Holy Thistle

Summary and Pharmaceutical Comment

The chemistry of holy thistle is well documented and the available pharmacological data support most of the stated uses. However, there is a lack of clinical research assessing efficacy and safety of preparations of holy thistle. In view of the lack of toxicity data, excessive use of holy thistle and use during pregnancy and lactation should be avoided.

Species (Family)

HCnicus benedictus L. (Asteraceae/Compositae)

Synonym(s)

Blessed Thistle, Carbenia Benedicta, Carbenia benedicta (L.) Arcang., Carduus Benedictus, Cnicus

Part(s) Used

Herb

Pharmacopoeial and Other Monographs

BHC 1992(G6) BHP 1996(G9)

Complete German Commission E(G3) Martindale 35th edition(G85)

Legal Category (Licensed Products)

GSL(G37)

Constituents

The following is compiled from several sources, including General References G2, G6, G30, G40 and G62.

Lignans Arctigenin, nortracheloside, 2-acetyl nortracheloside and trachelogenin.(1)

Polyenes Several polyacetylenes.(2)

Steroids Phytosterols (e.g. n-nonacosan, sitosterol, sitosteryl glycoside, stigmasterol).(3)

Tannins Type unspecified (8%).

Terpenoids Sesquiterpenes including cnicin 0.2–0.7%,(4) yielding salonitenolide as aglycone,(5) and artemisiifolin. Shoot and flowering head are reported to be devoid of cnicin.(4) Triterpenoids

including a-amyrenone, a-amyrin acetate, a-amyrin, multiflorenol, multiflorenol acetate and oleanolic acid.(3)

Volatile oils Many components, mainly hydrocarbons.(6)

Other constituents Lithospermic acid, mucilage, nicotinic acid and nicotinamide complex, resin.

Food Use

Holy thistle is listed by the Council of Europe as natural source of food flavouring (category N2). This category indicates that holy

thistle can be added to foodstuffs in small quantities, with a

possible limitation of an active principle (as yet unspecified) in the final product.(G16) Previously in the USA, holy thistle was

permitted for use in alcoholic beverages.(G65)

Herbal Use

Holy thistle is stated to possess bitter stomachic, antidiarrhoeal, antihaemorrhagic, febrifuge, expectorant, antibiotic, bacteriostatic, vulnerary and antiseptic properties. Traditionally, it has been used for anorexia, flatulent dyspepsia, bronchial catarrh, topically for gangrenous and indolent ulcers, and specifically for atonic dyspepsia, and enteropathy with flatulent colic.(G6, G64)

Dosage

Dosages for oral administration (adults) for traditional uses recommended in standard herbal reference texts are given below.

Dried flowering tops 1.5–3.0 g as an infusion three times

daily.(G6, G7)

Liquid extract 1.5–3.0 mL (1 : 1 in 25% alcohol) three times

daily.(G6, G7)

Pharmacological Actions

In vitro and animal studies

Antibacterial activity has been reported for an aqueous extract of the herb, for cnicin, and for the volatile oil.(6–9) Activity has been

Figure 1 Selected constituents of holy thistle.

Figure 2 Holy thistle (Cnicus benedictus).

documented against Bacillus subtilis, Brucella abortus, Brucella bronchoseptica, Escherichia coli, Proteus species, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus faecalis. The antimicrobial activity of holy thistle has been attributed to cnicin and to the polyacetylene constituents.(9)

Cnicin has exhibited in vivo anti-inflammatory activity (carrageenan-induced rat-paw oedema test) virtually equipotent to indometacin.(4) Antitumour activity has been documented in mice against sarcoma 180 for the whole herb,(8) and against lymphoid leukaemia for cnicin;(8) cnicin has also been reported to exhibit in vitro activity against KB cells.(8) An a-methylene-g- lactone moiety is thought to be necessary for the antibacterial and antitumour activities of cnicin.(8)

Lithospermic acid is thought to be responsible for the antigonadotrophic activity documented for holy thistle.(G30) The sesquiterpene lactone constituents are stated to be bitter principles.(G62)

Tannins are generally known to possess astringent properties.

Clinical studies

There is a lack of clinical research assessing the effects of holy thistle and rigorous randomised controlled clinical trials are required.

Side-effects, Toxicity

None documented. However, there is a lack of clinical safety and toxicity data for holy thistle and further investigation of these aspects is required.

The toxicity of cnicin has been studied in mice: the acute oral LD50 was stated to be 1.6–3.2 mmol/kg body weight and intraperitoneal administration was reported to cause irritation of tissue. In the writhing test, cnicin was found to cause abdominal pain with an ED50 estimated as 6.2 mmol/kg.(4)

Antitumour activity has been documented for the whole herb and for cnicin (see Pharmacological Actions; In vitro and animal studies).

Contra-indications, Warnings

None documented for holy thistle. Plants containing sesquiterpene lactones with an a-methylene-g-lactone moiety are generally considered to be allergenic, although no documented hypersensi-

Figure 3 Holy thistle – dried drug substance (herb).

Preparations

Proprietary multi-ingredient preparations

Austria: Mariazeller. Brazil: Digestron. Czech Republic:

Ungolen. Germany: Gallexier; Gastritol. Russia: Original Grosser Bittner Balsam (Оригинальный Большой Бальзам Биттнера). South Africa: Essens Amara of Groen Amara. Switzerland: Gastrosan. UK: Bio-Strath Artichoke Formula; Sure-Lax (Herbal).

References

1 Vanhaelen M, Vanhaelen-Fastré R. Lactonic lignans from Cnicus benedictus. Phytochemistry 1975; 14: 2709.

2Vanhaelen-Fastré R. Constituents polyacetyleniques de Cnicus benedictus L. Planta Med 1974; 25: 47–59.

3Ulubelen A, Berkan T. Triterpenic and steroidal compounds of Cnicus benedictus. Planta Med 1977; 31: 375–377.

4 Schneider G, Lachner I. A contribution to analytics and pharmacology of Cnicin. Planta Med 1987; 53: 247–251.

5Vanhaelen-Fastré R, Vanhaelen M. Presence of saloniténolide in

Cnicus benedictus. Planta Med 1974; 26: 375–379.

6Vanhaelen-Fastré R. Constitution and antibiotical properties of the essential oil of Cnicus benedictus. Planta Med 1973; 24: 165–175.

7 Cobb E. Antineoplastic agent from Cnicus benedictus. British Patent 1,335,181 (Cl.A61k) 24 Oct 1973, Appl.54,800/69 (via Chemical Abstracts 1975; 83: 48189j).

8Vanhaelen-Fastré R. Antibiotic and cytotoxic activities of cnicin isolated from Cnicus benedictus. J Pharm Belg 1972; 27: 683–688.

9Vanhaelen-Fastré R. Cnicus benedictus: Separation of antimicrobial constituents. Plant Med Phytother 1968; 2: 294–299.

Summary and Pharmaceutical Comment

The chemistry of hops is well documented and is characterised by the bitter acid components of the oleo-resin. Documented pharmacological activities support the herbal uses, although evidence from robust clinical studies is limited. Excessive use of hops and use during pregnancy and lactation should be avoided in view of the limited toxicity data.

Species (Family)

HHumulus lupulus L. (Cannabaceae/Moraceae)

Synonym(s)

Humulus, Lupulus

Part(s) Used

Strobile

Pharmacopoeial and Other Monographs

BHC 1992(G6) BHP 1996(G9) BP 2007(G84)

Complete German Commission E(G3) ESCOP 2003(G76)

Martindale 35th edition(G85) Ph Eur 2007(G81)

Legal Category (Licensed Products)

GSL(G37)

Constituents

The following is compiled from several sources, including General References G2, G6 and G52.

Flavonoids Astragalin, kaempferol, quercetin, quercitrin and rutin.

Chalcones Isoxanthohumol, xanthohumol, 6-isopentenylnarin- genin, 30-(isoprenyl)-20, 4-dihydroxy-40, 60-dimethoxychalcone, 20,60-dimethoxy-4, 40-dihydroxychalcone.(1)

Oleo-resin 15-30%. Bitter principles (acylphloroglucides) in a soft and hard resin. The lipophilic soft resin consists mainly of a- acids (e.g. humulone, cohumulone, adhumulone, prehumulone, posthumulone), b-acids (e.g. lupulone, colupulone, adlupulone), and their oxidative degradation products including 2-methyl-3- buten-2-ol(2, 3, G52) The hard resin contains a hydrophilic d-resin and -resin.

Tannins 2–4%. Condensed; gallocatechin identified.(4)

Volatile oils 0.3–1.0%. More than 100 terpenoid components identified; primarily (at least 90%) b-caryophyllene, farnescene and humulene (sesquiterpenes), and myrcene (monoterpene).

Other constituents Amino acids, phenolic acids, gamma-linoleic acids, lipids and oestrogenic substances (disputed).(5)

It has been stated that only low amounts of 2-methyl-3-buten-2- ol, the sedative principle identified in hops, are present in sedative tablets containing hops.(2) However, it is thought that 2-methyl-3- buten-2-ol is formed in vivo by metabolism of the a-bitter acids and, therefore, the low amount of 2-methyl-3-buten-2-ol in a preparation may not indicate low sedative activity.(6) Interestingly, relatively high concentrations of 2-methyl-3-buten-2-ol were found in bath preparations, suggesting that high concentrations of 2- methyl-3-buten-2-ol may be achieved in both tea and bath products containing hops.(2)

Food Use

Hops are listed by the Council of Europe as a natural source of food flavouring (category N2). This category indicates that hops can be added to foodstuffs in small quantities, with a possible limitation of an active principle (as yet unspecified) in the final

product.(G16) Previously, hops has been listed as GRAS (Generally Recognised As Safe).(G65)

Figure 1 Selected constituents of hops.

Herbal Use

Hops are stated to possess sedative, hypnotic and topical bactericidal properties. Traditionally, they have been used for neuralgia, insomnia, excitability, priapism, mucous colitis, topically for crural ulcers, and specifically for restlessness associated with nervous tension headache and/or indigestion. The German Commission E approved use for mood disturbances such as restlessness and anxiety as well as sleep disturbances.(G3) Hops are used in combination with valerian root for nervous sleeping disorders and conditions of unrest.(G3)

Dosage

Dosages for oral administration (adults) for traditional uses recommended in contemporary standard herbal reference texts are given below.

Dried strobile 0.5 g as an infusion two to four times daily.(G76)

Liquid extract 0.5–2.0 mL (1 : 1 in 45% alcohol) up to three times daily.(G76)

Tincture 1–2 mL (1 : 5 in 60% alcohol) up to three times daily.(G76)

Pharmacological Actions

In vitro and animal studies

Antibacterial activity, mainly against Gram-positive bacteria, has been documented for hops, and attributed to the humulone and lupulone constituents.(7) The activity of the bitter acids against Gram-positive bacteria is thought to involve primary membrane leakage. Resistance of Gram-negative bacteria to the resin acids is attributed to the presence of a phospholipid-containing outer membrane, as lupulone and humulone are inactivated by serum phospholipids.(7) Structure–activity studies have indicated the requirement of a hydrophobic molecule and a six-membered central ring for such activity.(8)

intraperitoneal administration) produced a dose-dependent increase in sleeping time in mice treated with pentobarbitol. An antinociceptive effect was noted by increased latency of licking forepaws in hotplate tests and hypothermic activity observed from

a time-dependent fall of rectal temperature at a dose of 500 mg/

kg.(13)

Hops have previously been reported to possess oestrogenic constituents.(5) However, when a number of purified components, including the volatile oil and the bitter acids, were examined using the uterine weight assay in immature female mice, no oestrogenic activity was found.(5)

Clinical studies

Clinical research assessing the effects of hops is limited and rigorous randomised controlled clinical trials are required.

Clinical studies have generally assessed hops given in combination with one or more additional herbs. For example, hops has been reported to improve sleep disturbances when given in combination with valerian (see Valerian, Clinical studies).(14)

356 Hops

Hops, in combination with chicory and peppermint, has been documented to relieve pain in patients with chronic cholecystitis (calculous and non-calculous).(15) A herbal product containing a mixture of plant extracts, including hops and uva-ursi, and alphatocopherol acetate was reported to improve irritable bladder and urinary incontinence.(16) However, these observations require confirmation in robust clinical studies.

Side-effects, Toxicity

There is a lack of clinical safety and toxicity data for hops and further investigation of these aspects is required.

Respiratory allergy caused by the handling of hop cones has been documented;(17) a subsequent patch test using dried, crushed flowerheads proved negative. Positive patch test reactions have been documented for fresh hop oil, humulone, and lupulone.

Myrcene, present in the fresh oil but readily oxidised, was concluded to be the sensitising agent in the hop oil.(G51) Contact

Hdermatitis to hops has long been recognised(G51) and is attributed to the pollen.(G41)

Small doses of hops are stated to be non-toxic.(G42) Large doses administered to animals by injection have resulted in a soporific

effect followed by death, with chronic administration resulting in weight loss before death.(G39)

Contra-indications, Warnings

Allergic reactions have been reported for hops, although only following external contact with the herb and oil.

Drug interactions None documented. However, the potential for preparations of hops to interact with other medicines administered concurrently, particularly those with similar or opposing

effects, should be considered. There are some conflicting data on the oestrogenic activity of hops,(5) although 8-prenylnaringenin,

documented as a constituent of hops, has been shown to have oestrogenic activity in preclinical studies.(G76) Concern has been expressed that herbs with oestrogenic effects may stimulate breast

cancer growth and oppose action of competitive oestrogen receptor antagonists such as tamoxifen.(18) However, this requires confirmation.

Pregnancy and lactation In vitro antispasmodic activity on the uterus has been documented. In view of this and the lack of toxicity data, the use of hops during pregnancy and lactation should be avoided.

Preparations

Proprietary single-ingredient preparations

Russia: Novo-Passit (Ново-Пассит). Switzerland: Klosterfrau

Nervenruh Dragees.

Proprietary multi-ingredient preparations

Australia: Extralife Sleep-Care; Humulus Compound; Natural Deep Sleep; Pacifenity; Passiflora Complex; Passionflower Plus; Prosed-X; Relaxaplex. Austria: Baldracin; Baldrian AMA; Hova; Montana; Nervenruh; Nerventee St Severin; Sedadom; Wechseltee St Severin. Canada: Herbal Sleep Aid; Herbal Sleep Well. Chile: Valupass. Czech Republic: Baldracin; Detsky Caj s Hermankem; Fytokliman Planta; Novo-Passit; Sanason; SchlafNerventee N; Species Nervinae Planta; Valofyt Neo; Visinal.

France: Nostress. Germany: Ardeysedon; Avedorm duo; Baldrian-Dispert Nacht; Baldriparan N Stark; Biosedon; Boxocalm; Cefasedativ; Dormeasan; Dormoverlan; Gutnacht; Ilja Rogoff; Klosterfrau Beruhigungs Forte; Kytta-Sedativum; Leukona-Beruhigungsbad; Luvased; Moradorm S; Nervendragees; Nervenkapseln; Nervinfant N; Nervoregin forte; Pascosedon; Schlafund Nerventee; Sedacur; Sedaselect D; Selon; Sensinerv forte; Valdispert comp; Valeriana mild; Valverde Baldrian Hopfen bei Einschlafstorungen und zur Beruhigung; Vivinox Day. Hungary: Hova. Israel: Nerven-Dragees. Italy: Emmenoiasi. Mexico: Nervinetas. Russia: Doppelherz Vitalotonik (Доппельгерц Виталотоник); Sanason (Санасон). South Africa: Avena Sativa Comp. Switzerland: Baldriparan; Dormeasan; Dragees pour le coeur et les nerfs; Dragees pour le sommeil; Dragees sedatives Dr Welti; Hova; Hyperiforce comp; Nervinetten; ReDormin; Relaxo; Soporin; Tisane calmante pour les enfants; Tisane pour le sommeil et les nerfs; Valverde Coeur; Valverde Sommeil; Zeller Sommeil. UK: Anased; Avena Sativa Comp; Boots Alternatives Sleep Well; Boots Sleepeaze Herbal Tablets; Calmanite Tablets; Fenneherb Newrelax; Gerard House Serenity; Gerard House Somnus; HRI Calm Life; HRI Night; Kalms Sleep; Kalms; Napiers Sleep Tablets; Napiers Tension Tablets; Natrasleep; Newrelax; Nodoff; Nytol Herbal; Quiet Days; Quiet Life; Quiet Nite; Quiet Tyme; Relax Bþ; Sleepezy; Slumber; Sominex Herbal; Stressless; Unwind Herbal Nytol; Valerina Night-Time; Ymea. Venezuela: Lupassin; Nervinetas.

References

1Song-San S et al. Chalcones from Humulus lupulus. Phytochemistry

1989; 28: 1776–1777.

2 Hänsel R et al. The sedative-hypnotic principle of hops. 3. Communication: Contents of 2-methyl-3-butene-2-ol in hops and hop preparations. Planta Med 1982; 45: 224–228.

3Wohlfart R et al. Detection of sedative–hypnotic hop constituents, V: Degradation of humulones and lupulones to 2-methyl-3-buten-2-ol, a hop constituent possessing sedative-hypnotic activity. Arch Pharm

(Weinheim) 1982; 315: 132–137.

4 Gorissen H et al. Separation and identification of (þ)-gallocatechin in hops. Arch Int Physiol Biochem 1968; 76: 932–934.

5Fenselau C, Talalay P. Is oestrogenic activity present in hops? Food Cosmet Toxicol 1973; 11: 597–603.

6Hänsel R, Wohlfart R. Narcotic action of 2-methyl-3-butene-2-ol contained in the exhalation of hops. Z Naturforsch 1980; 35: 1096–

1097.

7Teuber M, Schmalreck AF. Membrane leakage in Bacillus subtilis 168 induced by the hop constituents lupulone, humulone, isohumulone and humulinic acid. Arch Mikrobiol 1973; 94: 159–171.

8 Schmalreck AF et al. Structural features determining the antibiotic potencies of natural and synthetic hop bitter resins, their precursors and derivatives. Can J Microbiol 1975; 21: 205–212.

9 Mizobuchi S, Sato Y. Antifungal activities of hop bitter resins and related compounds. Agric Biol Chem 1985; 49: 399–405.

10Mizobuchi S, Sato Y. A new flavanone with antifungal activity isolated from hops. Agric Biol Chem 1984; 48: 2771–2775.

11Caujolle F et al. Spasmolytic action of hop (Humulus lupulus). Agressologie 1969; 10: 405–10.

12Wohlfart R et al. The sedative-hypnotic principle of hops. 4. Communication: Pharmacology of 2-methyl-3-buten-2-ol. Planta Med 1983; 48: 120–123.

13Lee KM et al. Effects of Humulus lupulus extract on the central nervous system in mice. Planta Med 1993; 59: A691.

14Müller-Limmroth W, Ehrenstein W. Untersuchungen über die Wirkung von Seda-Kneipp auf den Schlaf schlafgestörter Menschen. Med Klin 1977; 72: 1119–1125.

15Chakarski I et al. Clinical study of a herb combination consisting of

Humulus lupulus, Cichorium intybus, Mentha piperita in patients