Cramp Bark

Generic name: Viburnum Opulus L., Viburnum Opulus Var. Edule, Viburnum Opulus Var. Sargentii (Koehne) Takeda, Viburnum Opulus Var. Opulus, Viburnum Opulus Var. Americanum (Miller) Ait.
Brand names: American Cranberry Bush, Common Snowball, Cramp Bark, Cranberry Bush, Cranberry Tree, Dagdagan, European Cranberry Bush, Gilaboru, Gilaburu, Gildar, Gilgili, Guelder Rose, High Cranberry, Highbush Cranberry, Pimbina, Snowball Bush, Squaw Bush

Usage of Cramp Bark

There are no clinical data regarding use of cramp bark for any of the following indications.

Antimicrobial activity

The dried fruits and seed oil of European cranberrybush have been reported to exhibit antimicrobial activity.(Yilmaztekin 2015)

In vitro data

Cultivars of 6 V. opulus genotypes, including the americanum and sargentii variants, were evaluated for total phenolic and anthocyanin content and then tested for antimicrobial activity against human pathogenic bacteria and yeasts; ceftazidime was used as a positive control. Among the 6 cultivars, total phenolic content averaged 944 mg per 100 g and ranged from a high of 1,168.8 mg per 100 g in the Krasnaya Grozd cultivar to a low of 804.2 mg per 100 g in V. opulus var americanum. Total anthocyanins averaged 41.8 mg per 100 g and ranged from a high of 51.3 mg per 100 g in the P3 cultivar and a low of 24.3 mg per 100 g in V. opulus var americanum. The antimicrobial effects of the juice from V. opulus fruits varied widely depending on the organism and the cultivar tested. The most sensitive organisms overall were the gram-negative Salmonella typhimurium and Salmonella agona, whereas Pseudomonas aeruginosa exhibited the highest resistance. Significant inhibitory activity against the gram-positive organisms Listeria monocytogenes, Entercoccus faecalis, and Staphylococcus aureus was noted, with Micrococcus luteus and Staphylococcus epidermidis showing the most resistance. American cranberry bush demonstrated significant antibacterial activity against S. epidermidis, while V. opulus var. sargentii was more effective against E. faecalis and S. aureus. Ceftazidime was more effective than any of the V. opulus fruit juices against all bacteria tested; however, V. opulus showed inhibitory activity against S. aureus (mean, 23.3 to 26 mm zone of inhibition) comparable to that with ceftazidime (mean, 27 mm). In contrast, little to no antifungal activity was observed with V. opulus.(Cesoniené 2012)

Antioxidant activity

In vitro and animal data

Three cultivars of European cranberrybush (V. opulus var edule), grown over a 3-year period, were evaluated for total polyphenolic, flavonoid, and vitamin C content, as well as for antioxidant activity. The polyphenolic content was very high (6.8 to 8.29 g of gallic acid/kg fresh mass), approximately 10 times that of apples and 3 times higher than plums. Although the vitamin C content was high (1.01 to 1.64 g/kg), it was much less than the extreme amount observed in sea buckthorn (12 g of ascorbic acid/kg fresh mass). The flavonoid content was lower than in other fruits and ranged from 3.14 to 4.89 g/kg fresh mass. The variability among the cultivars was most evident with regard to total antioxidant activity, which ranged from 9.14 to 11.01 g of activity/kg fresh mass. In comparison, the antioxidant activity of cherries and plums is 0.9 g and 6 g of activity/kg, respectively. Fruit extracts of the European cranberry bush cultivars were more effective at inhibiting nitric oxide, superoxide anion, hydroxyl radical, and lipid peroxidation than other fruit species (ie, mulberry, apples).(Rop 2010)

The gastroduodenoprotective effects, including antioxidant activity, of proanthocyanidins in V. opulus at doses of 25, 50, and 75 mg/kg of body weight were investigated in rats with capsaicin-induced acute gastric lesions. Biomarkers of injury and oxidative stress (nitrate, nitrite, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase) were measured. Pretreatment with V. opulus proanthocyanidins (VOPA) applied intragastrically reduced malondialdehyde concentrations, reflecting reduced lipid peroxidation, and increased antioxidant enzyme activity in a dose-dependent manner.(Zayachkivska 2006)

Cancer

In vitro and animal studies

Iridoids and iridoid glycosides, the major constituents of the Viburnum genus (including V. opulus), have shown moderate inhibitory activity against HeLa S3 cancer cells.(Wang 2008) In a chemically induced colon cancer animal model, mice that received gilaburu (squeezed V. opulus juice) either for 30 weeks (starting with cancer induction) or for 18 weeks (starting after the end of cancer induction) exhibited no lesions in the promixal colon, which was a significant contrast to cancer control animals that exhibited a mean of 1.12 lesions proximally (P<0.05). Additionally, mice that received gilaburu along with initiation of the carcinogen experienced a significant reduction in the mean number of invasive adenocarcinomas (0.5) compared with controls (1.75) (P<0.05). Although not statistically significant, the total number of colonic lesions was also reduced in the 2 groups receiving gilaburu compared with controls (69 and 66 vs 90, respectively). The average number of tumors per tumor-bearing mouse was also lower in the gilaburu groups versus control (8.63 and 8.25 versus 11.25, respectively).(Ulger 2013)

Dysmenorrhea/Miscarriage prevention

Early pharmacologic studies of cramp bark and black haw did not demonstrate activity in uterine preparations (see Black Haw monograph). Both scopoletin(Jarboe 1967) and viopudial(Nicholson 1972) have been determined to be responsible for the uterine relaxant activity of V. opulus. However, viopudial has not been found in black haw bark, which may account for its weaker activity.

Animal data

Several Viburnum spp., including V. opulus, have produced uterine relaxation in isolated rat tissues.(Jarboe 1966) In a rat model of surgically induced endometriosis, V. opulus methanol and ethanol extracts administered at 100 mg/kg doses reduced posttreatment volumes of cystic and vascularized endometriotic implants by 67.6 mm3 and 66.7 mm3, respectively. The positive reference (buserelin acetate) reduced volumes by 86.4 mm3, whereas an increase of approximately 60 mm3 was observed in the control group. The severity of lesions was also reduced in the methanol and ethanol extract and reference groups. Additionally, no posttreatment adhesions were observed with the reference or ethanol extract, and the methanol extract group exhibited a significant decrease in adhesions. Estrous cycles were observed to be regular following treatment in the ethanol and methanol extract groups. Inflammatory biomarkers (ie, tumor necrosis factor-alpha, vascular endothelial growth factor, interleukin-6) were reduced after treatment with the alcohol extracts and buserelin. Chlorogenic acid was identified as the major compound of both alcoholic extracts; however, the amount was not correlated with the endometriotic effect, suggesting the activity was potentiated by other phenolic compounds. The hexane extract group results were similar to controls throughout the study.(Saltan 2016)

Metabolic disease

Animal and experimental data

Although less potent than orlistat, both V. opulus fresh and purified juices have demonstrated dose-dependent inhibitory effects on pancreatic lipase in vitro. Decreases in lipogenesis, secretion of glucagon-like proten-1, and insulin secretion, as well as stimulation of adipolysis have been observed for V. opulus fruit juices and/or phenolic-rich extracts. Antioxidant activity was involved in these effects. It was noted that purified juice had a higher cytotoxic potential than fresh juice in preadipocyte cells.(Zaklos-Szyda 2020, Zaklos-Szyda 2020) Activity of V. opulus fruit extracts on alpha-amylase, alpha-glucosidase, and antiglycation were also examined in vitro with positive results. Although weaker than acarbose, dose-dependent inhibition was demonstrated on both alpha-amylase and -glucosidase with the most potent inhibitory effects seen with the aqueous fraction and the ethyl acetate fraction of the purified extract, respectively. Similarly, the formation of end glycation products was also inhibited most strongly by the water and ethyl acetate fractions of the purified V. opulus fruit extract compared to the crude extract. Antioxidant capacity was strongest for these fractions compared to the purified or crude extracts alone.(Kajszczak 2021)

Stress-induced GI damage

Animal data

The gastroduodenoprotective effects of proanthocyanidins in V. opulus at doses of 25, 50, and 75 mg/kg of body weight were investigated in rats with capsaicin-induced acute gastric lesions. Biomarkers of injury and oxidative stress (nitrate, nitrite, malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase concentrations) were measured. VOPA reduced gastroduodenal lesions and activated the nitric oxide system in rats with intact vagal afferents but not in rats with capsaicin denervation. Pretreatment with VOPA applied intragastrically reduced the malondialdehyde concentrations, reflecting reduced lipid peroxidation, and increased antioxidant enzyme activity in a dose-dependent manner. Likewise, oral administration provided considerable gastroduodenal protection compared with controls. VOPA increased gene and protein expression of the nitric oxide system and promoted modifications of cell-surface and intercellular glycoconjugates as well as intracellular glycoconjugates.(Zayachkivska 2006)

Urolithiasis

In vitro and animal data

Gilaburu, has been used as an aid in passing kidney stones. To explore this ethnobotanical use, the antiurolithiatic effect of methanol extracts prepared from the fruits was evaluated in rats with sodium oxalate–induced urolithiasis. Juices from both fresh extract and a commercial product were tested at 100 mg/kg doses. The chlorogenic acid content of the fresh extract juice was 3.227%. All groups (commercial V. opulus fruit juice, Cystone [positive control], and fresh V. opulus extract juice) demonstrated improvements in urine creatinine and oxalate levels and in volume of urine. In contrast to the commercial preparation and Cystone, the fresh extract juice did not improve urine urea nitrogen, sodium, or microalbumin. However, both the fresh extract and commercial V. opulus fruit juice exhibited antioxidant activity similar to that of Cystone without any renal damage.(Ilhan 2014) Increasing the solubility of stones by raising the urinary pH with natural acid alternatives (ie, lemonade, orange, grapefruit, lime, tomato) is an effective way to alkalinize urine and treat hypocitraturia. V. opulus has been observed to contain citrate levels equal to those of lemon juice. Additionally, it is rich in potassium and low in calcium and sodium, which suggests that it would be a suitable citrate replacement option in hypocitraturic stone disease.(Tuglu 2014)

Clinical data

In a retrospective chart review of 103 adults with distal ureteral stones 5 to less than 10 mm in size (mean, 7.4 mm), the rate of stone expulsion (82% vs 66%; P=0.026) and the mean elapsed time to expulsion (9 vs 14 days; P=0.018) were significantly better in patients who received V. opulus plus as-needed diclofenac compared to those who received as-needed diclofenac alone. Also, the need for additional treatment (9.4% vs 20%; P=0.038) and analgesic usage rate (24.5% vs 44%; P=0.042) were significantly better in the V. opulus group. However, no differences were found between groups for admission to emergency service or in complication rates. Minor gastric complaints were the most common adverse event in the intervention group that led to study withdrawal in 5 patients.(Kizilay 2019) In a prospective comparator trial, patients with distal ureteral stones no more than 10 mm in size received diclofenac as needed plus either V. opulus or tamsulosin for medical expulsion. When stone sizes were more than 5 and no more than 10 mm, V. opulus patients experienced a significantly shorter mean duration of spontaneous passage (7.1 vs 11.8 days; P<0.05, respectively), lower rates of analgesic use (P=0.001), and fewer emergency department admissions (P=0.016) than those on tamsulosin. However, no differences were observed between groups for rate of stone expulsion (74% for each group) or other outcomes for stones 5 mm or less. No drug-induced adverse effects were reported in the V. opulus group.(Gok 2021)

Other uses

V. opulus fruit extract has been shown to have dose-dependent vasorelaxant effect in vitro. This may be in part due to its high concentration of chlorogenic acid that results in strong inhibition of arginase, an important contributor to endothelial dysfunction.(Bujor 2019)

Taxane-induced male reproductive toxicity was significantly improved with aqueous gilaburu fruit extract in male rats. Sperm motility, concentration, and other types of sperm and epididymal abnormalities were all improved significantly with gilaburu, which appeared to be a result of antioxidant effects in those tissues.(Sarıözkan 2017)

Cramp Bark side effects

No data.

Before taking Cramp Bark

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Cramp bark has been used in folk medicine for the prevention of miscarriage.Brinker 1987, Cesoniené 2012 In the absence of clinical data, consultation with a medicinal herbalist or other licensed practitioner experienced with the use of cramp bark is recommended.

How to use Cramp Bark

Clinical studies are lacking to provide dosing guidance.

In animal studies, doses of 25, 50, and 75 mg/kg of ethanol extracts and raw juice have been used to enhance antioxidant activity in stress-induced gastritisZayachkivska 2006; doses of 100 mg/kg of methanol or ethanol extract have been used in rats with induced endometriosis or urolithiasis.Ilhan 2014, Saltan 2016

Warnings

No data.

What other drugs will affect Cramp Bark

None well documented.

The potential for several herbal supplements commonly used by women to inhibit enzymes of the cytochrome P450 (CYP-450) system was screened in experimental studies using microplate assays. The ethanol extract of cramp bark was among the 4 products tested. Cramp bark was determined to be a potent inhibitor of CYP1A2 and 2C19, with a 50% inhibitory concentration (IC50) of approximately 1 mcg/mL (0.94 and 1.1 mcg/mL, respectively). The most potent inhibitors were chaste tree berry and black cohosh, which exhibited IC50 values ranging from 0.22 to 0.37 mcg/mL. None of the herbal supplements tested affected the CYP1A1 or 2C9 isozymes. Confirmation of the clinical significance of these results requires in vivo studies.Ho 2011

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