Cissus quadrangularis

Cissus Quadrangularis: A Comprehensive Reference

1. Identity

Botanical and Chemical Names

Cissus quadrangularis L. is a perennial herb native to tropical and subtropical regions of Africa, Asia, and the Arabian Peninsula. It belongs to the family Vitaceae and has been a cornerstone in traditional medicine for centuries, particularly in Ayurveda. Its synonyms include Cissus succulent; it is popularly known as Horjora in Hindi and Pirandai in Tamil. It is commonly known as "Harjor" or "Bone Setter." Additional vernacular names include Asthisamharaka and Asthishrinkhala in Sanskrit-based systems, and Hadjod in colloquial North Indian usage. In Thailand it is called Phet sang khat.

Morphological Description

This perennial succulent vine features distinctive four-angled (quadrangular) green stems, which turn reddish-brown when older. Leaves emerge in pairs, are ovate to oblong, 2–6 cm long, and dotted with tiny translucent glands. Clusters of small white or yellowish flowers bloom at the stem nodes and later give way to small globose berries. The plant can grow up to 10 meters tall.

Geographic Distribution

Cissus quadrangularis is a perennial herb with medicinal properties distributed throughout the tropical world. It is one of the most frequently used medicinal plants in India. It is believed that the plant is native to India, Sri Lanka, Malaysia, Java, and West Africa. It adapts to rocky hillsides and semi-arid climates.

Plant Parts Used and Common Preparations

Its leaves, stems, and roots are all utilized for their medicinal properties. Traditionally, Ayurvedic practitioners harvest and dry the succulent stems and inner bark — these are the parts used for bone-support formulations. Today, Cissus quadrangularis is a key ingredient in modern supplements, often presented in capsules, powders, or liquid extracts. These products typically use extracts derived from the plant's stems and leaves, focusing on the active compounds that make it unique. Modern supplements frequently use extracts of Cissus quadrangularis standardized for active compounds called ketosterones, which are reported to contribute to its anti-inflammatory and bone-strengthening effects.

2. Traditional and Historical Use

Ayurvedic Tradition (India and Sri Lanka)

Mentions of Cissus quadrangularis span back over two millennia. The plant finds references in the ancient Sushruta Samhita (circa 600–800 BCE) as "Asthisamharaka," literally meaning "that which unites bones." Early Sanskrit manuscripts describe its use for fractures, sprains, and arthritic stiffness. Ayurvedic scholars Charaka and Sushruta highlight Cissus quadrangularis under the rasa (taste) of tikta-kashaya and its Kapha-Pitta balancing properties.

Traditionally, village healers in central India powdered the dried vine and combined it with herbal decoctions, applying poultices directly to broken limbs. Over centuries, the perception evolved: by the 17th–18th century, Unani practitioners had adopted it for joint ankylosis, and Siddha texts recommended it for toothache when mixed with clove oil.

Siddha Medicine (Southern India)

This plant is an important herb in Siddha medicine, which has its origins in southern India. In Siddha medicine, it is used for conditions like blindness, epilepsy, and loss of appetite. It is regarded as a tonic and analgesic, promoting the healing of broken bones. The stem is antiscorbutic; its paste is used for asthma. In the Siddha system, it is used for healing bone fractures, piles, as an anti-aging herb, in asthma, cough, and gonorrhea, and also as an anthelmintic, blood-purifier, carminative, and stomachic.

African and Arabian Traditional Medicine

In traditional medicine, this plant is used to treat injured tendons, broken bones, injured ligaments, asthma, stomachache, scurvy, gout, digestive disorders, and as an aphrodisiac. Because of its significant source of carotenoids, triterpenoids, and ascorbic acid, Cissus quadrangularis is used for gastrointestinal diseases in traditional medicine.

Thai Traditional Medicine

Cissus quadrangularis has long been used in Thai folk remedies for hemorrhoids because of its vasoconstrictive effect and anti-inflammatory activity. In addition, it also has an analgesic effect. It is listed in the Thai National List of Herbal Products in the oral dosage form for the treatment of hemorrhoids.

3. Key Constituents and Active Compounds

Phytochemical Overview

A wide variety of chemical constituents have been isolated and identified from Cissus extracts, including steroids, flavonoids, stilbenes, iridoids, triterpenes, and gallic acid derivatives. The plant is particularly characterized by a high concentration of bioactive components including flavonoids, triterpenoids, ketosteroids, and phenolic compounds.

Flavonoids

Flavonoids identified in the plant include quercetin, daidzein, and genistein. Phytochemical investigation of Cissus quadrangularis growing in Nigeria led to the isolation of two flavonoids identified as quercetin and kaempferol. Flavonoids such as quercetin and rutin are evaluated as active compounds in the range of 0.01%–0.02% in aerial parts and analyzed by HPLC and UV spectrophotometry.

Stilbenes and Resveratrol Analogues

Phytochemical investigation led to the identification of three new stilbene derivatives — Quadrangularin A, B, and C — together with four known ones: resveratrol, piceatannol, pallidol, and parthenocissine A. The leaves specifically contain resveratrol, piceatannol, pallidol, parthenocissus, and alicyclic lipids.

Triterpenoids

The stem has been reported to contain two asymmetric tetracyclic triterpenoids (onocer-7-ene-3α,21β-diol and onocer-7-ene-3β,21α-diol) and two steroidal principles. The hexane extract of aerial parts has been identified to contain certain lipids and triterpenes including friedelan-3-one, taraxerol, and taraxeryl acetate.

Phytosterols and Ketosteroids

The presence of β-sitosterol, δ-amyrin, δ-amyrone, and flavonoids (quercetin) has also been reported. The stem parts contain β-sitosterol, ketosterols, phenols, tannins, vitamin, carotene, calcium oxalate, 31-methyl tritiacontanoic acid, taraxeryl acetate, taraxerol, isopentadecanoic acid, calcium ions, and phosphorus.

Other Bioactive Constituents

Phytochemical analyses showed high levels of ascorbic acid (Vitamin C), carotene, anabolic steroidal substances, and calcium. Two new iridoids identified from the plant include 6-0-[2,3-dimethoxy]-trans-cinnamoyl catalpol and 6-0-meta-methoxy-benzoyl catalpol, along with picroside-I. Root powder provides a source of mineral resources including potassium (67.5 mg), calcium (39.5 mg), zinc (3.0 mg), sodium (22.5 mg), and iron.

4. Established and Proposed Mechanisms of Action

Bone Healing and Osteogenic Activity

The bone healing activity of Cissus quadrangularis has been claimed to be related to its ability to act as a glucocorticoid antagonist. Modern studies suggest it stimulates osteoblast activity (cells that build bone) while reducing osteoclast activity (cells that break bone down). The plant's ketosteroids and flavonoids are reported to enhance osteoblast activity and accelerate fracture healing. A preclinical study published in PMC examined CQ's effect on RANKL-induced osteoclastogenesis: oral administration of a variety of CQ extracts and its phytoestrogenic steroids augments bone health via early regeneration and quick mineralization in animal models of osteoporosis.

In a rat model, the increase in absolute weight was appreciable in the CQ-aqueous extract treated group. Similarly, with respect to bone parameters, mean bone density, strength, and calcium content were found to be highest in the group treated with CQ-aqueous extract compared to groups treated with other extracts. However, one study did not find a correlation between ketosteroid content obtained by conventional methods and its biological effects, indicating that claims of ketosteroid content need not necessarily correlate to biological effects and warrants extensive phytochemical characterization of active principles.

Anti-inflammatory Mechanisms

In acute phases of inflammation, CQ inhibited edema formation in rat ears induced by ethyl phenylpropiolate as well as paw edema induced by carrageenan and arachidonic acid. It is likely that CQ is a dual inhibitor of arachidonic acid metabolism. CQ extract suppressed the mRNA expression of inflammatory mediators including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX), as well as pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and matrix metalloproteinases (MMP-2, MMP-3, MMP-9, and MMP-13), indicating strong anti-inflammatory and cartilage-protective effects.

Venotonic Effects

CQ exerted a venotonic effect on isolated human umbilical vein similarly to the mixture of bioflavonoids (90% diosmin and 10% hesperidin). These results confirmed the traditional use of C. quadrangularis for the treatment of pain and inflammation associated with hemorrhoid as well as reducing the size of hemorrhoids.

Metabolic and Adipose-Related Mechanisms

The ability of Cissus quadrangularis extracts to reduce weight has been confirmed. This activity may be related to its ability to inhibit key enzymes of metabolism such as pancreatic lipase, α-amylase, and α-glucosidase in vitro, all of which could contribute to weight reduction. A 2021 Scientific Reports study examined white adipocyte mechanisms: CQ treatment in obese humans significantly decreased waist circumference at weeks 4 and 8 compared with baseline values (p < 0.05), and significantly decreased hip circumference at week 8. Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels (p < 0.05).

Analgesic Activity

In the analgesic test, CQ provoked a significant reduction in the number of writhes in the acetic acid-induced writhing response in mice. CQ also significantly reduced licking time in both phases of the formalin test. These results suggest peripheral and central analgesic activity of CQ.

Antiulcer Activity

The antiulcer activity of Cissus quadrangularis is attributed to the enhancement of mucosal defense mechanisms and the reduction of gastric secretions.

5. Scientific Evidence by Area of Use

5.1 Bone Fracture Healing

Traditional basis: It is documented in Ayurvedic medicine for its effectiveness in bone fracture healing.

Human/clinical evidence: A study in nine people observed that taking 500 mg of Cissus quadrangularis three times per day for six weeks helped speed the healing of fractured jaw bones. (This was a pilot study by Singh et al. [2016], published in PubMed, with only nine subjects — see section on limitations.) A 3-month study in 60 people showed that taking 1,200 mg of Cissus quadrangularis daily promoted fracture healing and increased levels of a specific protein required for bone formation.

Numerous clinical studies have reported that treatment with CQ at a dose of 1.2–10 g/day for 4–12 weeks accelerated bone fracture healing without any severe adverse events. Previous pre-clinical and clinical studies revealed that administration of CQ at a dose of 1.2 to 10 g/day for one to three months fast-tracked the healing of bone fracture leading to bone setting with no noticeable side effects.

Systematic review evidence: A systematic review and meta-analysis published in Phytotherapy Research (Sawangjit et al., 2017) included nine RCTs with 1,108 patients: effects of Cissus on hemorrhoid symptoms were not different from any comparators, but it had significant effects on bone pain. Quality of evidence based on GRADE indicated low quality for bone fractures. A 2025 systematic review and meta-analysis (BMC Complementary Medicine and Therapies) searched PubMed, Embase, Scopus, and the Cochrane Library up to April 2025: The study included 1,108 patients and investigated both CQ alone and in combination products. Results indicated significant improvements in bone pain and metabolic parameters with CQ combinations. However, the pooled results for each outcome were based on studies using different formulations of CQ products, comparators, and a relatively small sample size, which may have contributed to imprecise estimates or findings influenced by variability and uncertainty.

Evidence strength: Preliminary to moderate. Positive signals exist in small RCTs and pilot studies, but overall quality remains low by GRADE criteria and larger, better-controlled trials are needed.

5.2 Osteoporosis and Bone Mineral Density

CQ, popularly known as Hadjod (bone setter) in Hindi, is a traditional medicinal herb exhibiting osteoprotective potential in various bone diseases, especially osteoporosis and fractures. However, the cellular mechanisms underpinning its direct effect on bone health through altering the host immune system have not been fully elucidated.

A preclinical study highlighted the potential of CQ in decreasing both pain and swelling along with accelerating the healing of fractured jaws. Histology data revealed that CQ administration had no cytotoxic effect on different organs of the body, and no change in body weight was observed after CQ administration.

A randomized placebo-controlled trial in postmenopausal women with osteopenia (Benjawan et al., 2022, published in Phytomedicine) assessed CQ's effect on delaying bone loss. Despite its promising therapeutic potential, significant gaps remain in understanding its effects on bone health at the molecular and systemic levels.

Evidence strength: Mostly preclinical (animal models) with limited human RCT data. Mechanistic evidence is emerging but clinical translation requires larger trials.

5.3 Obesity and Metabolic Syndrome

Key clinical trials: The most extensive human evidence comes from a series of randomized double-blind placebo-controlled studies conducted by Julius Oben and colleagues at the University of Yaoundé I, Cameroon.

One study (Oben et al., 2006; Lipids in Health and Disease) was a randomized, double-blind, placebo-controlled design involving 123 overweight and obese persons (47.2% male; 52.8% female; ages 19–50). The 92 obese (BMI >30) participants were randomized into three groups: placebo, formulation/no diet, and formulation/diet (2,100–2,200 calories/day). At the end of the trial period, statistically significant net reductions in weight and central obesity, as well as in fasting blood glucose, total cholesterol, LDL-cholesterol, triglycerides, and C-reactive protein were observed in participants who received the formulation, regardless of diet.

A 2007 study (Oben et al.; Lipids in Health and Disease) compared a proprietary extract of CQ (CQR-300) to a proprietary formulation containing CQR-300 (CORE) on weight, blood lipids, and oxidative stress in overweight and obese people. The double-blind placebo-controlled design involved initially 168 overweight and obese persons (38.7% males; 61.3% females; ages 19–54), of whom 153 completed the study. The dosages tested were 300 mg (CQR-300) or 1,028 mg (CORE) per day in two doses.

One double-blind placebo-controlled study showed a reduction in weight of 11.3 ± 0.8% in the obese group and 8.4 ± 1.1% in the overweight group compared with placebo groups after 8 weeks of the trial.

The study in obese and overweight Cameroonians showed that supplementation of 300 mg/day CQ extract (CQR-300) with no dietary restriction for 8 weeks decreased body weight, waist circumference, blood glucose levels, and LDL cholesterol levels but not body fat percentage when compared to the baseline values.

Meta-analytic evidence: Effects of Cissus combination products on body weight reduction, LDL, triglycerides, total cholesterol, and fasting blood sugar were superior to placebo, with weighted mean differences of −5.19 kg (−8.82, −1.55), −14.43 mg/dL (−20.06, −8.80), −37.50 mg/dL (−48.71, −26.29), −50.50 mg/dL (−70.97, −30.04), and −10.39 mg/dL (−14.60, −6.18), respectively.

Evidence strength: Moderate for combination products. Quality of evidence for body weight reduction is high per GRADE. However, for obesity/overweight, only combination products are pooled and show benefit; high-quality studies using CQ alone remain needed. A notable limitation is that the majority of the positive obesity trials were conducted by the same research group (Oben et al.) — independent replication is limited.

5.4 Hemorrhoids

One clinical study used CQ powder at a dose of 3 g/day for four days, then 2 g/day for three days (n = 240 patients, 7-day duration) with endpoints of hemorrhoidal pain and inflammation reduction (Panpimanmas et al., 2010).

A 2021 pilot clinical study in PMC evaluated rectal suppositories containing a combined CQ and Acmella paniculata extract versus a commercialized suppository (hydrocortisone/cinchocaine) in 105 hemorrhoid outpatients from eight hospitals in northern Thailand: hemorrhoid outpatients (n = 105) with different severity grades (I, II, or III) were included and were randomly allocated to two groups: CQ-AP group (n = 52) or the commercialized rectal suppository group (n = 53). Patients in the commercialized rectal suppository group experienced a higher incidence of adverse events, including anal pain and bleeding. The rectal suppositories containing a combined extract of CQ and AP showed potential in alleviating hemorrhoidal symptoms with a good safety profile.

Evidence strength: Effects of Cissus on hemorrhoid symptoms were not different from comparators in the systematic review meta-analysis. While CQ is included on the Thai National List of Herbal Products for hemorrhoids, the meta-analytic evidence does not demonstrate superiority over active comparators. Evidence quality is moderate to high per GRADE for this specific indication in the Thai context, but the benefit over established treatments is unclear.

5.5 Joint Health and Osteoarthritis

CQ extract suppressed mRNA expression of inflammatory mediators including iNOS, COX-2, 5-LOX, pro-inflammatory cytokines, and MMPs, indicating strong anti-inflammatory and cartilage-protective effects. CQE exhibits significant therapeutic potential in managing osteoarthritis by targeting multiple aspects of disease progression including inflammation, cartilage degradation, and bone erosion. Further research is needed to explore long-term efficacy, safety, and the molecular mechanisms of CQE, as well as to validate these findings in human clinical trials.

Evidence strength: Primarily in vitro and preclinical. Dedicated human RCTs for osteoarthritis using CQ specifically are lacking as of current literature.

5.6 Gastrointestinal and Antiulcer Effects

Pharmacological uses include cell reinforcement, free radical scavenging, anti-microbial activity, bone regeneration, anti-ulceration, pain relief, mitigation, and diuresis. Its antiulcer activity is attributed to the enhancement of mucosal defense mechanisms and the reduction of gastric secretions.

Evidence strength: Primarily preclinical (animal models). Human clinical evidence for antiulcer effects is not established.

5.7 Antidiabetic Effects

Antidiabetic potential of Cissus quadrangularis is confirmed through studies on alloxan and streptozotocin-induced diabetic models. The human metabolic studies described above (Oben et al.) showed improvements in fasting blood glucose as a secondary outcome, but dedicated human antidiabetic trials are limited.

Evidence strength: Animal/preclinical evidence only for diabetes specifically. The human metabolic syndrome trials show glucose improvements as a secondary outcome only.

5.8 Antioxidant Effects

The unique chemical constituents of C. quadrangularis such as flavonoids and indanes, as well as phytosterols and keto-steroids, have shown promise as powerful and efficient antioxidants. The antioxidant capacity of Cissus quadrangularis, facilitated by its secondary metabolites, supports its use in combating oxidative stress-related conditions.

Evidence strength: Primarily in vitro. Antioxidant effects are consistent across multiple laboratory assay methods.

6. Dosage Forms and Dosages Reported in Clinical Studies

The following dosages and durations are drawn directly from published clinical and pre-clinical research:

• 500 mg capsule three times daily for 6 weeks — evaluated for osteogenic effects in maxillofacial fracture healing (n = 5; pilot study).
• 300 mg/day (CQR-300) or 1,028 mg/day (CORE), administered in two divided doses — evaluated in a double-blind placebo-controlled obesity/oxidative stress trial; 168 subjects, ages 19–54.
• Multi-ingredient formulation containing CQ — administered to 123 overweight and obese participants over an 8-week randomized, double-blind, placebo-controlled trial.
• 3 g/day for 4 days, then 2 g/day for 3 days (CQ powder) — evaluated for hemorrhoidal pain and inflammation in 240 patients (Panpimanmas et al., 2010).
• 1,200 mg/day for 3 months — evaluated in a 60-person study for fracture healing and bone-formation protein levels.
• 1.2–10 g/day for 4–12 weeks — the range reported across numerous clinical studies of fracture healing, without severe adverse events.
• 0, 100, 1,000, and 2,500 mg/kg body weight/day for 90 days — doses evaluated in the subchronic toxicology (rat) study of CQR-300 (Kothari et al., 2011).

Standardization of commercial extracts varies. Some commercial preparations are standardized to 2.5% ketosteroids per capsule.

7. Safety Considerations

General Tolerance in Human Studies

Based on studies to date, Cissus extracts appear to be exceedingly safe and free of adverse effects at the doses commonly used. No serious adverse effects were reported in the systematic review and meta-analysis of nine RCTs (1,108 patients). CQ does not cause serious adverse drug events based on the evidence assessed in the Thai clinical literature.

Reported Minor Adverse Effects

Products containing Cissus quadrangularis can cause side effects such as headache, intestinal gas, dry mouth, diarrhea, and insomnia. However, there is not enough information to know how often these side effects might occur.

Subchronic Toxicology (Animal Studies)

In the subchronic study, Sprague-Dawley rats (20/sex/group) were administered CQR-300 at dose levels of 0, 100, 1,000, and 2,500 mg/kg body weight/day for 90 days. No treatment-related clinical signs of toxicity, mortality, or changes in body weights, body weight gain, or food consumption were noted. Functional observation tests and ophthalmological examination did not reveal any changes. No toxicologically significant treatment-related changes in hematological, clinical chemistry, urine analysis parameters, and organ weights were noted.

The results of mutagenicity studies as evaluated by Ames assay, in vitro chromosomal aberration, and in vivo micronucleus assay did not reveal any genotoxicity of CQR-300. Based on the subchronic study, the no-observed-adverse-effect level (NOAEL) for CQR-300 was determined as 2,500 mg/kg body weight/day — the highest dose tested.

Long-Term and Combination Use Safety

The results of studies in rats and mice, the cell culture studies, and the three clinical studies in humans taken together with the long history of traditional medicinal use indicate that Cissus stem powder and dried extracts given daily for extended periods of time (up to 10 weeks in humans and 90 days in rats) do not produce serious adverse events.

Limitations of Safety Data

In few cases have specific physiological effects been related to identifiable constituents. Better standardization of extracts and more well-controlled human studies are required. There are no published long-term human safety trials (beyond 10–12 weeks), and specific data on drug interactions, effects in pregnancy, lactation, pediatric populations, or with concurrent pharmaceutical use are not established in the peer-reviewed literature reviewed.

Anabolic Claims

No studies have been conducted demonstrating that Cissus exhibits anabolic and body-building activities in humans. Despite the frequent marketing of Cissus quadrangularis extracts for bodybuilding purposes, this claim lacks clinical support.

8. Body Systems and Health Areas of Association

• Musculoskeletal system: Bone fracture healing, osteoporosis prevention, osteopenia management, joint pain, cartilage protection.
• Metabolic system: Obesity, central adiposity, hyperlipidemia, hyperglycemia, metabolic syndrome.
• Gastrointestinal system: Hemorrhoids (venotonic and anti-inflammatory effects), peptic ulcer (preclinical), digestive complaints.
• Cardiovascular system: LDL and triglyceride reduction (as secondary outcomes in metabolic syndrome trials).
• Immune/inflammatory system: COX-2 inhibition, pro-inflammatory cytokine suppression, antioxidant activity.
• Analgesic: Peripheral and central pain modulation.

Recent studies highlight its potential to support bone health, address metabolic disorders, and serve as a food fortifier to improve nutritional value. Although C. quadrangularis has long been used traditionally and shows promising pharmacological properties, further clinical research is needed to confirm its safety and effectiveness.

References

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