Cissus sicyoides

Cissus sicyoides L. (Princess Vine / Vegetable Insulin)

1. Identity and Botanical Description

Cissus sicyoides Linnaeus is a flowering plant belonging to the family Vitaceae (the grape family). It is also known by the synonymous or closely related designation Cissus verticillata (L.) Nicolson & C.E. Jarvis, and carries a wide range of vernacular names, including vegetal insulin, anil-trepador, bejuco-caro, cipó-pucá, and puci. In Brazil, the plant is known as "Cortina," "cipó-pucá," "cortina japonesa," "uva brava," and "insulina vegetal." In Mexico, it is known as "sanalotodo" and is used in traditional medicine for relieving pain and inflammation.

Cissus sicyoides originates from the Dominican Republic, but its medicinal use is widespread in tropical America. It is considered a plant of the Neotropical region and is generally found in the Amazon region. This evergreen climbing vine features glossy, lobed leaves that measure around 6–12 cm, with tendrils helping it scramble up tree trunks or fences. Its small, greenish-white flowers form clusters, followed by purple-black fruits roughly 1 cm in diameter. The plant thrives in tropical to subtropical climates, adapting well to humid forest edges across Central and South America.

Taxonomic Classification

• Kingdom: Plantae
• Family: Vitaceae
• Genus: Cissus
• Species: C. sicyoides L.

Several active constituents — including quinolizidine alkaloids, triterpenes, sterols, flavonoids, stilbenes, and saponins — have been isolated and reported from plants of the Cissus genus more broadly.

Common Forms and Preparations

Leaves, stems, and roots have been incorporated into teas, poultices, and extracts for their purported health-promoting effects. Leaf decoctions of Cissus sicyoides (princess vine) are taken widely as a popular remedy for diabetes mellitus in Brazil, where its common name is "vegetal insulin." In laboratory and clinical contexts, the plant has been studied as aqueous extracts, hydroalcoholic extracts, and methanolic extracts prepared from leaves and aerial parts. A dry extract form has also been used in studies examining complementary treatment for diabetes mellitus.

2. Traditional and Historical Use

In Brazilian folk medicine, C. sicyoides has been generally used to treat epilepsy, stroke, diabetes, gastric ulcer, abscesses, inflammation, and rheumatoid arthritis. This medicinal species has also been used in folk medicine in some countries to treat respiratory diseases and hypertension.

In traditional medicine, C. sicyoides has been used for pain and inflammation relief, treatment of respiratory diseases, arterial hypertension, rheumatism, abscess, epilepsy, gastric ulcer, rheumatoid arthritis, stroke, and diabetes mellitus.

The plant is found abundantly in Brazil, especially in the Amazon, and its therapeutic properties are widely used in popular medicine as a diuretic, anti-influenza, anti-inflammatory, anticonvulsion, and hypoglycemic agent. In Mexico, this species is used in traditional medicine for relieving pain and inflammation. The plant has a long-standing place in traditional medicine across tropical regions, especially in the Caribbean, South America, and parts of Africa, where it has historically been used to address a variety of ailments including inflammation, metabolic disorders, and to support general wellness.

The plant's use has ancient and widespread roots. The identity of Cissus verticillata has been traced through pre-Linnaean botanical works and herbarium specimens; morphological and organoleptic characteristics of the bark and roots were published in 16th and 17th century literature and are confirmable in living plants. This indicates the plant was formally documented in European botanical and pharmaceutical literature as early as the 16th century, likely following its introduction from the Americas.

3. Key Constituents and Active Compounds

Phytochemical analysis of C. sicyoides has revealed the presence of coumarins, flavonoids, anthocyanins, steroids, and tannins. An earlier study detected the presence of steroids, terpenes, quinones, and phenolic compounds in C. sicyoides, while others showed no alkaloid in the plant, and cyanidins only in the fruit.

The most detailed phytochemical characterization comes from isolation studies on the aerial parts of the plant. From the aerial parts of Cissus sicyoides, a new coumarin glycoside — 5,6,7,8-tetrahydroxycoumarin-5β-xylopyranoside — was obtained together with the known coumarin sabandin, two flavonoids (kaempferol 3-rhamnoside and quercetin 3-rhamnoside), and two steroids (sitosterol and 3β-O-β-D-glucopyranosylsitosterol).

Additional specific flavonoid compounds have been confirmed by chromatographic analyses. Beltrame and colleagues identified from the aerial parts of C. sicyoides: quercetin 3-α-rhamnoside, cissosides I, II and III, kaempferol 3-α-rhamnoside, and cissusin. Ferreira and colleagues reported the presence of β-sitosterol (14%) and quercetin-3-O-β-d-rhamnoside (18%) as major constituents in the methanolic extract from leaves of C. sicyoides.

HPLC-PAD-MS (high-performance liquid chromatography with photodiode array detection and mass spectrometry) fingerprinting has further confirmed the chemical profile. The chemical fingerprinting of the hydroalcoholic extract of C. sicyoides confirmed the presence of flavonol-O-glycosides, derivatives of quercetin and kaempferol; these findings are consistent with those of other researchers who also identified kaempferol-3-α-rhamnoside, quercetin-3-α-rhamnoside, β-sitosterol, and quercetin-3-O-β-d-rhamnoside as major constituents.

The plant is also known to contain resveratrol, a stilbene-class polyphenol. C. sicyoides is known for containing a steroid called sitosterol and a polyphenol called resveratrol. The anthocyanidins cyanidin and delphinidin were identified in the methanolic extract of C. sicyoides. Kaempferol presence has also been identified in C. sicyoides.

Other compound classes identified in phytochemical screenings include: alkaloids, triterpenes and/or steroids, flavonoids, tannins, and saponins. A new coumarin glycoside, 5,6,7,8-tetrahydroxycoumarin-5β-xylopyranoside, has been isolated from the aerial parts of C. sicyoides.

The leaves of the plant have also been found to contain linalool (a monoterpene alcohol) and α-tocopherol (vitamin E). These results indicate an anxiolytic and anticonvulsant-like action from C. sicyoides extract on mice, attributed at least in part to the action of flavonoid(s), linalool, and α-tocopherol present in the C. sicyoides leaves.

Summary of Key Identified Constituents

• Flavonoids: Quercetin 3-α-rhamnoside, kaempferol 3-α-rhamnoside, cissosides I–III, cissusin, cyanidin, delphinidin
• Coumarins: 5,6,7,8-Tetrahydroxycoumarin-5β-xylopyranoside (novel), sabandin
• Steroids/Sterols: β-Sitosterol, 3β-O-β-D-glucopyranosylsitosterol
• Stilbenes: Resveratrol
• Terpenes: Linalool, triterpenes
• Vitamins: α-Tocopherol
• Other: Tannins, saponins, anthocyanins

4. Established Mechanisms of Action

Anti-inflammatory Mechanisms

The anti-inflammatory effect of the hydroalcoholic leaf extract was evaluated by oral administration against an acute model of edema induced by xylene, and the mechanisms of action were analyzed by the involvement of arachidonic acid (AA) and prostaglandin E₂ (PGE₂). The oral administration of the extract inhibited the edema induced by xylene and AA and was also able to significantly decrease the levels of PGE₂. The mechanism of action involved in the anti-inflammatory effect is related to PGE₂.

Antidiarrheal Mechanisms

The antidiarrheal effect of the hydroalcoholic extract was observed through analysis of motility and accumulation of intestinal fluid, and the mechanisms of action were evaluated through the role of the opioid receptor, α₂ adrenergic receptor, muscarinic receptor, nitric oxide (NO), and PGE₂. The extract exhibited significant anti-diarrheal activity by reducing motility and intestinal fluid accumulation, and significantly reduced intestinal transit stimulated by muscarinic agonist and intestinal secretion induced by PGE₂. The antidiarrheal effect may be mediated by inhibition of contraction by acting on the intestinal smooth muscle and/or intestinal transit.

Hypoglycemic Mechanisms

Lipid metabolism was not affected by the decoction treatment, nor was the level of hepatic glycogen in diabetic animals, which indicated that the mechanism responsible for the improvement in carbohydrate metabolism could not involve inhibition of glycogenolysis and/or stimulation of glycogenesis. The fact that normal animals treated with C. sicyoides exhibited no changes in any of the measured parameters suggests that its mode of action in diabetic animals does not resemble those of sulphonylurea or insulin. It may, however, act in a similar way to biguanide, via inhibition of gluconeogenesis.

In vitro enzyme inhibition data support this metabolic activity: Cissus sicyoides showed an inhibition rate for the alpha-glucosidase enzyme assay of 55.2 ± 1.7%.

Gastroprotective Mechanisms

The methanolic extract obtained from the leaves of Cissus sicyoides was evaluated for the ability to protect the gastric mucosa against injuries caused by necrotizing agents (0.3 M HCl/60% EtOH, absolute ethanol, piroxicam, and pylorus ligature) in rodents; microcirculation, antioxidant action, and participation of nitric oxide (NO) and sulfhydryls (SH) groups in the gastroprotective action were also evaluated. Administration of the extract significantly reduced gastric lesions induced by different ulcerogenic agents in rodents. The extract's effect involved an increase in the defense mechanisms of the gastrointestinal mucosa such as NO and SH groups that prevent and attenuate the ulcer process; the extract also has antioxidant properties against oxidative stress, but does not modify microcirculation response in gastric mucosa.

Antioxidant Mechanisms

According to studies on the chemical composition of C. sicyoides, it was discovered that the plant contains bioactive compounds with increased antioxidant activity. The plant contains several bioactive compounds with high antioxidant activity, such as phenolic compounds, which are compounds that prevent or delay oxidative stress, acting as free radical scavengers (FRSs), and thus reduce the onset of cardiovascular disease, cancer, diabetes, epilepsy, and stroke, among other diseases.

Anxiolytic and Anticonvulsant Mechanisms

In animal studies, treatment with the hydroalcoholic extract increased the duration of sleeping time induced by sodium pentobarbital and showed significant protection against pentylenotetrazole-induced convulsions; these results indicate an anxiolytic and anticonvulsant-like action, probably due to the action of flavonoid(s), linalool, and α-tocopherol present in the leaves. The plant also contains significant amounts of α-tocopherol, a compound proved to be a useful adjunct to anticonvulsant drugs in clinical studies.

Central Antinociceptive Mechanisms

Acute and chronic treatment of mice with a hydroalcohol extract from the leaves of C. sicyoides at doses of 300, 600, and 1000 mg/kg, by intraperitoneal administration, produced a significant central antinociceptive effect on the hot plate, tail immersion, and acetic acid-induced writhing tests, and the effect was inhibited by naloxone. The inhibition by naloxone implicates involvement of opioid receptors in the antinociceptive action of the extract.

5. Scientific Evidence by Area of Use

5.1 Blood Glucose Regulation (Hypoglycemic / Antidiabetic Activity)

This is the area with the most accumulated preclinical research. Evidence level: Preclinical only; no published randomized controlled trials in humans have been retrieved.

Alloxan-diabetic rat model (Viana et al., BMC Pharmacology, 2004): The hypoglycemic and anti-lipemic effects of the aqueous extract prepared from fresh leaves of the plant (AECS) were studied in the model of alloxan-induced diabetes in rats. Results showed that the daily treatment of diabetic rats with AECS for 7 days (100 and 200 mg/kg, p.o.) significantly decreased blood glucose levels by 25% and 22% respectively, compared to the same groups before treatment. The results justify the popular use of C. sicyoides, pointing to the potential benefit of the plant aqueous extract in alternative medicine, in the treatment of type 2 diabetes mellitus.

Alloxan-diabetic rat model — 60-day biomarker study (Salgado et al., Journal of Medicinal Food, 2009): This study analyzed the effects of aqueous extracts from the leaves and stem of C. sicyoides, administered for 60 days, for the control of glycemia in alloxan-induced diabetic rats, monitored by biomarkers. Data confirmed a hypoglycemic effect: administration of aqueous extracts promoted a 45% decrease in glucose levels after 60 days of administration.

Streptozotocin-diabetic rat model — long-term study (Pepato et al., Journal of Ethnopharmacology, 2003): The decoction treatment significantly reduced the intake of both food and fluid and the volume of urine excreted, as well as the levels of blood glucose, urinary glucose, and urinary urea, in comparison with controls.

Preliminary human data (herbal medicine review study, 2024): A study demonstrated hypoglycemic effects in 50% of patients submitted to the use of dry extract of Cissus sicyoides. However, this finding comes from a review rather than a primary controlled clinical trial, and details on methodology, sample size, and controls are not fully available in the abstract. This preliminary human finding requires confirmation through properly designed randomized controlled trials.

Overall assessment: The antidiabetic evidence base for C. sicyoides is composed predominantly of animal (rodent) experiments using alloxan- or streptozotocin-induced diabetes models, with very limited and methodologically unclear human data. While consistent preclinical results are promising, they cannot be extrapolated directly to clinical practice without confirmed RCT evidence.

5.2 Anti-inflammatory and Antidiarrheal Activity

Evidence level: Preclinical (animal and in vitro) only.

The anti-inflammatory effect was evaluated by oral administration of the hydroalcoholic extract against an acute model of edema induced by xylene, and the mechanisms of action were analyzed by involvement of arachidonic acid (AA) and prostaglandin E₂ (PGE₂). The oral administration of the extract inhibited the edema induced by xylene and AA and was also able to significantly decrease the levels of PGE₂. For antidiarrheal activity, the extract exhibited significant anti-diarrheal activity by reducing motility and intestinal fluid accumulation, and significantly reduced intestinal transit stimulated by muscarinic agonist and intestinal secretion induced by PGE₂. These studies were conducted in rodent models; no human clinical evidence exists.

5.3 Gastroprotective Activity

Evidence level: Preclinical only.

Administration of the methanolic leaf extract significantly reduced gastric lesions induced by different ulcerogenic agents in rodents, and this extract administered by oral route significantly increased gastric volume without exerting an antisecretory effect. The involvement of nitric oxide and sulfhydryl groups in the mucosal defense mechanism was demonstrated. There are no human studies on this indication.

5.4 Central Nervous System Effects: Anxiolytic and Anticonvulsant Activity

Evidence level: Preclinical only.

The anxiolytic and anticonvulsant effects of a hydroalcoholic extract obtained from the aerial parts of C. sicyoides were demonstrated on male and female mice using several behavioral assays. Groups treated via intraperitoneal (IP) with doses of 300, 600, and 1000 mg/kg showed significant action in the elevated plus-maze (EPM), time spent in the open arms, and number of entries in the open arms; the board-hole test also showed a significant increase in the time spent in head-dipping and in the marble-burying test. The same treatment increased the duration of sleeping time induced by sodium pentobarbital and showed significant protection against pentylenotetrazole-induced convulsions; diazepam was used as a positive control, confirming anxiolytic-like actions. These findings have not been extended to human trials.

5.5 Central Antinociceptive Activity

Evidence level: Preclinical only.

The hydroalcohol extract at doses of 300, 600, and 1000 mg/kg (intraperitoneal) produced a significant central antinociceptive effect on the hot plate, tail immersion, and acetic acid-induced writhing tests; the effect was inhibited by naloxone. The extract was given to mice daily for 30 days at a dose of 600 mg/kg, causing an effect similar to that of drugs with typical action on opioid receptors. The effective dose (ED₅₀) was approximately 600 mg/kg in mice.

5.6 Antitumor / Cytostatic Activity

Evidence level: Preliminary preclinical only.

A hydroalcoholic extract from the leaves of C. sicyoides showed an inhibition of tumor activity in sarcoma-180 of 48.7% and 62% at doses of 300 and 600 mg/kg respectively, compared to the control group. When Ehrlich carcinoma was considered, the inhibition was 69% and 84.4% at doses of 300 and 600 mg/kg, respectively. Extracts from the leaves of C. sicyoides suppressed the Ehrlich carcinoma in mice and the bioactivity was related to the content of β-sitosterol and resveratrol. The extract of C. sicyoides showed moderate cytostatic activity against HEp-2 cells. All cytostatic and antitumor evidence is from animal and cell-line studies only.

5.7 Antioxidant Activity

Evidence level: In vitro only.

Cissus sicyoides exhibited total antioxidant activity of 748.0 ± 104.5 μM in an in vitro assessment. Modern scientific interest in Cissus sicyoides has focused on its potential antioxidant, anti-inflammatory, and metabolic benefits, with several preclinical studies indicating the plant contains bioactive compounds like flavonoids, triterpenes, and stilbenes which may contribute to its medicinal properties.

5.8 Vasoconstrictor Activity

Evidence level: Preclinical only.

The plant has demonstrated a vasoconstrictor effect on guinea-pig aorta rings. No human pharmacodynamic studies on this effect have been identified.

5.9 Anti-allergic Activity

Evidence level: Preclinical only.

Different parts (leaves and stem) of C. sicyoides have been shown to exhibit anti-allergic activity in preclinical models. No clinical trials have been conducted on this indication.

6. Body Systems and Health Areas Associated with Cissus sicyoides

Based on the body of preclinical research, C. sicyoides has been investigated in relation to the following body systems:

• Metabolic system: Blood glucose regulation, anti-lipemic effects, alpha-glucosidase inhibition
• Gastrointestinal system: Gastroprotective effects against ulcerogenic agents, antidiarrheal activity via smooth muscle and intestinal transit modulation
• Cardiovascular system: Vasoconstrictor activity on aortic smooth muscle; traditional use for stroke and hypertension
• Central nervous system: Anxiolytic, anticonvulsant, and antinociceptive activity via opioidergic and GABAergic pathways
• Immune/inflammatory system: Anti-inflammatory effects via PGE₂ inhibition; anti-allergic activity
• Antioxidant/cellular defense: Free radical scavenging via phenolic constituents
• Oncology (preliminary): Cytostatic and antitumor activity attributed to β-sitosterol and resveratrol

7. Dosage Forms and Dosages Reported in Studies

No standardized clinical dosage has been established. The following dosages are those explicitly reported in the peer-reviewed studies identified:

• Hypoglycemic effect (alloxan rat model): Daily treatment with the aqueous extract of C. sicyoides (AECS) for 7 days at 100 and 200 mg/kg, p.o., significantly decreased blood glucose levels by 25% and 22% respectively.
• Anxiolytic and anticonvulsant effect (mice, intraperitoneal): Doses of 300, 600, and 1000 mg/kg administered via intraperitoneal (IP) injection showed significant anxiolytic action in the elevated plus-maze and other behavioral assays.
• Central antinociceptive effect (mice): Mice were given the extract daily for 30 days at a dose of 600 mg/kg; the effective dose (ED₅₀) was approximately 600 mg/kg.
• Anti-inflammatory effect (mice, oral): The hydroalcoholic extract was tested at 125, 250, and 500 mg/kg (p.o.) for production of PGE₂ in ear edema induced by arachidonic acid.
• Non-clinical toxicology (chronic study, rats): The extract was administered orally at the popular use dose (4.5 mg/kg), 3× the popular use dose (13.5 mg/kg), and 9× the popular use dose (40.5 mg/kg) over 90 days.
• Antitumor effect (mice): The hydroalcoholic extract showed inhibition of tumor activity in sarcoma-180 at doses of 300 and 600 mg/kg.

It should be noted that all of the above dosages were used in animal studies administered via routes (intraperitoneal injection or oral gavage in rodents) that cannot be directly extrapolated to human oral supplementation dosing. No published human pharmacokinetic or dose-ranging studies have been identified for this species.

8. Safety Considerations

Non-clinical Toxicology

A formal study to evaluate the acute and chronic non-clinical toxicity of hydroalcoholic extract from the leaves of Cissus sicyoides was conducted; the acute test was performed in Wistar rats, administering a single dose of 40.5 mg/kg. The non-clinical chronic toxicological testing trial was conducted for a period of 90 days and analyzed using parameters such as behavioral screening, body temperature, blood glucose, consumption of water and food, weight gain, hematology, blood biochemistry, and histopathology.

Key findings from this study: The ethanolic extract from the leaves of Cissus caused few blood changes at the 40.5 mg/kg dose in the acute study. In the chronic study, the extract showed no toxic effects at the popular dose (4.5 mg/kg). Only the 13.5 mg/kg dose in the chronic trial showed blood changes.

Gastroprotective Context and Acute Toxicity Observation

A single oral administration of the methanolic extract did not produce any signs or symptoms of acute toxicity in the treated animals. Despite the absence of acute toxicity, carefulness is necessary. Pharmacological evaluation from Cissus sicyoides showed anti-diabetic, anti-lipemic, anti-allergic, cytostatic, antibacterial, antinociceptive and anti-inflammatory effects. Other authors did not detect antiviral effect, toxicity, cytotoxic, or mutagenic actions.

In Vitro Cytotoxicity

C. sicyoides demonstrated statistically significant low cell viability only at the highest test concentration compared with the negative control; cell death mechanism investigation indicated no necrosis in contrast to the comparison plant. The results suggest low toxicity for C. sicyoides extract.

Genotoxicity Signal from Traditional Preparations

A safety concern has been raised by one study: studies with tea induced an increase in the amount of chromosomal damage in bone marrow cells without altering the cell division cycle (Vicentini et al., 2001). This finding, noted in the peer-reviewed literature, specifically concerns traditional tea preparations and has not been widely replicated, but it represents a documented safety signal that warrants attention in future research.

Potential Pharmacological Interactions

Based on documented pharmacological activities, theoretical clinically relevant interactions include:

• Antidiabetic agents: Given the demonstrated alpha-glucosidase inhibition (inhibition rate of 55.2 ± 1.7% in the alpha-glucosidase enzyme assay) and hypoglycemic effects in animal models, concurrent use with insulin or oral hypoglycemic drugs could theoretically potentiate blood glucose lowering.
• CNS depressants: The extract increased the duration of sleeping time induced by sodium pentobarbital, suggesting potential additive effects with sedatives, anxiolytics, or anticonvulsant medications.
• Antihypertensive agents: The traditional use for hypertension and documented vasoconstrictor effects on aortic tissue suggest a possible, though not clearly characterized, cardiovascular pharmacodynamic profile that could interact with antihypertensive drugs.

State of Evidence for Safety

All formal safety data for C. sicyoides currently derive from non-clinical studies in rodents. No systematic human safety trials, pharmacovigilance studies, or regulatory assessments from major bodies (NIH ODS, NCCIH, WHO, EMA, EFSA) specific to C. sicyoides have been identified in the peer-reviewed literature. The plant is not included in major international pharmacopeias or monograph databases (German Commission E, ESCOP, WHO monographs) as a formally evaluated medicinal herb. The evidence base is therefore insufficient to establish a human safety profile with confidence.

9. Overall Evidence Assessment

Cissus sicyoides represents a promising botanical ingredient with a rich history and encouraging early scientific validation. While definitive clinical evidence is still emerging, its traditional use and initial research suggest valuable contributions, warranting further exploration.

The scientific literature on C. sicyoides consists almost exclusively of preclinical studies — in vitro cell and enzyme assays, and in vivo rodent models. The hypoglycemic activity has the most consistent preclinical support, with multiple independent research groups reporting significant reductions in blood glucose in alloxan- and streptozotocin-diabetic rats. The anti-inflammatory, antidiarrheal, gastroprotective, anxiolytic, anticonvulsant, and antinociceptive activities have each been demonstrated in at least one rigorously designed animal study. However, for all of these indications, the translation to human clinical benefit remains unproven. No high-quality randomized controlled trials in humans have been published for any indication. The chromosomal damage signal observed with traditional tea preparations in bone marrow cells represents an unresolved toxicological concern that has not been adequately followed up in the literature.

References

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