Psychotria (PROSEA)

Plant Resources of South-East Asia
Introduction

Protologue: Syst. Nat. ed. 10, 2: 929, 1122, 1364 (1759).

Family: Rubiaceae

Chromosome number: x= 11, 22; P. curviflora: 2n= 22, 44, P. emetica: 2n= 22, P. ipecacuanha: 2n= 22, P. rubra: 2n= 22, P. serpens: 2n= 22

Major species

Psychotria curviflora Wallich,
P. ipecacuanha (Brot.) Stokes,
P. sarmentosa Blume.

Origin and geographic distribution

Psychotria comprises between 800-1400 species, distributed in Africa, South-East Asia and tropical America. About 115 species occur in Papua New Guinea and the Pacific islands.

Uses

The most important medicinal Psychotria is P. ipecacuanha, of which the rhizome, "Radix ipecacuanhae", has a long history of being used to treat amoebic dysentery as well as being a valuable expectorant and antispasmodic drug. In northern America, ipecac syrup has long played a principal role as an emetic in the management of acute childhood poisonings and overdoses. However, due to its side effects, many toxicologists nowadays discourage its use under any circumstances, and promote either the use of gastric lavage or better, activated charcoal, which inhibits absorption of poisonous substances. Milk does not interfere with ipecac-induced emesis. Patients with eating disorders frequently use ipecac, which can be freely bought, as an emetic, and its frequent use has been associated with serious cardiac toxicity. Several other Psychotria from South and Central America have emetic properties identical to those of P. ipecacuanha.

Most Psychotria from South-East Asia are of little medicinal use. Their leaves are mainly applied for poulticing skin complaints and swellings, or taken as a decoction after childbirth, for protection. In Peninsular Malaysia, any part of P. cantleyi Ridley, P. rhinocerotis Reinw. ex Blume or P. malayana Jack (synonym P. stipulacea Wallich) may be used as a medicine after parturition. The leaves and roots of P. mindorensis Elmer and P. extensa Miq. (synonym P. leptothyrsa Miq.) from the Philippines, and also P. malayana , are used for infected eyes, skin eruptions and ulcers, crushed as a poultice. For fever, the roots of P. malayana are boiled and the water used for bathing. In Peninsular Malaysia, a decoction of the roots of P. griffithii Hook.f. is drunk for pain in the bones.

P. adenophylla Wallich is used in Indo-China for stomach-ache, intestinal problems and breast pain. The epiphytic creeper P. serpens L. from Japan, Taiwan, southern China and Indo-China, is taken to improve the blood circulation, and to cure rheumatism, backache, arthritis and wounds, in southern China. In the Solomon Islands, the leaves of P. olivacea Val. are eaten with betel nut (Areca catechu L.) to relieve stomach-ache. The sap of the stem is used in the treatment of gonorrhoea, and the macerated, boiled leaves are applied to sore legs. The crushed leaves or a decoction of the leaves of P. rubra (Lour.) Poir., from Japan, Taiwan, southern China and Indo-China, is used as a remedy for contusions and swellings. A decoction of the leaves and stem is taken to calm moody children. It is considered resolvent and stimulant, useful for treating toothache and earache. An infusion of the root is prescribed for malaria. In Vietnam, a decoction of the roots is also used for oedema, boils, wounds, haematuria, backache and snakebite, the whole plant for joints inflamed by rheumatism, pain in the arms and legs. It is not to be used by pregnant women.

Production and international trade

The main world supply of P. ipecacuanha comes nowadays from South America, Peninsular Malaysia and Burma (Myanmar), and to a lesser degree from Central America and India. It is also experimentally cultivated in southern Nigeria. Recent production statistics are lacking. The best commercial drug ("Ipecac") comes from Brazil (Matto Grosso), and is collected from wild plants. Indian and Johore ipecac are from continental Asia and are also of good quality.

Properties

The roots and rhizomes of P. ipecacuanha contain a series of terpenoid tetrahydroisoquinoline type alkaloids, derived from the amino acid tyrosine, the most important being emetine, cephaeline and psychotrine. In smaller quantities, also 0-methyl-psychotrine, emetamine, the desmethyl-, proto- and neo- derivatives of the main alkaloids, and traces of ipecamine and hydroipecamine are isolated. In addition to the alkaloids, the roots contain several iridoids (monoterpenes) e.g. 6-O-methylipecoside, ipecosidic acid, demethylalangiside, neoipecoside, 7-O-methylneoipecoside, 3,4-dehydroneoipecoside, lipecoside, alangiside, sweroside and 7-dehydrologanin.

Ipecacuanha alkaloids display several biological activities. For instance, emetine, when taken internally, is a strong irritant, causing first strong salivation followed by nausea and vomiting. When injected subcutaneously, it does not show any irritation of the tissue, but is a strong antiamoebic. It acts only on the parasites present in the tissue, not on encysted amoebae or amoebae present in the lumen of the bowels. Cephaeline is an even more powerful emetic. Both compounds are active in the stomach and duodenum. Psychotrine was found to be almost inert. In general, toxic doses of the alkaloids cause gastro-enteritis, cardiac failure, dilation of the blood vessels, severe bronchitis and pulmonary inflammation.

According to several of the main Pharmacopoeias (European, USP), the standardized commercial drug should contain 1.9-2.1% alkaloids. In addition, the USP requires the ratio emetine (non-phenolic) to cephaeline (phenolic) to be 1-2.5:1. On the molecular level, emetine is a protein synthesis inhibitor, which is used as an amoebicide, but it has severe adverse effects. A range of alkaloids of the emetine-, tubulosine- and ochrolifuanine types having structural affinities to emetine were tested in vitro against Entamoeba histolytica (NIH 200) and for cytotoxic effects against guinea-pig ear keratinocytes (GPK). Emetine was most potent in both GPK and E. histolytica assays, while 2,3-dehydroemetine was equally cytotoxic but 2-3 times less potent than emetine against E. histolytica. Compounds without the 9,10-dimethoxy substituents had greatly reduced amoebicidal and cytotoxic effects, suggesting that this substituent is important in the mechanism of drug action. Furthermore, in an in vitro test, Trypanosoma cruzi, causing Chagas' disease, a major health problem in Central and South America, was markedly inhibited by emetine.

An extract of P. curviflora was evaluated for antileishmanial activity against Leishmania donovani infection in golden hamsters (Mesocricetus aureus) at 1 g extract/kg body weight orally for 5 days. The extract was found to possess considerable leishmanicidal action, defined as more than 52% reduction in numbers of amastigotes in treated animals, 7 days after cessation of treatment.

An unboiled water extract of stems and leaves of P. sarmentosa was investigated for analgesic and/or anti-inflammatory activity. Different doses of the extract (7.5, 15 and 22.5 ml/kg) were administered orally to rats, and the analgesic potential was determined using hot plate and tail flick tests. In another set of rats, the highest dose of the extract was orally administered, and paw oedema induced with 1% carrageenan. All the doses of the extract were well tolerated and the highest dose had potent analgesic activity and antihyperalgesic activity, comparable to that of an indomethacin reference. However, the extract had no anti-inflammatory activity.

The pyrrolidino-indole alkaloid quadrigemine B, isolated from P. rostrata, was shown to be cytotoxic with HEp-2 cells and normal human lymphocytes. The cytotoxicity was time- and dose-dependent. Bactericidal activity was also shown for this compound toward Escherichia coli and Staphylococcus aureus. In addition, also the pyrroloindoline alkaloids (+)-chimonananthine, (-)-calycanthine, calycosidine and hodgkinsine were isolated from its bark and twigs.

The crude extract of P. extensa showed moderate toxicity when administered intraperitoneally and slight toxicity when applied orally to Swiss mice in a 7 day LD₅₀ toxicity test. A slight analgesia and decrease in motor activity were observed.

A new naphthoquinone, isolated from the alcoholic extract of P. rubra, exhibited significant cytotoxicity in the KB cell assay (ED₅₀= 3 μg/ml). Naphthoquinone derivatives 6, 8, 13, and 14 were prepared and exhibited superior cytotoxic activity to that of psychorubrin. However, when a hydrophilic hydroxy group was present in such compounds, reduced in vitro activity was observed. A butanol extract inhibited platelet aggregation, induced by arachidonic acid, U46619, collagen and thrombin.

A phytochemical study of two Psychotria species from New Caledonia led to the isolation of several pyrrolidinoindoline alkaloids: meso-chimonanthine, N-b-desmethyl-meso-chimonanthine and hodgkinsine were isolated from P. lyciiflora Schltr. Hodgkinsine, quadrigemine C, isopsychotridine B, psychotridine, quadrigemine I, oleoidine, and caledonine, were isolated from P. oleoides Schltr. Several of these compounds isolated showed analgesic and anti-viral activity.

Adulterations and substitutes

The main adulterant of P. ipecacuanha rhizome is its stem, which contains much less alkaloids. Another common adulterant is almond meal. Many plant resources are used as a substitute for P. ipecacuanha for emetic purposes, especially Asclepias curassavica L. ("bastard Ipecacuanha"), Calotropis gigantea (L.) Aiton f. and Psychotria emetica L. but there are many more, some containing emetine, some others not. Synthetic anti-amoebic medicines have taken the place of P. ipecacuanha, as they do not have the strong side effects.

Description

Shrubs or small trees, climbers, rarely epiphytes or herbs, normally evergreen.
Leaves opposite, simple, normally entire; petiole absent or present and short; stipules interpetiolar, large or small, usually entire.
Inflorescence a terminal cyme, or spiciform, paniculiform to corymbiform; peduncle normally present.
Flowers bisexual, usually heterostylous, actinomorphic, normally 5-merous, often white, pedicel present; sepals all partly joined, usually persistent, corolla tube usually straight, rarely curved, lobes 5, caducous; stamens normally 5, filaments free, joined at various levels to the perianth, enclosed or exserted, anthers 2-loculed, basifixed, dehiscing by long slits; ovary inferior, 2-celled, 1 ovule per cell, style 1, enclosed or exserted, stigma variously 2-lobed.
Fruit a berry or drupe; 2 stones (pyrenes) per fruit.
Seed small, variable in shape, often flattened, albumen copious or little, wall thick or thin.
Seedling with epigeal germination.

Growth and development

Psychotria can be found flowering and fruiting throughout the year throughout its distribution area. In Brazil, observations of P. ipecacuanha show that flowering and fruiting occurs in more than one period, but flowering is concentrated in the rainy season of the region, December-April, while fruiting occurs between May-June.

In Indo-China, P. curviflora flowers from April-July, and fruits from August-October. Many Psychotria species have conspicuous domatia on the underside of the leaves, providing shelter for beneficial mites (acarodomatia) or, rarely, for bacteria (bacteriodomatia).

Other botanical information

A worldwide revision of Psychotria and related genera is urgently needed to clarify the relationships in this complex, paraphyletic group. Cephaelis is nowadays considered as belonging to Psychotria. According to some authors, P. curviflora belongs to the closely related Chassalia, of which several orthographic variants exist, Chasalia and Chasallia. Chassalia is considered different from Psychotria in that the corolla lobes are curved, the stipules usually bifid and usually subpersistent, the sepals persistent and the fruit is fleshy or not. These characters though, occur in different combinations in the huge genus Psychotria as well.

Psychotria , one of the primitive genera of the Rubiaceae, is able to accumulate large amounts of aluminium in its tissues.

Ecology

Psychotria prefers warm and humid conditions and partial shade and is commonly found in forests at low or medium altitudes. In Peninsular Malaysia, cultivation of P. ipecacuanha is nowadays successful in forest areas on sandy loams, rich in humus and minerals, and in rubber plantations on well-drained, coastal peat or clay soil. It thrives best in climates with an annual rainfall which is well distributed throughout the year, and temperatures between 20-38 °C, with narrow fluctuations.

Propagation and planting

Psychotria is propagated by seed and by soft wood cuttings. P. curviflora can also be propagated by marcotting. P. ipecacuanha has long been difficult to cultivate in South-East Asia and India, as the seeds do not germinate well and plantlets die often as they cannot stand heavy rains, cool or dry seasons, direct sunshine or sudden changes of weather.In a test in India, seeds sown in nursery beds and watered regularly failed to germinate even after 6 months, but soaking seeds for 24 h in water or in 200 ppm potassium dihydrogen phosphate gave 11% and 95% germination respectively, after 2 weeks. As the plants do not set seed in Peninsular Malaysia, multiplication is normally done there by stem cuttings or more often, by small rhizome parts. These pieces are kept under glass in wet sand, after which fine roots develop at the eyes. Rooted pieces of rhizome are kept in nurseries till the plants are 5-8 cm tall, after about 6 months, and subsequently transplanted. P. ipecacuanha seedlings can be hardened by transplanting them once or twice, which has a beneficial effect on biomass production and alkaloid content, which rose by 18-40% compared to the direct-sown control, in India. Possibly, some of the failures in the early times were due to the provenance of the seeds, some of them being hardier than others. Planting distance of P. ipecacuanha is 75 cm × 75 cm, on well-drained, raised beds, made of well-mixed sand and humus (3:2), and in partial shade to prevent direct sunshine and heavy rain.

In vitro production of active compounds

In vitro culture of P. ipecacuanha has been tried for a long time and several protocols have been developed.Callus was obtained from leaf explants from P. ipecacuanha on Murashige & Skoog (MS) basal medium supplemented with 0.5 mg/l kinetin, 4 mg/l 2,4-D and 3% sucrose. Plantlet regeneration through somatic embryogenesis was achieved on MS medium containing 2.5 mg/l kinetin, 1 mg/l 2,4-D and 3% sucrose. Maturation and germination of somatic embryos was achieved on MS basal salts supplemented with vitamins and 2% sucrose without growth regulators. In another experiment, callus cultures were established from hypocotyl explants on various media containing various combinations of growth regulators. The best callus growth in terms of both fresh and dry weight was obtained on B5 medium supplemented with 3% sucrose, 8 mg/l indole butyric acid, 4 mg/l indole acetic acid and 4 mg/l naphthalene acetic acid. The highest alkaloid yields were obtained with a medium containing the macronutrient elements of Shenk & Hildebrandt, supplemented with the above combination of growth regulators. Cephaeline at 0.9% and emetine at 0.4% were obtained. Somatic embryo derived plantlets were hardened in the greenhouse and eventually planted in the open field. Several other protocols also show successful in vitro production of alkaloids. Roots cultured for 7 weeks in 50 ml MS liquid medium supplemented with 5,6-dichloro-indole acetic acid at 0.01 mg/l yielded 0.6 mg emetine and 2.4 mg cephaeline. Shoots cultured in Woody Plant liquid medium supplemented with 0.01-0.1 mg butyric acid/l contained 0.04-0.07% dry weight emetine and 0.4-0.5% dry weight cephaeline. One-year-old regenerated plants cultivated in a greenhouse had similar alkaloid contents as the parents, the roots contained 0.82% dry weight emetine and 2.16% dry weight cephaeline.

The exogenous feeding of 2 precursors, shikimic acid and L-phenylalanine (50 mg/l), increased the overall bioproduction of cephaeline in leaf-callus cultures of P. ipecacuanha, but both precursors failed to influence emetine production in callus, cell and immobilized cultures.

Diseases and pests

Natural Psychotria stands exhibit little damage due to insects and other pests. In cultivated P. ipecacuanha sole cropping may face some problems, e.g. from fungi causing leaf blight.

Harvesting

Psychotria is harvested from the wild when needed. In Peninsular Malaysia, P. ipecacuanha reaches a height of 25 cm about 3.5 years after transplanting and can be uprooted. In India, the rhizomes are harvested 2.5 years after transplanting, when the alkaloid content exceeds 2%. The plants may be dug up at any time of the year.

Yield

A single plant of P. ipecacuanha may produce 6-10 rhizomes, weighing 75-85 g. The average dry weight of rhizomes per plant 1-5 years after transplanting increases from 3.5-16.5 g, whereas the total alkaloid content will increase from 1.5-2.5%, the percentage of non-phenolic alkaloids will decrease from about 80-53%, and the percentage of emetine will be about 1.2%. Cephaeline content of the roots of P. ipecacuanha from Panama of unknown age ranged from 0.7-1.2% and was highest in August and lowest in March. Emetine content was 0.5-1.3% and was highest in June and lowest in March.

Handling after harvest

In Peninsular Malaysia, the rhizomes of P. ipecacuanha are washed and dried in the sun, while during the night they are placed indoors. In India, the rhizomes are washed and dried in the shade. The roots and stem of P. curvifolia have thick bark and hard wood. They should be cut into small pieces and dried soon after harvest. Dried material can be kept in closed containers for a long time without being attacked by fungi or insects.

Genetic resources and breeding

There seems to be some danger of genetic erosion, because natural Psychotria populations occur mainly in forest areas, which are currently being destroyed. As some of the treated species have a large area of distribution, either naturally or as a result of cultivation, the risk of genetic erosion will probably be restricted.

In order to conserve P. ipecacuanha in Brazil, expeditions to collect genetic material for incorporation in the germplasm banks at the Centre for Agroforestry Research of the Eastern Amazon (CPATU), in Belem and in Campos dos Goytacazes have been carried out since 1990. Germplasm collections of locally adapted populations of P. ipecacuanha exist in India. There are no known breeding programmes of South-East Asian Psychotria.

Prospects

At present, increased interest in "ipecacuanha" is unlikely, as the demand for this product is decreasing. Due to its side effects as an emetic, many toxicologists nowadays discourage its use. The use of emetine as an anti-amoebic is also diminishing, as safer synthetic products nowadays exist. Thus, the prospects for Psychotria are not promising.

Literature

Backer, C.A. & Bakhuizen van den Brink Jr, R.C., 1965. Flora of Java. Vol. 2. Noordhoff, Groningen, the Netherlands. pp. 328-–333.
Guru, P.Y., Zaidi, A., Sharma, P. & Katiyar, J.C., 1996. Antileishmanial property of certain plants against experimental Leishmania donovani infection in golden hamsters. Journal of Parasitic Diseases 20(2): 181-184.
Keene, A.T., Phillipson, J.D., Warhurst, D.C., Koch, M. & Seguin, E., 1987. In vitro amoebicidal testing of natural products. Part 2. Alkaloids related to emetine. Planta Medica 2: 201-206.
Quisumbing, E., 1978. Medicinal plants of the Philippines. Katha Publishing Co., Quezon City, the Philippines. pp. 926-927.
Ratnasooriya, W.D. & Dharmasiri, M.G., 1999. A water extract of leaves and stems of Psychotria sarmentosa has analgesic and antihyperalgesic activity in rats. Medical Science Research 27(10): 715-718.
Rout, G.R., Samantaray, S. & Das, P., 2000. In vitro somatic embryogenesis from callus cultures of Cephaelis ipecacuanha A. Richard. Scientia Horticulturae 86(1): 71-79.

Selection of species

Authors

H.C. Ong & S. Brotonogoro