adrenal (HPA) axis, hypothalamic–pituitary–gonadal (HPG) axis, and placental steroidogenesis. Plant pregnane glycosides interact with adrenocortical steroidogenic enzymes.
• Hypothalamus / appetite regulation: The proposed ATP-hypothalamic and melanocortin/BDNF-mediated mechanisms of P57 and related glycosides place pregnane glycoside activity centrally in the hypothalamic appetite-regulation system.
• Metabolic system: Proposed antidiabetic (α-glucosidase inhibition), antihyperlipidaemic (pancreatic lipase inhibition), and anti-obesity effects link pregnane glycosides to metabolic disease pathways.
• Oncology: In vitro cytotoxic, pro-apoptotic, and MDR reversal activities have been identified across multiple cancer cell lines.
• Immune and inflammatory system: Anti-inflammatory activities have been documented in animal and cell models.
• Liver: The observed elevation of bilirubin and alkaline phosphatase in the human RCT raises hepatic safety questions for concentrated extracts.
• Cardiovascular system: Elevated blood pressure, pulse, and heart rate documented in the sole human RCT.

9. Dosage Forms and Dosages Reported in Studies

The following dosages are reported directly from identified sources and are not recommendations:

• Human RCT (Blom et al., 2011 — Hoodia gordonii purified extract): Subjects received 2 servings per day of 1,110 mg HgPE (Hoodia gordonii purified extract) or placebo formulated in a yogurt drink 1 hour before breakfast and dinner, for 15 days. Total daily dose: 2,220 mg of purified extract.
• Human trial (Caralluma extract): Fifty healthy volunteers received 1 g of Caralluma extract per day for 60 days in a double-blind, placebo-controlled trial.
• Animal toxicity study (rat gavage — Asclepias incarnata extract): The no-observable adverse effect level (NOAEL) for pregnane glycoside-enriched extract administered daily via oral gavage to rats was estimated at 40 mg/kg/day; a transitional increase in adrenal cortex vacuolization was observed in males given 50 mg/kg/day of the extract, which returned to normal during the recovery phase.
• Animal pharmacokinetics study (P57, mouse): Bioavailability, pharmacokinetics, and tissue distribution of P57 were determined in CD1 female mice after administration of a single dose of enriched methanolic extract of Hoodia gordonii (equivalent to a dose of 25 mg of P57/kg) by oral gavage, or a single dose of purified P57 (25 mg/kg) intravenously.

No standardised clinically validated dosage for pregnane glycosides as dietary supplements has been established. The commercial product market uses varying and often unvalidated dosages.

10. Safety Considerations and Interactions

10.1 Cardiovascular Adverse Effects

Blood pressure, pulse, heart rate, bilirubin, and alkaline phosphatase showed significant (P < 0.05) increases in the HgPE group; in comparison with a matched placebo, the consumption of HgPE for 15 days appeared to be associated with significant adverse changes in some vital signs and laboratory parameters. It is possible that a group of compounds other than pregnane glycosides may be responsible for the reported side effects or for the appetite suppressant activity of H. gordonii. The potential contribution of sympathomimetic compounds in the complex plant extract to cardiovascular effects has been proposed.

10.2 Gastrointestinal Tolerability

HgPE was less well tolerated than was the placebo because of episodes of nausea, emesis, and disturbances of skin sensation in the only published human RCT at the studied dose.

10.3 Adrenal and Endocrine Disruption

This is a particularly important mechanistically grounded safety concern. While the NOAEL for pregnane glycoside-enriched extract administered daily via oral gavage to rats was estimated at 40 mg/kg/day, a transitional increase in incidence and severity of vacuolization of the adrenal cortex was observed in males given 50 mg/kg/day, which returned to normal during the recovery phase. In human adrenocortical cell studies, administration of pregnane glycosides for 24 hours suppressed the basal and forskolin-stimulated release of androstenedione, corticosterone, and cortisone from H295R cells. This in vitro evidence of adrenocortical steroidogenesis suppression — combined with the animal finding of adrenal cortex vacuolisation — suggests that chronic or high-dose consumption of pregnane glycoside-rich extracts may pose risks to adrenal function.

10.4 Hepatic Parameters

A repeated-measures ANCOVA showed that total bilirubin concentrations were significantly (P < 0.05) higher from days 2 to 17 (mean difference ranging from 0.20 to 0.58 mg/dL) in the HgPE group than in the placebo group in the 2011 human RCT. Alkaline phosphatase was also elevated. These findings were described as clinically significant changes warranting caution, though no frank hepatotoxicity was reported in that short study.

10.5 Product Adulteration

In October 2011, the FDA notified consumers that the "P57 Hoodia" product marketed by Huikng Pharmaceutical was found to contain sibutramine, a controlled substance that was removed from the U.S. market in October 2010 for safety reasons. Sibutramine may substantially increase blood pressure and/or pulse rate in some patients and may present a significant risk for patients with a history of coronary artery disease, congestive heart failure, arrhythmia, or stroke.

Actual amounts of hoodia in advertised products cannot always be confirmed, and products may be counterfeit or contaminated. 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.

10.6 Regulatory Status

The Hoodia gordonii commercial powder, a native plant of Africa with purported appetite inhibitory action attributed to the active glycoside P57, was sold freely until its ban by the Brazilian National Sanitary Surveillance Agency (ANVISA) in February 2007 because of the absence of scientific proofs of its efficacy and safety. Despite the apparent lack of extensive clinical research and toxicological evaluations, Hoodia-containing remedies remain one of the most popular dietary pills on the loosely regulated US botanical dietary supplement market.

10.7 Conservation and Authenticity Concerns

Hoodia species are slow-growing, succulent desert plants, and the pregnane glycosides cannot be obtained synthetically at commercial scale. Hoodia species are protected in South Africa, affecting commercialization and cultivation efforts. These constraints have driven a market in adulterated or mislabelled products in which claimed Hoodia content may be absent or substituted with other materials.

11. Summary of Evidence Quality

The scientific evidence base for pregnane glycosides as dietary supplements can be summarised as follows: the chemistry and phytochemistry are well characterised across dozens of peer-reviewed studies; preclinical (in vitro and animal) evidence for appetite-suppressive, cytotoxic, anti-inflammatory, and antidiabetic effects is substantial but cannot be directly extrapolated to humans; and the clinical evidence base is extremely limited. The single adequately powered human RCT of Hoodia gordonii purified extract found no efficacy for appetite suppression or weight loss and documented significant adverse cardiovascular and hepatic changes. One small pilot RCT of Caralluma fimbriata suggested reduction in waist circumference and self-reported hunger. No clinical trials have validated isolated pregnane glycosides for cancer, inflammation, or metabolic disease in humans. The role of P57 specifically — as the purported "active" molecule — has been questioned by researchers, as the full chemical complexity of these plant extracts is not yet mapped and other constituents may contribute to observed effects, including adverse ones.

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