Wild Lettuce

Summary and Pharmaceutical Comment

The chemistry of wild lettuce is well documented, although it is not clear which constituents represent the active components. Early reports of hyoscyamine as a constituent have not been substantiated by subsequent study. No published information was found to support the traditional herbal uses of wild lettuce, although a sedative action in toads has been reported for a related species L. sativa. In view of the potential allergenicity of wild lettuce and the lack of toxicity data, excessive use and use during pregnancy and lactation should be avoided.

Related Lactuca species include Lactuca sativa (Garden Lettuce), Lactuca serriola L. (Prickly Lettuce), L. quescina L. subsp. quercina and Lactuca canadensis (Wild Lettuce of America).

Species (Family)

Lactuca virosa L. (Asteraceae/Compositae)

Synonym(s)

Bitter Lettuce, Great Lettuce, Lettuce Opium

Part(s) Used

Leaf, latex

Pharmacopoeial and Other Monographs

BHC 1992(G6)

BHP 1996(G9)

Martindale 35th edition(G85)

Legal Category (Licensed Products)

GSL(G37)

Constituents

The following is compiled from several sources, including General Reference G6.

All parts of the plant contain a milky, white latex (sap) which,

when collected and dried, forms the drug known as lactucar-

ium.(G33)

Acids Citric, malic and oxalic (up to 1%) acids; cichoric acid (phenolic).(1)

Alkaloids Hyoscyamine, later disputed.(2, G33) N-methyl-b-

Wphenethylamine, also disputed.(2)

Coumarins Aesculin, cichoriin.(1)

Flavonoids Flavones (e.g. apigenin, luteolin), flavonols (e.g. quercetin) and their glycosides.(1)

Terpenoids Bitter principles including the sesquiterpene lactones lactucin and lactupicrin (lactucopicrin); b-amyrin, germanicol, and lactucone (lactucerin). Lactucone is a mixture of a- and b- lactucerol acetates, b-lactucerol being identical to taraxasterol.

Figure 1 Selected constituents of wild lettuce.

Other constituents Mannitol, proteins, resins and sugars.

Food Use

Wild lettuce is not used in foods, although the related species L. sativa is commonly used as a salad ingredient.

Herbal Use

Wild lettuce is stated to possess mild sedative, anodyne and hypnotic properties. Traditionally, it has been used for insomnia, restlessness and excitability in children, pertussis, irritable cough, priapism, dysmenorrhoea, nymphomania, muscular or articular

pains, and specifically for irritable cough and insomnia.(G6, G7, G8,

G42, G64)

Dosage

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

Dried leaves 0.5–3.0 g as an infusion three times daily.(G6)

Figure 2 Wild lettuce (Lactuca virosa).

Figure 3 Wild lettuce – dried drug substance (herb).

Liquid extract 0.5–3.0 mL (1 : 1 in 25% alcohol) three times daily.(G6)

Lactucarium (dried latex extract) (BPC 1934) 0.3–1.0 g three times daily.

Soft extract (BPC 1934) 0.3–1.0 g three times daily.

Pharmacological Actions

In vitro and animal studies

Lactucarium has been noted to induce mydriasis.(G6) This effect may be attributable to hyoscyamine, although the dried sap is reportedly devoid of this alkaloid.

An alcoholic extract of a related species, L. sativa, has exhibited a sedative effect in toads, causing a reduction in motor activity and behaviour.(3) Higher doses resulted in flaccid paralysis. In addition, an antispasmodic action on isolated smooth and striated muscle, and in vitro negative chronotropic and inotropic effects on normal and stressed (tachycardic) hearts were observed. The antispasmodic action was noted to be antagonised by calcium.

Lactucin, lactupicrin and hyoscyamine have all been proposed as the sedative components in wild lettuce. However in the above study,(3) the active component was uncharacterised and acted mainly peripherally, not readily crossing the blood–brain barrier. The suggested mode of action was via interference with basic excitatory processes common to neural and muscular functions, and not via a neuromuscular block.

Low amounts (nanograms) of morphine have been detected in Lactuca species, although the concentrations involved are

considered too low to exert any obvious pharmacological effect.(G60)

Clinical studies

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

Side-effects, Toxicity

Clinical data

No side-effects documented for L. virosa. However, there is a lack of clinical safety and toxicity data for wild lettuce and further investigation of these aspects is required.Wild lettuce contains

sesquiterpene lactones which are potentially allergenic.(G19) Occupational dermatitis has been documented for L. sativa

together with an urticarial eruption after ingestion of the leaves.(4– 6, G51) The milky sap of L. sativa is reported to be irritant.(G51)

Preclinical data

Consumption of large amounts of L. scariola has caused poisoning in cattle, which developed pulmonary emphysema, severe dyspnoea, and weakness.(7) Only the immature plants were reported to be toxic.

L. sativa has been reported to produce only negative responses when tested for mutagenicity using the Ames test (Salmonella typhimurium TA98, TA100).(8)

Contra-indications, Warnings

Overdosage may produce poisoning(G42) involving stupor, depressed respiration, coma and even death. Wild lettuce may cause an allergic reaction in sensitive individuals, in particular those with an existing sensitivity to other members of the Asteraceae/Compositae family.

Drug interactions None documented. However, the potential for preparations of wild lettuce to interact with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered.

Pregnancy and lactation The safety of wild lettuce has not been established. In view of the lack of toxicity data and the possibility of allergic reactions, use of wild lettuce during pregnancy and lactation should be avoided.

Preparations

Proprietary multi-ingredient preparations

Canada: Sirop Cocillana Codeine. Russia: Speman Forte (Спеман Форте). South Africa: Choats Extract of Lettuce Cough Mixture. UK: Anased; Antibron; Calmanite Tablets; Gerard House Somnus; HRI Night; Kalms Sleep; Napiers Sleep Tablets; Nytol Herbal; Quiet Life; Quiet Nite; Slumber; Unwind Herbal Nytol. Venezuela: Cerylana.

References

1 Rees S, Harborne JB. Flavonoids and other phenolics of Cichorium and related members of the Lactuceae (Compositae). Bot J Linn Soc 1984; 89: 313–319.

2Huang Z-J et al. Studies on herbal remedies I: Analysis of herbal smoking preparations alleged to contain lettuce (Lactuca sativa L.)

and other natural products. J Pharm Sci 1982; 71: 270–271.

3Gonzálex-Lima F et al. Depressant pharmacological effects of a component isolated from lettuce, Lactuca sativa. Int J Crude Drug

6Zeller W et al. The sensitizing capacity of Compositae plants 6. Guinea pig sensitization experiments with ornamental plants and weeds using different methods. Arch Dermatol Res 1985; 277: 28–35.

7 Anon. Poisindex CD-ROM 1995; 85. Denver: Micromedex.

8White RD et al. An evaluation of acetone extracts from six plants in the Ames mutagenicity test. Toxicol Lett 1983; 15: 26–31.

Summary and Pharmaceutical Comment

Willow is rich in phenolic constituents, such as flavonoids, tannins and salicylates. Pharmacological actions normally associated with salicylates are also applicable to willow and supports most of the herbal uses. Robust clinical research assessing the efficacy and safety of willow is limited. In view of the lack of toxicity data on willow, the usual precautions taken with other salicylate-containing drugs are applicable. Products containing willow should preferably be standardised on their salicin content, in view of the considerable variation in salicylate concentrations between different Salix species. The use of willow during pregnancy and lactation should be avoided.

Species (Family)

Several Salix species are used including S. alba L., S. fragilis L., S. pentandra L., S. purpurea L. (Salicaceae)

Synonym(s)

Salix

Part(s) Used

Bark

Pharmacopoeial and Other Monographs

American Herbal Pharmacopoeia(G1)

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 G1, G2, G6 and G52.

Glycosides (phenolic) Various phenolic glycosides including salicin, salicortin, tremulacin, salireposide, picein and triandrin.(1) Acetylated salicin, salicortin, salireposide, and esters of salicylic

Wacid and salicyl alcohol may also occur.

Salicylates (calculated as salicin) Vary between species, e.g. 0.5% in S. alba, 1–10% in S. fragilis, 3–9% in S. purpurea.(2)

Flavonoids Flavanones, eriodictoyl-7-glucoside; naringenin-5- glucoside; chalcone; isosalipurposide; catechin.(2, G52)

Tannins Condensed.

Other constituents Catechins.

There is reported to be no difference between the phenolic glycoside pattern of the bark and leaf. The latter is also reported to contain flavonoids, catechins and condensed tannins.(2, 3)

Food Use

Willow is not used in foods.

Herbal Use

Willow is stated to possess anti-inflammatory, antirheumatic, antipyretic, antihidrotic, analgesic, antiseptic and astringent properties. Traditionally it has been used for muscular and arthrodial rheumatism with inflammation and pain, influenza, respiratory catarrh, gouty arthritis, ankylosing spondylitis, and specifically for rheumatoid arthritis and other systemic connective tissue disorders characterised by inflammatory changes. The German Commission E approved internal use for diseases accompanied by fever, rheumatic ailments and headaches.(G3)

Dosage

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

Dry bark 1–3 g as a decoction three times daily(G6, G7) corresponding to 60–120 mg total salicin daily.(G3)

Liquid extract 1–3 mL (1 : 1 in 25% alcohol) three times

daily.(G6, G7)

Pharmacological Actions

In vitro and animal studies

Pharmacological actions documented for salicylates include antiinflammatory, antipyretic, hyperglycaemic/hypoglycaemic and

Figure 1 Selected constituents of willow.

Figure 2 Willow (Salix spp.).

uricosuric/antiuricosuric activities, and increased blood-clotting time and plasma albumin binding.(G46) Anti-inflammatory activity for salicin and tremulacin (isolated from Populus spp.) has been assessed in the hen's egg choriollantoic test.(4, G52) The results indicate that the activity may be due to the metabolites of these compounds.(4) Salicin is probably the most active anti-inflamma- tory compound in willow; it is metabolised to salicylic acid.(5) The enzymatic degradation of salicin, salicortin and tremulacin by b- glucosidase and by esterase has been investigated.(6)

Tannins are known to have astringent properties.

Clinical studies

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

Willow bark extract (equivalent to 240 mg salicin/day) was compared with placebo in a two-week, randomised, double-blind trial involving 78 patients with osteoarthritis.(7) A difference in pain dimension in the treated group, compared with placebo, just reached statistical significance (p = 0.047).

The pharmacological actions of salicylates in humans are well documented, and are applicable to willow. Salicin is a prodrug which is metabolised to saligenin in the gastrointestinal tract and to salicylic acid after absorption.(2)

Side-effects, Toxicity

Clinical data

Clinical safety and toxicity data for willow are limited and further investigation of these aspects is required. Minor adverse effects

including stomachache, nausea, dizziness, sweating and rash have been reported for willow.(G52)

Side-effects and signs of toxicity normally associated with salicylates, such as gastric and renal irritation, hypersensitivity,

blood in the stools, tinnitus, nausea and vomiting, may occur. Salicin is documented to cause skin rashes.(G44)

Figure 3 Willow – dried drug substance (bark).

Contra-indications, Warnings

Precautions associated with salicylate therapy are also applicable to willow. Therefore individuals with known hypersensitivity to aspirin, asthma, active peptic ulceration, diabetes, gout, haemophilia, hypoprothrombinaemia, kidney or liver disease should be

aware of the possible risks associated with the ingestion of willow.(8, G46)

Drug interactions Drug interactions listed for salicylates are also applicable to willow and include oral anticoagulants, methotrexate, metoclopramide, phenytoin, probenecid, spironolactone and valproate. Concurrent administration of willow with other salicylate-containing products, such as aspirin, should be avoided. Irritant effects of salicylates on the gastrointestinal tract may be enhanced by alcohol, and barbiturates and oral sedatives have been documented to enhance salicylate toxicity as well as masking the symptoms of overdosage.(G46)

Pregnancy and lactation The safety of willow during pregnancy and lactation has not been established. Conflicting reports have been documented concerning the safety of aspirin taken during

pregnancy. Salicylates excreted in breast milk have been reported to cause macular rashes in breastfed babies.(G46) In view of this

information, the use of willow during pregnancy and lactation should be avoided.

Preparations

Proprietary single-ingredient preparations

Brazil: Zortrix. Germany: Assalix; Assplant; Rheumakaps;

Rheumatab Salicis. Switzerland: Assalix.

600 Willow

Dolosul; Jaquesor; Mesatil; Natusor Harpagosinol; Natusor Jaquesan. Switzerland: Dragees antirhumatismales; Strath Gouttes Rhumatisme; Tisane antirhumatismale. UK: BioStrath Willow Formula; Gerard House Reumalex; Herbal Pain Relief; Roberts Black Willow Compound Tablets; St Johnswort Compound. Venezuela: Passiflorum.

References

1Meier B et al. Identifikation und Bestimmung von je acht Phenolglykosiden in Salix purpurea und Salix daphnoides mit

moderner HPLC. Pharm Acta Helv 1985; 60: 269–274.

2 Meier B et al. Pharmaceutical aspects of the use of willows in herbal remedies. Planta Med 1988: 54: 559–560.

3 Karl C et al. Flavonoide aus Salix alba, die Struktur des terniflorins

und eines Weiteren Acylflavonoides. Phytochemistry 1976; 15: 1084– 1085.

4Albrecht M et al. Anti-inflammatory activity of flavonol glycosides and salicin derivatives from the leaves of Populus tremuloides. Planta Med 1990; 56: 660.

5Meier B, Liebi M. Salicinhaltige pflanzliche ArzneimittelÜberlegungen zu wirksamkeit und unbedenklichkeit. Z Phytother

1990; 11: 50–58.

6Julkunen-Tiitto R, Meier B. The enzymatic decomposition of salicin and its derivatives obtained from salicaceae species. J Nat Prod 1992;

55: 1204–1212.

7 Schmid B et al. Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized placebocontrolled, double blind clinical trial. Phytother Res 2001; 15: 344– 350.

8Baker S, Thomas PS. Herbal medicine precipitating massive haemolysis. Lancet 1987; i: 1039–1040.