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,
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
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).
CHEMISTRY AND PREPARATION
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
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
- O R3
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
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
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
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
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
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
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.
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.
Asystematic review was conducted on placebo-controlled
studies on the effects of bilberry preparations on night
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
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
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
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
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
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