An Evidence-Based Systematic Review of Gymnema ( Gymnema sylvestre R. Br.) by the Natural Standard Research Collaboration

Abstract

An evidence-based systematic review of gymnema (Gymnema sylvestre R. Br.), including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Full text

Journal of Dietary Supplements, 8(3):311–330, 2011
C
2011 by Informa Healthcare USA, Inc.
Available online at www.informahealthcare.com/jds
DOI: 10.3109/19390211.2011.597977
An Evidence-Based Systematic Review of
Gymnema (Gymnema sylvestre R. Br.) by the
Natural Standard Research Collaboration
Catherine Ulbricht, PharmD1, Tracee Rae Abrams, PharmD2, Ethan Basch, MD3,
Theresa Davies-Heerema, PhD4, Ivo Foppa, MD, ScD5, Paul Hammerness, MD6,
Erica Rusie, PharmD3, Shaina Tanguay-Colucci, BS3, Sarah Taylor, PharmD7,
Catherine Ulbricht, PharmD, MBA[c]1, Minney Varghese, BS8,
Wendy Weissner, BA3, & Jen Woods, BS3
1Massachusetts General Hospital, Boston, Massachusetts, 2University of Rhode Island,
Rhode Island, 3Natural Standard Research Collaboration, Somerville, Massachusetts,
4Boston School of Medicine, Boston, Massachusetts, 5University of South Carolina,
Columbia, South Carolina, 6Harvard Medical School, Boston, Massachusetts,
7University of Pittsburgh, Pittsburgh, Pennsylvania, 8Northeastern University,
Boston, Massachusetts
ABSTRACT. An evidence-based systematic review of gymnema (Gymnema sylvestre
R. Br.), including written and statistical analysis of scientic literature, expert opinion,
folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse ef-
fects, toxicology, and dosing.
KEYWORDS. Adverse effects, dosing, evidence-based, gymnema (Gymnema
sylvestre R. Br.), interactions, pharmacodynamics, pharmacokinetics, pharmacology,
systematic review
SYSTEMATIC AGGREGATION, ANALYSIS, AND REVIEW OF THE
LITERATURE
Search Strategy
To prepare this Natural Standard review, electronic searches were conducted
in several databases (including AMED, CANCERLIT, CINAHL, CISCOM, the
Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts,
Medline, and NAPRALERT) from inception to February 2008. Search terms in-
cluded the common name(s), scientic name(s), and all listed synonyms. Hand
searches were conducted of 20 additional journals (not indexed in common
Natural Standard Systematic Review (www.naturalstandard.com) Copyright ©2011.
Address correspondence to: Catherine Ulbricht, PharmD, Natural Standard, 1 Davis Square, Somerville, MA
02144, USA (E-mail: ulbricht@naturalstandard.com).
311

312 Ulbricht et al.
databases) and of bibliographies from 50 selected secondary references. No restric-
tions were placed on language or quality of publications. Researchers in the eld
of complementary and alternative medicine (CAM) were consulted for access to
additional references or ongoing research.
Selection Criteria
All literature was collected pertaining to efcacy in humans (regardless of study
design, quality, or language), dosing, precautions, adverse effects, use in preg-
nancy/lactation, interactions, alteration of laboratory assays, and mechanism of ac-
tion (in vitro, animal research, and human data). Standardized inclusion/exclusion
criteria were utilized for selection.
Data Analysis
Data extraction and analysis were performed by healthcare professionals conduct-
ing clinical work and/or research at academic centers, using standardized instru-
ments that pertained to each review section (dening inclusion/exclusion criteria
and analytic techniques, including validated measures of study quality). Data were
veried by a second reviewer.
Review Process
A blinded review was conducted by multidisciplinary research-clinical faculty at
major academic centers with expertise in epidemiology and biostatistics, pharma-
cology, toxicology, CAM research, and clinical practice. In cases of editorial dis-
agreement, a three-member panel of the Editorial Board addressed conicts, and
consulted experts when applicable. Authors of studies were contacted when clari-
cation was required.
Synonyms/Common Names/Related Substances
•Asclepiadaceae (family), Asclepias geminata Roxb., Gemnema melicida, GS4
(water-soluble extract of the leaves), gur-mar, gurmar, gurmarbooti, Gymnema
inodum,Gymnema montanum,Gymnema sylvestre, kogilam, madhunashini,
mangala gymnema, merasingi, meshashringi, meshavalli, miracle plant, periploca
of the woods, Periploca sylvestris, podapatri, Proβeta, ram’s horn, sarkaraikolli,
shardunika, sirukurinja, small Indian ipecac, vishani.
CLINICAL BOTTOM LINE/EFFECTIVENESS
Brief Background
•Gymnema leaves have been used for more than 2,000 years in India to treat
madhu meha or “honey urine.” It has been used alone and as a component of
the Ayurvedic medicinal compound, “Tribang shila,” a mixture of tin, lead, zinc,
Gymnema sylvestre leaves, neem leaves (Melia azadirachta), Enicostemma lit-
torale, and jambul seeds (Eugenia jambolana).
•Preliminary human evidence suggests that gymnema may be efcacious for the
management of serum glucose levels in type 1 and type 2 diabetes, as an adjunct
to conventional drug therapy, for up to 20 months. Gymnema appears to lower
serum glucose and glycosylated hemoglobin (HbA1c) levels following chronic

Systematic Review of Gymnema (Gymnema sylvestre R. Br.) 313
use but may not have signicant acute effects (Baskaran et al., 1990). Some of
the available research has been conducted by authors afliated with manufac-
turers of gymnema products. High-quality human trials are lacking in this area
(Cicero, Derosa, & Gaddi, 2004; Grover, Yadav, & Vats, 2002; Shapiro & Gong,
2002).
•There is also early evidence suggesting possible efcacy of gymnema as a lipid-
lowering agent. Gymnema was shown in one study to possess antimicrobial action
against Bacillis pumilis,B.subtilis,Pseudomonas aeruginosa,andStaphylococcus
aureus but not against E.coli and Proteus vulgaris (Satdive, Abhilash, & Fulzele,
2003).
•One of the major side effects or actions of gymnema is taste alteration. Studies
have shown that gymnema reduces the perception of sweetness inside the mouth
and seems to increase the perception of bitterness by neural inhibition (Brala &
Hagen, 1983; Lawless, 1979; Meiselman & Halperin, 1970; Meiselman & Halpern,
1970; Min & Sakamoto, 1998; Simons, O’Mahony, & Carstens, 2002; Warren, War-
ren, & Weninger, 1969).
Scientic Evidence
Type 1 diabetes mellitus B
Type 2 diabetes mellitus B
Natural Standard Evidence-Based Validated Grading RationaleTM
•Grades reect the level of available scientic evidence in support of the efcacy
of a given therapy for a specic indication.
•Expert opinion and historic/folkloric precedent are not included in this assess-
ment and are reected in a separate section of each review (“Expert Opinion
and Historic/Folkloric Precedent”).
•Evidence of harm is considered separately; the below grades apply only to evi-
dence of benet.
Level of Evidence Grade Criteria
A (strong scientific
evidence)
Statistically significant evidence of benefit from >2 properly randomized trials
(RCTs), OR evidence from one properly conducted RCT AND one properly
conducted meta-analysis, OR evidence from multiple RCTs with a clear
majority of the properly conducted trials showing statistically significant
evidence of benefit AND with supporting evidence in basic science, animal
studies, or theory.
B (good scientific
evidence)
Statistically significant evidence of benefit from 1–2 properly randomized
trials, OR evidence of benefit from >1 properly conducted meta-analysis
OR evidence of benefit from >1 cohort/case-control/non-randomized trials
AND with supporting evidence in basic science, animal studies, or theory.
C (unclear or conflicting
scientific evidence)
Evidence of benefit from >1 small RCT(s) without adequate size, power,
statistical significance, or quality of design by objective criteria,∗OR
conflicting evidence from multiple RCTs without a clear majority of the
properly conducted trials showing evidence of benefit or ineffectiveness,
OR evidence of benefit from >1 cohort/case-control/non-randomized trials
AND without supporting evidence in basic science, animal studies, or
theory, OR evidence of efficacy only from basic science, animal studies, or
theory.

314 Ulbricht et al.
Level of Evidence Grade Criteria
D (fair negative scientific
evidence)
Statistically significant negative evidence (i.e., lack of evidence of benefit)
from cohort/case-control/non-randomized trials, AND evidence in basic
science, animal studies, or theory suggesting a lack of benefit.
F (strong negative scientific
evidence)
Statistically significant negative evidence (i.e. lack of evidence of benefit)
from >1 properly randomized adequately powered trial(s) of high-quality
design by objective criteria.∗
Lack of evidence†Unable to evaluate efficacy due to lack of adequate available human data.
∗Objective criteria are derived from validated instruments for evaluating study quality, including the 5-point scale
developed by Jadad et al. (1996), in which a score below 4 is considered to indicate lesser quality methodologically.
†Listed separately in the “Historical or Theoretical Uses That Lack Sufficient Evidence” section.
Historical or Theoretical Uses That Lack Sufcient Evidence
•Allergy, antioxidant, antimicrobial (Satdive et al., 2003), aphrodisiac, cancer, car-
diovascular disease, constipation, cough, dental caries, digestive stimulant, di-
uresis, gout (Shimizu et al., 1997), hepatoprotection, hypertension (Preuss et al.,
1995, 1998), laxative, liver disease, malaria, metabolic disorders, obesity, rheuma-
toid arthritis (Shimizu et al., 1997), snake venom antidote (Kothe & Uppal, 1997),
stomach ailments, uterine stimulant, viral infection.
Expert Opinion and Historic/Folkloric Precedent
•Gymnema leaves have been used for more than 2,000 years in India to treat
madhu meha or “honey urine.” It has been used alone and as a component of
the Ayurvedic medicinal compound, “Tribang shila,” a mixture of tin, lead, zinc,
Gymnema sylvestre leaves, neem leaves (Melia azadirachta), Enicostemma lit-
torale, and jambul seeds (Eugenia jambolana). Traditional healers observed that
chewing the leaves of gymnema resulted in a reversible loss of sweet-taste per-
ception.
•The plant has also been used in African healing traditions; for example, Tanza-
nian healers used it as an aphrodisiac. Other traditional applications include use
as an antimalarial agent, digestive stimulant, laxative, diuretic, and snake venom
antidote.
Brief Safety Summary
•Possibly unsafe: When used in patients taking other hypoglycemic agents, be-
cause of possible potentiation of effects. Hypoglycemic effects associated with
gymnema have been noted in both diabetic and nondiabetic individuals (Khare,
Tondon, & Tewari, 1983). When used in patients taking weight loss agents be-
cause there may be a potential for additive effects (Preuss et al., 2005).
DOSING/TOXICOLOGY
General
•Listed doses are based on those most commonly used in available trials, on histor-
ical practice, or on manufacturer recommendations. However, with natural prod-
ucts, it is often not clear what the optimal doses are to balance efcacy and safety.

Systematic Review of Gymnema (Gymnema sylvestre R. Br.) 315
Preparation of products may vary from manufacturer-to-manufacturer and from
batch-to-batch within one manufacturer. Because it is often not clear what the
active components of a product are, standardization may not be possible and the
clinical effects of different brands may not be comparable.
Standardization
•At least one manufacturer offers an extract of gymnema standardized to 25%
gymnemic acid, but this extract has not yet been clinically evaluated.
•An ethanolic acid-precipitated extract from gymnema, labeled GS4, has been
used in human trials (Baskaran et al., 1990; Shanmugasundaram, Rajeswari, et al.,
1990). GS4 has since been patented as the product Proβeta, by a research team
who has conducted some of the research in this area. According to the makers
of Proβeta, the preparation is standardized to possess a specic biological result,
as measured by a test developed by the company that evaluates “pancreotropic”
effects.
•Examples of other standardized commercially available products include Beta
Fast GXR (Informulab, Omaha, NE, USA), 400 mg standardized to 25% gym-
nemic acids; Gymnesyl (Nature’s Herbs, Twinlab, American Fork, UT, USA), ex-
tract standardized for 150 mg of crude gymnemic acids; and Gymnema (Nature’s
Way, Lehi, UT, USA), 260 mg standardized to 75% gymnemic acids.
Dosing
Adult (age ≥18)
Oral
•Hyperlipidemia: In one study, patients with type 2 diabetes mellitus received 400
mg of gymnema extract for 18–20 months (Baskaran et al., 1990).
•Type 1 diabetes: GS4 (200 mg) has been taken orally, twice daily (Shanmuga-
sundaram, Rajeswari, et al., 1990), under careful continuation of insulin. Doses
of insulin or other concomitant hypoglycemic drugs may have to be adjusted or
discontinued under the supervision of a healthcare professional.
•Type 2 diabetes: GS4 (200 mg) has been taken orally, twice daily (Baskaran et al.,
1990), or 2 ml of an aqueous decoction (10 g shade-dried powdered leaves per 100
ml), three times daily (Khare et al., 1983). Doses of insulin or other concomitant
hypoglycemic drugs may have to be adjusted or discontinued under the supervi-
sion of a healthcare professional. Six to fteen drops of Gymnema sylvestre “Q”
with 1/4 cup of water has been taken two to four times daily for 6 months (Kothe
& Uppal, 1997).
•Weight loss:Gymnema sylvestre extract (GSE; 400 mg) has been studied in com-
bination with a water-soluble, calcium-potassium salt of (−)-hydroxycitric acid
(HCA-SX) (4,667 mg), and niacin-bound chromium (NBC; 4 mg) (Preuss et al.,
2005).
•Note: The manufacturer PharmaTerra recommends the dose for their product
Proβeta (GS4) to be two 250 mg capsules taken twice daily at mealtimes (for
adults weighing >100 pounds) or one 250 mg capsule taken twice daily at meal-
times (for adults weighing <100 pounds).

316 Ulbricht et al.
Children (age <18)
•Insufcient available evidence.
Toxicology
•Insufcient available evidence.
ADVERSE EFFECTS/PRECAUTIONS/CONTRAINDICATIONS
Allergy
•There is a lack of allergy/hypersensitivity to gymnema reported in the available
literature. In theory, allergic cross-reactivity may occur to members of the Ascle-
piadaceae (milkweed) family.
Adverse Effects
•General: Aside from hypoglycemia and potentiation of the effects of hypo-
glycemic drugs following chronic use of gymnema, no clinically signicant ad-
verse effects have been associated with oral gymnema in the available literature,
in studies up to 20 months in duration.
•Endocrine: Multiple animal studies have reported hypoglycemic effects asso-
ciated with ingestion of gymnema leaves. Gymnema reduced hyperglycemia in
experimentally and spontaneously diabetic rats and rabbits (Chattopadhyay,
1998; Gupta & Variyar, 1964; Okabayashi et al., 1990; Shanmugasundaram
et al., 1983; Shanmugasundaram, Gopinath, et al., 1990; Shanmugasundaram,
Rajeswari, et al., 1990; Srivastava et al., 1985; Tominaga et al., 1995), as well as in
normal and diabetic humans (Baskaran et al., 1990; Khare et al., 1983; Kothe &
Uppal, 1997; Shanmugasundaram, Gopinath, et al., 1990; Shanmugasundaram,
Rajeswari, et al., 1990). One subject with brittle diabetes had to discontinue
gymnema in a clinical trial due to repeated hypoglycemic episodes (Shanmu-
gasundaram, Rajeswari, et al., 1990). Hypoglycemic effects have been noted in
both diabetic and nondiabetic individuals (Khare et al., 1983).
•Oral (taste effects): Gymnema has been reported to possess a sweet-taste-
suppressing effect, attributed to the peptide gurmarin (Brala & Hagen, 1983;
Imoto et al., 1991; Kamei et al., 1992; Koch, Desaiah, & Cutkomp, 1973; Lawless,
1979). Historically, this phenomenon has been observed, prompting the Hindi
name gurmar or “sugar destroyer.”
Precautions/Warnings/Contraindications
•Use cautiously in diabetic patients using hypoglycemic medications, due to possi-
ble potentiation of effects. Serum glucose levels should be monitored, and doses
of concomitant hypoglycemic drugs may require adjustment under the supervi-
sion of a healthcare professional. Hypoglycemia may also occur in nondiabetic
patients (Khare et al., 1983).
•Use cautiously in patients taking weight loss agents because there may be a po-
tential for additive affects. GSE has been used in combination with other weight
loss agents (hydroxycitric acid and NBC), although a mechanism of action is un-
clear (Preuss et al., 2005).

Systematic Review of Gymnema (Gymnema sylvestre R. Br.) 317
•Use cautiously in patients taking antilipemic agents because there may be a
potential for additive effects. Reductions in levels of serum triglycerides, total
cholesterol, very low-density lipoprotein (VLDL), and low-density lipoprotein
(LDL) have been observed in animals following administration of gymnema
(Bishayee & Chatterjee, 1994; Terasawa, Miyoshi, & Imoto, 1994).
Pregnancy and Lactation
•Not recommended due to insufcient available safety information.
INTERACTIONS
Gymnema/Drug Interactions
•Antidiabetic agents: Gymnema may potentiate the effects of hypoglycemic drugs
in diabetic patients (Baskaran et al., 1990; Shanmugasundaram, Gopinath, et al.,
1990a; Shanmugasundaram, Rajeswari, et al., 1990). Doses of such medications
may therefore need adjustment. Serum glucose levels should be monitored,
and doses of concomitant hypoglycemic drugs may require adjustment under
the supervision of a healthcare professional. Multiple animal studies have
reported hypoglycemic effects associated with the ingestion of gymnema leaves.
Gymnema reduced hyperglycemia in experimentally and spontaneously diabetic
rats and rabbits (Chattopadhyay, 1998; Gupta & Variyar, 1964; Okabayashi et
al., 1990; Shanmugasundaram et al., 1983; Shanmugasundaram, Gopinath, et
al., 1990; Shanmugasundaram, Rajeswari, et al., 1990; Srivastava et al., 1985;
Tominaga et al., 1995), as well as in normal and diabetic humans (Baskaran et al.,
1990; Khare et al., 1983; Kothe & Uppal, 1997; Shanmugasundaram, Gopinath,
et al., 1990; Shanmugasundaram, Rajeswari, et al., 1990).
•Antilipemic agents: Reductions in levels of serum triglycerides, total cholesterol,
VLDL, and LDL have been observed in animals following administration of
gymnema (Bishayee & Chatterjee, 1994; Terasawa et al., 1994). A study of gym-
nema in type 2 diabetes patients reported decreased cholesterol and triglyceride
levels as a secondary outcome (Baskaran et al., 1990). Concomitant use of gym-
nema with other lipid-lowering agents may potentiate these effects.
•Antiobesity agents: Human study has investigated GSE (400 mg) in combination
with other agents for obesity, although a mechanism of action is unclear (Preuss
et al., 2005).
Gymnema/Herb/Supplement Interactions
•Antilipemics: Reductions in levels of serum triglycerides, total cholesterol,
VLDL, and LDL have been observed in animals following administration of
gymnema (Bishayee & Chatterjee, 1994; Terasawa et al., 1994). A study of gym-
nema in type 2 diabetes patients reported decreased cholesterol and triglyceride
levels as a secondary outcome (Baskaran et al., 1990). Concomitant use of gym-
nema with other lipid-lowering agents may potentiate these effects.
•Antiobesity herbs and supplements: Human study has investigated GSE (400 mg)
in combination with other agents for obesity, although a mechanism of action is
unclear (Preuss et al., 2005).

318 Ulbricht et al.
•Appetite suppressants: Human study has investigated GSE (400 mg) in combi-
nation with other agents for obesity, although a mechanism of action is unclear
(Preuss et al., 2005).
•Chromium: Human study has investigated GSE (400 mg) in combination with
niacin bound chromium, although a mechanism of action is unclear (Preuss et al.,
2005).
•Fat-soluble vitamins: In an animal study, absorption of oleic acid (a fatty acid)
was decreased by gymnema (Wang et al., 1998). It is unknown whether gymnema
exerts these effects in humans or affects the absorption of other nutritionally
important lipids or fat-soluble vitamins (A, D, E, K).
•Garcinia: Human study has investigated GSE (400 mg) in combination with hy-
droxycitric acid, a component of garcinia (Preuss et al., 2005).
•Hypoglycemics: Gymnema may potentiate the effects of hypoglycemic herbs or
supplements in diabetic patients (Baskaran et al., 1990; Shanmugasundaram,
Gopinath, et al., 1990; Shanmugasundaram, Rajeswari, et al., 1990). Doses of
these agents may therefore need adjustment. Serum glucose levels should be
monitored, and doses of concomitant hypoglycemic agents may require adjust-
ment under the supervision of a healthcare professional. Multiple animal studies
have reported hypoglycemic effects associated with ingestion of gymnema leaves.
Gymnema reduced hyperglycemia in experimentally and spontaneously diabetic
rats and rabbits (Chattopadhyay, 1998; Gupta & Variyar, 1964; Okabayashi et al.,
1990; Shanmugasundaram et al., 1983; Shanmugasundaram, Gopinath, et al.,
1990; Shanmugasundaram, Rajeswari, et al., 1990; Srivastava et al., 1985; Tom-
inaga et al., 1995), as well as in normal and diabetic humans (Baskaran et al.,
1990; Khare et al., 1983; Kothe & Uppal, 1997; Shanmugasundaram, Gopinath,
et al., 1990; Shanmugasundaram, Rajeswari, et al., 1990).
Gymnema/Food Interactions
•Fatty foods: In an animal study, absorption of oleic acid (a fatty acid) was de-
creased by gymnema (Wang et al., 1998). It is unknown whether gymnema exerts
these effects in humans or affects the absorption of other nutritionally important
lipids or fat-soluble vitamins (A, D, E, K).
Gymnema/Lab Interactions
•Blood glucose, glycosylated hemoglobin (HbA1c): On the basis of animal re-
search and preliminary human data, ingestion of gymnema may cause hypo-
glycemia in diabetic patients and reductions over time in HbA1c levels (Baskaran
et al., 1990; Chattopadhyay, 1998; Gupta & Variyar, 1964; Khare et al., 1983;
Kothe & Uppal, 1997; Okabayashi et al., 1990; Shanmugasundaram et al., 1983;
Shanmugasundaram, Gopinath, et al., 1990; Shanmugasundaram, Rajeswari, et
al., 1990; Srivastava et al., 1985; Tominaga et al., 1995). Hypoglycemic effects have
been noted in patients without diabetes as well as in patients with diabetes (Khare
et al., 1983).
•Lipid panel: In a small human study, patients with type 2 diabetes taking gym-
nema in addition to oral hypoglycemic drugs experienced reductions in choles-
terol, triglycerides, and free fatty acids, while subjects taking oral hypoglycemic
agents alone did not (Baskaran et al., 1990). Serum triglycerides, total cholesterol,

Systematic Review of Gymnema (Gymnema sylvestre R. Br.) 319
VLDL, and LDL cholesterol-lowering effects have been observed in animals
(Bishayee & Chatterjee, 1994; Terasawa et al., 1994). The mechanism of this effect
may be via decreased cholesterol synthesis, increased cholesterol metabolism, or
decreased fat absorption (Wang et al., 1998).
MECHANISM OF ACTION
Pharmacology
•Constituents: Few studies have closely evaluated the constituents of Gymnema
sylvestre leaf. Proposed active components include gurmarin, conduritol A, and
triterpene glycosides (Persaud, Al Majed, Raman, & Jones, 1999; Sinsheimer,
Rao, & McIlhenny, 1970; Yoshikawa et al., 1997). Gymnemoside b (Yoshikawa et
al., 1997) and gymnema acid V and VII appear to be the key saponin constituents
(Murakami et al., 1996).
•Antimicrobial effects: In one study, gymnema was shown to possess antimicrobial
action against Bacillis pumilis,B. subtilis,Pseudomonas aeruginosa,andStaphy-
lococcus aureus but not against E.coli and Proteus vulgaris (Satdive et al., 2003).
•Hypoglycemic effects: Multiple animal studies have reported hypoglycemic
effects associated with the ingestion of gymnema leaves. Gymnema reduced
hyperglycemia in experimentally and spontaneously diabetic rats and rabbits
(Chattopadhyay, 1998; Gupta & Variyar, 1964; Okabayashi et al., 1990; Shanmu-
gasundaram et al., 1983; Shanmugasundaram, Gopinath, et al., 1990; Srivastava
et al., 1985; Tominaga et al., 1995), as well as in normal and diabetic humans
(Ananthan, Baskar, et al., 2003; Ananthan, Latha, et al., 2003; Baskaran et al.,
1990; Gholap & Kar, 2003; Jiang, 2003; Khare et al., 1983; Kothe & Uppal,
1997; Porchezhian & Dobriyal, 2003; Satdive et al., 2003; Shanmugasundaram,
Gopinath, et al., 1990; Shanmugasundaram, Rajeswari, et al., 1990; Xie et al.,
2003). Gymnema may act by enhancing insulin secretion through increased
pancreatic β-cell number and improved cell function (Preuss et al., 1998; Shan-
mugasundaram, Gopinath, et al., 1990; Shanmugasundaram, Rajeswari, et al.,
1990). However, insulin resistance was not improved by gymnema in one animal
model of diabetes (Tominaga et al., 1995). Other proposed mechanisms include
stimulation of the release of endogenous insulin (Baskaran et al., 1990; Persaud
et al., 1999) via interactions with insulinotropic enteric hormones or increases in
glucose utilization (Shanmugasundaram et al., 1983). Such activities may explain
the observed hypoglycemic effects in type 2 diabetics. Gymnema has also been
reported to restore levels of glycoproteins in diabetic rats to normal, thereby
potentially preventing diabetic microangiopathy and other pathological organ
changes (Rathi, Visvanathan, & Shanmugasundaram, 1981).
•Lipid effects: Serum triglycerides, total cholesterol, VLDL, and LDL cholesterol-
lowering effects have been observed in animals (Bishayee & Chatterjee, 1994;
Terasawa et al., 1994). The mechanism may by via a decrease in the synthesis
or increase in the metabolism of cholesterol, or through decreased intestinal fat
absorption (Wang et al., 1998).
•Taste effects: Gymnema has been reported to possess a sweet-taste-suppressing
effect, attributed to the peptide gurmarin (Brala & Hagen, 1983; Imoto et al.,

320 Ulbricht et al.
1991; Kamei et al., 1992). This effect may result from interference with Na+/K+
ATPase activity of taste receptors (Koch et al., 1973) or from neural inhibition
(Lawless, 1979). Historically, this phenomenon has been observed, prompting the
Hindi name gurmar or “sugar destroyer.”
•Saponin I and the sodium salt of alternoside II (4) from gymnema exhibited an-
tisweet activity (Ye, Liu, Zhang, Che, & Zhao, 2001).
•Weight loss effects: Human study has investigated GSE (400 mg) in combination
with other agents for weight loss; however, the exact mechanism of action involv-
ing gymnema is unclear (Preuss et al., 2005).
Pharmacodynamics/Kinetics
•Absorption: In one small human study, it was reported that oral administration of
gymnema did not have acute effects on fasting serum glucose levels (after 45 min;
Baskaran et al., 1990)
HISTORY
•Gymnema sylvestre is a woody, climbing plant native to India. The leaves are most
commonly used medicinally, although the stem is also believed to possess some
pharmacological action. The leaves have been used for over 2,000 years in India
to treat madhu meha or “honey urine.” Chewing the leaves was noted to diminish
the ability to discriminate sweet tastes, which along with hypoglycemic properties
may have prompted the Hindi name gurmar or “sugar destroyer.” Gymnema has
a long history of use in individuals with diabetes.
•Extracts of gymnema are widely used in Australian, Japanese, Vietnamese, and
Indian folk medicine. Gymnema preparations modulate taste, particularly sup-
pressing sweet taste sensations, and are used in the treatment of diabetes mel-
litus and in food additives against obesity and caries. Gymnema has become a
popular natural product used in the management of blood sugar levels in indi-
viduals with diabetes and is believed by some to play a role in reducing serum
lipids (Porchezhian & Dobriyal, 2003).
EVIDENCE TABLE
Condition
•Refers to the medical condition or disease targeted by a therapy.
Study Design
Common types include the following:
•Randomized controlled trial (RCT): An experimental trial in which participants
are assigned randomly to receive either an intervention being tested or placebo.
Note that Natural Standard denes RCTs asbeing placebo controlled, while stud-
ies using active controls are classied as equivalence trials (see below). In RCTs,
participants and researchers are often blinded (i.e., unaware of group assign-
ments), although unblinded and quasi-blinded RCTs are also often performed.

Condition
Treated (Primary
or Secondary
Outcome)
Evidence/Study
Type Author, Year N
Statistically
Significant
Results?
Quality of Study:
0–2 =poor 3–4
=good 5 =
excellent
Magnitude of
Benefit (How
Strong is the
Effect?)
Absolute
Risk
Reduc-
tion
Number of
Patients
Needed to
Treat for One
Outcome Comments
Type 1 diabetes Controlled trial,
nonrandom-
ized,
nonblinded
Shanmugasundaram,
Rajeswari, et al.,
1990
64 Yes 0 Large 59% 2 GS4 (gymnema) plus insulin
vs. insulin alone, 11
dropouts, 40
nondiabetics also
studied, author affiliated
with manufacturer.
Type 2 diabetes Before and after
study, nonran-
domized,
nonblinded
Baskaran et al., 1990 47 Yes 1 Large 23% 4 GS4 (gymnema) added to
oral hypoglycemic drugs
improved fasting glucose
and HbA1c levels.
Type 2 diabetes Case series Kothe & Uppal, 1997 21 NA 0 NA NA NA Gymnema administered
over 6-month period,
uncontrolled, limited
reporting of numerical
results.
Type 2 diabetes Case series Khare et al., 1983 16 Yes 0 Large NA NA 10 days of gymnema
reduced serum glucose
levels in both diabetic
and nondiabetic patients.
321

Explanation of columns in Natural Standard EVIDENCE TABLE
12345678910
Condition Study design Author, year NStatistically
significant?
Quality of study 0–2 =poor
3–4 =good 5 =excellent
Magnitude of
benefit
Absolute risk
reduction
Number
needed to treat
Comments
322

Systematic Review of Gymnema (Gymnema sylvestre R. Br.) 323
True random allocation to trial arms, proper blinding, and sufcient sample size
are the basis for an adequate RCT.
•Equivalence trial: An RCT which compares two active agents. Equivalence trials
often compare new treatments to usual (standard) care and may not include a
placebo arm.
•Before and after comparison: A study that reports only the change in outcome in
each group of a study and does not report between-group comparisons. This is a
common error in studies that claim to be RCTs.
•Case series: A description of a group of patients with a condition, treatment, or
outcome (e.g., 20 patients with migraine headache underwent acupuncture and
17 reported feeling better afterwards). Case series are considered weak evidence
of efcacy.
•Case-control study: A study in which patients with a certain outcome are selected
and compared to similar patients (without the outcome) to see if certain risk
factors/predictors are more common in patients with that outcome. This study
design is not common in the complementary & alternative medicine literature.
•Cohort study: A study which assembles a group of patients with certain baseline
characteristics (e.g., use of a drug) and follows them forward in time for outcomes.
This study design is not common in the complementary & alternative medicine
literature.
•Meta-analysis: A pooling of multiple trials to increase statistical power (often
used to pool data from a number of RCTs with small sample sizes, none which
demonstrates signicance alone but in aggregate can achieve signicance). Multi-
ple difculties are encountered when designing/reviewing these analyses; in par-
ticular, outcomes measures or therapies may differ from study-to-study, hindering
direct comparison.
•Review: An author’s description of his or her opinion based on personal, nonsys-
tematic review of the evidence.
•Systematic review: A review conducted according to pre-specied criteria in an
attempt to limit bias from the investigators. Systematic reviews often include a
meta-analysis of data from the included studies.
Author, Year
•Identies the study being described in a row of the table.
N
•The total number of subjects included in a study (treatment group plus placebo
group). Some studies recruit a larger number of subjects initially, but do not use
them all because they do not meet the study’s entry criteria. In this case, it is
the second, smaller number that qualies as N.Nincludes all subjects that are
part of a study at the start date, even if they drop out, are lost to follow-up, or are
deemed unsuitable for analysis by the authors. Trials with a large number of drop-
outs that are not included in the analysis are considered to be weaker evidence
for efcacy. For systematic reviews, the number of studies included is reported.
For meta-analyses, the number of total subjects included in the analysis or the
number of studies may be reported.

324 Ulbricht et al.
Statistically Signicant?
•Results are noted as being statistically signicant if a study’s authors report sta-
tistical signicance, or if quantitative evidence of signicance is present (such as
p values). P =pending verication.
Quality of Study
•A numerical score between 0–5 is assigned as a rough measure of study de-
sign/reporting quality (0 being weakest and 5 being strongest). This number is
based on a well-established, validated scale developed by Jadad et al. (1996). This
calculation does not account for all study elements that may be used to assess
quality (other aspects of study design/reporting are addressed in the “Evidence
Discussion” sections of reviews).
•A Jadad score is calculated using the seven items in the table below. The rst
ve items are indications of good quality, and each counts as one point towards
an overall quality score. The nal two items indicate poor quality, and a point is
subtracted for each if its criteria are met. The range of possible scores is 0 to 5.
Jadad score calculation
Item Score
Was the study described as randomized (this includes words such as randomly, random, and
randomization)?
0/1
Was the method used to generate the sequence of randomization described and appropriate
(table of random numbers, computer-generated, etc)?
0/1
Was the study described as double blind? 0/1
Was the method of double blinding described and appropriate (identical placebo, active
placebo, dummy, etc)?
0/1
Was there a description of withdrawals and dropouts? 0/1
Deduct one point if the method used to generate the sequence of randomization was
described and it was inappropriate (patients were allocated alternately or according to date
of birth, hospital number, etc).
0/−1
Deduct one point if the study was described as double blind but the method of blinding was
inappropriate (e.g., comparison of tablet vs. injection with no double dummy).
0/−1
Magnitude of Benet
•This summarizes how strong a benet is: small, medium, large, or none. If results
are not statistically signicant “NA” for “not applicable” is entered. In order to
be consistent in dening small, medium, and large benets across different stud-
ies and reviews, Natural Standard denes the magnitude of benet in terms of
the standard deviation (SD) of the outcome measure. Specically, the benet is
considered:
•Large: if >1SD
•Medium: if 0.5 to 0.9 SD
•Small: if 0.2 to 0.4 SD
•In many cases, studies do not report the standard deviation of change of the
outcome measure. However, the change in the standard deviation of the out-
come measure (also known as effect size) can be calculated, and is derived by

Systematic Review of Gymnema (Gymnema sylvestre R. Br.) 325
subtracting the mean (or mean difference) in the placebo/control group from
the mean (or mean difference) in the treatment group, and dividing that quan-
tity by the pooled standard deviation (Effect size =[Mean Treatment −Mean
Placebo]/SDp).
Absolute Risk Reduction
•This describes the difference between the percent of people in the con-
trol/placebo group experiencing a specic outcome (control event rate), and the
percent of people in the experimental/therapy group experiencing that same out-
come (experimental event rate). Mathematically, Absolute risk reduction (ARR)
equals experimental event rate minus control event rate. ARR is better able to
discriminate between large and small treatment effects than relative risk reduc-
tion (RRR), a calculation that is often cited in studies ([control event rate – ex-
perimental event rate]/control event rate). Many studies do not include adequate
data to calculate the ARR, in which cases “NA” is entered into this column. P =
pending verication.
Number Needed to Treat
•This is the number of patients who would need to use the therapy under investi-
gation, for the period of time described in the study, in order for one person to
experience the specied benet. It is calculated by dividing the Absolute Risk
Reduction into 1 (1/ARR). P =pending verication.
Comments
•When appropriate, this brief section may comment on design aws (inadequately
described subjects, lack of blinding, brief follow-up, not intention-to treat, etc.),
notable study design elements (crossover, etc.), dosing, and/or specics of study
group/sub-groups (age, gender, etc.). More detailed description of studies is
found in the “Evidence Discussion” section that follows the “Evidence Table”
in Natural Standard reviews.
EVIDENCE DISCUSSION
Type 1 Diabetes Mellitus
•Summary: Multiple animal studies have noted gymnema to lower serum glucose
levels (Ananthan, Baskar, et al., 2003; Ananthan, Latha, et al., 2003; Chattopad-
hyay, 1998; Gholap & Kar, 2003; Gupta & Variyar, 1964; Jiang, 2003; Okabayashi
et al., 1990; Porchezhian & Dobriyal, 2003; Satdive et al., 2003; Shanmugasun-
daram et al., 1983; Shanmugasundaram, Gopinath, et al., 1990; Shanmugasun-
daram, Rajeswari, et al., 1990; Srivastava et al., 1985;; Tominaga et al., 1995; Xie
et al., 2003). Preliminary evidence from small, methodologically awed human
trials suggest hypoglycemic effects of chronic oral gymnema when used in pa-
tients with type 1 or type 2 diabetes, as an adjunct to insulin or oral hypoglycemic
drugs. The onset of effect has not been clearly described, although one study
noted that oral administration of gymnema did not have acute effects on fasting
serum glucose levels (after 45 min; Baskaran et al., 1990). The available studies

326 Ulbricht et al.
have assessed the effects of gymnema after 10 days, up to 20 months. Although
it appears that gymnema may act to lower serum glucose levels, further studies
of dosing, safety, and efcacy are merited before a strong recommendation can
be made. Multiple drugs are available that have been demonstrated to establish
good long-term control of blood glucose levels, and gymnema has not been thor-
oughly evaluated as a safe or effective alternative or adjunct to these agents.
•Evidence: Shanmugasundaram et al. conducted a study in 64 individuals with type
1 diabetes (Shanmugasundaram, Gopinath, et al., 1990; Shanmugasundaram, Ra-
jeswari, et al., 1990). All subjects were continued on insulin therapy during the
trial, and 27 patients were concurrently started on 200 mg of GS4 twice daily
(an ethanolic acid-precipitated extract of gymnema). Outcomes measures in-
cluded fasting glucose levels, HbA1c levels, and insulin requirements. The gym-
nema subjects were followed for a period, which varied, from 6 to 30 months,
while the 37 insulin-only controls were tracked for 10–12 months. Eleven sub-
jects dropped out during the initial 6 months (10 for nonmedical reasons, one
for brittle diabetes). In the gymnema group, mean insulin requirements were re-
duced by 50%, accompanied by signicant reductions in mean fasting blood glu-
cose levels, from 232 mg/dl to 152 mg/dl. HbA1c levels were also reportedly re-
duced. The insulin-only group exhibited no signicant mean decreases in insulin
requirements or blood sugar levels. Subjective measures of well being (alertness,
work, and school performance) were also reported to improve with gymnema
therapy. A secondary outcome of C-peptide level was measured in the two groups
and compared with values for 40 nondiabetic individuals. A statistically signi-
cant lower mean C-peptide value was found in the gymnema plus insulin group
(0.185) versus insulin alone (0.272) but was higher than the mean value in nondi-
abetics (0.105). During the study, no adverse effects besides hypoglycemia were
observed. Although these results are promising, the lack of blinding allows for
the possible introduction of bias, and the lack of randomization may allow for
the inuence of confounding factors. Baseline patient characteristics and statis-
tical analysis were not well described. The principal author is involved with a
company that produces a GS4 product.
Type 2 Diabetes Mellitus
•Summary: Multiple animal studies have noted gymnema to lower serum glucose
levels (Ananthan, Baskar, et al., 2003; Ananthan, Latha, et al., 2003; Chattopad-
hyay, 1998; Gholap & Kar, 2003; Gupta & Variyar, 1964; Jiang, 2003; Okabayashi
et al., 1990; Porchezhian & Dobriyal, 2003; Satdive et al., 2003; Shanmugasun-
daram et al., 1983; Shanmugasundaram, Gopinath, et al., 1990; Shanmugasun-
daram, Rajeswari, et al., 1990; Srivastava et al., 1985; Tominaga et al., 1995; Xie
et al., 2003). Preliminary evidence from small, methodologically awed human
trials suggest hypoglycemic effects of chronic oral gymnema when used in pa-
tients with type 1 or type 2 diabetes, as an adjunct to insulin or oral hypoglycemic
drugs. The onset of effect has not been clearly described, although one study
noted that oral administration of gymnema did not have acute effects on fasting
serum glucose levels (after 45 min; Baskaran et al., 1990). The available stud-
ies have assessed effects of gymnema after 10 days, up to 20 months. Although

Systematic Review of Gymnema (Gymnema sylvestre R. Br.) 327
it appears that gymnema may act to lower serum glucose levels, further stud-
ies of dosing, safety, and efcacy are merited before a strong recommendation
can be made. Multiple drugs are available that have been demonstrated to es-
tablish good long-term control of blood glucose levels, and gymnema has not
been thoroughly evaluated as a safe or effective alternative or adjunct to these
agents.
•Evidence: Baskaran et al. performed a controlled, nonrandomized, nonblinded
study in 47 patients with type 2 diabetes (Baskaran et al., 1990). GS4 extract
(400 mg daily) was administered for 18–20 months to 22 patients, in addition to
baseline conventional oral hypoglycemic agents. The control group remained on
conventional drug therapy alone without GS4 and was followed for 12 months.
After 18–20 months, in the gymnema group, fasting glucose levels were reported
to be 29% lower than baseline (p<.001), and mean HbA1c levels decreased
from a baseline value of 11.91%–8.48% (p<.001). Insulin responses ware re-
ported as being superior in the gymnema-supplemented group (p<.01). Five
subjects in the gymnema group were able to discontinue hypoglycemic medica-
tions. No signicant changes in glucose or HbA1c levels were observed in patients
continued on oral hypoglycemic medications alone after 8–10 months. As a sec-
ondary outcome, blood lipid levels were evaluated. In the GS4 group, there were
signicant reductions in plasma lipid levels, including cholesterol, triglycerides,
and free fatty acids, while lipid levels in patients on conventional drug therapy
alone remained elevated. Methodological limitations of this study include the
lack of randomization or blinding. Glucose and HbA1c levels were compared
with baseline values in each group, rather than compared between groups, mak-
ing this a “before-and-after” study design (a methodologically weaker design
than a between-group comparison).
•A briey described case series by Kothe and Uppal examined the use of gym-
nema in 21 subjects with type 2 diabetes over a 6-month period (Kothe & Uppal,
1997). This paper was presented at the Scientic Session of the 9th Annual Inter-
national Homeopathic Conference of the Asian Homeopathic Medical League,
Jaipur, India. All subjects received 6–15 drops of Gymnema sylvestre “Q” with
1/4 cup of water, taken two to four times daily, on a sliding scale based on blood
sugar measurements. Additional homeopathic remedies were allowed in “com-
plicated” cases. The authors reported that 16 of 21 patients demonstrated “mod-
erate” to “excellent” blood glucose control. Although suggestive, the lack of
a control group and vague description of baseline patient characteristics raises
questions about whether these results were due to the natural course of disease,
rather than a result of gymnema therapy. Details were not provided regarding
methodology or data analysis, and glucose levels during the study period were
provided only for two patients. Results may have been confounded by the use of
additional homeopathic remedies in some patients, which were not described.
•In a 10-day study described in a letter to the editor, Khare et al. investigated
the effects of gymnema on glucose levels in 10 healthy young adults (ages 19–25)
and 6 diabetic adults (age 35–50) with mild-to-moderate baseline hyperglycemia,
but without diagnosed diabetic complications (Khare et al., 1983). Subjects were
not receiving diabetes treatment prior to the trial. Glucose tolerance tests were
performed before and after administration of gymnema (2 g, three times daily

328 Ulbricht et al.
of a 10 g/100 ml aqueous decoction of shade-dried powdered leaves). Adminis-
tration of gymnema for 10 days signicantly reduced fasting blood sugar levels
compared with baseline in both normal and diabetic subjects and signicantly
reduced mean glucose levels in diabetics after oral glucose load at both 30 min
(110.7 mg/dl vs. 135.7 mg/dl) and 120 min (180.7 mg/dl vs. 220.0 mg/dl). As a case
series, this study lacked comparison to controls receiving placebo or a compar-
ison agent. Methodology and statistical analysis were not well described in this
brief publication.
BRANDS USED IN CLINICAL TRIALS/THIRD-PARTY TESTING
•Proβeta (PharmaTerra, Inc., Bellevue, WA): A patented ethanolic acid-
precipitated extract from gymnema, also called GS4. According to the makers of
Proβeta, the preparation is standardized to possess a specic biological result, as
measured by a test developed by the company, which evaluates “pancreotropic”
effects (Baskaran et al., 1990; Shanmugasundaram, Gopinath, et al., 1990; Shan-
mugasundaram, Rajeswari, et al., 1990).
•Beta Fast GXR (Informulab, Omaha, NE, USA), 400 mg standardized to 25%
gymnemic acids; Gymnesyl (Nature’s Herbs, Twinlab, American Fork, UT, USA),
extract standardized for 150 mg of crude gymnemic acids; Gymnema (Nature’s
Way, Lehi, UT, USA), 260 mg standardized to 75% gymnemic acids.
Declaration of interest: The authors report no conict of interest. The authors
alone are responsible for the content and writing of this paper.
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