Volume 3, Issue 1, March 2013, Pages 9–38
Stinging nettles leaf (Urtica dioica L.): Extraordinary vegetable medicine
Abstract
The
efficacy and safety of herbal medicines are dependent upon the
standards by which they are made and our knowledge base when prescribing
them. Stinging nettles is a staple among Western herbalists and is
widely used as a vegetable green, juice, tea, and freeze dried products,
predominantly as a blood nourishing tonic and for seasonal rhinitis.
The following botanical profile is excerpted from the American Herbal Pharmacopoeia® and Therapeutic Compendium.
Keywords
- Nettles;
- Stinging nettles;
- Standards;
- Pharmacology
1. Introduction
Stinging
nettle herb is a staple among Western herbal practitioners. Its
stinging effect is widely known by many who have been surprised by its
bite. Its genus name Urtica is derived from uro, to burn, or urere, meaning to sting ( Grieve, 1931).
Since ancient times, people have taken advantage of this sting by
flailing arthritic or paralytic limbs with fresh stinging nettle to
stimulate circulation and bring warmth to joints and extremities in a
treatment known as “urtication” ( Green, 1824). Ancient Egyptians also reportedly used the infusion for the relief of arthritis and lumbago ( Harrison, 1966).
The Roman troops were said to flail themselves with stinging nettle to
keep warm and brought the seeds of a similar species, the Roman nettle (U. pilulifera) to England for that purpose “having been told that the climate of Britain was so cold that it was not to be endured” ( Grieve, 1931).
This practice of urtication or rubefaction became a standard in folk
medicine as a remedy for arthritis, rheumatism, and muscular paralysis
and is perhaps the most ancient medicinal use of stinging nettle. The
stinging nettles species name dioica is Latin for “two houses”, from the Greek word oikia, meaning house, and refers to the plant's dioecious nature, bearing male and female flowers on separate plants ( Woodville, 1810, Photo 1).
- Photo 1.
Source: Woodville W. Medical Botany. 1810. William Philips (Publisher); London.
There
are currently no formal clinical studies proving the efficacy of any
stinging nettle preparation as an antirheumatic. The evidence of
putative effectiveness is solely based on few exploratory studies that
show a trend for improvement, especially as an adjunct to NSAID
treatment, particularly with diclofenac.
Nomenclature Latin name Urtica dioica L, Urtica urens L. Botanical Family Urticaceae Common names English Stinging nettle (U. dioica); dwarf stinging nettle (U. urens); nettle Europe Nettle German Brennessel Italian Ortica French Ortie Spanish Ortiga
2. Morphological description
2.1. Urtica dioica
Stinging
nettle leaf, often mixed with stem and sometimes seed, is sold in
fresh, dried, and freeze-dried forms. When stems are present, these
should not be too numerous and should be 3 mm or less in thickness. The
square stem pieces are pale-greenish brown in color, are hollow, their
external surface is ridged and often split. Leaves appear shriveled,
with coarsely cut margins, and can be rolled or clumped together into a
ball when squeezed, producing a quiet crunching sound. The upper leaf
surface is dark green, while the undersurface is a lighter green with a
clearly visible venation. Both stems and leaves bear stinging hairs that
are erect and bristly in nature. The hairs may be up to 70 mm in
length. Skin irritation may result from handling properly dried material
due to the coarseness and content of the hairs, even though a great
deal of the irritating contents of the stinging trichomes dissipates
upon drying. Occasional panicles of green flowers and unopened buds may
be present.
The fresh
leaves are bright vibrant green, with strongly serrated edges, and a
clearly visible venation on the lower leaf surface. Both the leaves and
stems are covered with erect and bristly glandular hairs that contain,
among other compounds, acetylcholine, formic acid, 5-hydroxytryptamine,
and histamine. Fresh material will typically cause skin irritation if
handled without gloves. The other characteristics of the fresh plant
material are similar to those of dried material.
2.1.1. Organoleptic characterization
Aroma: When fresh or freeze dried odorless or earthy smell. When dry faint and mildly fishy or earthy in nature.
Taste: Slightly bitter; when fresh it causes a burning and unpleasant stinging sensation.
Taste: Slightly bitter; when fresh it causes a burning and unpleasant stinging sensation.
2.2. Urtica urens
Dwarf
nettle is not grown commercially in the United States, although it is
possible that it gets mixed in with the leaves of stinging nettle (U. dioica L.) in wildcrafted supplies. U. urens is much smaller and darker green than U. dioica
(see Botanical Identification). However, it is acceptable as
interchangeable with stinging nettle herb in Europe and is available
there fresh or dried, with dried material sold whole, cut and sifted, or
powdered, either alone or in combination with stinging nettle. The
stinging hairs have the same structure as those found on U. dioica
leaf, having a bulbous or cylindrical opaque base and stiff translucent
apex. Much variation exists between plants in indumentum.
2.2.1. Organoleptic characterization
Aroma: Hay-like.
Taste: Bland, slightly sweet, chlorophyll taste; slightly bitter aftertaste.
Taste: Bland, slightly sweet, chlorophyll taste; slightly bitter aftertaste.
3. Microscopic identification
3.1. Urtica dioica
3.1.1. Leaf
Surface view:
Upper epidermis composed of cells with slightly sinuous anticlinal
walls; idioblasts (lithocysts) occur, containing ovoid or spherical
cystoliths 30–50 μm in diameter that are visible through the leaf
surface, appearing as light areas on the dark green leaf; covering
trichomes unicellular, thick-walled, rigid, tapering, up to ∼150–200 μm
in length, occurring more frequently towards the leaf margin; epidermal
cells form a rosette pattern around the trichome base; glandular
trichomes have a unicellular stalk and a 2-celled head (seldom 1, 3, or 4
cells), are ∼20 μm long and occur abundantly mainly along the veins;
stinging trichomes have a multicellular parenchymatous base in which a
single large needle-like cell up to 2 mm long is embedded; the wall of
this cell is heavily thickened; the cell is rounded at the base,
tapering, and closed at the apex with a small, lateral, globose head
that breaks off when touched, discharging a fluid irritant; stinging
trichomes may be frequent, rare, or absent on the upper surface; stomata
absent on the upper surface; lower epidermis has abundant anomocytic
(less frequently anisocytic) stomata; stinging trichomes present;
covering and glandular trichomes as on upper surface, may be absent,
moderate, or dense.
Transverse section:
Bifacial; palisade cells in a single row; cystoliths 2-3x the width of a
palisade cell, and not as long, often tapering towards the mesophyll,
with a stratified or warty surface; cystoliths on upper side
conspicuous, on lower side considerably smaller or absent.
3.1.2. Stem (may be absent)
Surface view: Trichomes as on the leaf; stinging trichomes may be present or absent.
Transverse section:
Quadratic with prominent corners; several vascular bundles are located
at each corner; between bundles the cells are thickened and pitted;
fiber caps with an irregular outline occur outside of the phloem; fiber
cell walls are only slightly thickened, with a large cell lumen; small
calcium oxalate cluster crystals 10–20 μm diameter are present; pith
parenchymatous with a central cavity.
Longitudinal section: Cluster crystals arranged in distinct columns.
3.1.3. Flowers (may be absent)
Unisexual;
pollen grains spheroidal with a smooth exine, ∼16–20 μm diameter; ovary
with numerous very small cluster crystals of calcium oxalate.
3.1.4. Powder
Fragments
of the leaves with cystoliths and small glandular trichomes; covering
trichomes; stinging trichomes (mostly broken); fragments of flowers
(pollen grains, calcium oxalate from ovary) and stems (fibers, calcium
oxalate) may be present.
3.2. Urtica urens
3.2.1. Leaf
Surface view:
Upper epidermis composed of cells with sinuous anticlinal walls;
abundant idioblasts (lithocysts) have a circular outline and contain
large cystoliths, up to 70 μm in diameter, with wrinkled surface,
appearing as bright dots on the leaf surface; stinging trichomes
numerous, with a narrow, parenchymatic, multicellular base and a long
and thick-walled terminal cell having a small bulbous apex, overall
length approx. 1–1.5 mm; covering trichomes unicellular, up to 350 μm in
length, swollen at the base, tapering, wall thickened, frequently
secondarily, cuticle smooth or warted, occurring predominately along the
leaf margin; glandular trichomes with unicellular stalk and mostly a
bicellular glandular head, sometimes head 1- or 4-celled, occurring
predominately along the veins; stomata usually absent; lower epidermis
with numerous anomocytic stomata 20–30 μm in length; lithocysts
frequent; glandular trichomes scattered over the surface, covering
trichomes along the veins, stinging trichomes may be present.
Transverse section:
Bifacial; palisade cells in a single row; lithocysts larger than
epidermal cells, cystoliths roundish, elliptical, or ovoid; cystoliths
on both sides of the leaf are well developed.
3.2.2. Stem
Surface view: Unicellular covering and multicellular stinging and glandular trichomes present.
Transverse section:
Quadrangular, densely covered with unicellular covering trichomes and
stinging hairs; angular collenchyma conspicuous beneath the epidermis at
the corners; vascular bundles usually three at each corner; parenchyma
with cluster crystals of calcium oxalate.
3.2.3. Flowers
Unisexual;
tepals with trichomes similar to those found on leaves; perianth
segments with stinging hairs; pollen grains spheroidal with smooth
exine, ∼15–20 μm in diameter; ovary with numerous small cluster crystals
of calcium oxalate.
3.2.4. Powder
Fragments
of leaves with cystoliths; stinging trichomes mostly broken; covering
trichomes along margin and veins; fragments of flowers may be present
(cluster crystals from ovary, pollen grains); fragments of stem
(collenchyma, parenchyma with cluster crystals, vessels) (Oeder, 1883, Photo 2).
- Photo 2.
Source: Oeder GC. Flora Danica. 1883. Hafniæ, typis [fratrum] C. [& A.] Philiberti; Denmark.
4. Commercial sources and handling
The
largest percentage of stinging nettle herb is wild-harvested.
Cultivated supplies are available, however, and quantities continue to
increase. Primary producers of stinging nettle include Eastern Germany,
the former USSR, Bulgaria, the former Yugoslavia, Hungary, and Albania (Bombardelli and Morazzoni, 1997, Patten, 1993 and Wichtl, 2004).
4.1. Collection
Collection
of stinging nettle herb should be done in select areas, avoiding
locations where agribusiness and industrial runoffs occur. Gloves are
recommended during the harvesting process to prevent skin exposure to
the contents of the stinging hairs of the plant, though gloves are not
needed in those with calloused and adept harvesting hands. Gloves need
to be rubber not linen, though polythene bags worn on the hands can be
useful to prevent stings. It is also important to wear long-sleeves that
go all the way down to the gloves as the inside of the wrists can be
more sensitive than the hands. The herb should be collected early in the
day after the dew has dried (Grieve, 1931)
though it can be gathered any time of the day after it is dry. The herb
can be cut just above the ground, using care to avoid harvesting any
plants that show excessive signs of insect damage or disease.
Alternatively, the leaves can be stripped off the stems, taking care to
avoid excessive bruising, which damages leaf cells and can result in
oxidation and dark discoloration of the material. Careful inspections
are needed to avoid the inclusion of excessively damaged material. Older
leaves are not ideal for harvest as they are tough and gritty, but
generally still make an acceptable tea or tincture. Plant material
should be delivered to the processing area as soon as possible as plants
will mold and begin to oxidize quickly after harvesting. After drying,
the leaves can be stripped off the stems and the stems discarded.
Harvesting
time varies for stinging nettle depending on what type of preparation
is made. Harvesting in the spring or early summer before flowering is
recommended for use in juice preparations and other fresh plant
preparations (Moore, 1993)
though juice preparations can be made as long as fresh material is
available. Early season harvested leaves can be used as a fresh
vegetable green and also dry well to be used to make tea. Harvesting at
any time between mid-spring and late summer is recommended for dried
preparations. Sources differ in their opinions about whether stinging
nettle should be picked before flowering, or while flowering, but before
seeding (BHP, 1983, Blumenthal et al., 1998, Bombardelli and Morazzoni, 1997, Kraemer, 1920, Moore, 1982 and Moore, 1993).
After seeding stinging nettle leaves lose their vitality quickly so it
is recommended to harvest stinging nettle before seeding or immediately
after seeding and before the leaves wilt.
Both
species of stinging nettle prefer to grow in soil that is nitrogen rich
and it is common to find them growing in areas high in inorganic
nitrates and heavy metals. Heavy metals are poorly processed by the
plant and tend to accumulate in the leaves (Moore, 1993).
The leaves can contain 10–20% of the nitrate stored by the stems, the
physiologically older leaves containing less than the younger leaves (Frank et al., 1998).
It is also recommended that stinging nettle be gathered in areas that
have a short growing season or in regions where the winters are harsh
enough to cause the stinging nettle to die back fully to the ground.
Longer seasons lead to on-going growth of the stinging nettle (Moore, 1993).
4.2. Cultivation
Cultivated
nettle herb is becoming more and more widely available. Yields are
directly influenced by the age and harvest cut. Second-year plantings
are reported to provide the highest yields. Third- and fourth-year
plantings gave much smaller yields. A higher yield is possible if the
harvest cut is taken just before flowering occurs. A two-year New Mexico
study found that transplantation increased stinging nettle stand
establishment compared to direct seeding and increased dry weight yields
by a factor of 3 or more (Kleitz et al., 2008).
Plant
age and harvest cut influence certain constituent levels. Beta-carotene
concentration is found to vary in plants depending upon the season and
age of the plants harvested. Chlorophyll and carotenoid contents are
found to be higher in 2-year-old plants. Calcium and magnesium are
higher in the leaves than in the roots, and are not affected by the age
or harvest date of the plant. Iron and manganese content is higher in
the leaves of young plants, whereas nickel and lead are lowest in older
plants. Flavonoid content does not seem to be affected by plant age.
Habitat location and plant age do not seem to contribute widely to
variance of other mineral content in stinging nettle (Bombardelli and Morazzoni, 1997 and Weglarz and Karaczun, 1997).
One study found elevated levels of nitrogen, phosphorous, and iron in
the leaves of stinging nettle and attributed the variation in samples to
the influence of agricultural wastes (fertilizers) on mineral levels in
the soil on which the plant was growing (Konieczynski and Wesolowski, 2007).
Tannins
in leaves containing pyrocatechol, protocatechuic acid, and
ploroglucinol triple in yield from March (3.5%) to August (10.2%) and
then decrease from September (7.6%) to October (5.8%). Chlorophyll
content diminishes from March to August and September to October (Ramic et al., 1987).
Grevsen et al. (2008)
in a three-year harvest study found that high N levels in soil
significantly reduced the concentration of total flavonoids, but the
effect of N levels on total phenolic acids was only significant in the
second harvest each year. The findings suggest that cultivation of U. dioica
for medicinal purposes with a high yield of bioactive compounds is a
compromise between a high yield of plant material and the content of
flavonol glycosides and phenolic acids in the harvested product.
4.3. Handling and processing
When
handling and processing dried or fresh material, gloves are
recommended. The irritating contents of the stinging hair are abundant
in fresh plant. Much of the irritating contents of the stinging hairs
are dissipated upon drying, but can still cause skin irritation when
handling dry material. Fresh plant material should not be accepted if it
is black or brownish-black in color. This is a sign of oxidation and/or
improper handling, drying, or storage.
Dried
herb is processed for teas, tablets and capsules, and other
preparations. Freeze-dried herbs are processed mainly for use in
capsules. Preparations from fresh plant material include juice,
homeopathic products, and liquid extracts (Bombardelli and Morazzoni, 1997 and Patten, 1993).
In a comparison study of total phenolic concentrations in cultivated
versus wild stinging nettle, cultivated samples contained significantly
higher (P < 0.05) levels of phenolics than wild samples ( Spina et al., 2008).
4.4. Drying
Drying
can be done in a well-ventilated area at 40 ˚C protected from direct
light, moisture, and excessive heat. Drying can also be accomplished by
tying and hanging the fresh plant material in small bunches of 6–10
plants in a warm dry area with good airflow. Another way of drying
stinging nettle is to cut the stems down and place the leafy stems on a
tarp in full sunlight, turning occasionally during the day and bringing
in at night if not fully dry. When fully dry, nettle leaves are easily
removed and will crackle and crumble when broken apart. Dried stinging
nettle will also loosely cohere into a ball when squeezed in one's hand
due to the fibrous nature of the plant. When completely dry, the leaves
should be stripped from the stems and the large stems discarded.
Removing leaves from the stem prior to drying reduces drying time.
4.5. Storing
Follow
general storage guidelines protecting the herb from direct light, air,
and moisture. Though definitive data regarding storage is lacking, 18
months is considered an appropriate shelf life for properly dried nettle
herb. Fresh nettle juice may be preserved for 6 months using 25%
alcohol and refrigeration.
4.6. Qualitative differentiation
High
quality nettle herb has a rich deep green color with few stems present
and those present are small in size. Faded or darkened coloration or
presence of large stems is an indication of poor quality material.
4.7. Adulterants
Lamium album,
commonly known as white deadnettle, is noted to be an occasional
adulterant of stinging nettle. While the leaves of the two plants are
similar, Lamium has irregularly serrated leaf margins and no stinging hairs present and so is easily distinguished ( Wichtl, 2004).
In
June 2002 a major commercial supplier of herbal dietary supplements in
the United States recalled four lots of its nettle capsules due to
excessive amounts of lead. The problem was traced to a single batch of
raw material (FDA, 2002).
4.8. Preparations
There
are numerous types of stinging nettle products available. Herbalists
and “green food” enthusiasts commonly use the fresh stinging nettle for
urtication, as a steamed vegetable or raw juice, or as a tea. Dried
nettle leaves (often with stem and seed) are widely available for use as
bulk herbal teas or teabags both alone and in combination with other
herbs. In addition to these more traditional preparations, there are a
variety of liquid and dry extracts. Liquid juice preparations are widely
available and are popular in Europe and more recently freeze dried
preparations in capsules and tablets have become among the most popular
in North America. The seeds, however, should not be over looked for
their nutritive and therapeutic value as these can be present in herb
preparations and many herbal practitioners purposely use the seeds
either alone or in conjunction with stinging nettle leaves both for
nutritive and diuretic effects.
Soup: Prepared as a vegetable with up to 100 g crude herb daily. Infusion: 15 g of stinging nettle leaf in 1 L of boiled water 4–8 h. In one study, the optimum time for mineral diffusion into herbal infusions was reported as 10 min (Özcan et al., 2008). Decoction: Prepare with up to 5 g of herb to 250–350 mL water; bring to a boil, and gently simmer for 10 min and strain. Liquid Extracts: Tincture (1:5 g/mL; 45% alcohol) or fresh leaf extract (1:2; 80% alcohol). Fluid Extract (1:1; 25% alcohol) (BHP, 1983).
5. Constituents
The
leaves of the stinging nettle contain a fairly wide variety of chemical
constituents although only a few compounds belonging to various classes
of natural products have been identified. The compounds responsible for
the stinging/burning action of the hairs on the leaves of Urtica dioica are acetylcholine, histamine, 5-hydroxytryptamine (serotonin), and small amounts of leukotrienes ( Czarnetzki et al., 1990).
The shikimic acid derived phenylpropanes, caffeic acid, and various
esters of this acid such as chlorogenic acid and caffeoylmalic acid ( Budzianowski, 1991 and Schomakers et al., 1995) as well as the coumarin scopoletin have been identified ( Wichtl and Schäfer-Korting, 1994). Other studies confirm the presence of flavonoids, fatty acids, terpenes, protein, vitamins, and minerals ( Bombardelli and Morazzoni, 1997, Ellnain-Wojtaszek et al., 1986, Kudritsata et al., 1986, Rafajlovska et al., 2001 and Wetherilt, 1992).
The distinctive constituents of the herb are the stinging constituents
(acetylcholine, histamine, serotonin) and caffeoylmalic acid whereas
Urtica Dioica Agglutinin (UDA) and ceramides are characteristic of the
root.
5.1. Flavonoids
The
flavonoids present in the fresh herb (inflorescences and foliage) are
mainly kaempferol, isorhamnetin, quercetin, and their 3-rutinosides and
3-glycosides (Bucar et al., 2006 and Ellnain-Wojtaszek et al., 1986). The flavonoid patuletin, as well as its glycosidic derivatives are derived from the leaves U. urens. Patuletin was identified as the major compound of interest ( Saeed et al., 1995).
Apart from glycosides and aglycone flavonoids, it appears that no
constituents have been found which can be considered responsible for the
effects of preparations of dried stinging nettle herb.
5.2. Phenolics
Shikimic
acid derivatives phenylpropanes, caffeic acid, and various esters of
this acid such as chlorogenic acid and caffeoylmalic acid (up to 1.8%)
(AHP Validation) as well as the coumarin scopoletin have been identified
(Wichtl and Schäfer-Korting, 1994). Bucar et al. (2006) confirmed these findings and further reported on the absence of caffeoylmalic acid in U. urens. Pinelli et al. (2008)
reported chlorogenic and caffeoylmalic acid concentrations to be 71.5%
of total phenolics in 1.5 g of cultivated and 76.5% in 1.5 g of wild
samples of stinging nettle leaf.
5.3. Essential oil
The
essential oil of the aerial parts contain esters (14.7%), free alcohols
(2%), and ketones (38.5%) identified as 2-methyl-2-hepten-2-one,
acetophenone and ethylketone, and traces of nitrogenous substances,
phenols, and aldehydes (Frank et al., 1998 and Naves and Ardizio, 1955).
These values must be taken as relative rather than absolute values due
to the age of the analytical studies and the non-specificity of the
techniques used at the time.
5.4. Fatty acids
Rafajlovska et al. (2001)
investigated the presence and relative quantity of fatty acids in
stinging nettle herb extracts. As much as 6.8%, 1.1%, 3.6%, 20.2%, and
12.4% of the lipid fraction of C16:0 (palmitic), C18:0 (stearic), C18:1
(oleic), C18:2 (linoleic), and C18:3 (linolenic), respectively, were
found. In contrast, Guil-Guerrero et al. (2003) found that 〈-linolenic acid was the predominant fatty acid in leaves, while seeds are richer in linoleic acid.
5.5. Carotenes
The
main carotenoid in stinging nettle is β-carotene (2.95–8 mg/100 g in
fresh plants, 20.2 mg/100 g in dry young plants, and 25–300 mg/100 kg in
the dried plants collected in May; this content is reduced to
2.5 mg/100 g in September) (Bertok, 1956; Frank et al., 1998).
The amount of the total carotenoids from fresh nettle leaves has been
reported as 29.6 mg/100 g dry weight and their relative percentages were
reported as β-carotene (61%), hydroxy-α-carotene (0.9%), lutoxanthin
(10.3%), lutein epoxide (13.1%), and violaxanthin (14.7%) (Kudritsata et al., 1986). Rohricht (2007) reported total carotenoids as 0.10–0.16% and total flavonoid content as 0.75–0.88%.
5.5.1. Primary metabolites
A
number of primary metabolites have been identified. Stinging nettle
contains 5–6% protein in fresh plants and 23–24% in dry plants; 70% of
these quantities are digestible proteins (Bombardelli and Morazzoni, 1997). Other substances that have been identified are: a neutral and acidic glycoprotein, including one with a serine O-galactoside glycopeptide bond ( Andersen and Wold, 1978), wax, mucilage, and lipase.
5.6. Other constituents
Stinging
nettle leaves are rich in vitamins such as C (20–60 mg/100 g of dry
material), the B group, and K (0.16–0.64 mg), and minerals such as
calcium (853–1050 mg/100 g), iron (2–200 mg/100 g dry material),
magnesium (175 mg/100 g), phosphorus (50–265 mg/100 g), potassium
(532–613 mg/100 g), and sodium (16–58 mg/100 g) (Frank et al., 1998 and Wetherilt, 1992). In a study of the wild vegetables of South Africa, U. urens contained the highest concentrations of calcium, potassium, phosphorus, and zinc (values not reported) of all species tested ( Afolayan and Jimoh, 2009).
However, large variations in the nutrient content have been observed
due to the seasons and regions of harvest. Porphyrins, namely
coproporphyrin and protoporphyrin, and tannins were identified as well (
Andersen and Wold, 1978). Stinging nettle also contains 1–1.2% fat in fresh plants and 4.8–8.1% in dry plants ( Bertók, 1956). A lower fat content was reported in the whole of dry young plants (3.37%) and in dry adult leaves (2.92%) ( Candussio, 1956).
Other
important substances present are all of the essential amino acids,
glucokinnins, and a very high content of chlorophyll (0.08–0.3% in fresh
leaves and 0.6–1% in dry leaves) (Bombardelli and Morazzoni, 1997, Frank et al., 1998, Lapke et al., 1993 and Wichtl and Schäfer-Korting, 1994).
Several low molecular weight carboxylic acids such as formic, acetic,
and others have been identified. Finally,
3-hydroxy-α-ionyl-β-D-glucopyranosides were isolated from the methanol
extract of stinging nettle leaves (Neugebauer et al., 1995).
5.7. Constituents of the stinging hairs
Early studies of nettle leaf stings identified 5-hydroxytryptamine (serotonin) in the stinging hairs of the fresh leaves of U. dioica ( Collier and Chesher, 1956 and Vialli et al., 1973). However, the serotonin rapidly diminishes in unboiled nettle-sting liquid suspensions due to its enzymatic degradation ( Collier and Chesher, 1956). Histamine is concentrated in the fresh stinging hairs of U. dioica ( Vialli et al., 1973). In association with choline acetyltransferase, acetylcholine is found in leaf homogenates of U. dioica ( Barlow and Dixon, 1973). The choline acetyltransferase enzyme activity in U. dioica that produces acetylcholine is about two orders of magnitude greater than for other plants containing acetylcholine ( Smallman and Maneckjee, 1981). Frank et al. (1998)
confirms the presence of serotonin (5 ng per hair, 0.2 mg/kg fresh
leaf), histamine (0.01 g per hair, 30 mg/kg fresh leaf), and
acetylcholine (0.1–0.2 g per hair, 20 mg/kg fresh leaf).
Earlier, U. urens had been shown to contain histamine and acetylcholine in its stinging hairs ( Emmelin and Felfberg, 1947). These two neurotransmitter substances are primarily responsible for the stinging sensation associated with the U. urens hairs, but are also found in Urtica
leaves themselves apart from the hairs. Along with the inflammatory
histamine, the stinging hairs of this species also contain high levels
of leukotrienes B4 and C4 that act as mediators of urtication ( Czarnetzki et al., 1990). Frank et al. (1998) confirms the presence of histamine (5 ng per hair), acetylcholine (53 ng per hair), and the leukotrienes B4 (0.15 pg per hair) and C4 (0.3 pg per hair) in U. urens.
Freezing the fresh leaves or their extracts is an effective means of preserving the components in the stinging hairs (Maitai et al., 1980 and Saxena et al., 1965). For example, an extract of Urtica massaica
fresh hairs is inactive when kept at room temperature for 5 days, but
retains its activity when stored at 0–2 °C. Also, the activity due to
histamine and acetylcholine is lost after the leaves have been air-dried
( Maitai et al., 1980).
6. Therapeutics
Both
the herb and the root of stinging nettle are used therapeutically,
although in different capacities. The herb is primarily recommended as
an adjuvant treatment of rheumatic conditions, lower urinary tract
infections, as a nutritional tonic, and more recently, the fresh
freeze-dried leaves for the treatment of allergies. The root is used to
reduce complaints associated with benign prostate hyperplasia. For both,
clinical, in vitro, and animal data have shed some light into the
mechanism of action and provide support for some of these traditional
uses. This review focuses on research regarding stinging nettle herb,
while research on the root is reviewed in a separate Therapeutic Compendium.
A
diuretic effect of stinging nettle herb was documented in the medical
literature of the first half of the 19th century. Since then stinging
nettle herb has been more subject to pharmacological than clinical
research. It remains to be established if the pharmacological findings
are surrogate markers for clinical improvements.
Various
stinging nettle herb preparations have been studied experimentally, but
for treatment effects in humans, only stinging nettle tea or juice,
stew, and proprietary extracts (IDS23, in capsules with 335 mg,
recommended daily dosage 2 × 2 capsules, drug to extract ratio (DER)
8–10:1, solvent 50% ethanol and IDS30, in capsules with 145 mg,
recommended daily dosage 2–3 capsules, DER 19 to 33:1, solvent 95%
propanol), and encapsulated fresh freeze-dried leaf powder (300 mg) have
been investigated. Topical application of the fresh leaves has also
been used traditionally and tested clinically (urtication; see Medical
Indications Supported by Traditional or Modern Experience).
6.1. Pharmacokinetics
Detailed
data on the pharmacokinetics of stinging nettle herb constituents taken
as a stinging nettle preparation are completely lacking. There is some
information regarding the pharmacokinetics of some constituents found in
stinging nettle, namely, caffeic acid derivatives and flavonol
glycosides, tested as components of extracts of Echinacea spp. and Ginkgo biloba.
Similarly, consumption of spinach and eggplant with relatively high
histamine content resulted in measurable histamine excretion in the
urine, indicating its absorption following oral ingestion ( Feldman, 1983).
While the theoretical kinetics between the same or similar compounds in
one plant may be the same or similar as in another, differences in the
matrix or companion compounds may alter their actual kinetics. However,
the constituents as they occur in finished products (e.g. teas,
extracts) and the matrices between these botanicals are very similar,
suggesting that some of this pharmacokinetics data may be relevant.
The pharmacokinetics of caffeic acid derivatives was studied in combined liquid hydro-ethanolic extracts of Echinacea purpurea and E. angustifolia
roots. These studies showed that caffeic acid derivatives diffused
across intestinal epithelium only poorly indicating the likely absence
of intestinal absorption ( Matthias et al., 2004, Matthias et al., 2005a and Matthias et al., 2005b). Studies were done on the pharmacokinetics of flavonol glycosides, specifically flavonol aglycones, in Ginkgo biloba.
They found that the flavonol aglycones quercetin, kaempferol, and
isorhamnetin, also found in stinging nettle herb, were bioavailable and
fit a one-compartment model with zero-order absorption without lag time (
Neider, 1991 and Wójcicki et al., 1995). Other studies also found that these flavonol aglycones were readily metabolized and absorbed intact into the blood stream ( Pietta et al., 1995 and Watanabe et al., 2001).
6.2. Clinical efficacy and pharmacodynamics
Part
of the use of stinging nettle herb is due to a putative
anti-inflammatory activity. An anti-inflammatory activity can be
associated with the clinical use of stinging nettle herb for arthritic
conditions and allergic rhinitis. Its diuretic effect has been
demonstrated in vivo. Use of stinging nettle herb as a nutritional tonic
has not been subject to clinical or pharmacological study and cannot be
sufficiently assessed, but rather only partially assessed based on its
constituent profile (see Constituents). There has been limited
scientific investigation of the use of external application of stinging
nettle (urtication) in arthritic conditions although extensive folk use
is reported.
The etiology
and pathogenesis of rheumatoid arthritis and osteoarthritis is not yet
fully understood. Both diseases result in some degree of inflammation,
cartilage destruction, and pain. Major factors affecting degree of risk
for developing osteoarthritis include age, joint location, obesity,
genetic predisposition, joint malalignment, trauma, and gender.
Rheumatoid arthritis appears to require the complex interaction of
genetic and environmental factors with the immune system, and ultimately
in the synovial tissues, the primary target of the autoimmune
inflammatory process, throughout the body. Such an autoimmune response
results in synovitis that can cause the destruction of cartilage and
bone and stretch or rupture the joint capsule as well as tendons and
ligaments.
Nonsteroidal
anti-inflammatory drugs (NSAIDs) are typically the drugs of choice for
the alleviation of rheumatic complaints though patients with rheumatoid
arthritis are often on a multiple drug regimen for treatment. NSAIDs
inhibit cyclooxygenase and thereby reduce prostaglandin production.
Discovery of the central role of cytokines, such as interleukin-(IL)-1β
and tumor necrosis factor-α (TNFα) (Zangerle et al., 1992)
has enabled a new synthetic treatment approach. Joint destruction is
mediated by enzymes such as serine proteases, matrix metalloproteinases
(MMPs), and the cathepsins (Cunnane et al., 1998). The cytokines stimulate chondrocytes to release cartilage-degrading proteinases (Goldring, 1999).
Allergic rhinitis also is associated with inflammatory mechanisms,
specifically, when exposed to an allergen endogenous antibodies (e.g.
IgE) bind to the allergen and attach to a mast cell. This triggers a
reaction that causes the mast cells to release its contents, including
histamine, and the subsequent inflammatory cascade leads to allergy
symptoms.
There is evidence
that stinging nettle herb interferes with the arachidonic acid
metabolism and the production of proinflammatory cytokines and also with
cell adhesion molecules that facilitate both the migration of cells
into the joint, and the attachment of synovium to bone and cartilage.
This mechanism of action is, thus broader than that of the NSAIDs though
not yet fully elucidated. It seems likely that the anti-inflammatory
effect of stinging nettle herb is linked to lipophilic compounds.
Investigations with fractions of stinging nettle herb have indicated
that a lipophilic hexane fraction was most effective at inhibiting the
biosynthesis of the inflammatory mediators thromboxane B2 and leukotriene C4
in whole human blood (Sporer F. as per Chrubasik, 2008 personal
communication to AHP). In contrast, aqueous stinging nettle herb
preparations (tea or freshly squeezed juice) did not elicit any
analgesic activity (Chrubasik, 2008 personal communication to AHP).
Topical activity is related to the histamine content of stinging nettle
and the counterirritant effect caused by the sting resulting in local
irritation that blocks the ability of afferent sensory nerves to carry
pain signal from the area of urtication (e.g. arthritic joint). This is
the same activity attributed to topical capsaicin cream.
Ex
vivo and in vitro data indicate that a sufficient concentration of the
active principle may reach the targets to interfere with
anti-inflammatory mediators. No data, however, are presently available
that demonstrate clinical effects associated with changes in these
inflammatory mediators and confirmatory studies proving any clinically
relevant anti-inflammatory effect are lacking. All the other observed
stinging nettle herb actions (e.g. analgesic, local anesthetic,
spasmodic, central depressive, diuretic, cardiovascular, hyperglycemic)
are less well investigated.
6.2.1. Anti-Inflammatory, analgesic, and local anesthetic activity
6.2.1.1. Human clinical studies
There
are currently no formal clinical studies proving the efficacy of any
stinging nettle preparation as an antirheumatic. The evidence of
putative effectiveness is solely based on few exploratory studies that
show a trend for improvement, especially as an adjunct to NSAID
treatment, particularly with diclofenac. However, whether the effect
size is clinically relevant remains to be shown.
A post marketing survey in 71 centers included 219 patients suffering mainly from osteoarthritis of the hip and knee (n = 185), rheumatoid arthritis (n = 46), fibromyalgia (n = 33), and other rheumatic diseases (n = 33).
The subjects were treated with 1340 mg of a stinging nettle herb
extract (IDS23) over 3 weeks (71 solely with the extract, 147 patients
consumed additional NSAIDs, mainly diclofenac). Pain was assessed on a
visual analogue scale and improved in 70% of the patients in the study,
with 51% improvement in patients treated solely with the extract and 58%
improvement in patients treated with extract and NSAIDs ( Hansen, 1996).
In
a multi-center post-marketing surveillance review including 8955
patients (5953 females, 2920 males) suffering from osteoarthritis (n = 7935) or rheumatoid arthritis (n = 1550) subjects received 1340 mg of stinging nettle extract (IDS23) over 3 weeks as mono- or co-treatment ( Ramm and Hansen, 1997).
Fifty percent of the patients were pretreated with NSAIDs (82%
diclofenac), while 8% received other treatments. The aim of this open
study was to assess efficacy in terms of clinical improvement, reduced
consumption of NSAIDs, and the safety of the extract. Outcome measures
included pain at rest and movement as well as physical impairment (all
assessed on a verbal rating scale 0 to 4), consumption of NSAIDs, and
incidence of patient reported adverse effects. Pain at rest improved by
55%, pain during movement by 45%, and physical impairment by 38%. In 38%
of the patients NSAID consumption was reduced by 50% and a further 26%
of patients were satisfied with stinging nettle extract treatment alone.
In 28% of the patients NSAID requirement was unchanged and in 8%
additional NSAIDs were necessary. There was no difference in the score
improvement (rest, movement, physical impairment) between patients
pretreated with NSAIDs and those not pretreated. A marked limitation of
this study was the lack of a control group. Since the per-se improvement
over time is unknown the clinical effectiveness of this stinging nettle
extract (IDS23) remains to be established. The most important result of
this open study is the low incidence (1.2%) of adverse events during
treatment. From the 110 reported events, 57 consisted of
gastrointestinal complaints, 12 to allergy, 11 to polyuria, 6 to
pruritus, and 24 to others.
A
low toxicity of the stinging nettle herb extract IDS23 was also
confirmed in a 12-month post-marketing surveillance review that included
819 patients suffering from osteoarthritis of the knee. Patients
included in the study met international criteria for osteoarthritis and
had to have had at least two severe, therapy-requiring episodes within
the previous year. Adverse events consisting predominantly of allergic
and minor gastrointestinal events occurred in 3% of the patients.
Clinical symptoms such as pain, joint stiffness, and impaired joint
function improved on average by 61% (Wolf, 1998).
In an open uncontrolled study in two centers (Wolf et al., 2001),
20 patients suffering from acute exacerbations of osteoarthritis of the
hip or knee received 2–3 capsules of 145 mg stinging nettle herb
extract (IDS30; Strath 59) per day over 12 weeks. Pain scores assessed
in a patient diary decreased by 42%. WOMAC component stiffness and
component disability improved by 35% and 32%, respectively, in 17
patients (there were 3 drop-outs due to insufficient efficacy). Four of
the 17 patients rated the efficacy as good or very good and all 17
patients rated the tolerability as good or very good. Adverse events
were not observed. At the end of treatment stimulated TNFα release ex
vivo-in vitro was decreased by 30% (n = 17) whereas in patients
receiving NSAIDs, stimulated TNFα release increased by 31% (no data on
the diclofenac clinical changes stated). Interleukin-1β inhibition was
most pronounced after 4 weeks (58%), but increased towards the end of
treatment.
Another 763
osteoarthritis patients from 158 centers received the same stinging
nettle herb extract (IDS30; Strath 59) over 6 months (mainly 3 capsules
per day initially followed by 2 capsules per day in the course of
treatment) (Hubbe, 2002).
Osteoarthritic complaints decreased by more than 50% (57 patients were
excluded from analysis because ACR criteria were not fulfilled). The
results of the study showed the WOMAC index scores of 662 patients
decreased by 52% (components pain by 55%, stiffness by 52%, disability
by 51%), the quality of life (index not stated) improved by 45%, and the
swelling and pain threshold of the affected knee each decreased by 61%
(per protocol analysis, 93 dropped out). Of the 363 patients who
consumed additional NSAIDs prior to study, 42% did not require any
NSAIDs during the course of treatment and 34% needed only half of the
initial NSAID dose, while NSAID requirement was unchanged in 24% and
increased in 2 patients. Seventy-eight percent and 97% of the patients
rated the efficacy and tolerability as good or very good, respectively.
Eleven patients suffered from adverse events including gastro-intestinal
problems, joint swelling, and nausea.
In
an open randomized study, 40 individuals suffering from acute arthritis
(rheumatoid arthritis, gouty arthritis, activated arthrosis) received
either diclofenac (50 mg) plus 50 g of stewed nettle herb (with 95.5%
water content and yielding 20 mg caffeoylmalic acid) or diclofenac alone
(200 mg) (Chrubasik et al., 1997).
Thirty-six patients completed the study. Assessment was based on the
normalization of the elevated acute phase protein C-reactive protein
(CRP), patient assessment of physical impairment, subjective pain, and
pressure pain (the clinical signs of acute arthritis) and physician
assessment of stiffness. All assessments were done on a verbal rating
scale from 0 to 4. In both groups median scores improved by
approximately 70% relative to the initial value. CRP did not correlate
with the number of affected joints (r = 0.19, P = 0.24; big joints r = 0.16, P = 0.34; small joints r = 0.23, P = 0.17).
CRP and total joint scores improved significantly in both groups
(Wilcoxon paired rank sum), and there were no significant differences
between the two groups. Only mild adverse effects occurred during
treatment. Since effective pain relief from diclofenac in rheumatoid
arthritis typically requires at least 125 mg daily, the authors
concluded that stewed stinging nettle herb might enhance the
antirheumatic effectiveness of a subtherapeutic dose of diclofenac. A
pilot study investigating the analgesic effect of squeezed nettle juice
and nettle tea (aqueous extract) for the relief of osteoarthritic pain
did not show any trend of effectiveness (Chrubasik, 2008 personal
communication to AHP) indicating that the active principle may be
contained in the lipophilic fraction of stinging nettle herb.
In
1994, Randall reported a case using the sting of the common stinging
nettle (urtication) to treat osteoarthritic pain. He then collected data
on another 18 self-selected patients suffering from osteoarthritis (Randall et al., 1999).
All except one respondent were sure that stinging nettle had been very
helpful and several had considered themselves cured. No observed side
effects were reported, except a transient urticarial rash. Consumption
of analgesics were frequently stopped or otherwise very much reduced.
Based on these data, a randomized controlled double-blind cross-over
study was carried out, though it was noted that “blindness” was possibly
incomplete due to patients’ exposure to both treatments during the
course of the study. Twenty-seven patients with osteoarthritic pain at
the base of the thumb or index finger applied fresh stinging nettle leaf
daily for 1 week to the painful area with gentle pressure for about
30 seconds, moving the leaf twice. The effect of this treatment was
compared with that of a placebo similar in appearance of fresh white
deadnettle leaf (Lamium album), which lacks any stinging hairs,
for 1 week after a after a 5-week washout period. Thirteen patients
started with stinging nettle and 14 with the placebo. Patients were
instructed to cut a leaf (with hand in a plastic bag) and apply the
underside to the painful area of the thumb. After treatment for 1 week
with stinging nettle, score reductions on both visual analogue scale
(pain) and health assessment questionnaire (disability) were
significantly greater than with placebo ( Randall et al., 2000).
The local rash and slight itching associated with stinging nettle was
acceptable to 23 of 27 patients. In the remaining patients, 2 considered
the sting to be unpleasant but not distressing, 1 discontinued for
reasons not necessarily due to the stinging nettle sting, and 1
discontinued treatment because he needed to wear heavy gloves.
Randall et al. (2008) also conducted a small (n = 42)
randomized controlled pilot study to explore the feasibility of
treatment of chronic knee pain with urtication by stinging nettle and
found a mean reduction in pain score (WOMAC) at the end of treatment in
the stinging nettle groups of 1.7 and in the controls 1.6. Both groups
reduced pain scores significantly. Study problems included some stinging
that occurred, with the placebo species, Urtica galeopsifolia, which had been believed to be a non-stinging species.
In 2008 Randall carried out a consensus study with stinging nettle users to establish Guidelines for use of topical nettle sting to treat arthritis pain.
This work involved a group interview with 9 users and reiterative
repeated feedback of joint experiences of mode of use and outcomes.
These guidelines are expected to be available in 2009.
6.2.1.2. Animal studies
There
are mixed preclinical data regarding an anti-inflammatory effect of
stinging nettle herb preparations. No anti-inflammatory effect was
detected when an unspecified ethanol stinging nettle extract was
administered in the carageenin paw edema test in rats (dose not stated) (Tita et al., 1993).
However, for the 50% ethanolic stinging nettle extract (IDS23)
anti-inflammatory action was demonstrated in rats in which gonarthritis
was induced with 100 g bovine gammaglobulin and 500 g silicon particles.
The rats were treated over 25 days with the extract IDS23 at a daily
intraperitoneal (ip) dose of 25, 100, or 300 mg/kg or 10 mg/kg
diclofenac, or remained untreated as controls. The reduction of paw
circumference by the stinging nettle extract relative to that of
diclofenac (100%) were 12%, 36%, and 67% for the 3 doses, respectively.
Behavior, food intake, and body weight remained unchanged and mortality
was not increased. Histopathological evaluation confirmed a
significantly lower lymphocyte infiltration in animals treated with
stinging nettle extract compared to control (P < 0.05). The effect of the stinging nettle extract was similar to diclofenac (Strathmann GmbH, proprietary data on file).
Toldy et al. (2009) investigated the effects of stinging nettle leaf supplementation and swimming exercise on N-Methyl-D-aspartate
(NMDA) injection-induced brain lesion, and subsequent inflammation, in
Wistar rats. Sixty-eight four-month-old male Wistar rats were divided
into 8 experimental groups: sham control (SH), NMDA lesion (NM), swimmer
and sham-operated (SWSH), and swimmer and NMDA lesion (SWNM) groups fed
with either standard or 1% w.w nettle-enriched lab chow. Swimming group
protocol was 1.5 h/day, five times a week, for a total of 7–9 weeks.
The results showed that combined effects of nettle leaf and exercise was
additive in significantly (P < 0.5) decreasing the nuclear factor kappa B (NF-kB) binding activity to DNA, suggesting a strong anti-inflammatory effect.
Khalifeh et al. (2008) explored the effects of an U. dioica, Plantago major, and Hypericum perforatum
L. herbal mixture (Hb) in the collagen induced arthritis rat model
(MCIA). Ethanolic extracts of aerial parts of the three herbs were mixed
in a 1:1:1 ratio and rats in herbal treatment group were given 1 mL
daily by mouth for the whole of the experiment (90 days). It was found
that the percentage of rats showing severe arthritic histopathological
lesions was similar in both experimental groups, though slightly higher
in the MCIA + Hb group. The disagreement with clinical findings was
attributed to the employed clinical scoring system in the study
accounting for changes that were present in all the joints and not on a
separate joint lesion. It was concluded that clinical severity of the
disease decreased, in terms of number of joints involved, with the
herbal extract though further work is needed to investigate the effects
of each individual herb in the mixture.
The
potential for anti-inflammatory activity was studied for the major
compound patuletin isolated from the dwarf stinging nettle. When
administered orally, patuletin (10 mg/kg) reduced the carageenan-induced
edema volume significantly (P < 0.05) to the same degree as
an equivalent dose of diclofenac and reduced carageenan-induced pleural
fluid volume to a greater degree than diclofenac ( Saeed et al., 1995).
The
effect of stinging nettle extract (IDS30) was studied in three
different experimental mouse models for inflammatory bowel disease (Konrad et al., 2005).
In a chronic colitis model, dextran sulphate sodium was used to induce
colitis in mice, which were subsequently subject to severe weight loss.
The weight loss is associated with more frequent signs of colitis
(redness and ulcerations of the anus, bloody diarrhea), reduced colon
length, and more severe histological scores. Similar differences were
observed in IL-10 gene-deficient mice suffering from chronic murine
colitis and receiving the stinging nettle extract or water as placebo.
During 3 cycles of dextran sulphate sodium application over 4 days, the
loss of weight was earlier and more severe than in the control group. In
the population given the stinging nettle extract, no significant
difference in weight over time was observed. Significantly lower fecal
IL-1β and mucosal TNFα levels in the treated mice supported the clinical
observations. Furthermore, mononuclear cell proliferation after
stimulation with LPS was significantly reduced in mice treated with the
stinging nettle extract. Since there was only a limited effect in mice
treated over 5 days with dextran sulphate sodium to induce colitis and
receiving the stinging nettle extract over 4 days, the authors concluded
that the duration of treatment was too short in the acute colitis
model.
The
hot-plate test in rodents is an established model to test central
analgesia. An aqueous stinging nettle extract at a dose of 1200 mg/kg ip
induced much greater resistance to thermal stimulation in mice (a 190%
longer reaction time) than was found with control animals (Lasheras et al., 1986).
In contrast, an ethanolic stinging nettle extract (DER and ethanol
percentage not stated) at unspecified tested doses was ineffective in
the hot plate test in rodents. The same extract, however, significantly
reduced the number of writhes as a response to phenylquinone when the
extract doses given were 1 g/kg per os or 500 mg/kg ip (Tita et al., 1993). The study indicates weak antinociceptive activity of the stinging nettle herb extract. Mahmoudi et al. (2007)
confirmed this antinociceptive activity with a methanolic extract of
stinging nettle in mice. Treatment with stinging nettle extracts
(100 mg/kg) significantly decreased number of writhes in the hot plate
test compared to diclofenac (50 mg/kg). Likewise, aqueous stinging
nettle extract produced a dose-dependent inhibition in writhing and a
more pronounced effect than metamizol in the acetic acid-induced
writhing test in mice (Gülçin et al., 2004).
The analgesic effect of isolated palutein from dwarf stinging nettle
was more pronounced that that of diclofenac in electric shock tests in
rats (Saeed et al., 1995) indicating that this compound may contribute to the overall effect of this stinging nettle herb.
In
the tail flick test, local application of a lyophilized aqueous
stinging nettle herb extract (100 mg/mL) to the tail of mice was
associated with an increase of the thermal threshold. The effect was
comparable to that of lidocaine, which was used as a control indicating
local analgesic activity (Lasheras et al., 1986).
6.2.1.3. In vitro studies
Tunón et al. (1995)
investigated the in vitro inhibitory activity on prostaglandin
biosynthesis and platelet activating factor PAF-induced exocytosis of an
aqueous stinging nettle herb extract (high doses of 200 g/mL). No
effect on the production of prostaglandins from radioactively labeled
arachidonic acid was observed. At a dose of 250 g/mL PAF-induced
exocytosis of elastase from human neutrophils was inhibited by 93%.
Obertreis et al. (1996a)
investigated the effect of a 50% ethanolic extract (IDS23) and
caffeoylmalic acid on the biosynthesis of mediators involved in
inflammation and pain. In a dose range of 0.1 g to 1 mg/mL the extract
showed only a partial inhibitory effect on 5-lipoxygenase products.
However, caffeoylmalic acid inhibited the biosynthesis of leukotriene B4 in a concentration-dependent manner. The half maximal inhibition (IC50) concentration for caffeoylmalic acid was 83 g/mL in this assay. The cyclooxygenase-dependent biosynthesis of prostaglandins D2 and F2〈 was inhibited with IC50 values of 92 g/mL (extract) and 38 g/mL (caffeoylmalic acid). The IC50
of indomethacin was 72 g/mL. The authors concluded that the stinging
nettle leaf extract and its constituent caffeoylmalic acid interfere
with the arachidonic acid metabolism, however, exerting their effects
via different targets. Thus, constituents other than caffeoylmalic acid
also contribute to the in vitro antiphlogistic effect.
Obertreis et al. (1996b)
reported that the stinging nettle extract IDS23 inhibits the
lipopolysaccharide (LPS)-stimulated release of the pro-inflammatory
cytokines TNFα and IL-1β ex vivo dose-dependently. Human whole blood
from healthy volunteers was assayed and it was found that after 24 h
complete inhibition of IL-1β was achieved and maintained up to 65 h with
the highest stinging nettle extract dose examined (5 mg/mL). The same
doses inhibited TNFα release by 51% at 24 h and by 39% at 65 h. In
contrast, IL-6 release was stimulated by the stinging nettle extract in
the absence of LPS, comparable to giving LPS alone, without a further
increase with concomitant administration. Isolated phenolic carbon acid
derivatives such as caffeoylmalic acid, caffeic acid, and chlorogenic
acid as well as the flavonoids rutin and quercetin in a dose range of 10−8 up to 5 × 10−5 mol/L
did not affect LPS stimulated cytokine release. The authors concluded
that stinging nettle extract might modulate the elevated cytokine
release in osteoarthritis or rheumatoid arthritis.
The same group (Teucher et al., 1996)
investigated the effect of stinging nettle extract (IDS23; daily
consumption of 1340 mg over 21 days) on cytokine release measured in
whole blood of 20 healthy volunteers. Basal concentrations of TNFα,
IL-1β, IL-4, IL-6, or IL-10 (which were below detection limits before
extract consumption) remained uninfluenced. However, LPS-stimulated
release of TNFα and IL-1β from ex vivo cells were inhibited by 15% and
24% (TNFα) and 19% and 39% (IL-1β) after 7 and 21 days of stinging
nettle consumption, respectively (P < 0.01 on day 7; P < 0.001
on day 21). When the extract (20–160 g/mL) was added to the whole blood
in vitro, dose-dependent inhibition of LPS-stimulated TNFα and IL-1β
release was achieved with maximum effects after 3 weeks. As previously
observed, in vitro addition of the stinging nettle extract (160 g/mL)
resulted in IL-6 release quantitatively similar to that of LPS
(0.5 g/mL) and without a further increase when administered
concomitantly with LPS. No IL-6 changes were noted ex vivo in whole
blood after oral administration of IDS23. The authors suggested that
these results indicate the extract contains different pharmacologically
active principles with different bioavailabilities related to its
anti-inflammatory action.
Dose-dependent
inhibition of stimulated TNFα and IL-1β release ex vivo by stinging
nettle extract (IDS23) was also seen in patients suffering from
rheumatoid arthritis as well as healthy controls. The effects were not
due to a non-specific effect on gene expression as no inhibition was
seen on the GAPDH gene. The same stinging nettle extract (IDS23) also
inhibited IL-10 dose-dependently, but had no significant effect on IL-6 (Pearce et al., 1999).
In
order to determine the molecular target for the inhibiting effect of
stinging nettle extract (IDS23) on cytokine release, the effect of the
extract on phorbol myristate acetate-stimulated NF-κB activation was
evaluated by electro-mobility shift assay (EMSA) (Riehemann et al., 1999).
Stinging nettle extract doses of 1.25–10 mg/mL inhibited NF-κB DNA
binding dose-dependently. In addition, by using reporter gene analysis, a
dose-dependent inhibition of TNFα stimulated expression of an NF-κB
driven luciferase gene was found. The authors also showed by Western
blot assay that the degradation of its inhibitory subunit IκB-α was
prevented by the stinging nettle extract.
The
same group investigated the influence of stinging nettle extract
(IDS23) on T-cell derived cytokine pattern and the phenotype cells Th1
and Th2 by using RT-PCR and commercial immunoassays. Interleukin-2
(IL-2) and interferon-γ (IFN-γ) protein expression was evaluated by
ELISA with phytohemagglutinin-stimulated peripheral blood mononuclear
cells in vitro. Dose-dependent inhibition up to 50% IL-2 and 77% IFN-γ
was observed. In contrast the stinging nettle extract stimulated the
secretion of Th2-specific IL-4. The dose-dependent inhibiting effect on
IL-2 and IFN-γ expression was also detected with RT-PCR, while the
amount of actin-specific mRNA transcript was not modified by the
stinging nettle extract. The authors suggested that the effective
ingredient of the extract acts by mediating a switch in T-helper
cell-derived cytokine patterns (Klingelhoefer et al., 1999).
Dendritic
cells (DCs) are important antigen presenting cells. They play an
important role in the initiation of rheumatoid arthritis. Human DCs were
generated from peripheral blood mononuclear cells cultured in
granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-4. DC
maturation was induced by keyhole limped hemocyanin (KLH). DC phenotype
was characterized by flow cytometric analysis and their cytokine
production by ELISA. The ability of DC to activate naive autologous
T-cells was evaluated in the mixed leukocyte reaction. The stinging
nettle extract (IDS30) reduced the maturation stage of DC, but did not
affect their viability. The stinging nettle extract reduced the
KLH-induced expression of CD 83 and CD 86, increased the expression of
CCR 5 and CD 36 in a dose dependent manner, and reduced secretion of
TNFα. Application of extract to DCs in culture caused a high endocytosis
of dextran and a low capacity to stimulate T-cell proliferation. These
in vitro results showed the suppressive effect of this stinging nettle
extract on the maturation of human myeloid DC, leading to a reduced
induction of primary T-cell responses (Broer and Behnke, 2002).
The authors concluded that this effect might contribute to the
therapeutic effect of stinging nettle extract on T-cell-mediated
inflammatory diseases such as rheumatoid arthritis.
In
another study, stinging nettle extract (IDS30) was found to
significantly suppress in vitro IL-1β-induced expression of matrix
metalloproteinase-1 (interstitial collagenase), matrix
metalloproteinase-3 (stromelysin-1), and matrix metalloproteinase-9
(gelatinase B) by human chondrocytes (Schulze-Tanzil et al., 2002).
The authors concluded that the cartilage-protective effect of the
stinging nettle extract might be produced by down-regulation of matrix
metalloproteinases.
6.2.2. Histamine desensitization
6.2.2.1. Human clinical studies
6.2.2.1.1. Allergic rhinitis
T-Helper
cells, Th2 cytokines specifically, play a pivotal role in the allergic
inflammatory cascade. In order to target these factors, stinging nettle
has been investigated in a placebo-controlled double-blind pilot study
in allergic rhinitis. By potentially preserving most of the bioactive
amines and acetylcholine found in the stinging hairs, the freeze-dried
fresh leaves provide a phytochemically unique preparation. Ninety-eight
patients with seasonal allergic rhinitis received 300 mg freeze-dried
stinging nettle herb (Eclectic Institute, Sandy, Oregon) or placebo
twice daily (Mittman, 1990).
Assessment was based on daily symptom diaries and global response to
treatment was recorded at the follow-up visit after 1 week of therapy.
The stinging nettle preparation was rated higher than placebo in
positive global assessments of efficacy. When scoring treatments as
equally or more effective than previous medications, significantly more
in the nettle group (48%) than the placebo group (21%) found stinging
nettle to be superior to previous medications (P = 0.02). Of
those taking stinging nettle, 58% rated it as moderately or highly
effective, compared to 37% using placebo, which approached statistical
significance (P = 0.079). Also, there was a slight difference
in favor of the stinging nettle herb for subjective amelioration of
symptoms when comparing the diary data that did not reach statistical
significance. The incidence of mild gastrointestinal adverse events was
similar in both groups. Two patients of the stinging nettle group
suffered from intensification of their allergic symptoms. Since only 69
patients finished the study, it still remains to be established if
stinging nettle herb is effective in the treatment of allergic rhinitis.
In
the early 1950s at the Mayo Clinic, subcutaneous and intravenous
injections of histamine were successfully administered in 15 cases often
associated with allergic reactions including headaches, migraine,
cluster headache associated with vasomotor rhinitis, penicillin
reaction, allergic arthritis, and cold urticaria with associated
anaphylaxis (Horton, 1951).
Absorption of histamine after oral ingestion was proven when spinach
and eggplant (both high in histamine) produced measurable histamine
excretion in the urine (Feldman, 1983).
Both of these studies lend credence to the biological availability of
histamine and it's plausible positive effect on symptoms of allergic
rhinitis.
6.2.2.2. Animal studies
Histamine
in a 2.5 g intravenous dose in mice produced a desensitizing effect by
preventing anaphylaxis when administered 30 min prior to an antigen
challenge with horse serum (Bogdanova and Kopytovskaya, 1983).
Severe antigen aerosol-induced bronchoconstriction in dogs was produced
when plasma levels of histamine were low. However, high plasma levels
of histamine were associated with reduced bronchoconstriction at 90 min
after a strong histamine release was induced (Zimmermann and Ulmer, 1981).
Histamine at concentrations of 10−3–10−5 M
inhibited 48-h heterologous passive cutaneous anaphylaxis in rats
induced by anti-mouse IgE. This suppressed reaction was blocked by a
histamine (H)2, but not an H1, antagonist. Delayed
allergic hypersensitivity reactions were also suppressed by histamine,
probably from acting on lymphocyte H2-receptors to inhibit the increase of cellular cAMP levels (Saiga, 1981).
The inhibition of delayed-type hypersensitivity in mice following
antigen challenge was effective when 0.1–10 mg/kg histamine was injected
intraperitoneally twice daily for two days. Lymphocyte accumulation at
the implanted sponge site and production of lymphokine (macrophage
chemotactic factor) was suppressed by histamine, but blocked by the H2 antagonist cimetidine. Cell accumulation was only slightly blocked by the H1 antagonists pyrilamine and diphenhydramine (Tasaka et al., 1986).
In the case of histamine-induced inhibition of delayed hypersensitivity
reactions, skin tuberculin reaction, lymphocyte transformation, and
migration inhibitory factor production in BCG-vaccinated guinea pigs,
these were nearly abolished by the H2-receptor blocker metiamide, but not by mepyramine, an H1-receptor blocker (Janaszek and Maslinski, 1979).
6.2.2.3. In vitro studies
In white blood cell populations taken from guinea pig lymph nodes, histamine at 10−4 M induced T-lymphocytes with H2-receptors to release a soluble factor with immunosuppressant properties (Rocklin et al., 1979) that suppressed humoral and cellular immunoreactivity (Koenig and Bock, 1986). By its action on leukocytic H2-receptors histamine in concentrations as low as 10−8 M inhibited chemotaxis of human basophils, and this inhibition was blocked by the H2-receptor antagonist metiamide (Lett-Brown and Leonard, 1977).
Besides being a mediator of immediate hypersensitivity allergic
reactions, histamine acts as an autacoid (“self medication”) to modulate
the immune response. It activates adenylate cyclase via H2-receptors
of leukocytes, thereby stimulating the conversion of ATP to cAMP and
preventing antigen-induced mediator release from sensitized basophils
and mast cells, such as histamine release from ragweed-sensitized cells (Bourne et al., 1974 and Melmon et al., 1981).
6.2.3. Platelet anti-aggregation activity
6.2.3.1. In vitro studies
The
ability of stinging nettle preparations to inhibit platelet aggregation
has been reported in various in vitro models. Aqueous stinging nettle
extract demonstrated weak inhibition of thrombin and ADP-induced
platelet aggregation (Mekhfi et al., 2004), while weak antithrombotic activity was reported for a methanolic extract (Goun et al., 2002). Adrenaline-induced aggregation of human platelets by stinging nettle was described by Sajid et al. (1991). El Haouari et al. (2006)
investigated different stinging nettle leaf extracts in different
concentrations on thrombin, ADP, epinephrine, and collagen-induced
platelet aggregation. Crude aqueous stinging nettle extract inhibited
thrombin-induced aggregation dose-dependently (at 1 mg/mL by 17%). The
more lipophilic the solvent, the more potent the effect. Ethyl acetate
extract exhibited the greatest anti-aggregation effect (77% inhibition
at 1 mg/mL). Flavonoids inhibited platelet aggregation by all inducers.
The authors concluded that flavonoids are mainly indicated in the
antiplatelet action of stinging nettle leaf. In contrast, Antonopoulou et al. (1996)
identified a phospholipid that induced platelet aggregation. The HPLC
fractions of polar lipids derived from leaves and stems as well as roots
were able to induce aggregation of washed rabbit platelets in a
dose-dependent manner similar to PAF, but were 5 orders of magnitude
less potent. The effect was not inhibited by indomethacin, but by a PAF
receptor-specific agent indicating a receptor mechanism.
6.2.4. Antioxidant activity
6.2.4.1. Animal studies
The
effects of stinging nettle herb ethanol extract were studied for its
effects on various antioxidant and detoxification enzyme systems. Two
doses of stinging nettle herb extract (50 and 100 mg/kg, solvent 80%
ethanol) were administered orally over 14 days in mice. The antioxidant
BHA served as a positive control. Preparations of subcellular fractions
from liver, lung, kidney, and forestomach were prepared and used to
determine the effects of the extract on (i) phase I enzymes (cytochrome
P450, cytochrome b5 and their reductases); (ii) phase-II
enzymes (gluthathione-S-transferase, DT-diaphorase); (iii) the
antioxidant enzymes superoxide dismutase (SOD), superoxide catalase,
glutathione peroxidase, and glutathione reductase; (iv) sulfhydryl
groups (total, non-protein and protein-bound); (v) lactate
dehydrogenase; and (vi) lipid peroxidation. Treatment with stinging
nettle extract had a marked effect on selective hepatic
biotransformation and antioxidant enzyme systems. The ratio of liver
weight and final body weight was not increased following oral treatment,
indicating a lack of toxicity of adjustment on general body metabolism.
Kidney, lung, and forestomach biotransformation enzymes were less
attenuated as there was no evidence of damage as observed via the
measurement of LDH activity as an index of damage at the cellular level.
Oral treatment augmented the levels of all the measured components of
cyt b5 and cyt b5 R, flavoproteins involved in
electron transport in the cyt P450 detoxification enzyme system. The
authors concluded that stinging nettle extract might have an important
effect on liver drug metabolism enzyme systems due to its
chemopreventive and antioxidant profiles (Özen and Korkmaz, 2003).
The
effect of forced swimming training and nettle supplementation, enriched
lab chow containing 1% w/w dried stinging nettle leaf, was investigated
for oxidative stress, inflammation, and neurotrophic markers in Wistar
rat brains (Toldy et al., 2005).
Oxidative stress was measured by electron spin resonance and by the
concentration of carbonylated proteins. Stinging nettle supplementation
significantly reduced the free electron accumulation in the cerebellum
and frontal lobe, whereas regular exercise did not affect electron spin
resonance signals. Stinging nettle supplementation also increased the
DNA-binding of activator protein-1. The combination of stinging nettle
and exercise increased NF-κB activity. The authors concluded that
stinging nettle might be an effective antioxidant and possibly an
antiapoptotic agent promoting brain cell survival.
Cetinus et al. (2005)
investigated the potential role of stinging nettle for prevention of
oxidative stress in muscle tissues generated by tourniquet application
in Wistar rats. Homogenized stinging nettle leaf or 1.15% KCl aqueous
solution was given to each group of 8 rats once a day for 5 days through
esophageal gavage. No treatment was applied to a third group.
Tourniquets were applied to the left posterior limb of rats for 1 or 2 h
followed by a reperfusion period of 1 h. Malonyldialdehyde levels,
markers of ischemic damage, were lower in the stinging nettle-treated
rats than those in untreated and KCl-treated rats after either 1 or 2 h
of ischemia and 1 h reperfusion. The authors concluded that stinging
nettle has a potential antioxidant effect on ischemic muscle tissues.
Celik and Tuluce (2007)
conducted a study to investigate the protective effects of stinging
nettle infusions (2.5 g dried herb/L boiled water) against chemical
carcinogen trichloroacetic acid (TCA) exposure in rats. Exposure to TCA
induces oxidative stress in tissues to which it is exposed. For 50 days
24 healthy rats, randomly allotted into control or treatment groups,
were given no treatment (control), TCA, TCA + green tea (Camellia sinensis)
infusion, or TCA + stinging nettle leaf infusion. The stinging nettle
preparation, like green tea, was found to significantly reduce the
amount of injury to tissues as evidenced by reduced elevation of serum
transaminase ALT, liver catalase, and brain superoxide dismutase (P < 0.05) compared to TCA-treated rats not receiving the infusions.
Antioxidant
activity was also investigated for the steam-distilled volatile oil of
stinging nettle seed. Rats were treated with carbon tetrachloride (CCl4)
twice a week subcutaneously for 90 days and exhibited signs of
oxidative damage including lipid peroxidation and elevated liver
enzymes. Liver weight increased in the groups treated with stinging
nettle, preventing the weight loss induced by the CCl4 treatment. The stinging nettle seed oil (2 mL/kg ip) attenuated the oxidative damage caused by CCl4. The authors concluded that stinging nettle seed oil significantly (P < 0.05) increased the antioxidant defense system activity in CCl4-treated rats ( Kanter et al., 2003).
6.2.4.2. In vitro studies
Stinging
nettle herb extract (solvent 80% ethanol) was tested for its free
radical scavenging activity in the diphenylpicrylhydrazil (DPPH)
screening assay, for in vitro non-enzymatic inhibition of bovine brain
lipid peroxidation and for inhibition of xanthine oxidase. Stinging
nettle extract inhibited brain lipid peroxidation by more than 50% and
resulted in an approximately 30% inhibition in the xanthine oxidase
assay, but had no effect in the DPPH assay (Pieroni et al., 2002).
The
antioxidant properties of an aqueous stinging nettle extract was
further studied in established test procedures including free-radical
reducing power, free radical scavenging, superoxide anion radical
scavenging, hydrogen peroxide scavenging, and metal chelating activities
(Gülçin et al., 2004).
The percentage inhibition of peroxidation in linoleic acid emulsion of
the stinging nettle extract was dose-dependent and more pronounced than
that of α-tocopherol (vitamin E). Likewise, its reductive capability was
higher than that of α-tocopherol. In the same concentrations, the
extract showed a greater percentage inhibition of superoxide generation
than of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
or α-tocopherol. The extract and BHA had equal DPPH-scavenging
activities, which were lower than that of quercetin. The metal chelating
capacity of the extract was higher than that of BHT, α-tocopherol, or
BHA.
Mavi et al. (2004)
determined the aqueous stinging nettle extract concentrations required
for a 50% inhibition of peroxidation and of DPPH radical absorbance were
1012 and 335 mg/L, respectively. A low ferric reducing/antioxidant
power (3 vs. > 20 mM/L) and a moderate phenol antioxidant coefficient
(2.2 vs. > 3) for aqueous stinging nettle extract were also observed
(Katalinic et al., 2006).
With respect to nitric oxide (NO) production by murine peritoneal macrophages, lipopolysaccharide-stimulated NO2−
production was inhibited by aqueous stinging nettle extract in a
dose-dependent manner at concentrations from 50 to 500 g/mL without
affecting cell viability. The expression of iNOS protein measured by
western blotting was not affected (Harput et al., 2005).
The authors concluded that the suppressive effect of the stinging
nettle extract was in part due to its NO radical scavenging activity.
Polyphenol oxidase was identified as an antioxidative principle (Gülçin et al., 2005).
The
changes of the antioxidant (AOA) and antiradical activities (ARA) of
aerial sections of nettle after application of polyamine and phenolic
biosynthesis regulators were studied by Hudec et al. (2007).
The treatment with ornithine decarboxylase inhibitor, a polyamine
inhibitor, and a phenol biosynthesis stimulator was analyzed
spectrophotometrically. Both regulators increased the AOA of the
stinging nettle extract, measured as inhibition of peroxidation.
6.2.5. Chemopreventive and immunomodulatory activity
6.2.5.1. In vitro studies
Stinging
nettle has been investigated for its potential as an anticarcinogenic
agent. The Epstein-Barr virus early antigen (EBV-EA) promoted by phorbol
ester (TPA) has been employed for identification of chemopreventive
agents that are effective in inhibiting the promotion stage of
carcinogenesis. Three different doses of an ethanol extract (95%) were
compared against a positive control. The mean relative percentage
inhibitions of EBV-EA activation at 100, 10, and 1 g/mL doses were 94%,
52%, and 8% (relative to control), respectively, indicating a potential
chemopreventive effect (Kapadia et al., 2002).
Immunomodulatory
activity of an aqueous stinging nettle extract was observed in mouse
splenocytes. At 400 g/mL, the stinging nettle extract stimulated
lymphocyte proliferation and an increase in the proportion of
T-lymphocytes as compared to a control (Harput et al., 2005). A moderate increase of CD4+ over CD8+ lymphocyte cell proportion was also seen.
There is some evidence that the compounds quercetin-3-O-rutinoside, kaempherol-3-O-rutinoside, and isorhamnetin-3-O-glucoside
present in the methanolic extract of the aerial parts of the plant
contribute to the immunomodulatory activity of stinging nettle. The
results of random migrations towards a chemotactic stimulus showed that
neutrophils were stimulated by the flavonoid fraction and these isolated
flavonoids at concentrations of 4, 8, and 16 g/mL. Quercetin-3-O-rutinoside was the major chemoattractant (Akbay et al., 2003).
Evidence
regarding the use of stinging nettle herb in cancer is limited.
However, in Turkey, stinging nettle is among the most prevalent herbal
complementary and alternative medicines used by cancer patients (Kav et al., 2008 and Kultur, 2007).
According to another survey in Turkey, stinging nettle, either as tea
or eaten as a steamed or boiled green, was reportedly used by more than
93% of children receiving conventional therapies at a pediatric oncology
unit (Gözüm et al., 2007). Nettle use by diabetic patients in Jordan is also common (Otoom et al., 2006).
6.2.6. Central nervous system activity
6.2.6.1. Animal studies
Intraperitoneal
administration of a stinging nettle herb preparation (infusion prepared
according to the Spanish Pharmacopeia) and an aqueous extract prepared
via Soxhlet extraction (lipid extraction from solid material via warm
water and alcoholic solvent passes; ratio 3:1) produced a dose-dependent
decrease of spontaneous motility and body temperature in rodents at
very high doses of 1.74 and 3.75 g/kg (infusion) and 303 and 606 mg/kg
(extract) (Broncano et al., 1987b).
These four doses also prevented convulsions induced by caffeine,
pentamethylenetetrazole, and strychnine. In a different study, a
sedative activity was also demonstrated for aqueous stinging nettle herb
extract (750 mg/kg ip) in terms of reducing spontaneous activity in
mice during the first 16 h after administration (Lasheras et al., 1986).
6.2.6.2. In vitro studies
Botulinum
neurotoxins are zinc metalloproteases that cleave and inactivate
cellular proteins essential for neurotransmitter release. Because the
paralytic effect of these toxins is a consequence of its enzymatic
activity, selective inhibitors may be useful as agents for further
research. Gul et al. (2004)
investigated the inhibitory effect of stinging nettle leaf extract on
the protease activity of botulinum neurotoxin type A and B light chains.
The stinging nettle leaf infusion was fractionated and HPLC-based
enzymatic assays were performed to determine the capacity of each
fraction to inhibit the protease activity of botulinum neurotoxin type A
and B light chains. Assay results demonstrated that a water-soluble
fraction obtained from the stinging nettle leaf infusion inhibited type
A, but did not inhibit type B light chain protease activity.
6.2.7. Cardiovascular and smooth muscle activity
6.2.7.1. Animal and in vitro studies
Various
actions of stinging nettle herb on the cardiovascular system and smooth
muscle have been reported. Some studies have reviewed these activities,
but the pharmacological mechanisms for both aqueous and ethanolic
stinging nettle herb extract remain unclear.
The
following studies on cardiac, smooth muscle, and intestinal strips to
suggest the effects of stinging nettle extract should be taken into
consideration, but do not represent the type of systemic phytochemical
exposure and activity that will be achieved in vivo, due to relative
differences in kinetics of each of the different phytochemicals in the
complex extract. These tissues and membranes will not be exposed
directly to such a local application of the constituents present in the
entire extract.
An aqueous
stinging nettle extract (1 and 2 g/L) was studied in the isolated,
spontaneously beating, Langendorff rat heart and the isolated rat
thoracic aorta in order to characterize the cardiac and vascular effects
(Legssyer et al., 2002).
Following application of 1 g/L, a positive inotropic effect associated
with a marked decrease in heart rate, but no effect on heart pressure
rate was seen. In doubling the dose to 2 g/L of the extract a more
pronounced negative chronotropic effect associated with a stronger
positive inotropic effect was produced. Increasing the stinging nettle
extract dose to 5 g/L resulted in cardiac arrest. Various mechanistic
studies were conducted and the authors concluded that aqueous stinging
nettle extract produced vasoconstriction of the aorta via α1-adrenergic
receptors. However, stinging nettle induced bradycardia via
non-cholinergic and non-adrenergic pathways, which might compensate for
the effect and account for its hypotensive effect.
The
effect of aqueous stinging nettle leaf extract (1:3) on smooth muscles
was investigated by using isolated smooth muscle strips. A slight
contraction followed by relaxation was seen in strips from uteri of
non-pregnant mice in a dose of 50 mg extract equivalent to 165 mg of dry
plant which was similar to the effect of 0.8 mg dihydroergotamine and
could be reversed by 2 g of adrenaline. In strips from pregnant mice
comparable results were obtained. The authors concluded that aqueous
stinging nettle leaf extract had an adrenolytic potential similar to the
action of dihydroergotamine. This effect may be attributable to a
coumarin derivative (Broncano et al., 1987a). Scopoletin derived from Viburnum opulus and V. prunifolium was shown by Jarboe et al. (1967) to inhibit contractions of rat uterus in vitro and in vivo.
6.2.8. Hypotensive effect
6.2.8.1. Human clinical studies
Of
the reported cardiovascular actions of stinging nettle, the most
notable is the potential for stinging nettle herb to lower blood
pressure. An adrenolytic effect as well as an effect on potassium has
been discussed.
In an open
study 19 patients suffering from cardiac insufficiency and 13 patients
suffering from chronic vascular insufficiency (unknown stages) received a
daily dose of 45 mL squeezed stinging nettle leaf juice (Kirchhoff, 1983).
Mean urine volume was increased in the course of the 2-week treatment
by 1000 mL. This was associated with a loss in body weight (kg), edema
reduction, and a slight decrease in systolic blood pressure. Diastolic
blood pressure and serum electrolytes remained unchanged. Occasionally,
diarrhea was observed as an adverse event.
6.2.8.2. Animal studies
The
effect of continuous intravenous perfusion of aqueous stinging nettle
herb extract (dried decoction of 10 g/100 mL at a dose of 4 or
24 mg/kg/h) or of furosemide at a dose of 2 mg/kg/h (control) was
studied in rats. The blood pressure decreased dose-dependently by 15%
and 38% in rats treated with stinging nettle (decrease of control 28%),
which was associated by an increase in diuresis (11% and 84%) and
natriuresis (28% and 143%; increase of control 85% and 155%). The effect
of the low dose stinging nettle herb extract and the furosemide
infusions were reversible, whereas that of the high dose stinging nettle
infusion was not (Tahri et al., 2000).
The authors hypothesized a possible direct effect of stinging nettle
herb on the cardiovascular system besides an action on renal function.
They concluded that higher stinging nettle leaf dose is toxic because of
the persistence of its hypotensive action.
In
an early study, the effect of a 50% ethanol extract was investigated in
the rabbit ear model. Intravenous administration of 1 mL of stinging
nettle leaf extract (equivalent to 0.83 g extract in 200 mL) resulted in
a weak vasodialating effect (Ludwig, 1945).
The same researcher also reported a dose-dependent decrease in systolic
blood pressure by 11–29 mmHg, when rabbits were given a 50% ethanol
extract (1:10) in doses of 1–3.5 mL intravenously. Keeser (1940)
had also seen such effects and described a transient decrease in blood
pressure in rabbits after administration of a 50% ethanolic stinging
nettle extract and its ether fraction.
Following
intravenous administration of 25 mg/kg of a lyophilized aqueous
infusion prepared from dried flowering stinging nettle, a rapid but only
transient (within 2–3 min) decrease of 32% on the blood pressure of
anesthetized rats was observed. Lasheras et al. (1986)
assumed that this hypotensive effect could be attributed to the local
anesthetic effect observed with this extract. A marked hypotensive
effect associated with bradycardia was also seen in cats receiving
aqueous stinging nettle extract (extract ratio 3.3:1) at a dose of
27 mg/kg iv (equivalent to 88 mg crude drug). This effect was reversed
by adrenaline (0.05 mg/kg). The hypotensive effect of a macerate at a
dose of 333 mg/kg and an infusion (1:3) at a dose of 166 mg/kg in rats
was not reversible by atropine. Since the stinging nettle effect was
similar to that of dihydroergotamine (0.5 mg/kg), the authors concluded
that the blood pressure-lowering effect of aqueous stinging nettle leaf
extract is caused via adrenolytic activity (Broncano et al., 1983). Tita et al. (1993)
also observed a transient blood pressure decrease in anesthetized rats
and rabbits that was associated with supraventricular arrhythmias at
doses ≥500 mg/kg of an unspecified ethanolic stinging nettle leaf
extract given intravenously. These extracts contained high
concentrations of potassium (0.225 M) and calcium (0.0435 M) ions.
Equimolar doses of potassium and calcium nitrates given intravenously
gave similar results. The authors concluded that the cardiovascular
effects might be based on the high potassium content in stinging nettle.
6.2.8.3. In vitro studies
Legssyer et al. (2002)
found a positive inotropic effect associated with a marked decrease in
heart rate, but no effect on heart pressure rate was seen following the
application of 1 g/L aqueous stinging nettle extract.
6.2.9. Diuretic, natriuretic, and uricosuric activity
6.2.9.1. Human clinical studies
Stinging
nettle herb has traditionally been used as a diuretic. After having
observed a diuretic effect of a stinging nettle herb decoction in an
early case report of a patient suffering from cardiac insufficiency, Wantoch (1935)
reported that 200 mL of a stinging nettle herb decoction (5 g in 200 mL
boiled for 5 min) exhibited a considerable (from a baseline of around
1000 mL to 1800 mL) and repeatable increase of urine output compared to
black tea as a control. There were no reported adverse effects.
6.2.9.2. Animal studies
Oral
administration of aqueous extract of flowering stinging nettle herb at a
dose of 1 g/kg had no effect on diuresis or ion excretion in rats (Lasheras et al., 1986). This result is in contrast to the findings of Cárceres et al. (1987)
who reported an increase in urine production by 20% after a similar
oral dose in a 10% decoction in rats. The diuretic effect of stinging
nettle was approximately 25% of that achieved with hydrochlorothiazine
(25 mg/kg). Oral administration of an unspecified ethanolic extract
1 g/kg also had no effect on diuretic activity within 2 h of dosing,
while urine output increased significantly after 500 mg/kg ip. This was
associated with increased total potassium excretion and its
concentration in urine. Sodium excretion remained uninfluenced (Tita et al., 1993). The authors suggested that the diuretic effect was caused by the electrolytes in the stinging nettle herb preparation.
Oral
administration to rats of 5 mL water with a 10% solution of freshly
squeezed juice from stinging nettle leaf increased the urine output from
5 mL (3 mL water as a control) to 13 mL. Urine sodium, potassium, and
chloride concentrations increased from 3, 18, and 15 mmol/L to 6, 25,
and 30 mmol/L, respectively. Urea content remained unaffected (Frank et al., 1998). In an earlier study, Balansard (1952)
had observed increased chloride and urea excretion in rabbits after
parenteral administration of 0.05 g/kg glycolic or glyceric acid (which
are metabolites of fatty acids contained in stinging nettle). In another
experiment in rats, a 10% suspension of tablets containing 185 mg crude
stinging nettle or 35 mg of a stinging nettle herb macerate 7:1, urine
volume increased from 7.8 to 12 mL in association with an increase of
sodium, potassium, and chloride concentrations from 7, 21, and 29 mmol/L
to 13, 49, and 32 mmol/L. Both stinging nettle preparations had only a
weak effect in dogs. Due to the lack of statistical analysis and great
variation of data, further studies are necessary to clarify the diuretic
effect of stinging nettle herb (Frank et al., 1998).
A
50% ethanolic extract from 50 g dried stinging nettle leaf (A) was used
to prepare an ether (B) or a lead acetate (C) fraction and to
investigate their effect on the enzyme urokinase. In contrast to
ascorbic acid (250 mg/100 mL blood), the fractions were ineffective.
After geese and ducks had been deprived of food for 24 h, uric acid
levels in the animals remained rather constant (fluctuation about
1 mg/100 mL blood during a 2-h period). The stinging nettle leaf
preparation (A) resulted in a reduction, while fraction B (minus the
substances transferred to the petroleum ether phase) resulted in a
considerable increase in uric acid blood levels. Neither effect was
attributable to uric acid metabolism. The author discussed the potential
for a vasodilating and/or diuretic action that requires further
evaluation (Keeser, 1940).
The
coumarin component scopoletin given intraperitoneally at 50, 100, and
200 mg/kg was found to immediately and dose-dependently reduce serum
uric acid levels in hyperuricemic mice (induced by potassium oxonate),
but not in normal mice. Scopoletin produced a uricosuric effect at the
two higher doses and was also shown to inhibit xanthine oxidase in
vitro, so it both reduced excessive uric acid production and increased
its excretion (Ding et al., 2005).
6.2.9.3. In vitro studies
Atomic
emission spectrometry was applied to determine potassium and sodium
concentrations in crude botanicals and decoctions in order to evaluate
the basis for the diuretic activity of plant extracts. The
potassium-sodium ratio of stinging nettle herb decoctions was 448:1 for
stinging nettle leaf and 34:1 for stinging nettle root. For the leaf the
dissolution ratio of potassium was higher than that of sodium whereas
for the root it was opposite (Szentmihályi et al., 1998).
6.2.10. Antidiabetic activity
6.2.10.1. Animal studies
There
is some data that suggests that stinging nettle herb may have an affect
on blood sugar. The effects from animal studies are inconsistent and
may be due to different doses, different modes of application, different
timing of administrations, and/or study designs. Further studies are
required before a definitive conclusion regarding any activity of
stinging nettle herb on blood sugar levels can be drawn.
Two
studies, one in rats the other in rabbits, reported hypoglycemic
activity of stinging nettle herb aqueous extract, which included
significant decreases in blood sugar of 30% (Haznagy, 1943) and significant increases in insulin by one fraction injected ip that was also accompanied by reductions in blood sugar (Farzami et al., 2003). In contrast, other studies reported either no affect on blood sugar (Günes et al., 1999, Keeser, 1940, Ludwig, 1945 and Swanston-Flatt et al., 1989) or a hyperglycemic effect (Neef et al., 1995 and Roman-Ramos et al., 1992).
Oral glucose tolerance tests in male Swiss mice, given stinging nettle
herb preparations by oral gavage 2 h prior, resulted in hyperglycemic
effects for both the aqueous extract (decocted 5 min and infused 30 min)
and an 80% ethanolic macerated extract. However, each was given in
exaggerated doses, amounts derived from 25 grams of dried herb per kg
body weight (Neef et al., 1995).
6.2.10.2. In vitro studies
Two
potential hypoglycemic activities of stinging nettle herb that have
been reported include a decrease in intestinal glucose absorption
through an inhibition of intestinal glucosidases (Bnouham et al., 2003 and Önal et al., 2005) and an increase in serum insulin (Farzami et al., 2003). These data are limited and their application to human use is unclear.
6.2.11. Gastrointestinal activity
6.2.11.1. Animal studies
Limited
animal studies have shown that stinging nettle herb can enhance
selective gastric functions and protect the gastric mucosa from
chemical-induced damage. A hydrolysate fraction from 2.6 g stinging
nettle herb was administered subcutaneously to 2 dogs in the Pawlow
experiment. The amount of gastric juice produced increased from a
baseline of about 2 mL to more than 25 mL per aliquot and was
repeatable. Quantitative analysis of total acidity and free HCl
demonstrated a significant increase of both. An increase in pancreas
secretion was also observed (Dobreff, 1924).
Pretreatment with freeze-dried aqueous stinging nettle herb extract at doses of 50, 100, and 200 mg/kg in rats significantly (P < 0.005)
inhibited gastric mucosal injury by 68%, 61%, and 78%, respectively,
when induced by 70% ethanol and was significantly (P < 0.001) more pronounced than the 39% inhibition by the synthetic control famotidine ( Gülçin et al., 2004).
Keeser (1940)
observed a decrease of intestinal tone and contractions in isolated
rabbit intestine, when a 50% ethanolic extract (equivalent to 0.41 g
stinging nettle herb) in 300 cm3 was added. An increase in
tone and contractions, was, however, observed with higher doses that
finally resulted in irreversible damage of the intestine. The ether
fraction of that ethanol extract had the same effect and decelerated
intestinal peristalsis. The extract had no effect on leech muscle. In
another experiment contractility was stimulated in the isolated guinea
pig uterus and intestine stripes and in rabbit intestine stripes by
stinging nettle herb fluid extract and the remaining filtrate (not,
however, by the mercury fraction). The inorganic compounds of stinging
nettle leaf were ineffective. Glycosides, alkaloids, and proteins were
not detectable in the preparations (Starkenstein and Wasserstrom, 1933).
6.2.12. Liver protecting activity
6.2.12.1. Animal studies
A
diethyl extract concentrating the oils of dried stinging nettle seeds
(2 mL/kg ip, biweekly) or a decoction from herb (50 g/1000 mL) in tap
water, weekly over 12 weeks prevented CCL4-induced
hepatotoxic effects in rats. Neither coagulation necrosis and hydropic
degeneration nor fibrosis was detected in the liver parenchyma of
animals treated with the stinging nettle preparation indicating a
hepatoprotective effect (Türkdogan et al., 2003). Similar hepatoprotective findings of stinging nettle seed oil treatment (2 mL/kg) were reported by Kanter et al. (2003) (see also Antioxidant section for additional lipoprotective studies).
6.2.13. Antilipidemic activity
6.2.13.1. Animal studies
Stinging
nettle aqueous extract (150 mg/kg/day) and to a lesser extent its
petroleum ether extract (20 mg/kg/day) given for 30 days to rats fed a
normal or high-fat diet, improved the blood lipid profile. Significant
decreases in total cholesterol, low density/high density cholesterol
(LDL/HDL) ratios via lower concentrations of LDL, and plasma total
apoprotein B were observed. Liver enzymes remained unaffected (Daher et al., 2006).
Avci et al. (2006)
assayed the effects of the administration of plant extracts on serum
total cholesterol, triglyceride, HDL/LDL cholesterol, glucose, aspartate
transaminase (AST), and alanine transaminase (ALT) concentrations in
mice fed a cholesterol-rich diet. In addition, plasma total
antioxidative activity, malondialdehyde (MDA), and nitric oxide
metabolites (NOx) levels in the same animals were assayed to
study the antioxidant effect. None of the aqueous plant extracts
affected the serum cholesterol concentration, whereas the ethanolic
extract of stinging nettle leaf increased serum HDL cholesterol and
decreased serum LDL cholesterol, showing a modest hypocholesterolemic
activity. No antioxidant activity was observed.
Rau et al. (2006)
conducted a study to examine the activation of peroxisome
proliferator-activated receptors (PPAR), which are pivotal in lipid
homeostasis, by 52 ethanolic herbal extracts. An ethanolic extract of
stinging nettle was among the most active, for which a
concentration-dependent effect could be shown, significantly activating
PPAR© and PPAR〈 at concentrations between 30 and 100 mg/L.
6.2.14. Effect on erythropoiesis
6.2.14.1. Animal studies
One
of the primary uses of stinging nettle herb among medical herbalists is
as a nutritional tonic for the treatment of anemia. There are some
studies that support this belief. Persistent anemia via bleeding was
produced in rabbits and stinging nettle herb juice (10 mL per day) was
administered resulting in a resolution of the anemia within 20 days
compared to 6 weeks for untreated animals (Cremer, 1934).
The beneficial effect on the erythropoiesis was similar to that of
iron-containing preparations. The excretion of porphyrins (chlorophyll
metabolites) was increased. The author suggested that the improvement of
well-being during stinging nettle juice treatment was based on these
effects.
Treatment with the oil of stinging nettle seeds (2 mL/kg) countered the negative effects of CCl4-treated rats. Specifically, CCl4 treatment for 45 days significantly (P < 0.05) increased the serum K and Ca and decreased (P < 0.05)
the red blood cell count (RBC), white blood cell count (WBC), packed
cell volume (PCV), and Hb levels without changing (P > 0.05) the serum Na and Cl levels. Stinging nettle oil and Nigella oil treatments (alone or combined) significantly (P < 0.05) decreased the elevated serum K and Ca levels and also increased (P < 0.05) the reduced RBC, WBC, PCV, and Hb levels ( Kanter et al., 2003). The author concluded that the oils might ameliorate the CCl4-induced disturbances of anemia, some minerals, and the body's defense mechanism in CCl4-treated rats.
6.2.15. Antimicrobial and antiviral activity
6.2.15.1. In vitro studies
Various
investigations have shown that stinging nettle elicits selective
antimicrobial activity. Antimicrobial activity of a diethyl acetate
extract of stinging nettle has been reported for Staphylococcus areus, Enterococcus faecalis, Bacillus subtilis, and Escherischia coli ( Brantner and Grein, 1994 and Keles et al., 2001). An aqueous extract (250 g/disc) was found to have an inhibitory zone diameter of 8 mm or more against Proteus mirabilis, Citrobacter koseri, S. aureus and S. epidermidis, Streptococcus pneumoniae, Enterobacter aerogenes, Micrococcus luteus, E. coli, and Candida albicans ( Gülçin et al., 2004). With the same preparations, no activity was seen against Pseudomonas aeruginosa ( Gülçin et al., 2004), Klebsiella pneumoniae, and M. luteus ( Dostbil et al., 2005). In one additional study, 24-h treatment of Paramecium primaurelia and Lepidium sativum
with an aqueous preparation from 0.5 g dried stinging nettle leaf
caused the death of all paramecia within 92 min and 70% inhibition of
growth of the Lepidium. Diluted extract appeared to be less toxic ( Oswiecimska et al., 1980).
The
antibacterial activities of ethyl acetate, ethanol, chloroform, and
acetone extracts of four plant species, including stinging nettle were
tested in vitro against 12 bacterial species and strains, including Bacillus brevis, M. luteus, Mycobacterium smegmatus, E. coli, Listeria monocytogenes, and S. aureus,
by the agar diffusion method. The results indicated that these whole
plant extracts of stinging nettle showed no antibacterial activity
against any of the test microorganisms ( Erdogrul, 2002).
Turker and Usta (2008)
conducted a biological screening of aqueous extracts of twenty-two
Turkish medicinal plants. Screening of antibacterial activity was
performed with six bacteria including E. coli, P. aeruginosa, K. pneumoniae, Streptococcus pyogenes, S. aureus, and S. epidermidis.
Collected plants were dried in the oven at 40 °C and then ground into a
powder before 20 g were extracted with 200 mL water at 80 °C for 2 h
twice and then filtered. The resulting liquid was evaporated under
vacuum and each residue was then dissolved in water to produce a final
concentration of 100 mg/mL. Of the twenty-two plants examined, extracts
from U. dioica leaves, among others including T. farfara leaves, Helichyrsum plicatum flowers, and S. dulcamara aerial parts, showed significant (P < 0.05) inhibitory activity against S. pyogenes, S. aureus, and S. epidermidis.
Flavonoids
from dwarf stinging nettle were isolated and its major compound
patuletin tested for antimicrobial properties. It showed significant
activity against S. aureus, S. faecalis, E. coli, and C. albicans with MICs of 0.02, 0.02, 0.002, and 0.001 g/mL, respectively ( Saeed et al., 1995).
6.3. Conclusion
Studies
of the effects of stinging nettle herb extracts on anti-inflammatory
processes and rheumatic conditions yield varied results with
inconclusive evidence regarding efficacy. Human clinical studies of
proprietary nettle herb extract preparations, namely IDS23 and IDS30,
show a trend toward improvement of arthritic conditions and in one study
of freeze-dried stinging nettle herb capsules showed slight improvement
in treatment of allergic rhinitis. More significantly, human clinical
studies showed little to no adverse effects with these preparations.
Animal studies showed some, though minimal, anti-inflammatory activity
of a 50% ethanol extract of nettle herb in rats and of the proprietary
extract IDS30 in mice. Other animal studies showed a mixed central
analgesic effect, though positive effects were found with ethanol
extracts and no effect was found with an aqueous extract of stinging
nettle. In vitro studies illuminated a possible mechanism of these
anti-inflammatory effects of ethanolic nettle leaf extracts. Studies
showed its effect to be on cytokine release rather than cytokine levels.
Cytokine release was influenced through DNA binding mechanisms and DC
maturation and not through non-specific gene expression.
The
traditional use of stinging nettle as a diuretic was investigated.
Clinical studies showed that a decoction (200 mL) of nettle increased
urine flow while the juice increased urine flow associated with a
decrease in body weight, edema reduction, and systolic blood pressure.
Animal studies were inconsistent, showing no effect or an increase in
potassium and sodium concentrations in urine rather than a change in
urine flow. Both ethanolic and aqueous extracts were ineffective when
compared to controls and any change in diuresis and natriuresis was
suggested to be the result of the overall potassium content of stinging
nettle leaf.
Antioxidant
activity of nettle has been demonstrated. In vitro studies have shown
moderate radical scavenging abilities for both ethanolic extracts and
aqueous extracts of nettle herb. Other studies have demonstrated the
ability of nettle herb to inhibit peroxidation and phenol oxidation as
well as showing low ferric reducing activity. Polyphenol oxidase was
identified as an antioxidant principle. Animal studies also showed
aqueous stinging nettle extracts, herb and seed oil, and lab chow
enriched with dried stinging nettle herb to elicit antioxidant activity
in rats. One study in mice found that an ethanolic extract of nettle had
an important effect on drug metabolism due to its antioxidant profile.
Cardiovascular
activity of nettle herb most notably shows potential to lower blood
pressure, though the mechanism remains unclear. Animal studies have
shown weak vasodilation effect and decreases in systolic blood pressure.
Rapid, transient hypotensive effects have been attributed to either a
possible adrenolytic activity or high potassium content of stinging
nettle. In vitro studies of aqueous extracts of nettle herb have shown
it to have a positive inotropic effect associated with a marked decrease
in heart rate and an adrenolytic effect similar to that of
dihydroergotamine. However, higher doses of stinging nettle herb can
cause vasoconstriction via α1-adrenergic receptors though
this hypotensive effect may be compensated for by induced bradycardia
via non-cholinergic and non-adrenergic pathways.
Other
therapeutic properties of stinging nettle extracts have been supported
by limited laboratory research. These include: inhibiting thrombin-,
ADP-, adrenaline-, and collagen-induced platelet aggregation,
chemopreventive and immunomodulatory activity, sedation of central
nervous system as well as inhibition of metalloproteases, anti-diabetic
activity (though inconsistent because of animal model and study design),
stimulation of gastrointestinal activity, hepatoprotective activity,
anti-lipidemic activity, nutritional tonic for anemia, and selective
antimicrobial and antiviral activity.
6.4. Medical indications supported by clinical trials
Used for symptomatic treatment of arthritis and allergic rhinitis (freeze-dried), as well as a nutritional tonic and diuretic.
6.5. Medical indications supported by traditional or modern experience
The
primary use of stinging nettle herb among a sampling of traditional
herbalists in the US, Australia, Canada, New Zealand, and the United
Kingdom is as a tonic or nutritive agent, alterative, and for arthritic
conditions. Other common uses are as an astringent to tone mucosa
(reduce secretions, slow blood loss), a diuretic for general water
retention as well as kidney stones, and an
anti-inflammatory/anti-allergic. A wide array of preparations can be and
are utilized. These include water- or alcohol-based extracts, cooked
preparations, such as steamed greens, soup, or tea, or external
application of the fresh juice on wounds. Older texts mention leaf,
seed, or flower in honey, for external or internal application. The
fresh leaf plant is also used externally for urtication (the whipping of
sore or inflamed tissues) for topical treatment of sore joints. Due to
the intense irritation of the stinging hairs, chewing of any part of the
fresh plant is not advised. Though the contents in the hairs are mostly
lost on extraction, drying, and cooking, histamine and other amines
partly responsible for the characteristic sting of fresh stinging nettle
can persist if the material has been properly dried. Closely related
varieties of U. dioica as well as U. urens are used interchangeably (European Pharmacopoeia, 2008; Felter and Lloyd, 1898). The European dog or dwarf nettle, U. urens, has a more pronounced sting than U. dioica, but is much smaller in size ( Moore, 1993).
In the historical and contemporary literature, authors specify use of whole plant for flagellation (Pahlow, 1992; Stille et al., 1896; Vickery, 1995 and Weiss and Fintelmann, 2000) versus the more common use of stripped-off leaves for internal use (Bradley, 1992, Duke, 1997, Mills, 1991, Randall et al., 1999, Randall et al., 2000 and Randall, 2001 per Kavalali, 2003, Schauenberg and Paris, 1977 and Stary, 1991). Culpeper (1826)
described applications of leaves to painful joints. Stearns described
using either fresh crushed leaf held to the upper palate or juice
“snuffed up” to reduce nosebleeds, and leaves applied to arms, legs, and
thighs for palsy (Stearns, 1801). Other sources describe whipping limbs for paralysis or applying leaves to bleeding surfaces (Felter and Lloyd, 1898).
A widespread method of using stinging nettle as a warming analgesic and
anti-inflammatory is to rub a liniment of fresh plant on affected
muscles and joints (Weiss and Fintelmann, 2000). Less commonly used are poultices of boiled leaves or ointments of various compositions (Cyran, 1981, Kloss, 1939, Randall et al., 1999, Vickery, 1995 and Weiss and Fintelmann, 2000).
The
single formal clinical study on freeze-dried stinging nettle for its
treatment of allergic rhinitis underemphasizes its therapeutic value.
Some practitioners consider it the most effective remedy for the
sneezing, itching (eyes, ears, throat, nose), and other common symptoms
of this disorder, including prescription and over-the-counter
medications. Its efficacy and lack of side effects makes it the
treatment of choice for some. Furthermore, some also observe that after a
time of using only the freeze-dried leaf to treat symptoms (and
avoiding suppressive medications), allergic rhinitis diminishes and
often disappears to a point where patients no longer require treatment
(Weil, 2008, personal communication).
There
is confusion among some authors regarding traditional uses of stinging
nettle herb as opposed to nettle root. Early 19th century writers
described nettle root as an astringent diuretic and tonic while later
writers simply ascribed to “nettle” these same actions. Still later
sources confuse this information with data on the herb. While there is
overlap of actions, the use of herb and root are not identical. The
decoction of stinging nettle root is a tonic, astringent, diuretic, and
formerly the “premier” antihemorrhagic for kidney function and against
kidney stones (Jones and Scudder, 1858).
The root is still used by traditional herbalists as it was used by
Eclectic physicians, not only for hematuria, but also for reproductive
bleeding, hemoptysis, and gastro-intestinal bleeding with or without
diarrhea. The root decoction, but now more commonly the extract, is used
for benign prostatic hyperplasia (BPH).
In
addition to the historical data, a survey regarding the use of stinging
nettle herb by professional members of the American Herbalists Guild (AHG, 2004)
was conducted and the findings from the 26 respondents are provided
below. The use of nettle seed is taken to increase energy, as a kidney
trophorestorative, and as an anti-inflammatory.
Dosage
forms of nettle herb include the steamed or cooked vegetable in spring.
Young shoots less than five inches or before stinging hairs develop,
are picked, chopped, and steamed like spinach. These are taken liberally
and to taste while available. Freshly pressed juice can be taken for
its various indications, 1 tablespoon 3 times a day (Weiss and Fintelmann, 2000),
or as much as 0.5–1 oz “at intervals of several hours” to treat
hemorrhage, dysentery, diarrhea, and kidney stones, and cardiac edema
(dropsy) (Stillé et al., 1896). Moore describes preserving juice with 25% alcohol or freezing in ice cube trays (Moore, 1993).
The
lower dosage range for an infusion is 2 teaspoons (about 1.5 g dried
herb) of leaf or aerial parts, infused in 1 cup (250 mL) boiling water
for 10 min, strained, 1 cup (250 mL) taken several times a day up to 1 L
daily (Weiss and Fintelmann, 2000).
A higher dosage range is more common among some herbalists based on the
recommendation of the BHP which uses up to 4 teaspoons dried herb
(about 3 g) per 5 fluid ounces (150 mL) of water 3 times per day (Bradley, 1992).
In
modern use, dosages of 8–12 g of dried herb per day are used for
arthritis. Liquid extracts (e.g. 1:2) may be given as 3–6 mL per day or
7–14 mL per day of 1:5 tincture (Mills and Bone, 2000).
There is less consensus on preferred forms in the literature and among
the respondents of the AHG survey. Half of respondents preferred fresh
over dry material and hydro-alcohol extract over tea (AHG Survey, 2004).
Freeze-dried leaf is also a commonly used preparation at doses of
300–600 mg taken 1–3 times daily specifically for allergic rhinitis.
6.5.1. Tonic effects
6.5.1.1. Nutritive
Internal
use of stinging nettle leaf is primarily as a tonic food in Europe and
America. For this purpose, it can be used as a steamed green, a pureed
ingredient in soups, as a decocted tea, or in solid dosage forms (pills,
tablets, capsules). Of the respondents to the AHG survey, 92% agreed
that this nourishing action was a primary defining difference between
stinging nettle herb and other alteratives, astringents, diuretics, or
anti-inflammatories (AHG Survey, 2004). Stinging nettle is frequently
used for the treatment of anemia and convalescing patients as well as a
“green drink” for general purposes.
Internal
use of stinging nettle herb is also common in holistic cosmetic support
for improving the integrity of the integument. Benefits of stinging
nettle herb considered common in practice by traditional herbalists
include clearer skin, improved condition of hair, and even
well-nourished bones, although only 3 out of 26 herbalists reported
this. A long list of compounds is considered to play a role in the
putative effects of nettle herb (anti-oxidant chlorophyll, protein,
vitamins A, D, and C, minerals calcium, potassium, iron, and choline,
amines, and 5-HTP) (Patten, 1993).
As iron and vitamin C are associated with increased hemoglobin,
stinging nettle herb may play a role, albeit unsubstantiated, in
treatment of people with iron deficient anemia, an indication suggested
by 9 of 26 herbalists surveyed (AHG Survey, 2004). Since erythropoiesis
(the formation of red blood cells) takes about 20 days, a regimen of
tea, tincture, juice, or capsules, 5–6 days a week for a minimum of 3
weeks is suggested. In an open trial, herbalists Burgess and Baillie (1999)
studied the effects of stinging nettle herb infusion on blood work in
ten healthy women. They infused 15 g of stinging nettle herb in 1 L of
boiling water, letting it cool 4–8 h, and drinking a liter of the
strained tea daily for 12 days. Blood samples before and after showed a
significant increase in vitamin B12. Burgess and Baillie
suggest this could be due to an effect on the intrinsic factor in the
stomach, an effect on the absorption of the B12-intrinsic factor complex, a possible encouragement of B12 producing bacteria in the gut, or a possibility that stinging nettle contains B12
analogs. The small study showed an increase in red cell folate and a
significant increase in iron binding capacity. There was no noted change
in ferritin levels (Burgess and Baillie, 1999).
Many pregnant women or elderly people reportedly use stinging nettle to
avoid conventional iron supplements due to their common side effect of
constipation, requiring additional laxative products. The ‘drying’
quality of stinging nettle mentioned above does not usually progress to
constipation. The prominent phytotherapist Hein Zeylstra noted in a 1984
lecture (College of Phytotherapy, unpublished) continued use of
stinging nettle should be accompanied by demulcents to counteract the
dryness it may cause.
Because
of its long history as a nutritive tonic, stinging nettle has commonly
been given to weak, breastfeeding mothers and to expectant mothers in
their second and third trimesters (McQuade Crawford, 2008, personal
communication to AHP; Romm, 2001 and Stillé et al., 1896).
Four of 26 survey respondents reported using stinging nettle herb for
lactating mothers needing nourishment (AHG Survey, 2004). Three of 26
herbalists surveyed give stinging nettle herb as a galactagogue (AHG
Survey, 2004), echoing its historical use (McQuade-Crawford, 2008,
personal communication to AHP; Mills, 1991) and its former use in the dairy industry to increase milk yields (Grieve, 1931).
The
nutritive tonic effects of stinging nettle herb and other actions bring
it into women's reproductive care. Culpeper wrote that a decoction of
leaves in wine is an emmenagogue (Culpeper, 1826)
though not all emmenagogues are abortifacients. This suggests a
contraindication of stinging nettle in early pregnancy, to clarify the
modern use of stinging nettle by some herbalists in pregnancy. However,
this discrepancy also requires a deeper understanding of terms. Culpeper
mentions provoking women's courses in the context of stinging nettle
herb as warming “cold” conditions, drying excess moisture, and opening
avenues of elimination for clearing congestion. Many herbalists today
advise avoiding nettle and all herbs in the first trimester of pregnancy
without need and experienced supervision. An infusion of stinging
nettle herb was reportedly given to pregnant Native American women who
were overdue (Moerman, 1998).
It is not known whether this was given to strengthen the expectant
mother for delivery, diminish risk of excess bleeding, or because of a
modern interpretation assuming an oxytocic action.
Many writers describe the activity of stinging nettle herb on cutaneous eruptions and skin wounds as anti-hemorrhagic (Barton and Castle, 1877, Culpeper, 1826, Hill, 1812, Mills and Bone, 2000, Moore, 1982, Moore, 1993, Patten, 1993, Stearns, 1801 and Stillé et al., 1896). A traditional remedy for menorrhagia, some authors suggest that stinging nettle is not as fast acting (Moore, 1993) as shepherd's purse (Capsella bursa-pastoris)
though nettle adds a nutritive action. Other reproductive uses include
treatment of PMS Type H (with water retention), alluding to nettle's
diuretic actions.
6.5.1.2. Astringent
For
diarrhea with persistent watery or mucous discharge, success has been
achieved by mixing 2 mL of a hydroalcohol extract of the fresh plant in 2
oz water and administering a teaspoonful every 1–2 h (McCann, 1893).
The astringent properties of stinging nettle are described as useful in
hematuria, menorrhagia and bleeding hemorrhoids. The plant decoction or
400–600 mg encapsulated powder for children is advocated as good for
diarrhea (Lust, 1974 and Mitchell, 2003).
Worldwide use of related species of stinging nettle focuses on its
value as an external styptic for nosebleed and wounds, as well as an
internal anti-hemorrhagic.
Though
botanical astringents are considered to act in various ways to reduce
fluid loss, the end result of over-using stinging nettle herb appears to
lead to the development of symptoms that are termed ‘drying’ as
understood within humoral medicine. A case of excessive use of stinging
nettle beyond the body's need to clear excess fluid or congestion
produced a symptom likened to sensations of internal scratchiness during
urination. This and other symptoms of excess such as rash were resolved
by discontinuing stinging nettle use (Ryan Drum personal communication
1990; ryandrum.com 2006). Some herbalists blame late harvests for this
unwanted effect (AHG Survey, 2004). Two of 26 herbalists surveyed
volunteered that the herb is constitutionally drying (AHG Survey, 2004),
a view articulated by Dioscorides, Galen, and Culpeper. In traditional
herbal medicine, practitioners may recommend temporal limits for
long-term use (more than three months) of stinging nettle and prescribe
breaks of one day per week or one week per month. Additionally, for
long-term use, herbalists may combine stinging nettle with demulcent
diuretics to avoid the drying qualities of the stinging nettle.
6.5.2. Diuretic activity
In
urinary conditions, stinging nettle herb is used for reducing hematuria
due to infection or stones, increasing volume of urine, and for
reducing kidney stone size or recurrence, though clinical efficacy still
needs to be established. Dysuria associated with infections in general
responds to stinging nettle, though the herb is not commonly viewed as
antimicrobial. Fourteen of 26 herbalists surveyed reported on the use of
nettle herb internally as a diuretic, while an additional 3 of 26
consider diuresis a secondary action after the main use of stinging
nettle herb as a tonic (AHG Survey, 2004).
This
diuretic effect may explain the traditional use of stinging nettle herb
internally as an anti-rheumatic, not as a direct analgesic, but as an
antidyscratic. Water-based nettle herb preparations (infusion and
decoction) are the preferred diuretic treatment to prevent recurrence of
kidney stones, though other antilithics, demulcent diuretics, and
antispasmodics are combined with stinging nettle to treat existing
stones or gravel. While the Eclectics stressed using root decoction for
hematuria, stinging nettle herb works well also (Mills and Bone, 2000 and Yarnell and Abascal, 2003).
The understanding in the modern tradition is that the astringency heals
damaged urinary linings while the diuretic effect increases the volume
of urine voided. Because stinging nettle herb may also increase
excretion of uric acid and nitrogenous wastes, it may be found in
formulas for people with conditions as diverse as gout, rheumatoid
arthritis, and diabetes, not because of immune or blood sugar effects
necessarily, but for improved kidney function.
6.5.3. Alterative effects
The
alterative action, described by Rudolf Weiss as “antidyscratic,” of
stinging nettle is reported to occur in four main body systems:
musculoskeletal, skin, respiratory, and urinary. Both Native Americans
and pan-Europeans relied on stinging nettle for yearly cleansing each
spring. The diuretic effect is hard to separate from the action of
detoxification, as in the use of stinging nettle to relieve gout.
Despite the strong traditional use of stinging nettle herb as a
cleansing tonic, only 6 of 26 herbalists who responded to the AHG survey
described stinging nettle herb as an alterative (AHG Survey, 2004).
Because it is traditionally given as a nutritive and a cleansing herb,
large numbers of patients have been given nettle in substantial amounts
over many years.
Anti-inflammatory
effects of stinging nettle have been somewhat established in the
literature (see Clinical Studies and Pharmacodynamics). Perhaps based on
this action, modern herbal practitioners utilize stinging nettle herb
to relieve inflammation of the musculoskeletal system. Preparations of
stinging nettle herb may reduce dependence on NSAIDS, a combination
illustrative of a beneficial drug interaction. Despite an emphasis in
literature, self-help resources online, and popular usage, some
educational training may not emphasize the use of stinging nettle for
arthritis and joint inflammation. Only 5 of the 26 professional
herbalists surveyed reported the herb as modulating inflammation (AHG
Survey, 2004). Yet some traditional herbalists use stinging nettle herb
internally for people with arthritis while categorizing it otherwise.
The alterative and diuretic actions of stinging nettle may partly
explain why practitioners report changes in underlying disease
characterized by inflammation, such as in osteoarthritis and autoimmune
conditions (Mills and Bone, 2000 and Weiss and Fintelmann, 2000).
In
skin conditions, the European treatment of acne often begins with
standard dosage ranges of decoction or juice of stinging nettle herb (Bradley, 1992).
Allergic or nervous rashes (urticaria, hives) are indications for
short-term use (three weeks or less) of stinging nettle herb. Chronic
diseases where stinging nettle herb is used include all those
characterized by inflammation and disruption of skin structure,
especially when wet, but also if dry skin is red underneath an itchy
surface (Lloyd and Lloyd, 1915).
Nettle
herb is considered an alterative in respiratory conditions when there
is a need to decrease secretions, especially mucus congestion (Culpeper, 1826, Grieve, 1931 and Lloyd and Lloyd, 1915;
Stille et al., 1896). Stinging nettle preparations including
decoctions, infusion, juice, and syrups are used to promote elimination
from the respiratory tract (Patten, 1993).
Because of this, stinging nettle herb is a common adjuvant for
children's lung and sinus formulas. Stinging nettle leaf is also used
traditionally during bronchial infection, to lessen the symptom of
shortness of breath, or after bronchial damage (Grieve, 1931 and Moore, 1982).
6.5.4. Allergic rhinitis
Eight
of 26 herbalists surveyed use stinging nettle herb alone or in
combination with other botanicals for control of hemoptysis, while 18 of
26 respondents use it in their treatment of seasonal allergic rhinitis.
Only 6 of 23 specified freeze-dried herb in capsules as the preferred
form, one commenting that under-dosing may help explain the perception
that capsules are unreliable or unremarkable. Eleven of 26 herbalists
surveyed use nettle herb for unspecified allergies (AHG Survey, 2004).
Only a small percentage of respondents (3 of 26) reported using stinging
nettle for reducing allergic asthma (AHG Survey, 2004). The effects,
possibly due to modification of cytokines and eicosanoids or toning
effects on mucus production, or perhaps due to flavonoids reducing free
radical damage, are best seen after ten or more days of consecutive use.
Traditionally, herbalists may recommend starting a three-month course
of stinging nettle herb in anti-allergy combinations suited to the
individual, prior to the onset of allergy season. Long-term
recommendations given elsewhere about herbal combinations and routine
breaks from stinging nettle apply. Euphrasia officinalis
(eyebright) is an herb often combined with stinging nettle herb for hay
fever; though many others reflect the notion that stinging nettle is a
synergist rather than the single best remedy for this application ( Moore, 1993).
The mucus-thinning effects of stinging nettle herb may explain its use
in respiratory tract infections. German phytotherapists include the herb
among antitussives such as coltsfoot (Tussilago farfara), heartsease (Viola tricolor), and plantain (Plantago spp.) ( Bradley, 1992).
6.5.5. Topical use
According
to traditional herbalists surveyed, stinging nettle leaves may be
applied topically as a counter-irritant and anti-inflammatory and as an
anodyne for arthritic conditions, muscle pain, tendonitis, nerve
injuries, lack of nerve sensation, or muscle weakness. Urtication is
paradoxical in nature: first, the initial pain of urtication is followed
by reduced inflammation at sites distant from the local inflammation;
secondly, the process is locally anesthetic yet is believed to “wake up”
numb or paralyzed limbs. Few practitioners recommend self-flagellation
with stinging nettle though it remains a popular traditional use,
usually limited to once daily for three days. Benefits such as reduced
pain and stiffness have been reported and may last from weeks to months.
Topical
use of stinging nettle leaves also extends to styptic applications and
vulnerary use for wounds, bites, insect stings, stings from the nettle
hairs themselves, allergic rash, weeping eczema, secondary infections,
and psoriasis with or without exudate. Six of the 26 respondent
herbalists surveyed reported on the use of stinging nettle leaves for
all such skin conditions (AHG Survey, 2004). Historical records refer to
the use of stinging nettle herb externally for any red or inflamed skin
conditions, whether dry or moist, as a poultice of mashed leaves or as a
wash with decoction (30 g per 450 mL).
Stinging
nettle juice, decoction, or other extract has been used as a styptic
for nosebleeds in many parts of the world for approximately 2000 years,
including by Dioscorides and numerous others (Culpeper, 1826, Patten, 1993 and Stearns, 1801).
During the US Civil War, the Confederate doctor, Francis Procher,
applied cloth bandaging soaked in stinging nettle herb tea to the
wounds, burns, and rashes of soldiers. The leaf (or aerial) decoction is
still traditionally used when symptoms are reminiscent of stinging from
nettle hairs: hot, itchy, or painful (Mills and Bone, 2000 and Stillé et al., 1896).
A widely credited use of stinging nettle herb is in hair tonics as a
mineralizing or nourishing conditioner. Whether or not stinging nettle
preparations have any positive effect on hair growth is not established.
Recipes for making a stinging nettle salve were given in the Leech Book of the Bald (AD 25) ( Cockayne, 1865). Stinging nettle leaf was mixed with woad (Isatis tinctoria),
pounded together, boiled in butter, strained through a cloth, white
salt was added, and the mixture shaken thoroughly, and allowed to set.
Another was made by mixing stinging nettle leaf with hemlock (Tsuga sp.), wenwort (probably Ranunculus ficara), and moorwort (possibly Drosera sp. or Andromeda glaucophylla) boiled in butter and sheep's tallow and then mixed with ship's tar, garlic (Allium sativum), cropleek (Allium spp.), sedgeleek (Allium schoenoprasum), and salt. The salve was spread on a cloth, heated, and applied to sebaceous cysts.
In the Primitive Physic,
John Wesley, the founder of the Methodist Church, recommended bruised
stinging nettle pressed directly onto bleeding wounds and a fomentation
and poultice of boiled stinging nettle applied directly to relieve pain
of sciatica ( Wesley, 1761).
The
Lloyd Brothers’ Specific Urtica Dioica was a hydroalcohol extract
prepared from fresh choice material. The bottle label noted that it must
be used with utmost care and given in small doses. Dr. J.D. McCann
reported (1893) his experience after reading in a Lloyd dose book its
use in eczema, having exhausted his repertoire without success in a case
of eczema that had also baffled two other doctors. The eczema had
spread over an entire side of the face, around and inside the ear and
down the neck. Mixing 8 mL of the Lloyd extract in 1 oz of rose water,
it was applied locally every 3 or 4 h and obtained a rapid and complete
cure. He subsequently used it often, always with satisfaction. A similar
case involved a child with a crust-covered head that was raw and
bleeding in spots. He ordered the parents to soften the surface with
olive oil, wash with soap, dry with a soft cloth, and apply the same
formula as above, after which they obtained the desired result (McCann, 1893). Some physicians prescribed it internally simultaneously with its local use (Felter and Lloyd, 1898). Felter and Lloyd (1898) further noted that the seeds and flowers prepared in wine induced lethargic sleep in doses over approximately 3.7 mL (Felter and Lloyd, 1898).
6.5.6. Less common modern and traditional uses
Use
of nettle herb as a cardiovascular tonic is less common, but has been
reported. There may be three actions associated with a putative
beneficial cardiovascular effect. First, it is a diuretic, an action
well established to relieve some forms of high blood pressure by
reducing blood volume. According to the BHP (Bradley, 1992),
potassium and flavonoids in stinging nettle herb may contribute to
diuresis. Second, 5-hydroxytryptamine found in stinging nettle herb is
associated with lowering blood pressure (see Clinical Studies and
Pharmacodynamics). Stinging nettle herb decoction or juice is often
given to people with hypertension and is well tolerated. Finally,
reducing C-reactive protein as a result of nettle's anti-inflammatory
activity may have positive implications for heart, muscles, and joints (Mills and Bone, 2000).
Mitchell (2003)
described the leaves as invaluable and very effective in treating
migraine headaches reporting relief in some patients within 15 min of
taking a recommended dose of 2 capsules (200 mg each) at the first sign
of migraine, repeated every 2 h for up to 5 doses (Mitchell, 2003).
Other
reported uses of stinging nettle herb by traditional herbalists include
for hypothyroid, adrenal tonification, and amenorrhea.
In
the digestive tract, ulceration, bleeding, and diarrhea are all
indications for stinging nettle herb, usually as a decoction. Folk use
specifies nettle when conditions are “loose,” whether with secretions,
infections, or blood loss (Culpeper, 1826 and Patten, 1993).
In contrast to the reported “drying” qualities of the plant itself, the
water extracts and juice have a slippery, viscous quality and are
considered by some to be associated with stinging nettle's stimulation
of proper elimination. In Russia, it is used for gall bladder and liver
problems (Kavalali, 2003).
In the Herbarium of Apuleius (CE 400), Apuleius Platonticus suggested the use of stinging nettle combined with Cannabis to treat symptoms of feeling cold after being burnt (shock) and nettle alone for “cold injury” ( Cockayne, 1865). In the Leech Book of the Bald (AD 25), stinging nettle mixed with calamus (Acorus calamus) and cress (species unknown) was used in a bath to promote diaphoresis ( Cockayne, 1865).
Hildergard
von Bingen classified nettle leaf as “very warm in its type” and
reported on the use of nettle leaf juice with equal parts of mullein
leaf and the leaves or bark of the walnut tree mixed with vinegar and a
larger amount of honey for the treatment of intestinal worms. She
reported that drunk “moderately” for 15 days while fasting but after
sufficient food, the worms will die. Hildegard suggested that nettle
leaf juice mixed with olive oil be anointed to the chest and temples
when going to sleep in order to reduce forgetfulness (Von Bingen, 2001).
6.6. Actions
Anti-inflammatory,
local analgesic, antioxidant, diuretic, galactagogue, anti-allergenic,
rubefacient, counter-irritant, nutritive, and hemostatic.
6.6.1. Dosage
Freeze-dried powder: 300–600 mg up to 3 times daily. Juice: Up to 15 mL 3 times daily. Infusion: Up to 1 liter daily in divided doses. Decoction: Up to 350 mL 3 times daily. Tincture (1:5, 25% ethanol): 6 mL up to 3 times daily. IDS 23 (DER 8–10:1, 50% ethanol): 270 mg twice daily. IDS 30 (DER 19–33:1, 95% propanol): 290–435 mg daily in divided doses.
7. Safety profile
With
the exception of the contact urticaria commonly associated with fresh
stinging nettle, generally speaking, internal consumption of dried or
cooked stinging nettle preparations is very safe as the irritating
principles of the trichomes are mostly or completely dissipated with
processing. There is a very long history of the use of stinging nettle
as a steamed vegetable, soup ingredient, tea, juice, and a variety of
dried preparations. This lack of irritating principles does not rule out
the potential for idiosyncratic reactions to other compounds of
stinging nettle.
7.1. Adverse reactions
Allergic
skin reactions and mild gastrointestinal adverse events have occurred
after intake of commercial stinging nettle extracts (see Clinical
Studies and Pharmacodynamics).
An
early adverse drug reaction from 1836 reported that a woman who drank 2
cupfuls of decoction experienced pain and almost universal
inflammation, with eventual skin eruptions, all of which resolved in 6
days (Stillé et al., 1896).
Atropine poisoning was reported in a woman who had consumed a tea
labeled as stinging nettle. Upon analysis, the tea was shown to be
contaminated with belladonna (Atropa belladonna), a plant known to contain atropine ( Scholz et al., 1980). Bossuyt and Dooms-Goossens (1994) reported a case of gingivostomatitis due to contact sensitivity from a stinging nettle tea.
A case involving nettle use and breast function was recently reported (Sahin et al., 2007).
A 33-year-old man admitted to a clinic in Turkey with enlargement of
the left breast with a retroareolar glandular component. Hormone tests
were normal and no pathological explanations could be determined. The
patient had drunk 2 cups/day of nettle tea for one month prior to the
onset of the breast enlargement, but no other herbs or drugs were
reported taken. Nettle tea consumption was stopped and a significant
decrease in the breast size was noted by physical and ultrasonographic
exams after 2 months. However, the authors note that “nettle tea is a
commonly used commercial tea in Turkey,” but “no previous reports of
this reaction have been reported.” According to the Merck Manual
gynecomastia “is usually physiologic and tends to resolve spontaneously
within 6 to 12 months.” Though the authors note that nettle tea was the
only “etiologic factor” identified, this does not necessarily infer that
it was the cause.
7.1.1. Contact urticaria and local pain
Contact
urticaria and burning pain is well established for stinging nettle and
is associated with the trichomes that line the stem and leaves and break
off upon contact causing urticaria. The histamine, acetylcholine, and
serotonin contained in the trichomes cause the burning pain (Thurston, 1974).
In addition to the contact urticaria that is obvious, there is one case
report of a 47-year-old female who reported the lodging of numerous
stinging nettle needles (trichomes) in her legs causing a rapid onset of
facial and lip edema, scalp pruritis, dyspnea, and lightheadedness as
well as acute hypotension (Morgan and Khan, 2003). Similarly, Caliskaner et al. (2004)
reported on a woman who put a fresh leaf of dwarf nettle leaf on her
tongue and tried to suck the sap of the plant. About 5 min after the
application, severe tongue edema and pain occurred and continued over
the following hours. All signs of irritation were resolved 5 days later.
Besides an immediate response, delayed hypersensitivity to dwarf nettle
leaf was also observed (Edwards and Edwards, 1992).
Starkenstein and Wasserstrom (1933)
observed in a self-experiment that intracutaneous administration or
local application into wounds of a 50% ethanolic stinging nettle herb
extract in contrast to aqueous or ether extracts resulted in painful
skin urticaria similar to that of the sting of fresh plants (a 90%
ethanol extract was less effective). In contrast, topical administration
of a 50% ethanol extract had no irritating effect on the conjunctiva of
rabbits or on intact human skin (Ludwig, 1945).
The filtrate of a lead acetate fraction induced only pain. The authors
quantified the content of formic acid to be 0.003–0.005% in the total
extract and the lead acetate fraction and suggested that formic acid may
be responsible for the local pain, but not for urticaria and toxicity.
In
1947, Emmelin and Feldberg observed that histamine and acetylcholine in
the same concentration as in stinging nettle hairs reproduced the
stinging nettle response such as vascular changes and immediate
discomfort. Skin was challenged by repeated stroking with the stem and
leaves of fresh stinging nettle plant for about 30 seconds on a skin
area of 2 × 2 cm above microdialysis probes inserted intradermally 5 cm
apart in the anterolateral aspect of the brachium. However, wheal size
and detected histamine did not correlate. Histamine levels increased in
the first 15 min fraction from 5–100 nM and decreased thereafter
continuously. No changes in leukotriene C4 (LTC4) levels were observed
in the fractions after the insertion of the microdialysis probes (up to
90 min), or after the stinging nettle exposure. However, under identical
microdialysis conditions, LTC4 release was detected (Taskila et al., 2000).
The same group also investigated a 10% aqueous stinging nettle extract
that contained 373 ng/mL histamine that resulted in negative skin-prick
and basophile histamine-release tests and confirmed a previous finding.
Extracts
from stinging nettle hairs (equivalent to 15 hairs per incubation) did
not demonstrate histamine release from dispersed rat mast cells in
vitro, suggesting that the immediate urticaria effect is mediated by the
histamine introduced from the nettle hairs (Oliver et al., 1991). Others have already suggested the involvement of leukotrienes (e.g. B4 and C4) and serotonin components of the trichomes as inflammatory mediators (Collier and Chesher, 1956 and Czarnetzki et al., 1990).
Unidentified neurotoxic compounds or compounds released from
degranulated mast cells like platelet-activating factor capable of
secondary release of other (possibly neurotoxic) mediators are probably
associated with persistent paraesthesia (Oliver et al., 1991). Antonopoulou et al. (1996) identified a phospholipid that induced platelet aggregation that may also be involved in the mechanism of urtication.
The
cellular response of mononuclear cells, polymorphonuclear cells, and
mast cells was examined in 6 people 5 min and 12 h after stinging nettle
contact. Only mast cell numbers were significantly increased at 12 h.
Ultrastructurally, some mast cells showed evidence of degranulation at
5 min and 12 h. At 12 h, mast cells were closely associated with dermal
dendritic cells and lymphocytes suggesting a functional unit. The mean
histamine and serotonin contents of a stinging nettle hair were found to
be 6 ng and 33 pg, respectively (Oliver et al., 1991).
Stinging nettle pollen showed a slight allergenic similarity to pellitory-of-the-wall (Parietaria diffusa) pollen (both species belong to the Urticaceae family) due to a common antigenic determinant with poor allergenic significance ( Corbi et al., 1985).
A screening in 42 patients revealed that most patients were either
allergic to pellitory-of-the-wall or stinging nettle and that both
reactions were uncommonly associated. Thus, cross-allergenicity cannot
be predicted ( Bousquet et al., 1986).
7.2. Interactions
No
adverse interactions have been reported. Enhanced clinical outcomes
with combinations have been documented using stinging nettle
preparations as adjuncts to NSAID treatment, especially with diclofenac (Chrubasik et al., 1997, Hansen, 1996 and Hubbe, 2002).
7.3. Reproductive and developmental effects
Graf et al. (1994)
conducted a study testing genotoxicity of stinging nettle tea using the
wing Somatic Mutation And Recombination Test (SMART). The standard
herbal teas were prepared by adding 20 g dry tea to 100 mL boiled water
and allowing it to infuse for 10 min. The tea concentrates were obtained
by simmering 40 g dry tea in 500 mL water for 20 min, then filtered and
reduced to 50 mL and subsequently lyophilized to give approximately 4 g
dry powder. This powder was stored at room temperature and was
redissolved in distilled water immediately before use to final
concentrations of 20% and 40%. The author concluded that the Drosophila
SMART can be used for detection of genotoxicity of herbal tea with
stinging nettle tea showing weak genotoxic effects both with standard
tea and with concentrated tea when direct contact occurs with the entire
solute complexity of the extract in vitro (mimicking pre-absorption
exposure).
7.4. Lactation
Traditionally, nettle plant juice or infusion was used as a galactagogue (Lust, 1974). Therefore, the possibility that lactation can be induced or enhanced by stinging nettle leaf is possible.
7.5. Carcinogenicity
Nettle is reported to elicit some anticarcinogenic and antioxidant activity in animal models (Celik and Tuluce, 2007, Kanter et al., 2003 and Kapadia et al., 2002).
In Turkey, this botanical, either as tea or eaten as a steamed or
boiled green, is used by more than 93% of children receiving
conventional therapies at a pediatric oncology unit (Gözüm et al., 2007).
The mutagenicity of stinging nettle herb and its flavonoid fraction were tested in Salmonella typhimurium microsomal activation assay (AMES test) using strains TA98 and TA100 with and without S9. Rutin and kaempferol-3-O-rutinoside
were added to the samples and they were all examined on human
lymphocytes in the alkaline single cell gel electrophoresis assay (Comet
Assay). Flavonoids as well as their aglycones were nonmutagenic (AMES
test negative), but not completely safe (responding to DNA strand
breakage in the COMET test) ( Basaran et al., 1996). Kalaycioglu et al. (1997)
studied the antimutagenic effect of stinging nettle extract (solvent
70% ethyl alcohol). Homogenates were centrifuged for 20 min at
13,200 rpm. The supernatants were filtered and 0.1 mL was used in the
assay (Salmonella typhimurium strains TA98 and TA100 with and
without the metabolic activation of rat liver S9 fractions). The
mutagenic effect of the fungicides captan and folpet and the insecticide
dichlorvos was inhibited by 33%, 27%, and 42%, respectively. Since
glutathione, cysteine, and ascorbic acid had an antimutagenic effect,
the authors concluded that the natural antioxidants in stinging nettle
contribute to the antimutagenic effect.
The
direct cytotoxic effect of essential oils from stinging nettle
(1.2–300 mg/mL) on L1210 leukemia cells in hybrid-BDF1 mice was studied
using the in vitro-in vivo method for determination of surviving
tumor-cells fraction. The direct toxic effect was concentration and time
of incubation-dependent (Ilarinova et al., 1992).
7.6. Toxicology
In
toxicity studies, rabbits of about 2 kg received orally 50 mL of a 50%
ethanol extract of stinging nettle for 10 days. Occasional diarrhea was
observed. A single subcutaneous injection of 5–20 mL was well tolerated,
but a dose of 15 mL/kg resulted in death of the animals after 24–36 h.
Chronic subcutaneous administration of 5–10 mL after an initial bolus of
15–20 mL of the same extract was associated with diarrhea. After 8 days
body weight had decreased by 40% and several days later the animals
died. Autopsy revealed purulent blisters around the injection site. The
lethal dose of intravenous extract was 1.5 mL of a 5-fold concentration,
3 mL of a 3-fold concentration, and 10 mL of the non-concentrated fluid
extract. Prior to death the animals’ respiration increased and a
central excitatory behavior was observed in the rabbits. Boiling of the
extract decreased its toxicity (Starkenstein and Wasserstrom, 1933).
Replacement
of the protein content of the diet by dried powdered stinging nettle
herb was tested in young growing guinea pigs, rats, and mice and in
mature guinea pigs for a period of 3 weeks. The intraperitoneal LD50
of young guinea pigs, mice, or rats was unaffected if 66% of the
dietary protein was replaced by dried powdered stinging nettle herb. If
the whole protein portion of the animal diet was replaced by stinging
nettle, the normal growth of young rats was impaired, an effect which
could be abolished by supplementation with methionine. Similarly, chicks
whose sole dietary protein was whole nettle meal only grew at 50% of
the rate of chicks fed a standard diet. Results varied with species and
their developmental stage when given a diet composed of 50% nettle
protein. In young growing guinea pigs liver and kidney weights were
increased significantly (P < 0.01), in mature rats liver and
kidney weights were decreased, in mice the liver weights were
decreased, however, the relative kidney weights increased. In mature
guinea pigs kidney weights and cholesterol levels were increased
significantly ( Hughes et al., 1980).
Whether these findings indicate a direct toxicity of stinging nettle
extract or a lack of amino acids cannot be definitively determined from
these experiments.
Acute and chronic toxicity of stinging nettle herb was studied by determining the LD50 using the Reed Muench-Pizzi technique. The intraperitoneal LD50
of aqueous nettle leaf extract was found to be 3625 mg/kg in mice.
Doses greater than 750 mg/kg were associated with a decrease in
spontaneous activity, loss of muscle tone, and hypothermia (Lasheras et al., 1986).
A low toxicity was also observed after oral and intraperitoneal
administration of an unspecified ethanol extract up to 2 g/kg (Tita et al., 1993).
Intravenous doses greater than 500 mg/kg caused transient hypotension
and cardiac arrhythmias. Following intravenous injection the LD50
was 19,286 mg/kg for a stinging nettle infusion 100 mg/mL and
17,213 mg/kg for an aqueous extract (3:1) 109 mg/mL in mice. Chronic
application was performed in rats with intragastric tubes; the LD50 was 1310 mg/kg (Baraibar et al., 1983). The hydrosoluble compound(s) that contribute to the toxic effect may have a pyran-coumarin structure (Broncano et al., 1987a).
Three
horses with an apparent neurological disorder resulting from stinging
nettle rash showed signs of ataxia, distress, and muscle weakness, and
two of them had urticaria. The condition resolved within 4 h (Bathe, 1994).
7.7. Contraindications
None Reported.
7.8. Precautions
Diuretics
are routinely applied for edema due to renal or cardiac insufficiency.
In such therapies, care must be taken to avoid electrolyte imbalance. If
symptoms of persistent fatigue, muscle weakness, or anxiety occur soon
after taking diuretics, consult with your health care practitioner.
Leaves are a powerful topical counterirritant and may cause blistering as well as wheal and flare. Allergies are rare (Bradley, 1992), but do occur and may develop in individuals previously able to tolerate stinging nettle herb (Mills and Bone, 2000). Caution has been advised by some in the first trimester of pregnancy (Mills, 1991)
and also for longer use than three weeks without intermittent breaks or
concomitant use of demulcents (Zeylstra, 1984, Lecture notes, College
of Phytotherapy, unpublished).
7.9. Influence on Driving
No
negative effects of using stinging nettle herb while driving are to be
expected unless with excessive consumption of stinging nettle wine.
7.10. Overdose
No data available.
7.11. Treatment of Overdose
No data available.
7.12. Classification of the American Herbal Products Association
The Botanical Safety Handbook (1997) of the American Herbal Products Association (AHPA) assigns Urtica dioica as a Class 1 herb: Can be safely consumed when used appropriately.
8. Original reference
Upton R, editor. Urtica dioica, Urtica urens:
American Herbal Pharmacopoeia. McCrone G, Upton R, Bencie R, Graff A,
Hartung T, Laenger R, Xavier-Garneau F, Blatter A, Reich E, Reif K,
Brinckmann J, Chrubasik S, McQuade Crawford A. Scotts Valley, CA; 2009.
Comment
from the Author and the Editor-in-Chief: “The goal of the American
Herbal Pharmacopoeia is to present a comprehensive review of the
totality of the evidence that is available on any given botanical. This
is primarily to establish both the safety and efficacy of the botanical
in light of antagonistic regulatory and social pressures against herbal
medicines. This is especially important due to the prevalence of
adulteration of skullcap with the potentially hepatotoxic germander.
Whilst neither AHP nor JHM support or endorse the use of animal studies
it is hoped that by reporting on all evidence on studies that have
already been done will prevent the same experiments being repeated”.
References
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