Cissus is a joint health supplement that is anecdotally popular among martial artists. With the ability to suppress joint inflammation and pain, Cissus appears to be moderately healthy overall and has some interesting anti-osteoporosis and bone regeneration abilities that await further testing
This page features 39 unique references to scientific papers.
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Cissus Quadrangularis is a herbal supplement that is most commonly known for its anti-inflammatory effects (and relief of joint pain) as well as its usage for bone health and increasing the rate of healing associated with fractures. Both of these claims are supported by in vitro studies, and merely await more human trials to assess potency and biological relevance.
Cissus is sometimes touted as a muscle-building agent, for which there is no evidence for (anabolism in a bone cell is not necessarily anabolism in muscle tissue) and its influences on fat metabolism are not highly investigated; it appears to reduce body fat when given to obese persons with metabolic syndrome, but this may be exclusive to unhealthy and obese persons and confer no benefit to normal weight humans. Both are topics needing more evidence behind them.
It does possess estrogenic activity, mostly in rats that are a research model for menopause. It has not been investigated as to whether this estrogenic activity influences male performance or sexuality, however.
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Harjor
The ethanolic extract appears to be more potent than the water soluble extracts for most of the benefits, suggesting that the bioactive compounds are fat soluble
The estrogenic effects have not been investigated in male rats nor humans at this moment in time
The human studies that noted benefits used 150mg (of 2.5% ketosteroid) Cissus Quadrangularis twice a day (300mg total), taken before meals with 8oz of water or so.
Toxicity of Cissus Quadrangularis overdose does not seem to be a pertinent issue, at least in rats, as 5g/kg bodyweight in mice acutely have shown no harm and 3g/kg bodyweight over a period of 90 days showed no harm.
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The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Cissus Quadrangularis has in your body, and how strong these effects are.
| Grade | Level of Evidence |
|---|---|
| A | Robust research conducted with repeated double blind clinical trials |
| B | Multiple studies where at least two are double-blind and placebo controlled |
| C | Single double blind study or multiple cohort studies |
| D | Uncontrolled or observational studies only |
| Level of Evidence | Effect | Change | Magnitude of Effect Size | Scientific Consensus | Comments |
|---|---|---|---|---|---|
| C | Hemorrhoids | 100% See study | No significant influence on hemorrhoids noted. | ||
| C | Weight |   Minor | 100% See study | Weight loss may be secondary to appetite reduction | |
| C | Total Cholesterol | Minor | 100% See study | Reductions in total cholesterol not overly remarkable and confounded with weight loss | |
| C | Triglycerides | Minor | 100% See study | Reduction in triglycerides is not overly potent | |
| C | Plasma Serotonin | Notable | 100% See study | Increase in plasma serotonin was significant (30-39%) and fairly noteworthy, deserves more research. | |
| C | Creatinine | Minor | 100% See study | Minor increase in creatinine | |
| C | Lipid Peroxidation | Minor | 100% See study | Decrease noted is not overly remarkable | |
| D | Bone Healing Rate | 100% See study | More evidence is required, as the one study noting that cissus was ineffective in isolation noted that combination therapy with cissus and calcium was quite effective.... show |
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Cissus Quadrangularis is an Ayurvedic herb used traditionally for digestive, eye and ear diseases, irregular menstruation, and asthma;[1] it is also further suggested to aid in ulcers and accelerate the healing rate of bone fractures.[2] It belongs to the plant family of Vitaceae and is indigenous to India, Malaysia, Sri Lanka, Thailand, and Africa.
As a herb, Cissus Quadrangularis contains a variety of molecules including:
The molecules that tend to be seen as the bioactives of Cissus Quadrangularis are shown below, in particular the asymmetrical triterpenoids seem to be the main component (also known as the ketosteroids).
Cissus Quadrangulus extract (stem) has an anti-oxidative phenolic capacity of 585.40±0.16mg Gallic Acid equivalents/100g.[8] Cissus possesses anti-oxidative properties through its constituent molecules.[8][9]
Cissus Quadrangularis extract, in vitro, has been shown to greatly enhance Insulin-Like Growth Factor signalling (IGF-1, IGF-II, IGF receptor) in bone cells treated with Cissus; specific details can be read in the IGF section.[10]
A general upregulation of Alkaline Phosphatase (ALP) is commonly seen with Cissus.[11][12][13]
The mRNA of the protein Runx2, a transcription factor in bone synthesis, may also be implicated in the mechanisms of Cissus.[11]
One longer term study (4 weeks) found that, in vitro, Cissus extract was able to induce stem cell production into osteoblasts and create more of these cells.[13]
One aspect of Cissus Quadrangularis' pro-bone mass effects are estrogenic in nature. These pro-estrogenic effects are clearly shown with a 75-100mg/kg oral dose of a phytoestrogen enhanced (IND-HE) fraction over the course of 8 weeks in rats.[7][14] These results suggest the Freidelin content is important to the anti-osteoporotic effects, as without said enhancement of Freidelin content a dose 5-fold higher is required to achieve preservation of bone mass.[15]
When investigating components of Cissus Quadrangularis that in isolation exert anti-osteoporotic effects (in particular, anti-resorption and osteogenic) it was found that rutin, agnuside and negundoside, and luteolin.[12] Specific to Cissus, 6-O-{2,3-dimethoxy}-t-cinnamoyl-catalpol appears to have anti-osteoporotic effects and may be an active ingredient, increasing Alkaline Phosphatase activity at concentrations about 1000-fold less than Daidzein.[12]
General phytoestrogens (potent ones such as Freidelin, weaker ones such as daidzein and Quercetin) as well as the catapol molecules may be the cause of osteogenesis, mostly. Required dose of the catapol is low and may be biologically relevant, but no in vivo studies have looked at it in particular
Cissus Quadrangularis is the most frequently used and effective Ayurvetic medicine for the purpose of bone fractures, according to local surveys.[16] Only one human study of moderate quality has investigated this claim[17], despite a plethora of research of questionable quality from decades past.[18][19][20][21][22]
The mechanisms by which this occurs appear to be preserving anabolism when high glucocorticoids are present by acting as a receptor antagonist,[19][18] and also due to the osteogenic actions of Cissus molecules.
A 'well-demonstrated' topic anecdotally, good studies investigating the practical relevance are far and few. It may very well enhance the rate of bone healing, but some higher quality human trials would be appreciated
Cissus Quadrangularis appears to exert anti-osteoporotic effects, attentuating the inherent loss in bone mass associated with aging. Various studies in ovariectomized rats find enhanced bone mass associated with Cissus consumption in the range of 500mg/kg bodyweight daily over 8-12 weeks.[15] These effects are enhanced when the phytoestrogen content is enhanced.[7][14]
The petroleum-ether extract appears to be most well used and potent, suggesting the bioactive components are fat-soluble.
When looked at in vivo, a Cissus extract with a high Friedelin content (IND-HE) was able to increase female rat sexuality at dosages of 75-100mg/kg bodyweight in a research model to mimick menopause. These same rats experienced an increase in circulating Estrogen from 15.83+/-1.8pg/ml to 46.67-52.67pg/ml after ingestion of this Friedelin-enhanced Cissus.[7] Estrogen-like effects, such as uterine size, were increased in correlation with estrogen after 2 months.[7] This same phytoestrogen (friedelin) rich fraction was later shown to prevent bone loss over 8 weeks.[14]
Without said phytoestrogen-rich fraction, a dose 5-fold higher is required to exert anti-osteoporotic effects via estrogen in rats.[23][24]
Cissus Quadrangularis is shown to increase circulating estrogen levels when the phytoestrogen part is enhanced, and may influence estrogen in humans; however, there are no studies addressing this part nor studies in male rats
Compounds in Cissus Quadrangularis have been shown to act as glucocorticoid antagonists in bone tissue, which would reduce their catabolic effects by occupying the receptor.[19][18]
Through Cissus Quadrangularis' ability to act as a glucocorticoid antagonist, it has been proposed to possess anabolic/androgenic activity.[18] At this moment in time, no studies have been held to investigate this hypothesis.
When investigating osteoblasts in vitro, it was found that the ethanolic extract of the aerial parts of Cissus at concentrations of 1ug/mL and 10ug/mL were able to increase mRNA translation of the Insulin-Like Growth Factor-1 receptor (IRS-IR) as well as increase production of IGF-1 and IGF-II with no influence on IGF Binding Protein mRNA (also an increase in the total binding protein content was seen).[10] 1ug/mL was associated with +42.6% and +38.4% IGF-1 mRNA and protein content, respectively, while 10ug/mL increased these by +69.26% and +84.6%. IGF-II at these dosages had its mRNA increased by 35.51% and 77.95%, respectively, and it's protein content by 71.43% and 104%.[10] The mRNA content for the receptor increased 50.66% and 62.66% respectively, and the actual receptor content by 27.39% and 67.8%.
It is hypothesized that these effects are due to the β-sitosterol content, which is a weak agonist for estrogen receptors, with preference for β[25] and estrogen activity in osteoblasts induces IGF activity.[26] However, flavonoids in Cissus (Quercetin and Naringenin mainly) can theoretically also induce IGF production in osteoblasts vicariously though cAMP (activation via PDEs) influencing the AP-1 signalling pathway to influence estrogen receptors.[27][28]
Increases in IGF hormones were seen in bone cells, and have not yet been shown to affect muscle tissue. May be downstream of estrogenic effects, and practical significance of these effects are unknown
At least one in vitro study has implicated the ethanolic extract of Cissus Quadrangularis as a proton pump inhibitor[29] which could be one of the mechanisms by which Cissus Quadrangularis has been shown to protect the stomach from, and reduce the size of pre-existing, ulcers not from heliobactor pylori[30] such as Aspirin or NSAID-induced ulcers.[31][32]
Cissus Quadrangularis (ethanolic extract), in RAW 264.7 macrophages, is able to dose-dependently inhibit NO release as induced by lipopolysaccharide and exert anti-inflammatory effects via inducing Heme-Oxygenase 1, which then inhibits nF-kB nuclear activation.[33] This induction of HO-1 (and the subsequent nuclear translocation of Nrf2) have been by other researchers in the same cell line[2] alongside suppression of proinflammatory cytokines at an IC50 value of approximately 65ug/mL.[2]
Cissus Quadrangularis (acetone extract) has also been shown to inhibit the 5-Lipoxygenase enzyme and both COX enzymes with IC50 values of 20ug/mL, 7ug/mL and 0.4ug/mL for 5-LOX, COX-1 and COX-2 respectively.[2]
After feeding of Cissus Quadrangularis at 10g/100g dietary intake (final amount ingested not stated) in rats with fructose-induced metabolic syndrome, Cissus was able to alleviate most (approximately 66%) of the adverse changes in liver enzymes (ALP, GGT, SGPT, SGOT) while the control group fed Cissus did not have any significant alterations.[8] The metabolically obese group treated with Cissus also experienced an elevation in antioxidant enzymes (Glutathione, Superoxide dismutaste).[8]
Vicariously through its anti-oxidative effects, Cissus is implicated in reducing damage done to hepatocytes via fructose-induced obesity as assessed by histopathological examination.[8]
The stem parts of Cissus Quadrangularis at a high dose of 10g per 100g dietary intake in rats was able to alleviate adverse changes in blood glucose, insulin, and insulin sensitivity seen with fructose-induced obesity.[8] There were no significant effects of Cissus on rats that were not induced with obesity.[8]
In a sample of obese persons (n=72), 300mg Cissus daily standardized to 2.5% ketosteroids was able to reduce body fat levels from 33.07+/-10.26% to 30.81+/-5.92% by 4 weeks and 28.23+/-6.12% by 10 weeks, in which only 10 weeks was significantly different than placebo.[34] This dose was able to reduce body weight by 8lbs over 10 weeks, and was slightly more effective when paired with Irvingia Gabonensis.[34]
Another study utilizing Cissus (standardized to 2.5% ketosteroids and 15% fiber) but with other confounds in the same capsules (Green Tea Catechins and B-vitamins) found that obese persons had a weight reduction of 6.9% over 8 weeks and overweight persons 4.8% over the same time period; pairing a 2200kcal diet with the supplement in obese persons resulted in 8.5% body weight reduction.[35] Obese persons lost 6% of their body fat and overweight persons 4.7% without diet.[35] Another study using this same formulation found similar results, although did not have a group taking only Cissus without a dietary intervention.[36]
As the drastic reductions in body weight seen above are attenuated with dietary intervention, and the method of taking Cissus was with 8oz of water or more before meals, it is possible that Cissus exerts some anti-obesity effects through appetite suppression vicariously though its fiber component.
All human interventions appear to be related to fat mass, and it appears to be an effective weight loss agent in obese persons. No evidence on what mechanisms are practically relevant, nor anything to suggest it works in this manner in thinner people
One toxicology study found that, when using CQR-300 in rats, that a dose of 2500mg/kg bodyweight for 90 days was not associated with any observable side-effects (and established the NOAEL at this level), although some non-toxic changes occurred in blood clotting parameters at the higher doses.[1] Previously, a rat study on dosages up to 3g/kg bodyweight over a period of 3 months did not find any abnormal effects of Cissus supplementation,[37] the last dose (3g/kg) being 100-fold greater than the human therapeutic dose equivalent, and also noted non-toxic changes in blood parameters such as RBC count and clotting time (all within normal physiological range). From these results, it is postulated that a dose of 150g Cissus Quadrangularis daily is free from observable side-effects.[1][37]
Two human trials using Cissus at dosages of 300mg daily (from CQR-300) found no observable side-effects.[36][35]
Appears to be safe at the doses commonly consumed, as toxicity has not been recorded in animal studies or traditionally via Ayurveda. The human studies using 300mg daily did not experience any differences from placebo in regards to side-effects
Cissus has been shown to produce genotoxic effects in vitro using a concentration of 500 and 1000ug/plate.[38] Replicated these tests in revertant colonies failed to replicated the results, and in vivo tests do not show this method of damage;[1] this concern does not appear to be practically relevant at this point in time.
(Common misspellings for Cissus Quadrangularis include Quadrangulus, Quadranglus, Sissus, Cisus, Sisus, Sisis, Quadralangus, Quadralangis)
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