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Uva ursi

Arctostaphylos uva-ursi, also known as uva ursi or bear’s grape, is a plant that grows in cool climates. The leaves of the plant are used in the treatment of urinary tract infections, but more human studies are needed before it can be recommended for supplementation.

Our evidence-based analysis on uva ursi features 44 unique references to scientific papers.

Kamal Patel
Research analysis led by Kamal Patel.
All content reviewed by the Examine.com Team. Published:
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Summary of Uva ursi

Primary Information, Benefits, Effects, and Important Facts

Arctostaphylos uva-ursi, also known as uva ursi or bear’s grape, is a plant found in North America and Eurasia. It is a fruit-bearing plant, and grows in cooler climates suitable for similar berries bears eat.

The leaves of uva ursi are traditionally brewed into a tea and used to improve urinary health.

Current research suggests that uva ursi may be a useful treatment option for urinary tract infections (UTIs), but there is insufficient evidence to support its use for other urinary issues, like kidney stones or bladder damage.

Uva ursi has antibacterial properties because of its main bioactive, arbutin. Arbutin creates a metabolite called hydroquinone glucuronide. When this metabolite is eliminated through urine, it also prevents bacteria from adhering to tissue in the area. This is why uva ursi may be effective at alleviating UTIs.

Though the mechanisms behind uva ursi’s effects are known, there is a lack of human evidence assessing the effect of supplementation on UTIs, so it cannot be specifically recommend at this time.


Things To Know & Note

Is a Form Of

Primary Function:

Also Known As

Arctostaphylos uva-ursi, bearberry, bear's grape, foxberry, crowberry, kinnikinnick, tinnick

Caution Notice

Examine.com Medical Disclaimer

  • Uva ursi may require storage in a dark and air-tight location for shelf life

  • Possible drug interactions due to effects on enzymes involved in drug metabolism (P-glycoprotein and some CYPs including CYP3A4)

How to Take Uva ursi

Recommended dosage, active amounts, other details

The standard uva ursi dose for the treatment of urinary ailments is determined by the arbutin content of the supplement. The recommended dose is between 420-600mg, taken once a day in three doses throughout the day (140-220mg, three times).

Uva ursi tea and capsules are both effective for delivering arbutin to the urinary tract.

Uva ursi supplementation is usually recommended in response to a specific ailment, rather than as a daily preventative. The leaf does not need to be taken with a meal. Supplementation should not last longer than one to two weeks.

Scientific Research on Uva ursi

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1Sources and Composition

1.1Sources and Composition

Arctostaphylos uva-ursi (of the family Ericaceae) is a plant by the common name of uva-ursi with other common names including bearberry, bear's grape, and kinnikinnick (referring to a mixture used in smoking from the Algonquin language[2]). It has been traditionally used in Canada where it is prominently found in the wild, with some usage dating back to ancient Rome, and was usually used for the treatment of kidney stones and other renal disorders when the leaves were brewed into a tea.[2] It is related to the species Arctostaphylos pungens grown in southwestern US and Mexico.[3] 'Uva ursi' itself can be translated to bear grape, named after the apparent consumption of this berry by bears in the regions it is grown.[2]

It has been reported that consumption of the plant at traditionally-used doses may color the urine green[2][4] which intensifies upon exposure to the air due to oxidation of hydroquinone.[5] Its contemporary use is primarily due to its long-standing usage in traditional medicine for the treatment of issues related to painful urination and urinary tract infections (UTIs).[4] It seems to be traditionally used primarily for female usage and not for men, youth, or pregnant women.[4]

Uva ursi, or 'bear's grape' in English, is a fruit-bearing plant which appears to have traditional usage in both North America and Europe for the treatment of urinary conditions in women. It seems to also have the odd side-effect of turning urine a greenish hue, and its medicinal usage in traditional medicine is limited to this one specific use.

The plant Arctostaphylos uva-ursi (leaves unless otherwise specified) contains:

  • Arbutin (hydroquinone-1-O-β-D-glucoside; synonymous with arbutoside), one source citing 100-210mg in three grams of leaves (after steeping in 150mL water[3]) but others varying between 5-15% dry weight of the leaves.[4][5][6][7][8] While relatively unique among plants in its genus (Arctostaphylos ), one study has found comparable levels of arbutin in uva ursi as in Origanum majorana (marjoram)[9]

  • Methylarbutin (up to 4% dry leaf weight[5])

  • Coralagin[10]

  • Piceoside[11]

  • Gallic acid[5] (between 634-980µg/mL in freshly prepared water extracts[12]) also in the form of galloyl arbutin.[5] Gallotannins in general (tannin compounds formed from gallic acid) are claimed to comprise up to 20% of the leaf by dry weight[13]

  • Myrcitrin, a glycoside of myricetin, higher in bulk leaves (4,984-7,786µg/mL) than in encapsulated (517-1,360µg/mL) water extracts according to one study[12]

  • Isoquercitrin, a glycoside of quercetin, in trace amounts in water extracts of leaves (32.8µg/mL) or undetectable[12]

  • Ursolic acid[5]

  • Uvaol[5]

  • Magnesium[14]

  • Manganese[14]

  • Copper[14]

The recommended dose, according to 1998 Commission E (Germany), appears to be a tea of 150mL brewed from 3g of the leaf taken four times a day; as each tea brewed this way is though to confer 100-210mg arbutin the total daily dose varies between 400-840mg.[3]

Other compounds in the leaves include the essential oil component which is predominately linalool (7.3% of the total essential oil) and α-terpineol (7.8%) and predominately composed of terpenoid structures (46.8% total essential oil) and fatty acid-derived compounds (10.7%);[15] there is, overall, 243 unique molecules detectable in the essential oil.[15]

Uva ursi contains a variety of phenolic compounds like most plants, but due to the high arbutin content and relatively low content of most other compounds tested for (with exception to the tannins) it could be seen as essentially a herbal vessel for arbutin.

1.2Physicochemical Properties

It is recommended to store uva ursi preparations in a well-closed container in a dark location for stability.[5] The tea should be used immediately after preparation.[4]

Uva ursi may require darkness and being stored in a container that is air tight for long term storage, particularly if it is already brewed as a tea (as liquid solutions that were once heat treated, such as tea, tend to have reduced stability when compared to the raw leaf).

2Pharmacology

2.1Absorption

Arbutin is stated (via review[6]) to not be hydrolyzed into hydroquinine and glucose in the stomach.

In the small intestine, both the rat and the human appear capable of absorbing arbutin via sodium dependent glucose transporters like most phenylglucosides (small phenolics like hydroquinone bound to glucose).[16]

Tablets of uva ursi (472.5mg dry leaf extract containing 105mg arbutin) and loose leaves (945mg containing 210mg arbutin) both appear to be absorbed after oral ingestion as assessed by urinary elimination (which requires absorption from the gastrointestinal tract at some point) with an approximate bioavailability of between 67.3-70.3% for the main bioactive arbutin.[17]

Arbutin appears to travel to the intestines where it is absorbed intact via glucose transporters, and when assessing urinary concentrations of arbutin's metabolites it appears to be well-absorbed.

2.2Cellular Kinetics

At a concentration of 5mg/mL (dry leaf equivalents), uva ursi appeared to inhibit the P-glycoprotein (P-gp) transporter, a protein that imports and exports xenobiotics from cells, after 15-60 minutes of measurement in monocytes (with little effect being seen in colorectal Caco-2 cells) while increasing its activity in both monocytes and Caco-2 cells following 18 continuous hours of incubation; potency of tested extracts varied,[12] and due to relatively rapid absorption and elimination of uva ursi in humans[17][18] it could be speculated that the acute measurement is more relevant rather than the latter.

Uva ursi may have a short-term inhibitory effect on the order of minutes on P-glycoprotein in vitro, and a stimulatory effect on the order of hours, but the short-term effect are not seen in intestinal cells. This is of uncertain significance at this time.

2.3Metabolism

Arbutin, following absorption, seems to be deglycosylated rapidly and then acted upon by phase II enzymes to either sulfonate the free hydroquinone into hydroquinone sulfate (via SULT enzymes) or glucuronidate them into hydroquinone glucuronide (via glucuronidase enzymes); there seems to be twice as much glucuronidation as there is sulfation, as assessed by urinary metabolites of arbutin.[17]

Arbutin is readily metabolized into hydroquinone in the liver, and subsequently conjugated in the liver as well. The liver is thought to release mostly hydroquinone glucuronide or hydroquinone sulfate into circulation where it proceeds to be eliminated in the urine.

2.4Phase I Enzyme Interactions

When uva ursi extract has been tested in vitro for P450 enzyme inhibition, the water extract showed inhibitory activity against CYP19-aromatase, CYP2C19, CYP3A7, CYP3A5, CYP3A4 (upwards of 70% inhibition at 1.25mg/mL dry mass equivalents).[12] The methanolic extract also had inhibitory properties to a more variable degree with exception of CYP19 where it was inactive.[12]

One study has shown a potentially large inhibition of many enzymes in Phase I metabolism that mediate drug metabolism, including CYP3A4 (the enzyme that St. John's Wort inhibits). This could theoretically lead to several drug interactions, although the effect has not been observed directly.

2.5Elimination

Arbutin from uva ursi appears to be eliminated in the urine, where it is thought to act locally via its hydroquinone metabolites.

Hydroquinone glucuronide can be detected in the urine following oral ingestion of uva ursi within three to four hours (when about half the oral dose can be detected[18]), reaching peak concentrations of 0.7-1.14µM/mL (700-1,140µM) or 199-327µg/mL (from 105-210mg arbutin orally)[17] with no detectable metabolites after 24 hours.[17] Hydroquinone sulfate can also be detected (at about a third the concentration of the glucuronide) while free hydroquinone was only found in trace levels in this study (0.1% total hydroquinones),[17] although it has shown variability between undetectable and 5.6% in another study.[19] Arabutin itself is not eliminated in the urine.[17][18]

Bacteria in the urinary tract may bioactive hydroquinone (from hydroquinone glucuronide) by metabolizing the bond between the two molecules, leading to a high bacterial intracellular concentration of hydroquinone in vitro.[20]

Arbutin metabolites (the hydroquinones) appear to be primarily eliminated in the urine, which would in theory be useful in the treatment of urinary tract infections.

3Cardiovascular Health

3.1Absorption

Uva ursi leaves appear to have inhibitory actions on pancreatic lipase, an enzyme which aids in the absorption of dietary triglycerides, and is thought to be unrelated to its polyphenolic content; inhibition exceeding 70% at the tested concentration (16μL in vitro), and performed comparably well to Tilia platyphyllos and garden pea extract.[21]

Uva ursi may have inhibitory actions on pancreatic lipase in vitro. Whether this applies to oral ingestion, and whether it can subsequently prevent triglyceride absorption from the intestines, remains unknown.

4Neurology

4.1Neuroinflammation

Arbutin, when tested in vitro in microglial cells, has been shown to have antiinflammatory properties in the concentration range of 100-200μM when incubated with the inflammatory agent lipopolysaccharide (LPS) with a full suppression of inducible NO synthase at 500μM.[22]

One study noted antiinflammatory properties of arbutin in microglial cells. It is uncertain if this applies to supplementation due to arbutin (rather than its metabolites) being tested, and the high concentration used.

5Inflammation and Immunology

5.1Bacterial Interactions

One compound found in the leaf extract of uva ursi known as coralagin appears to potentiate the efficacy of beta-lactam antibiotics on methicillin-resistant Staphylococcus aureus (MRSA) by reducing the required MICs in vitro when at a concentration of 16μg/mL, despite having weak potency when tested alone (128μg/mL).[10]

An aqueous extraction of uva ursi (leaf and berry) in vitro appeared to have inhibitory properties against the growth of Staphylococcus aureus with an MIC value of 90ug/mL,[23] performing less potently than the references of vancomycin (MIC 2.5ug/mL) and tetracycline (MIC 0.035ug/mL) but stronger than most other tested herbals in both MIC[23] and inhibiting quorum sensing (a cell-to-cell method of communication among bacteria that can activate virulence factors).[24] It has been reported (indirectly via review[25]) that uva ursi showed efficacy in over 70 strains of bacteria known to exist in the urinary tract, and the antibacterial effect of the extract seems to be partially related to reducing the ability of the bacteria to adhere to tissue walls;[26] a required mechanism for many infectious bacteria and the molecular target of cranberry procyanidins as well.[27][28]

Uva ursi appears to have general antibacterial properties that affect a large amount of bacterial strains, and this antibacterial effect appears to be due to several possible mechanisms, including preventing bacteria from attaching themselves to target tissue (a similar function to cranberry procyanidins in the urinary tract, and similar to how pelargonium sidioides works in the upper respiratory tract).

6Interactions with Oxidation

6.1General

The leaves of uva ursi appear to be relatively potent antioxidants ex vivo, being able to almost fully inhibit oxidative spoilage of meat in refrigerated conditions up to a week.[7][29] This is likely due to a high presence of gallic acid and tannins,[7] which tend high antioxidative capacities ex vivo (with in vivo potency being uncertain).

Uva ursi has antioxidant properties prior to ingestion could be useful in preservation (similar to oregano usage) but it is not yet known if this applies to the human body following oral ingestion.

7Peripheral Organ Systems

7.1Lungs

One study conducted in cats (who may have different physiological responses to arbutin, as suggested by a dramatically lower LD50 of 42-86mg/kg relative to rodents and dogs at 300-1,300mg/kg[5]) noted that intragastric or intraperitoneal administration of 50-100mg/kg arbutin was as effective as a lower dose of codeine (10mg/kg) in suppressing coughs.[30]

One study has suggested antitussive properties at high doses in cats. Practical significance of this study towards supplementation of uva ursi in humans is not certain at this point in time.

7.2Bladder

Uva ursi has been stated to require an alkaline pH in the urine to facilitate degradation of arbutin (hydroquinone glucoside) into free hydroquinone to exert antibacterial effects, leading to recommendations for pairing it with 6-8g sodium bicarbonate or a high vegetable diet.[31][3] This is no longer thought to be a relevant mechanism,[6] and more likely it is the urinary tract bacteria themselves that hydrolyze arbutin, and accumulate free hydroquinone in 20-fold higher concentrations intracellularly compared to outside the bacteria.[20] Uva ursi itself, in the rat, does not appear to influence urinary pH.[32]

Arbutin can be detected in the urine following oral administration of uva ursi leaves, with ingestion of tablets (472.5mg dry leaf extract containing 105mg arbutin) or the leaves in an aqueous solution (945mg containing 210mg arbutin) increasing urinary arbutin metabolites.[17] Hydroquinone glucuronide is the most prominent metabolite four hours after ingestion (67.3-70.3%), reaching concentrations of 0.7-1.14µM/mL at peak, with only trace hydroquinone detected (pH of urine not measured); no metabolites are detectable within 24 hours after ingestion.[17]

Uva ursi also contains corilagin, which significantly reduces the MICs of some antibiotics, [10] suggesting that leaf extracts may have additional antibacterial properties over isolated arbutin.

Upon absorption, arbutin is metabolized to hydroquinone glucuronide, which then is broken down to hydroquinone by bacteria in the urinary tract, which then accumulate the free hydroquinone, which is thought to underlie the therapeutic effects of uva ursi on urinary tract infections.

When tested in rats, administration of a liquid suspension of uva ursi in one study failed to influence the rate of urination when compared to control water[32] whereas elsewhere intraperitoneal injections of 50mg/kg bodyweight uva ursi water extract caused an increase in urination over the next 24 hours (24% increase) relative to saline.[33]

Uva ursi in drinking water of rats did not appear to influence calcituria (urinary calcium) or citraturia (urinary citrate) suggesting a possible lack of efficacy in stone formation or dissolution.[32]

Beyond the antibacterial effects, there is mixed evidence as to whether uva ursi has a weak diuretic effect or none at all while preliminary evidence suggests that it does not increase urinary calcium (which suggests it may not be able to dissolve calcium-based kidney stones).

In women who have experienced at least three episodes of cystitis during one year, supplementation of uva ursi tablets (three tablets of UVA-E, which also contained an unspecified amount of dandelion) over the course of one month and then monitoring over the remaining year saw a low recurrence of cystitis in the placebo group (23%) and no recurrence in the treatment group.[1]

One study has been conducted showing benefits towards cystitis, but it was conducted using a product also containing dandelion and has not yet been replicated.

8Interactions with Aesthetics

8.1Skin

Arbutin has been used in cosmetic products for its claimed skin-whitening properties secondary to inhibiting melanin synthesis.[34] Isolated arbutin has shown this property in melanoma cells[35][36] and has shown inhibitory actions against tyrosinase;[37] the activity of α-arbutin and β-arbutin differ with the former being 10-fold as potent and possessing an IC50 of 480µM in mixed type inhibition (β-arbutin being noncompetitive) in melanoma cells.[37] 500µM of α-arbutin has been shown to reduce melanin synthesis to 76% of control in vitro.[38]

α-arbutin failed to inhibit tyrosinase in mushrooms while β-arbutin had an IC50 of 8.4mM[37] whereas elsewhere a mixture of the two showed an IC50 of 24mM in a medium containing cofactors (in this case, L-DOPA which is substrate to tyrosinase) and oxygen.[39] Application of 250µg arbutin to a human skin model appears to possess melanin-inhibiting properties, reducing synthesis to 40% of control.[38]

These properties seem to apply to uva ursi as well; a 50% ethanolic extract of the leaves appears to be inhibit melanin synthesis in vitro, although to a lesser degree than other plants in the same genus (Arctostaphylos).[40]

Uva ursi, primarily through arbutin, appears to have a melanin-inhibiting properties and may confer whitening effects on the skin when topically applied. Human studies assessing the potency of arbutin against other drugs (ie. kojic acid) have not yet been conducted and it is very unlikely this applies to oral ingestion due to the high concentrations required in the skin to produce this effect.

9Safety and Toxicology

9.1General

Some sources indicate that chronic uva ursi ingestion may not be fully safe[3] due to the bioactive molecule, arbutin, being a glucuronide of hydroquinone. Hydroquinone, based on industrial exposure reports, may be a carcinogen following long-term exposure.[41] These concerns have led to uva ursi being recommended for short-term treatment (of two weeks) rather than as a daily preventative.[3] It is currently thought that hydroquinone does not accumulate in the body following chronic exposure,[6] and when metabolized by P450 enzymes (hydroquinone sulfate or hydroquinone glucuronide) this potential toxicity is not apparent.[6][4]

A risk assessment for hydroquinone specifically from uva ursi preparations suggests that it is safe for therapeutic usage and there is no evidence establishing a link between hydroquinone's known effects in high concentrations (cancer promotion and toxicity of the liver and kidneys) and uva ursi usage.[6] Estimated maximal human exposure to hydroquinone via uva ursi is 11µg/kg[6] and the threshold of hydroquinone exposure which is seen as negligible for human health is 100µg/kg (calculated here[6] based on rat studies observing the lowest available no observed adverse effect level or NOAEL (rabbit)[42]).

Hydroquinone can also be found in other food products that are known to be relatively safe such as coffee and tea (20-90µg per 200-300mL) and red wine (562µg per 250mL)[43] and even unfiltered cigarettes which boast 110-300µg hydroquinone each would miss the NOAEL of hydroquinone (hitting 33-90µg/kg) assuming the European average (for smokers) of 18 a day.[43]

While hydroquinone, one of the metabolites of the bioactive arbutin, is technically a carcinogenic compound, the overall exposure a human gets from consumption of uva ursi is likely well below the carcinogenic level when proper doses are adhered to. The limitation of supplementation for two weeks at a time is not scientifically supported, but precautionary.

9.2Case Studies

One case study reports a patient (otherwise healthy 56 year old woman) who continuously used uva ursi tea for three years who reported bilateral Bull's-eye maculopathy;[44] while causation was not placed on the herb, the plant possesses melanin-inhibitory properties[40] which were hypothesized to play a role.

One case study associated eye damage with uva ursi ingestion, but a direct connection was not confirmed. Supporting evidence for this hypothesis lacks at the time, although a plausible mechanism for this adverse effect exists.

References

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  40. ^ a b Matsuda H1, et al. Studies of cuticle drugs from natural sources. IV. Inhibitory effects of some Arctostaphylos plants on melanin biosynthesis. Biol Pharm Bull. (1996)
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This page features 44 references. All factual claims are followed by specifically-applicable references. Click here to see the full set of references for this page.

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