IngredientesThe term pentacyclic alkaloids, as used in the dietary supplement and natural products context, most commonly refers to pentacyclic oxindole alkaloids (POAs) — a structurally distinct class of indole-derived alkaloids characterized by a five-ring (pentacyclic) core scaffold built around an oxindole nucleus. These are the principal bioactive marker compounds of Uncaria tomentosa and its related species, and they are distinct from the broader category of pentacyclic triterpenoids (such as ursolic acid, oleanolic acid, or betulinic acid) that also bear the "pentacyclic" descriptor in some literature. This article focuses on the pentacyclic oxindole alkaloids as the primary class of pharmacologically investigated pentacyclic alkaloids in the dietary supplement context.
Uncaria tomentosa (Ut) is a Rubiaceae widely used in Peru's traditional medicine, mainly known by the vernacular name of Cat's Claw due to its morphological aspects, and found in tropical low mountain forests of Central and South America. This species grows at altitudes between 600 and 1000 m in tropical low mountain forests of Central and South America, from Belize and Guatemala to Peru, Venezuela, Trinidad, Suriname, Colombia, Bolivia, and Brazil.
In the Amazon rainforest there are two important Uncaria species known as "cat's claw": Uncaria tomentosa (Willd. ex Schult.) DC. and Uncaria guianensis (Aublet) Gmell. These species are popularly known as "cat's claw" and have attracted attention for their value in medicine, displaying a wide range of pharmacological activities, such as anticancer, anti-inflammatory and immunomodulation effects. Most commercial preparations of cat's claw in the United States contain U. tomentosa.
U. tomentosa and U. guianensis species are found in South America and are lianas, or high-climbing, twining, woody vines growing up to 305 m in length and several centimeters in diameter. Both species are known in Peru as uña de gato (Spanish for cat's claw). Large amounts of U. guianensis are collected in South America for the European market, while American sources prefer U. tomentosa.
Oxindole has emerged as a valuable scaffold in medicinal chemistry possessing a diverse range of pharmacological activities. Its value has further been increased by its natural occurrence as alkaloids in a variety of plants. It was first extracted from the cat claw's plant Uncaria tomentosa found in the Amazon rainforest and other tropical areas of South and Central America. Traditionally, as well as in present emerging therapeutic potential, the oxindole nucleus has captured the interest of medicinal chemists.
The plant is known as 'uña de gato', 'samento', 'minsho-mentis' and 'garabato' and is revered as 'the life-giving vine of Peru'. In some European commercial traditions, POA-enriched extracts are sold under trade names such as Saventaro or C-Med-100.
The parts most often used are the inner bark and root bark, typically dried and made into tea, tinctures, or standardized extracts. A critical phytochemical distinction exists within this species: U. tomentosa exists in two distinct chemotypes.
The first chemotype, which contains pentacyclic oxindole alkaloids (POAs), is regarded by some researchers as the most active component of the cat's claw plant and contains just a few — or even none — tetracyclic oxindole alkaloids (TOAs). The second chemotype contains predominantly TOAs, both with no POAs at all and with a considerable amount of POAs. The TOAs are believed to be POA antagonists with respect to the POAs' desirable effects, and therefore it is important to tell the two chemotypes from one another. Thus, the determination of the chemotype is crucially important in the plant's analysis and processing for the purpose of obtaining a pharmaceutical preparation. This is due to the fact that the pentacyclic and tetracyclic alkaloids possess different activity mechanisms, and may even be antagonists to each other.
There is an increasing demand for medicinal extracts with biological activity attributed mainly to oxindole alkaloids (OA), where the ratio between tetracyclic (TOA) and pentacyclic oxindole alkaloids (POA) determines its feasibility for medicinal applications. The ratio is affected by distinct factors including the dynamics of environmental conditions during seasons.
Several formulations of cat's claw (e.g., tinctures, decoctions, capsules, extracts, and teas) are available in the market. Cat's claw is prepared traditionally as a hot tea to be drunk either hot or cold as a supplement in the treatment of many human disorders. By 1997, more than 50 dietary supplement manufacturers in the United States were offering cat's claw products.
Uncaria tomentosa is a Rubiaceae used for at least 2000 years among some Peruvian tribes, especially the Asháninka. Cat's claw (U. tomentosa) has been used medicinally by the Aguaruna, Asháninka, Cashibo, Conibo, and Shipibo tribes of Peru for at least 2,000 years. The Asháninka Indian tribe in central Peru has the longest recorded history of use of the plant.
Researchers have investigated the use of the plant by the Asháninka tribe of Peru, who use the plant as a general health tonic, contraceptive, anti-inflammatory agent for the gastrointestinal tract, and as a treatment for diarrhea, rheumatic disorders, acne, diabetes, cancer and diseases of the urinary tract.
Uncaria tomentosa is an important medicinal plant in the pharmacopoeia of the Asháninka Indians in Peru. U. tomentosa is also referred to as "savéntaro," or powerful plant, and as such was believed to possess good spirits that could repair disruptions in body-spirit interactions with such conditions as anxiety. Indeed, specialized healers in Peru boiled sliced root bark of U. tomentosa to create a bitter medicinal drink to address anxiety.
A decoction of Ut bark, root and leaves is used traditionally for different health problems, including arthritis, weakness, viral infections, skin disorders, abscesses, allergies, asthma, cancer, fevers, gastric ulcers, haemorrhages, inflammations, menstrual irregularity, rheumatism, urinary tract inflammation and wounds, among others, which gave rise to scientific and commercial interest.
Cat's claw (U. tomentosa) has been used medicinally by the Aguaruna, Asháninka, Cashibo, Conibo, and Shipibo tribes of Peru for at least 2,000 years. The medicinal system of the Asháninka Indians in Peru is portrayed. Three categories of medical disorders and healers are recognized. A human is viewed to consist of a physical and a spiritual being who communicate with each other by means of a regulating element. The significance of Uncaria tomentosa (Willd.) DC. (Rubiaceae), locally known as uña de gato, in traditional medicine is emphasized by its exclusive use by priests to influence this regulation.
Indigenous tribes in Piura use cat's claw to treat tumors, inflammations, rheumatism, and gastric ulcers. Other Peruvian indigenous tribes use cat's claw to treat diabetes, urinary tract cancer in women, hemorrhages, menstrual irregularity, cirrhosis, fevers, abscesses, gastritis, and rheumatism.
Scientific and commercial interest in U. tomentosa developed primarily during the 20th century, originating from documented traditional use. Rumours of miraculous healings evoked scientific and commercial interest which can be traced back at least a quarter of a century. A 2005 review of the scholarly literature on Cat's Claw indicates there is supporting evidence toward its use in treating cancer, inflammation, viral infection and vascular conditions, and for its use as an immunostimulant, antioxidant, antibacterial and CNS-related agent.
U. tomentosa is rich in alkaloids, including tetracyclic indole, tetracyclic oxindole, pentacyclic indole, pentacyclic oxindole, and glycoindole alkaloids. It also contains triterpenoids derived from quinovic acid and polyphenols.
The six principal pentacyclic oxindole alkaloids identified in U. tomentosa are: isomitraphylline, isopteropodine, mitraphylline, pteropodine, speciophylline, and uncarine F. The principal tetracyclic oxindole alkaloids present in the other chemotype include isorynchophylline and rynchophylline. Mitraphylline and isopteropodine are considered the chemical markers of this species (USP, 2023).
Key compounds common to the genus are primarily the indole and oxindole alkaloids, pentacyclic triterpenoids, and flavonoids. Alkaloids found in most of the species include hirsuteine, hirsutine, mitraphylline, and rhynchophylline. The terpenoids include cytotoxic phenolic acid esters, uncarric acids, and glycosides, while other novel compounds include quinic acids, sterols, and coumarins.
U. tomentosa is rich in many phytoconstituents such as oxindole and indole alkaloids, glycosides, organic acids, proanthocyanidins, sterols, and triterpenes. Oxindole alkaloids (pentacyclic oxindole alkaloids (POA) and tetracyclic oxindole alkaloids (TOA)) have been recognized as fingerprint of this species in some pharmacopeias, and several pharmacological activities are linked to this kind of alkaloids.
An improved HPLC method for the determination of pentacyclic oxindole alkaloids in Uncaria tomentosa (Cat's Claw) has been described. The antitumor activity of Uncaria tomentosa, a native vine from the Amazonian rainforest, has been ascribed to pentacyclic oxindole alkaloids occurring in its bark. Former studies have shown that this activity, as well as its intensity, depends on whether cat's claw alkaloids occur as original compounds or isomerized derivatives.
Mitraphylline, speciophylline, uncarine F, and, to a lesser degree, pteropodine were more susceptible to isomerization under the incubation conditions — a finding with important implications for standardization and quality control of commercial preparations.
Pentacyclic but not tetracyclic oxindole alkaloids from Uncaria tomentosa (Willd.) DC. (Rubiaceae) induced EA.hy926 endothelial cells to release some yet to be determined factor(s) into the supernatant; this factor was shown to significantly enhance proliferation of normal human resting or weakly activated B and T lymphocytes. In contrast, proliferation of normal human lymphoblasts and of both the human lymphoblastoid B cell line Raji and the human lymphoblastoid T cell line Jurkat was inhibited significantly while cell viability was not affected. Tetracyclic oxindole alkaloids dose-dependently reduce the activity of pentacyclic oxindole alkaloids on human endothelial cells.
Treatment of THP-1 monocyte-like cells with Uncaria tomentosa for 24 h can inhibit the ability of lipopolysaccharide (LPS) to increase TNF-α production by inhibiting the activation of the NF-κB p52 subunit. The active metabolites decreased expression of nuclear factor kappa B (NF-κB) and decreased tumor necrosis factor (TNF) levels. Cat's claw is a potent inhibitor of production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha in vitro.
Interestingly, U. tomentosa extracts can either stimulate or inhibit the release of different cytokines, depending on the animal's health status or the modeled disease. This was observed for IL-1: in a sepsis model, U. tomentosa increased IL-1 levels throughout the infection; in a non-alcoholic fatty liver disease model, extracts of U. tomentosa decreased IL-1 levels. Some authors refer to this regulatory effect as immunomodulation.
Alkaloid-rich extract from Uncaria tomentosa (cat's claw) has been reported to cause apoptosis in cancer lines. Oxindole pentacyclic alkaloids of the plant are responsible for this effect, yet their biological mechanism of action is not fully understood. Computational results indicate that inhibition of several important targets including dihydrofolate reductase and mouse double minute 2 homolog (MDM2) may be responsible for the biological activity of the alkaloids. The docking results also show that the alkaloids can interact with Dvl-2, Akt-2, and leukotriene A4 hydrolase.
Cat's claw contains many different alkaloids that have been shown to have antiproliferative effects in breast cancer cells, leukemic and lymphoma cell lines; these are not cytogenic or mutagenic, but rather exert these effects through an induction of apoptosis (programmed cell death).
Uncaria tomentosa water extracts (C-Med-100) have been shown to enhance DNA repair, mitogenic response and leukocyte recovery after chemotherapy-induced DNA damage in vivo.
It has been demonstrated that Uncaria tomentosa exerts an antiviral effect on human monocytes infected with dengue virus 2 (DENV-2) and herpes simplex virus type 1 (HSV-1).
The most rigorously studied clinical application of POA-rich U. tomentosa extract is rheumatoid arthritis (RA). To evaluate safety and clinical efficacy of a plant extract from the pentacyclic chemotype of Uncaria tomentosa (UT) in patients with active rheumatoid arthritis (RA), forty patients undergoing sulfasalazine or hydroxychloroquine treatment were enrolled in a randomized 52-week, 2-phase study. During the first phase (24 weeks, double-blind, placebo-controlled), patients were treated with UT extract or placebo. In the second phase (28 weeks) all patients received the plant extract.
Twenty-four weeks of treatment with the UT extract resulted in a reduction of the number of painful joints compared to placebo (by 53.2% vs. 24.1%; p = 0.044). Patients receiving the UT extract only during the second phase experienced a reduction in the number of painful (p = 0.003) and swollen joints (p = 0.007) and the Ritchie Index (p = 0.004) compared to the values after 24 weeks of placebo.
This small preliminary study demonstrates relative safety and modest benefit to the tender joint count of a highly purified extract from the pentacyclic chemotype of UT in patients with active RA taking sulfasalazine or hydroxychloroquine. The study's small size (n=40) and the fact that all patients were already on disease-modifying antirheumatic drugs represent important limitations.
One study of 40 participants using 60 mg of cat's claw as an adjunctive therapy for rheumatoid arthritis was done over 52 weeks. All participants had active rheumatoid arthritis and were taking either sulfasalazine or hydroxychloroquine treatment. Results indicated a modest improvement in joint tenderness with few side effects.
Human tests with U. tomentosa were carried out in patients with osteoarthritis and rheumatoid arthritis and demonstrated that it was able to reduce pain, morning stiffness and swelling joints. Treatment of mice with Uncaria extracts (or components) can inhibit carrageenan-induced edema and inflammation by 40%.
Evidence strength assessment: For both RA and osteoarthritis, clinical evidence is preliminary. The available randomized controlled trials are small, short to medium duration, and often combine cat's claw with other treatments, limiting attribution of effects solely to the POA fraction. There have been very few high-quality clinical trials (studies done in people) of cat's claw. There's no conclusive scientific evidence based on studies in people that supports using cat's claw for any health purpose.
The most promising findings in systematic review were observed for crude aqueous bark extracts (72-h incubation) against squamous cell carcinoma, and POA-rich extracts against prostate cancer and leukemia. In contrast, tetracyclic oxindole alkaloid (TOA)- and proanthocyanidin (PAC)-rich fractions showed limited cytotoxicity. Most extracts were non-toxic to normal cells, except for the crude aqueous bark extract, which exhibited cytotoxicity in keratinocytes.
U. tomentosa extracts exhibited selective cytotoxicity in some cancer cell lines. The most promising findings were observed for crude aqueous bark extracts (72-h incubation) against squamous cell carcinoma and POA-rich extracts against prostate cancer and leukemia. In contrast, tetracyclic oxindole alkaloid (TOA)- and proanthocyanidin (PAC)-rich fractions showed limited cytotoxicity. Most extracts were non-toxic to normal cells, except for the crude aqueous bark extract, which exhibited cytotoxicity in keratinocytes.
In one study, the effectiveness of U. tomentosa as an anti-cancer agent was assessed using the growth and survival of B16-BL6 mouse melanoma cells. B16-BL6 cell cultures treated with both ethanol and PBS extracts of U. tomentosa displayed up to 80% lower levels of growth and increased apoptosis compared to vehicle controls. Treatment with ethanolic extracts was much more effective than treatment with aqueous extracts. U. tomentosa was also shown to inhibit B16-BL6 cell growth in C57/bl mice in vivo. Mice injected with both the ethanolic and aqueous extracts showed a 59 ± 13% decrease in tumour weight and a 40 ± 9% decrease in tumour size.
Two published randomized clinical trials examined U. tomentosa (300 mg/day dry extract) as an adjuvant during chemotherapy:
Evidence strength assessment: In vitro and animal evidence for anticancer activity of POA-rich fractions is promising but largely preclinical. Human clinical evidence is limited to small adjuvant trials with mixed results. U. tomentosa has potential as a source of selective anticancer agents, particularly through crude aqueous bark and POA-rich extracts. The observed cytotoxic effects vary considerably depending on the extraction method and chemical composition, underscoring the need for standardization in future studies. No large-scale randomized controlled trials in oncology have been completed.
Pharmacological studies using different U. tomentosa extracts have confirmed their antiasthmatic, antidiabetic, antimicrobial, anticancer, antioxidant, and anti-inflammatory properties, as well as their neuroprotective effects against Parkinson's and Alzheimer's diseases.
A key feature of POA activity is the dual regulatory action on the immune system. U. tomentosa extracts preserve CD4+ and CD8+ T cells and possibly stimulate cytokines that favor the polarization of CD4+ Th2 cells. These cells play an important role in autoimmune diseases, such as rheumatoid arthritis, by modulating the excessive activity of Th1 cells. Regarding the effectiveness of pentacyclic oxindole alkaloids in reducing inflammatory processes, the results are conflicting.
Evidence strength assessment: Immunomodulatory effects of POAs are well-documented in cell and animal models. Human evidence is supportive but limited by the small size and number of clinical trials.
The effect of the C-Med-100 supplement (a standardized aqueous extract) was evaluated in a human volunteer study. Twelve apparently healthy adults were randomly assigned into 3 groups. One group was daily supplemented with a 250 mg tablet containing an aqueous extract of Uncaria tomentosa of C-Med-100, and another group with a 350 mg tablet, for 8 consecutive weeks. DNA repair after induction of DNA damage by a standard dose of hydrogen peroxide was measured 3 times before supplement and 3 times after. There were no drug-related toxic responses to C-Med-100 supplement when judged in terms of clinical symptoms, serum clinical chemistry, whole blood analysis and leukocyte differential counts.
Evidence strength assessment: The DNA repair study is promising but very small (n=12 per group) and limited to healthy volunteers. Replication in larger, disease-specific populations is needed.
Biological activities of U. tomentosa have been examined against various microorganisms and parasites, including pathogenic bacteria, viruses, and Plasmodium, Babesia and Theileria parasites. It has been demonstrated that Uncaria tomentosa exerts an antiviral effect on human monocytes infected with dengue virus 2 (DENV-2) and herpes simplex virus type 1 (HSV-1).
Regarding SARS-CoV-2, after 48 hours of treatment, U. tomentosa showed an inhibition of 92.7% of SARS-CoV-2 at 25.0 μg/mL (p < 0.0001) by plaque reduction assay on Vero E6 cells. In addition, U. tomentosa induced a reduction of 98.6% (p = 0.02) and 92.7% (p = 0.03) in the CPE caused by SARS-CoV-2 on Vero E6 cells at 25 μg/mL and 12.5 μg/mL, respectively. However, these findings are in vitro only.
Evidence strength assessment: Antiviral data for cat's claw alkaloids are predominantly in vitro or from cell culture models. There's no conclusive scientific evidence based on studies in people that supports using cat's claw for any health purpose, including COVID-19.
Uncaria tomentosa total alkaloids exert a beneficial effect on memory impairment; this effect is partly attributed to the oxindole alkaloids. Neuroprotective effects against Parkinson's and Alzheimer's diseases have been described in pharmacological studies. These observations, however, derive predominantly from animal and in vitro models. No large-scale human clinical trials of POAs for neurodegenerative disease have been published at the time of writing.
One gram of root bark given 2 to 3 times daily is a typical dose, while 20 to 30 mg of a root bark extract has been recommended. Clinical trials are generally lacking to support appropriate dosages.
A standardized extract containing 8% to 10% carboxy alkyl esters and less than 0.5% oxindole alkaloids has been used in clinical studies in doses of 250 to 300 mg.
In the published rheumatoid arthritis RCT, one study of 40 participants used 60 mg of cat's claw as an adjunctive therapy for rheumatoid arthritis over 52 weeks.
In both published chemotherapy adjuvant trials, the UT group received chemotherapy plus 300 mg of Uncaria tomentosa daily.
In the human DNA repair volunteer study, twelve apparently healthy adults were randomly assigned into 3 groups. One group was daily supplemented with a 250 mg tablet containing an aqueous extract of C-Med-100, and another group with a 350 mg tablet, for 8 consecutive weeks.
The traditional preparation is a decoction: cat's claw is prepared traditionally as a hot tea to be drunk either hot or cold. No standardized traditional dose has been formally established. Commercial products vary widely in alkaloid concentration and chemotype composition.
No adverse effects were reported in the rheumatoid arthritis RCT, which showed the relative safety of a highly purified extract from the pentacyclic chemotype of Uncaria tomentosa in patients with active RA taking sulphasalazine or hydroxychloroquine. Although reports of adverse effects are rare, GI complaints (nausea, diarrhea, stomach discomfort), renal effects, neuropathy, and an increased risk of bleeding with anticoagulant therapy are possible.
Until a full pharmacokinetic profile is investigated it would be prudent to avoid its use in women attempting pregnancy, during pregnancy and lactation. While there are no definitive data, it is plausible that the contraceptive effects of cat's claw are related to its antiproliferative effects and induction of apoptosis. Thus, while conception may still take place, the fetus may be aborted due to the failure of cellular replication and/or differentiation. Historically, the Asháninka used the plant as a contraceptive, which aligns with this mechanistic concern.
Given the immunomodulatory properties of POAs — particularly their capacity to enhance lymphocyte proliferation — caution is warranted in individuals on immunosuppressive regimens, such as organ transplant recipients. Use should be avoided during pregnancy and breastfeeding, and avoided with organ transplants unless supervised.
An increased risk of bleeding with anticoagulant therapy is possible. The mechanism for this is not fully elucidated, but it may relate to the platelet-modulating properties associated with some alkaloid classes. Individuals taking anticoagulant or antiplatelet medications should exercise caution.
The observed cytotoxic and pharmacological effects vary considerably depending on the extraction method and chemical composition, underscoring the need for standardization in future studies. The commercially critical issue of chemotype identity — whether a product contains POA-dominant or TOA-dominant material — is frequently not disclosed on supplement labels, making reproducibility of clinical effects uncertain for consumers.
There is an increasing demand for medicinal extracts with biological activity attributed mainly to oxindole alkaloids, where the ratio between tetracyclic (TOA) and pentacyclic oxindole alkaloids (POA) determines its feasibility for medicinal applications. The ratio is affected by distinct factors including the dynamics of environmental conditions during seasons.
There have been very few high-quality clinical trials of cat's claw. There's no conclusive scientific evidence based on studies in people that supports using cat's claw for any health purpose, including COVID-19. This position reflects the broader limitation of the evidence base: mechanistic and preliminary clinical signals are encouraging but have not been confirmed in large, well-controlled human trials.
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