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Bilberry, Vaccinium myrtillus L., is a shrub with edible

fruits that is native to Circumboreal regions from Europe

to Asia as well as the Rocky Mountains in North America.

Bilberries are related to other edible berries including

blueberry, cranberry, huckleberry, and lingonberry.

Bilberry fruits contain anthocyanins, which are natural

pigments, responsible for the dark blue color of the fruits

and for many of the health benefits. In vitro studies have

shown that bilberry extracts have antioxidant activity, inhibit

platelet aggregation, prevent degradation of collagen

in the extracellular matrix surrounding blood vessels and

joints, and have a relaxing effect on arterial smooth muscle.

Bilberry extracts have also demonstrated anticancer

and antibacterial actions, in vitro. Pharmacokinetic studies

in animals and humans show that a small percentage

of the anthocyanins is absorbed into the body and widely

distributed. Human clinical studies have been conducted

evaluating the potential benefits of bilberry preparations

in treating venous insufficiency and visual disorders ranging

from night vision to diabetic retinopathy as well as

cancer prevention. No serious toxicities have been associated

with preparations of the fruits in animal screens and

no serious side effects have been identified in humans.


Bilberries are edible fruits from V. myrtillus L. of the family

Ericaceae. Bilberry is the standardized common name for

the fruit in the United States, but the fruit is also known

as European blueberry, huckleberry, and whortleberry (1).

Related to bilberry, and in the same genus of Vaccinium, are

other edible berries including blueberry, cranberry, huckleberry,

and lingonberry.

Bilberry is a shrub, 1–6 dm high, found in heaths,

meadows, and moist coniferous forests in Circumboreal

regions from Europe to Asia, with populations in the

American and Canadian Rocky Mountains (2).

The blue-black berries are harvested when ripe,

usually during the months of July through September.

The berries are oblate-globose, 5–9 mm diameter, with

4–5 locules containing many seeds. The seeds are approximately

1 mm long with a yellow/brown-dimpled

surface (2).

Both the leaves and fruits of bilberry have been used

medicinally since the Middle ages.

The leaves were used topically for inflammation, infections,

and burns, as well as internally as a treatment for

diabetes. According to the herbalist Grieve, the fruits were

used to treat dysentery, diarrhea, gastrointestinal inflammation,

hemorrhoids, vaginal discharges, scurvy, urinary

complaints, and to dry up breast milk. More recently, it

was found that bilberry was used by World War II pilots

to improve their night vision (2,3).

Bilberry fruit preparations are still used to improve

vision as well as for their benefits to the circulatory system

treating fragility and altered permeability of blood

vessels that is either primary or secondary to arterial hypertension,

arteriosclerosis, or diabetes (3).


Bilberry fruits contain anthocyanins that are natural pigments

in the chemical class known as flavonoids. Anthocyanins

are glycosides or compounds with sugars

attached at the 3 position, while anthocyanidins are aglycones

(the same basic structure without the sugars attached)

(see chapter 74, “Polyphenol Overview”). The majority

(64%) of anthocyanins in the fruit are glycosides of

cyanidin and delphinidin (Fig. 1). The quantity of anthocyanin

in the fruit ranges from 300 to 700 mg per 100 g.

Bilberry fruits also contain flavonols, tannins, phenolic

acids, organic acids, sugars, vitamins, and volatile compounds


The primary commercial source of bilberry fruits is

“wild harvest” from regions in Europe and Scandinavia.

The fruits are sold fresh, frozen, or dried. Besides the

whole fruit, commercial products include cold macerates,

decoctions, and dry extracts. The dry extracts are commonly

prepared using alcohol, methanol or ethanol (2).

Until recently, a single-wavelength spectrophotometric

technique (UV) was commonly used to standardize

the anthocyanin content of bilberry products. However,

this technique did not detect adulteration of bilberry

preparations with substances of similar color (4). A high performance

liquid chromatographic technique that can

detect and quantitate both anthocyanins and anthocyanidins

has recently been developed enabling a better assurance

of product identity and quality (5).

Most studies on bilberry have been conducted using

extracts characterized as containing 36% anthocyanins or

25% anthocyanidins.


In vitro studies have shown that bilberry extracts have

antioxidant activity, inhibit platelet aggregation, prevent

  • Cyanidin 3-O-glycoside OH OH H arabinose, glucose, or galactose

  • Delphinidin 3-O-glycoside OH OH OH arabinose, glucose, or galactose

  • Malvidin 3-O-glycoside OCH3 OH OCH3 arabinose, glucose, or galactose

  • Peonidin 3-O-glycoside OCH3 OH H arabinose, glucose, or galactose

  • Petunidin 3-O-glycoside OH OH OCH3 arabinose, glucose, or galactose

  • OH

  • HO

  • O R3

  • R2

  • R1

  • R

  • O+

degradation of collagen in the extracellular matrix

surrounding blood vessels and joints, and have a relaxing

effect on arterial smooth muscle. These actions are vasoprotective,

increasing capillary resistance and reducing

capillary permeability (3). Bilberry extracts have also

demonstrated anticancer and antibacterial actions in

vitro. There is no evidence of toxicity in animals at the

effective doses.

Antioxidant Activity

Bilberry fruits have demonstrated antioxidant activity in

in vitro and in animal models. In the oxygen radical absorbance

capacity(ORAC)assay, an in vitro test measuring

free radical quenching, bilberry fruits had potent activity

compared with other fresh fruits and vegetables (44.6 +

2.3 mol Trolox equivalents (TE)/g) (6). In another assay,

a bilberry extract (25% anthocyanins) exhibited antioxidant

activity in protecting keratinocytes in culture from

damage due to UVA and UVB light (7,8). The bilberry

extract attenuated UVA-induced reactive oxygen species

formation, peroxidation of membrane lipids, and depletion

of intracellular glutathione in concentrations of 10–50

mg/L (7). In the same concentration range, the extract inhibited

UVB-induced generation of reactive oxygen and

nitrogen species, DNA strand breaks, as well as caspase-

3 and caspase-9 activity (mediators that execute apoptotic

cell death) (8).

In an animal study, a bilberry extract characterized

as containing 38% anthocyanins reduced oxidative stress

caused in mice by removal of the animal’s whiskers. The

extract administered orally at a dose of 100 mg/kg for

7 days ameliorated the increase in oxygen radicals (thiobarbituric

acid reactive substances), protein carbonyl formation,

and lipid peroxidation in the brain, heart, kidney,

and liver. The extract also suppressed the stress-induced

changes in dopamine levels (9).

A bilberry extract (42% anthocyanins) reduced oxidative

stress to the liver in a restraint-stress mouse model.

The extract, administered at a dose of 200 mg/kg for

5 days, ameliorated the increase in plasma levels of alanine

aminotransferase, a liver enzyme. The extract also reduced

plasma and liver ORAC levels and increased plasma glutathione

and vitamin C levels in the liver (10). A similar

study was conducted in mice with kidney damage induced

by potassium bromate. Oral administration of the

same extract ameliorated the increase in blood urea nitrogen

levels and the decreases in kidney malondialdehyde,

nitric oxide, and xanthine oxidase levels. The bilberry extract

also improved the kidney ORAC levels (11).

MyrtoSelectTM, an extract containing approximately

40% anthocyanins, was tested for its effects on gene expression

(DNAmicroarray) in a macrophage cell line stimulated

with lipopolysaccharide (LPS). The extract, at a

concentration of 75 g/mL, appeared to mitigate the effect

of LPS, targeting genes involved in inflammation and

immune defense. Pretreatment with the bilberry extract

affected 45% of the genes downregulated by LPS and 36%

of genes upregulated by LPS (12).


Bilberry extracts have demonstrated beneficial effects on

the circulation.

including inhibiting platelet aggregation,

reducing capillary permeability, facilitating vasodilation,

and inhibiting the development of atherosclerosis and angiogenesis.

Myrtocyan R (also known as MirtoSelectTM, containing

36% anthocyanins) inhibited platelet aggregation in

vitro induced by adenosine diphosphate (ADP), collagen,

and sodium arachidonate in rabbit platelet-rich plasma

with IC50 values ranging from 0.36 to 0.81 mg/mL. Myrtocyan

administered orally to rats (400 mg/kg) prolonged

the bleeding time in the animals, without affecting coagulation

pathways. The same dose administered to mice reduced

the adhesiveness of platelets to glass (3). Myrtocyan

administered to healthy human subjects, 480 mg/day

(173 mg anthocyanins/day) for 30–60 days, reduced the

aggregation response ex vivo to ADP and collagen (13).

In a rabbit skin model, oral treatment with 400 mg

anthocyanins per kilogram body weight 30 minutes before

topical application of chloroform reduced the capillary

permeability caused by the irritant by 66%. In rats, administration

of bilberry anthocyanins, 200 mg/kg orally,

decreased bradykinin-induced capillary permeability by

39%. The same dose reduced carrageenin-induced rat paw

edema by 45% (14). In a rat model of experimentally induced

hypertension, 500 mg anthocyanins per kilogram

body weight given orally for 12 days completely ameliorated

the increase in blood–brain barrier permeability and

reduced the increase in aortic vascular permeability by

40% (15). In a hamster cheek pouch model, 100 mg bilberry

extract per kilogram daily for 4 weeks reduced the

circulatory damage due to ischemic reperfusion (16).Arat

model suggested that bilberry anthocyanins (50mg/kgIP)

inhibited the enzymatic degradation of collagen, decreasing

the permeability of the blood–brain barrier caused by

proteases (17).

Bilberry preparations are reported to relax arterial

tissues in vitro.

Preliminary experiments pointed

to a mechanism involving prostaglandins. However, a

more recent study using porcine coronary arteries demonstrated

a mechanism involving nitric oxide (endothelialderived

relaxing factor) (18).

A bilberry extract was reported to inhibit the development

of atherosclerosis in apolipoprotein E–deficient

mice. The mice received diets supplemented with 0.02%

of a bilberry extract (52% anthocyanins) for 16 weeks. The

Bilberry 39

extract reduced lipid deposits and the development of

lesions. It did not affect plasma antioxidant capacity or

plasma lipid levels (19).

A bilberry extract (25% anthocyanins) was tested

for its effect on angiogenesis both in vitro and in vivo.

The extract at concentrations of 0.3–30 g/mL inhibited

tube formation and the migration of human umbilical

vein endothelial cells induced by vascular endothelial

growth factor A. The extract also inhibited the induction

of retinopathy in newborn mice, which was induced

with oxygen. Intravitreal administration of 300 ng extract

per eye significantly inhibited the area of neovascular

tufts (20).


Anthocyanins have been reported to mediate several

physiological functions that ultimately may result in cancer

suppression. Anthocyanins suppress the growth of

cancer cell lines in vitro, including HL60 human leukemia

calls and HCT116 human colon cancer cells. A bilberry extract

induced apoptotic cell bodies and nucleosomal DNA

fragmentation in HL60 cells (21). A bilberry extract (Mirtocyan)

has also been shown to suppress the activity of

receptor tyrosine kinases, which are thought to play a crucial

role in carcinogenesis and tumor progression. When

tested over a number of tyrosine kinases, the activity was

consistent but not specific (22).


Phenolic compounds in bilberry have demonstrated in

vitro antimicrobial effects against strains of Salmonella and

Staphylococcus possibly through interfering with adhesion

of the bacteria. Treatment of bilberry preparations with

pectinase released phenolics from the cell wall matrix and

increased the antibacterial activity (23). In experiments

with Neisseria meningitidis, the bacteria that causes meningitis

and septicemia, a bilberry juice fraction was reported

to inhibit the binding of the bacteria to epithelial cells

in culture. Fractions of the juice also bound to the bacterial

pili. The authors concluded that anthocyanins were

partly responsible for the activity but that there appeared

to be other compounds in bilberry that may also interact

directly with the pili or act synergistically with the anthocyanins


Safety Studies (Animal Toxicology)

Myrtocyan (25% anthocyanins) has been tested for acute

and chronic toxicity in animal studies. There were no

deaths with an acute dose in rats up to 20 g/kg orally

and in mice up to 25 g/kg. Six months treatment with

doses of 125–500 mg/kg in rats and 80–320 mg/kg in

dogs found no evidence of toxicity. The preparation was

tested in guinea pigs for 2 weeks and in rats for 6 weeks

with doses up to 43 mg/kg without incident (2,3).


Animal studies show that bilberry anthocyanins are absorbed

intact, or after methylation. This is unlike other

flavonoid glycosides which are hydrolyzed to their aglycones

and metabolized to glucuronidated or sulfated

derivatives (25). Following administration of 400 mg/kg

orally to rats, peak blood levels of anthocyanins were detected

within 15 minutes and afterwards declined rapidly.

Only 1% of the anthocyanins was eliminated in the urine

and 4% in the bile. The absolute bioavailability of bilberry

anthocyanins was estimated to be 1.2–5% (26). A study in

mice reported that malvidin 3-glucoside and malvidin 3-

galactoside were the principal anthocyanins in the plasma

60 minutes after oral administration of 100 mg/kg. When

the mice were maintained on a diet containing 0.5% bilberry

extract, plasma levels of anthocyanins reached 0.26

M. Anthocyanins were detected in the liver, kidney,

and lung. They were not detected in the spleen, thymus,

heart, muscle, brain, white fat, or eyes (25).

A pharmacokinetic study with six human subjects

detected anthocyanins in the plasma 1.5–6 hours following

intake of a bilberry–lingonberry puree. The study

examined the production of urinary phenolic acids and

found the greatest increase in methylated compounds.

The amount of urinary phenolic acids was low, and the authors

suggested that the fragmentation of anthocyanins

to phenolic acids was not a major metabolic pathway

(27). Another pharmacokinetic study with 20 subjects

that consumed 100 g/day of berries, including black currant,

lingonberries, and bilberries, for 8 weeks reported

an increase in serum quercetin (up to 51% higher) compared

with control subjects who did not consume berries

(28). A study with 25 subjects administered 1.4–5.6 g

Mirtocyan (25% anthocyanins) daily for 7 days reported

detection of anthocyanins as well as methyl and glucuronide

metabolites in the plasma and urine but not in the

liver (29).


Human clinical studies have been conducted evaluating

the potential benefits of bilberry preparations in treating

venous insufficiency and visual disorders ranging from

night vision to diabetic retinopathy as well as cancer prevention.

Vascular Health

Clinical studies have been conducted evaluating the potential

benefits of bilberry preparations in treating venous

insufficiency. A review of studies conducted between 1970

and 1985 included 568 patients with venous insufficiency

of the lower limbs who were treated with bilberry preparations

(30). The studies reported an improvement in circulation

and in lymph drainage resulting in a reduction

in edema. A more recent placebo-controlled study which

included 60 participants with varicose veins reported improvement

in edema in the legs and ankles, sensation of

pressure, cramps, and tingling or “pins and needles” sensations

with a dose of 160 mg Tegens R , three times daily

for 1 month (31). Tegens (Inverni della Beffa, Italy) contains

a bilberry extract named Myrtocyan or MirtoSelect

(25% anthocyanins), manufactured by Indena SpA, Italy.

Visual Health

Asystematic review was conducted on placebo-controlled

studies on the effects of bilberry preparations on night

40 Barrett

vision. Literature searches identified 30 clinical studies,

and 12 of those met the inclusion criteria of being placebo

controlled. Of the 12 studies, 5 were randomized. Healthy

subjects with normal or above average eyesight were

tested in 11 out of the 12 studies. Many of the studies

were acute, using a single dose, and the longest treatment

period was 28 days. Full characterization of the products

used in the studies was not available, but assuming

25% anthocyanin content, the doses of anthocyanin

ranged from 12 to 2880 mg. The techniques used to measure

the extent and rate of dark adaptation ranged from

visual acuity, contrast sensitivity, and critical flicker fusion

to electroretinographic monitoring of response to light

flashes. The four most recent randomized controlled studies

with rigorous methodology reported negative results.

One randomized controlled study and all seven of the nonrandomized

studies reported positive effects. The authors

concluded that the present studies do not support the use

of bilberry by those who are healthy with normal vision to

improve their night vision. However, uncontrolled studies

report a benefit for those with eye disorders, including

retinal degeneration, myopia, simple glaucoma, and

pathological fundus. Furthermore, studies with synthetic

anthocyanins suggest a positive benefit for those with myopia,

central retinal lesions, and night blindness (32).

Two studies on diabetic retinopathy, using a dose of

160 mg Tegens twice daily, demonstrated a trend toward

improvement in mild cases of the disease. The first study

was a 1-month, placebo-controlled study that included

36 subjects. At the end of the month, 10 of 13 patients in

the Tegens group with ophthalmoscopic ally detectable

retinal abnormalities (microaneurysms, hemorrhagic foci,

exudates) were improved, while all 15 patients with these

abnormalities in the placebo group remained unchanged.

A similar trend was observed among those patients with

fluoroangiography abnormalities (33). The second study

lasted 1 year and included 40 subjects who were given

Tegens or placebo in addition to the usual therapy for

retinopathy. As a result, in 50% of patients given bilberry,

the retinal lesions and associated edema were improved

compared with 20% in the control group (34).

A mixture of vitamin E and bilberry (FAR-1, Ditta

Farmigea SpA, Italy) showed a trend toward prevention

of senile cataracts after 4 months of 180 mg bilberry

anthocyanins (25% anthocyanidins) and 100 mg DLDL tocopheryl

acetate twice daily. When the placebo group

was changed from placebo to the bilberry preparation,

and the trial continued for an additional 4 months, there

was no statistical difference between the two groups. The

rationale for this study was previous indications that

antioxidants might prevent the development of senile

cataracts (35).

A mechanistic study using Myrtocyan examined

changes in pupillary reflexes to light following a single

high dose of 240 mg anthocyanosides or placebo in

40 healthy volunteers. The study was conducted to explore

the use of bilberry in work situations where exposure

to high light intensities dampens pupillary reflexes

and leads to vision fatigue. The authors of the study suggested

that the pigments in bilberry might increase sensitivity

to light and improve blood flow in the capillaries of

the eye. Improvement in pupillary reflexes was observed

in both groups, with the improvement in the treatment

group being only slightly better than that in the placebo

group (36).

Cancer Prevention

In an open label study, 25 colorectal cancer patients scheduled

to undergo surgery were given 1.4, 3.8, or 5.6 g

bilberry extract (Mirtocyan) containing 0.2–2.0 g anthocyanins

for 7 days before surgery. Availability of anthocyanins

was determined by detection in the plasma,

colorectal tissue, and urine but not in the liver. Anthocyanins

detected in the body were unaltered, or products

of metabolic glucuronidation and O-methylation. Proliferation

of cells in the tumor tissue was decreased by 7%

compared with before the bilberry intervention (29).

Side Effects and Adverse Effects

No side effects were reported in the clinical studies mentioned

earlier. In a 1987 postmarketing surveillance study

with 2295 subjects, only 94 (4.1%) complained of minor

side effects, most of which involved the gastrointestinal

track. Most of the participants took 160 mg Tegens twice

daily for 1–2 months (3).

Observed Drug Interactions and Contraindications

No drug interactions or contraindications have been reported

in the literature for bilberry.


Bilberry fruit extracts and anthocyanins have been the

subject of pharmacological studies and human clinical trials.

In vitro and in vivo studies demonstrate good evidence

for the antioxidant activity of bilberry extracts

along with strong indications of benefit to the cardiovascular

system. Animal and human pharmacokinetic studies

demonstrate bioavailability of anthocyanins, but absorption

appears to be limited. Human clinical studies

on the effects of bilberry extracts on eyesight and vascular

diseases suffer from poor methodology, including

small sample sizes and short-term exposures. While it

appears doubtful that bilberry preparations benefit the

night vision of healthy subjects, the benefit for those with

diabetic retinopathy and other eye disorders merits exploration.

Another area that appears promising is that of

benefits to the cardiovascular system, specifically vasculitis

or venous insufficiency. Bilberry products have been

safely consumed, without significant adverse events or

side effects.


Bilberry is a food and preparations are also used medicinally

In the United States, preparations of bilberry are

sold as foods and dietary supplements. The U.S. Pharmacopoeia

has published a standard monograph for powdered

bilberry extract (37). The German Commission

E completed a monograph for bilberry fruits in which

preparations of the ripe fruit are indicated orally for

Bilberry 41

nonspecific, acute diarrhea and topically for mild inflammation

for the oral and pharyngeal mucosa (38). The European

Scientific Cooperative on Phytotherapy (ESCOP)

monograph lists the internal use of bilberry fruit preparations

(enriched in anthocyanins) for symptomatic treatment

of problems related to varicose veins, such as painful

and heavy legs. The ESCOP monograph also lists the dried

fruit as supportive treatment of acute, nonspecific diarrhea

(39). In Canada, bilberry products are approved as natural

health products for traditional use orally as an astringent

and as a source of antioxidants as well as for use as a

gargle to relieve mild inflammation of the mouth and/or

throat (40).


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42 Barrett

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