RANUNCULACEAE

The buttercup or crowfoot family is considered to be one of the more primitive of the dicotyledons and contains both common weeds and some important garden plants. There are 1900 species most common in the northern temperate regions. Most of them are perennial herbaceous plants, and may be aquatic or semi-aquatic growing in ponds or damp places, but there are also some shrubs and lianes e.g. Clematis.

N.B. Many species are toxic e.g. the fresh leaves of the genera Adonis, Anemone, and Ranunculus contain a highly irritant oil called protoanemonin which is poisonous to cattle, sheep and horses, but which breaks down to anemonin when the leaves are dried. Some genera like Aconitum contain poisonous alkaloids.

Anemone pulsatilla

Pulsatilla, pasque flower

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Family Ranunculaceae

Description

A softly hairy perennial to 25 cm growing from a thick woody rhizome. Basal leaves finely divided and pinnately cleft at the base with long, linear, pointed segments. Flowers solitary, to 5 cm across, erect, with 6 deep purple sepals and many golden stamens, above a ruff of involucral leaves to 2 cm long. Fruit small brown achenes with long feathery tails. Flowers in spring and summer.

Habitat and cultivation

Native to central and northern Europe, growing in open, sunny situations and well-drained limey soils. Grown in gardens elsewhere from seed sown as soon as it is ripe, or by root division in spring or autumn. Drought and frost resistant.

Parts used

The herb collected at the time of flowering and dried before use.

Active constituents

1) Lactones including ranunculin (around 3%) which, on crushing the plant, is converted to protoanemonin1 and this, being unstable, is degraded into the stable constituent, anemonin

2) Triterpenoid saponins

Also contains tannins, volatile oil, chelidonic and succinic acids and flavonoids. The flowers have in addition, delphinidin and pelargonidin glycosides.

Actions

1) Anodyne

2) Sedative

3) Antispasmodic

4) Antimicrobial

Scientific information

Very little pharmacological information is available.

In vitro—Protoanemonin is antifungal2,3 including against Candida albicans1 and Trichophyton mentagrophytes4 and antibacterial against both Gram-positive and Gram-negative bacteria including pathogenic cocci, bacilli and also Mycobacterium tuberculosis.1 Anemonin does not have this same activity.5

Protoanemonin is also anti-mutagenic6 and a skin irritant that can cause blistering.7

The BHP maintains that the herb is a bactericidal and lists the treatment of infections amongst its uses.

Medicinal uses

Respiratory tract

Nervous system

Reproductive tract

Used for pain and tension in this tract including:

Externally

Pharmacy

Infusion of dried herb –   0.1-0.3 g
Tincture 1:10 (40%) –   0.5-3 ml
Fluid Extract (25%) –   0.1–0.3 ml

For earache a few drops of the tincture are inserted into the outer ear.

CONTRAINDICATIONS—Pregnancy and lactation.

Precautions and/or safety

The herb must not be used fresh because it causes irritation and blistering on surfaces with which it comes in contact. Excessive doses can cause severe gastritis.

Historical uses

Spasmodic coughs including asthma, whooping cough, bronchitis. Catarrhal conditions—“watery and phlegmatic humours”; as an emmenagogue and for nervous exhaustion in women. Leprosy and cutaneous conditions including “malignant and corroding ulcers”. All afflictions of the eyes and Weiss includes here “iritis, scleritis, diseases of the retina, glaucoma and possibly senile cataract”.

Cimicifuga racemosa

Black cohosh

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Family Ranunculaceae

Description

A perennial which dies back completely in winter, and grows up to 3 × 2 m in flower. Rootstock thick and blackish. Leaves alternate and triternately divided, with the terminal leaflet the largest; dark green and sharply toothed. Flowers creamy-white, with long stamens; growing in long, simple or compound spikes, blooming in summer.

Odour—slight; taste—slightly bitter.

Habitat and cultivation

Native to rich woods in Canada and USA from South Ontario to Georgia. Plants are available elsewhere and may be grown in semi-shady situations in good, rich, leaf-mouldy soil. It takes 20 months or more for seeds to germinate.8 Drought and frost resistant.

Parts used

The root and rhizomes harvested in autumn8 and used after drying.

Active constituents

1) Triterpene glycosides9–14 (about 2%)15 many are of the cycloartane type. Over 40 have been reported. The main ones are actein, 23-epi-26-deoxyactein (27-deoxyactein), acetylshengmanol-3-O-xyloside, cimigenol-3-O-arabinoside and cimigenol-3-O-xyloside16

2) Isoflavones including formononetin17 (the presence of this constituent is controversial—it may be present in very low concentrations15 but has recently been reported as undetectable18,19)

3) Phenolic constituents (about 0.6%).20–26 More than 20 have been isolated, either free or as derivatives they include isoferulic, ferulic, caffeic, fukinolic and cimicifugic acids A, B, E and F and a lignan—actaealactone.

Also contains tannin, resin, an alkaloid (cimipronidine22), fatty acids, salicylic acid, starch and sugars. C. racemosa does not contain cimicifugin or its glucoside.16

Interestingly a sample of Cimicifuga collected in 1919 had a similar constituent profile, though levels were lower, than a modern specimen suggesting that these constituents are relatively stable.27

Nutritional constituents

Minerals: Calcium, iron, magnesium, potassium and zinc28

Actions

1) Sedative

2) Antitussive

3) Antirheumatic

4) Emmenagogue

Scientific information

Cimicifuga also known as Actaea racemosa is one of a number of this genus that grows in similar habitats in North America. There are also similar species used medicinally in Eastern herbal medicine. Black cohosh, a traditional medicine of the Native Americans, was introduced to early settlers and became an official medicine in the United States Pharmacopoeia remaining as such till 1926. It is also recorded as a medicine in the British Pharmacopoeia having been used as a bitter and mild expectorant.29 German Commission E has approved its use for premenstrual discomfort, dysmenorrhoea and menopausal symptoms.

Cimicifuga has been officially used in Europe for over 40 years for treating menstrual and menopausal symptoms. It has become one of the most frequently used herbs which has increased demand and put pressure on its survival as it has mostly been wild-crafted. The chemical profiles of various species in this genus are very similar and there are many triterpenoid constituents. These facts have combined to make species identification difficult16 so that a large amount of effort has been expended on developing chemical tests to unequivocally identify the different species. It is likely that other species of Actaea have been, or are being, substituted for C. racemosa,11 partly to meet world demand and partly through incorrect identification.20 Furthermore in spite of all the trials that have so far been conducted into the pharmacological activities of the herb the active constituents and mechanism of action have not been fully elucidated. Scientific studies may have been confounded by the above factors, further complicated by the usual chemical variations due to geographical conditions, time of harvest and extraction processes. The conflicting results reported on the actions of the herb may be due, at least in part, to these considerations.11

Some of the research particularly pertaining to Cimicifuga's use for menstrual problems is relatively old and as a result hard to access. The current focus of its use in hormonal problems has been confined to menopause.

Gynaecological

The unacceptable side-effects of HRT prompted a great deal of interest in natural medicines to achieve relief from what can be quite disabling symptoms for women entering menopause.

In vitro—Early studies reported that Cimicifuga was oestrogenic,30–33 the exact constituents responsible were not known although, until doubt arose as to its presence, formononetin was considered the most likely candidate. Many tests have concluded that neither the herb nor its metabolites have activity at α- or β-oestrogenic receptor sites.34–37

However a lypophilic extract had some oestrogen-like activity in endometrial tissue possibly via a postulated third type of receptor, the γ-oestrogen receptor site.38 The herb reduces oestrogen formation in normal breast tissue, tissue from pre-menopausal women being more sensitive to this action. Conversion of circulating pro-hormone by an enzymatic process to produce active hormone in tissues is believed to occur giving rise to local levels different from that in serum. Inhibition of this enzyme could be a possible mechanism by which black cohosh exerts a hormone lowering effect.39 It is also possible that it could influence menopausal symptoms by acting directly through dopaminergic,40 serotonergic41 and/or opiate agonist receptors in the central nervous system.42

Cimicifuga and its triterpenoids also inhibit osteoclastogenesis.43,44

In vivo—A number of trials have been conducted, over a large time frame, into the effectiveness of Cimicifuga in treating the physiological effects of menopause. Not all are in accord as to the herb's effectiveness. The positive studies found benefit for:-

The benefits of Cimicifuga may be greater in women whose menopausal symptoms are more marked58 and in those who have just entered the climacteric period.59 No changes are observed in endometrial tissue, hormone levels or oestrogenic activity.51,60

Combining Cimicifuga and Hypericum relieved menopausal symptoms, both physical and psychological,45,61 the improvement in depression was not due to Hypericum alone.45

The negative studies suggest that Cimicifuga was no better than placebo in moderating vasomotor symptoms (hot flushes and night sweats)62–64 even after 12 months use,65 although both groups recorded some improvement in symptoms.

Reviews of the various clinical trials of black cohosh to treat menopausal symptoms have found the herb was:

The quality of most of these trials has been criticised, however, as not being rigorous enough to draw definitive conclusions.65,74,75

Other hormonal effects reported were a herbal combination, which included Cimicifuga, reducing the frequency of menstrual migraines76 and the herb alone reducing LH levels.77 This latter effect has not been corroborated by more recent trials which found hormone levels were not altered even after 12 months use of black cohosh supplements.54,64,112,116

Anticancer

In vitro—Increasing use of black cohosh for treating menopausal symptoms prompted safety checks on its potential to stimulate proliferation of breast cancer cells. Cimicifuga and its constituents are devoid of proliferative activity in these cells78 and have no oestrogenic activity on breast tissue—see above. In fact the triterpenoid fraction,79,80 the cinnamic acid esters79 and the whole extract inhibit growth of breast cancer cells, whether oestrogen receptive or not,81–83 an action occurring at gene-level, through anti-proliferation and apoptotic mechanisms.84–86 Cimicifuga additionally inhibits oestrogen-stimulated proliferation of breast cancer cells87,88 and the invasive potential of malignant cells89 and enhances their effective growth inhibition by chemotherapy treatments like tamoxifen.87,90,91 It reduces the conversion of oestrone to the more active oestrodiol in breast cancer cells.92

The herb and/or its constituents also inhibit the growth of prostate cancer cells,93,94 whether hormone dependent or not,95 and oral squamous carcinoma cells.96 It seems, therefore, that black cohosh may have potential as a cancer preventative.97

In vivo—Reviews of trials52,56,63,64 into Cimicifuga's efficacy for alleviating menopausal symptoms in women who either had breast cancer, a history of the disease or risk factors for developing the disease found it safe for use by them.98 (It has again been suggested that the studies to-date are not scientifically rigorous enough to be certain).99 However women who had had breast cancer were not at increased risk from a re-occurrence of the disease after using black cohosh and it may actually have increased their disease-free survival time.100 Further, a retrospective study of women who had used the herb for menopausal symptom relief suggests it may have had a protective effect against their developing breast cancer.101

Other

In vitro—Various other actions have been demonstrated for Cimicifuga or its constituents including:-

In vivo—In some of the above studies checks were also made on any changes to women's risk factors for cardiovascular disease. Again there are conflicting results, some showing no apparent benefit whether Cimicifuga was used alone or in combination with other botanicals,110,111 whilst others found on its own, or combined with Hypericum, it improved HDL-cholesterol levels54,112 and reduced LDL-cholesterol.54

Cimicifuga was one of 3 constituents in a cream that reduced wrinkles113 and it may enhance wound healing, as the triterpenoid fraction can inhibit several collagenolytic enzymes114 whose excessive activity inhibits normal tissue repair.

Medicinal uses

Respiratory tract

Nervous system

As a sensory depressant:

Reproductive tract

It is a safe alternative to HRT:

Musculoskeletal

Pharmacy

Three times daily  
Decoction or powdered –   0.3–2 g of dried root or rhizome
Tincture 1:10 (60%) –   2.0–4 ml
Fluid Extract (90%) –   0.3–2 ml

N.B. The BHC daily dosage for tincture 1:10 is 0.4–2 ml or 40–200 mg dried herb.

Trials with extracts in tablet-form were based on 40–80 mg/day.

Precautions and/or safety

Standard mutagenicity tests on the herb were negative.115 No safety concerns arose during the clinical studies and there were no adverse changes in breast, endometrial tissue or reproductive hormone levels in women who used the extract116,117 even after one year of continuous use.118 Specific reviews on Cimicifuga's safety conclude it is safe for short term use (up to 12 months).56,119–121 More studies are needed to assess safety for longer periods of time.

Minor side effects include gastro-intestinal disturbances (nausea and vomiting), rashes, headache, dizziness, mastalgia and weight gain.74 (These are similar to the side effects reported for placebos45). It should be used with caution and only with professional guidance in pregnancy.122 It use is usually confined to the third trimester or to labour induction.122

To-date a total of 42 cases of suspected liver toxicity due to the herb have been reported66,123–126 but no direct causal link has yet been established.74,127,128 Only two of these cases have been adjudged to be “probably” related to the use of Cimicifuga.127 There is very high usage of black cohosh world wide, based on commercial sales, so that the likely incidence must be deemed to be very small.127 Clinical trials that monitored liver function found no abnormalities54,55,60—reviewed.98 However there may be a potential for idiosyncratic reactions of this nature.

There are other reported cases of serious side-effects including reversible cutaneous pseudolymphoma (erythematous plaques on the limbs),129 autoimmune hepatitis,130 acute renal transplant rejection,131 muscle damage leading to reversible myopathy,132 reversible nocturnal seizure133 and two cases of cutaneous vasculitis.134

Interactions

In vitro—Black cohosh is a moderate inhibitor of organic anion-transporting polypeptide-B, an intestinal transporter, and could theoretically alter the uptake of medications that use it, if the two are co-administered.135 It was also a strong inhibitor of CYP3A4 which could potentially increase the serum levels of drugs metabolised by this isozyme.136 (This was not corroborated in vivo).

In vivo—A brand of Cimicifuga that was tested was not found to have any effect on CYP1A2, CYP2D6 (weak inhibition only), CY2E1 or CYP3A4 drug metabolism137,138 or on P-glycoprotein transport mechanism (it did not for example interfere with the uptake of digoxin).139

Historical uses

Insecticidal; snake bites; sore throats; scarlet fever; scirrhous tumours; backache; colds; constipation; consumption; fatigue; hives; insomnia; kidney problems.

Hydrastis canadensis

Golden seal

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Family Ranunculaceae

Description

A small, herbaceous, perennial herb up to 30 cm tall in flower. Rhizome yellowish-brown outside, thick, oblong, irregular and knotted with a bright yellow interior pulp, and numerous roots. Stem simple, erect, thick and hairy, growing from the root in spring, surrounded at the base by several sheathing, greenish-yellow bracts. Leaves two, alternate, dark green and wrinkled, the lower larger than the upper, growing near the top of the stem, orbicular-cordate at the base, and palmately 5–7-lobed. Flower solitary, terminal, with 3 pale rose sepals which fall when the bloom opens. There are no petals but numerous greenish-white stamens and twelve or more short pistils. Fruit a succulent, globose berry looking like an enlarged raspberry. Seeds obovate, nearly black and glossy. Flowers from April to May in USA and fruits in July.

Habitat and cultivation

Native to North America in moist, rich deciduous woodlands from Vermont to Michigan, Minnesota, Virginia, Tennessee and Arkansas. Now an endangered species due to over-gathering. Grown from stratified seeds or root cuttings planted in autumn 5 cm deep and 20 cm apart in rows. It requires 75% shade and moist, well-drained soil rich in humus and a leafy mulch. It is drought tender.

Parts used

The fresh or dried roots and rhizomes which are generally harvested in the second or third year. In the fourth year the roots may be divided to provide more plants.

Active constituents

1) Alkaloids including berberine (min. 2.5%), (-)-β-hydrastine (min. 2%), canadine (tetrahydroberberine) and hydrastinine,140–144 highest levels found in rhizomes143

2) Chlorogenic acid and other quinic acid derivatives143,145

Also contains volatile oil, resin, lipids, sterols (a derivative of α-sitosterol),143 flavonoids146 and carbohydrates. Commercial samples of Hydrastis have shown great variability.141,142,147–149 The presence of the alkaloid palmatine is considered indicative of adulteration by other berberine-containing herbs.147 Hydrastine and canadine are alkaloids specific to Hydrastis.143

Nutritional constituents

Vitamins: A, B-complex, C and E

Minerals: Calcium, copper, potassium and high content of phosphorus, manganese, iron, zinc and sodium

Actions

1) Antihaemorrhagic

2) Choleretic

3) Antimicrobial

4) Stomachic

5) Oxytocic

6) Laxative

Scientific information

Hydrastis has been an official medicine in many countries, its first reported medicinal use occurring in 1798. It's indicated uses were as an antihaemorrhagic for excessive uterine bleeding, to alleviate dysmenorrhoea and as a bitter.29

As one of the top selling herbs in the USA there has been high demand for it resulting in a short supply of roots and rhizomes. As has occurred with Cimicifuga, much of the recent scientific study has been directed at correctly identifying the herb and/or part used due to the apparent adulteration of commercial supplies.

The alkaloids berberine, for which there is a relatively large amount of information, and hydrastine are believed to be the major active constituents. The pharmacological actions of berberine include anti-proliferative,150 antimicrobial, anti-inflammatory, antihaemorrhagic, anticholinergic, anti-arrhythmic and potentially beneficial for hypercholesterolaemia and congestive cardiac failure151 (see Berberis vulgaris). Hydrastine is a peripheral vasoconstrictor with astringent properties and is considered a stimulant to uterine contractractions.29

For such a commonly used herb there is very little modern information available on the whole herb.

In vitro—Hydrastis has a strong potential for lowering cholesterol and lipids, an effect that is greater for the whole herb than for berberine alone.152 The herb itself and/or a number of its constituents are antimicrobial to oral pathogens,146 15 strains of Helicobacter pylori153 and a range of bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus sanguis and Escherichia coli.154 The extract and berberine are also active against Mycobacterium tuberculosis.145

It is a good antioxidant.155

In vivo—There are no clinical trials using Hydrastis. Berberine has been tested in trials and had beneficial cardiovascular effects—preventing ischaemic induced-arrhythmia, increasing heart contractility, lowering peripheral vascular resistance and consequently reducing blood pressure.156 The whole herb however is contraindicated in hypertension.

Hydrastis is considered a tonic for mucous membranes.

Medicinal uses

Respiratory tract

Gastro-intestinal tract

Reproductive tract

Externally

Pharmacy

Three times daily  
Decoction of dried herb –   0.5–1 g
Tincture 1:10 (60%) –   2.0–4 ml
Fluid Extract (60%) –   0.3–1 ml

CONTRAINDICATIONS—Hypertension, pregnancy.

Pharmacokinetics

Only a small amount of berberine is measurable in plasma after oral administration.151

Precautions and/or safety

The herb is toxic in large doses but it is so bitter that over-dosing is unlikely. Golden seal's alkaloids are phototoxic to keratinocytes,157 causing damage to DNA,158 and berberine is phototoxic to lens epithelial cells.159 This should not present problems for internal use.

There is one case reported of a newly diagnosed type 1 diabetic child suffering reversible hypernatraemia suspected to have been exacerbated by Hydrastis160 and another of a reversible photosensitivity reaction occurring in a woman taking a supplement containing multiple ingredients, of which golden seal was one. It is not known which constituent caused the reaction.161

Interactions

In vitro—Golden seal and its alkaloids have strong inhibitory activity on the cytochrome P450 isozymes including CYP2E1,162 CYP2C8,163 CYP2D6,163–165 CYP3A4,163–166 CYP2C9164,165 and CYP2C19.164 Based on calculations and assuming 100% absorption of the main alkaloids, the likelihood of a drug/herb interaction using recommended doses was deemed to be unlikely.142

In vivo—Hydrastis did inhibit the metabolism of probe drugs using CYP3A4/5167,168 and CYP2D6168 suggesting it may significantly affect the handling of other drugs using these enzymes if they are consumed concomitantly. When used with digoxin169 and indinavir, an antiretroviral,170 the herb did not affect their pharmacokinetics. No drug/herb interactions have yet been reported.

Historical uses

Varicose veins; haemorrhoids; acne; ringworm; in spring tonics; cancer; cracked and bleeding lips; cankers. Colds; flu; whooping cough; pneumonia; heart trouble. Leaves were used for snake bite and fits.

Ranunculus ficaria

Lesser celandine, pilewort

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Family Ranunculaceae

Description

A low growing perennial plant, arising from small figshaped tubers with fibrous roots. The plant becomes dormant in late summer, and reappears early in the following spring. Basal leaves grow in a rosette and are dark green, glabrous, heart shaped and fleshy with long stems, sheathed at the base. Stem leaves similar but smaller. Flowers have 3 green sepals and 8–12 shining buttercup-yellow petals sometimes white at the tip. Fruit achenes finely beaked and keeled, about 2–2.5 mm long. Some sub-species bear bubils at the base of the leaf stalks. Blooms early in spring.

Habitat and cultivation

Native to Britain and Europe, growing along streams and in meadows and woods. Dies back in summer and comes up in autumn. May be propagated from tubers and grown in gardens. Root tubers and mature leaves poisonous to stock. Ranunculus ficaria var. grandiflora is a larger species whose medicinal use is unknown.

Parts used

Herb harvested when the plant is in flower and dried. The root has also been used for medicinal purposes.

Active constituents

1) Saponins of the triterpenoid type based on hederagenin and oleanolic acid171–174

2) Flavonoids175

3) Lactones—including anemonin and protoanemonin

4) Tannins

Actions

1) Astringent

2) Demulcent (local)

Scientific information

Ranunculus was valued by early herbalists, its common name, pilewort, indicating the specific use of the herb. This same use is found in the traditional practices from a number of different countries.176,177 However it did not find favour with Weiss who claimed no success using it either internally or as an ointment in the treatment of haemorrhoids.

For actions of anemonin and protoanemonin see Anemone. Hederagenin derivatives generally have been examined and found to be biologically active but there are no recent studies on those specifically found in pilewort.

Medicinal uses

Gastro-intestinal tract

For the internal and external treatment of:-

The specific use given in the BHP is for prolapsed or internal haemorrhoids with or without bleeding.

Pharmacy

Dosage three times daily  
Infusion of dried herb –   2–5 g
Fluid Extract (25%) –   2–5 ml

Ointment 3% in base material.

Ointment BPC (1934) 30% fresh plant in lard or made into suppositories.

Historical uses

Kernels by ears or throat or scrofula (tuberculous lesions), tumours, wens.

_________________

†SERM have a mixed and selective pattern of estrogen agonist–antagonist activity, which largely depends on the tissue targeted.