The Amanitas

A number of Amanita species, in addition to promoting hallucinogenic effects, are extremely toxic. The appearance of the serious symptoms is considerably delayed (particularly with amatoxins, formula Fig. 39.1) after ingestion, by which time effective treatment becomes difficult. Three classes of toxins are recognized in the genus—tryptamines (e.g. bufotenine), cyclic peptides (phallotoxins and amatoxins) and isoxazole alkaloids (e.g. ibotenic acid, formula Fig. 39.1). The three classes of compound appear to be restricted to certain specific sections of the genus.

Fig. 39.1 Toxic and hallucinogenic constituents of fungi.

The fly agaric

The fly agaric (Amanita muscaria) is readily distinguished by its red or orange cap, often covered with white flecks. It contains a mixture of isoxazole alkaloids ibotenic acid and muscimol. Polysaccharides and a carboxymethylated derivative of the fungus have been shown to possess antitumour activity (T. Kiho et al., Biol. Pharm. Bull., 1994, 17, 1460). The pigments (betalains) of the fungus, also found in the Caryophyllales, are formed from tyrosine and the rapid development of pigment formation in A. muscaria has given an ideal system for isolating the enzymes involved (L. A. Mueller et al., Phytochemistry, 1996, 42, 1511; 1997, 44, 567).

The pharmacological effects appear within an hour or so of ingestion, with an initial period of excitation followed by muscular twitches, a slowed pulse rate, impaired breathing, delirium and coma; however, ingestion of the fungus is rarely fatal. The mushroom has a traditional use as an inebriant in regions of Siberia; one hypothesis suggests it to be the soma of the Rig Veda. The panther cap, A. pantherina, contains similar principles including pantherine (5-aminomethyl-3-hydroxyisoxazole), a flycidal alkaloid. A branched (1→3)-β-D-glucose isolated from an alkaline extract of the fungus exhibited significant activity in mice.

Hallucinogenic Mexican mushrooms

A number of small toadstools—particularly species of Psilocybe (P. mexicana), Conocybe (C. cyanopus) and Stropharia—constitute the Mexican hallucinogenic mushrooms (teonanacatl, ‘flesh of the gods’, much revered by the Aztecs). The onset of symptoms after ingestion of the fungi is rapid, and includes inability to concentrate and the occurrence of hallucinations. The active constituents are the tryptamine derivatives psilocybin and psilocin, compounds related to serotonin. These compounds are also found in similar toadstools (e.g. Psilocybe and Paneolus, Copelandia, Gymnopilus, Inocybe, Panneolina, Pluteus and Stropharia spp.) which are found in temperate regions. In Britain the ‘liberty cap’, Psilocybe semilanceata, a small toadstool common on lawns and parkland, and in Australia P. subaeruginosa both contain psilocybin. What is claimed to be the highest proportion of psilocin contained in any mushroom (3.3%, dry weight) was reported in Psilocybe cubensis; for a review of the mushroom alkaloids (567 refs), see R. Autkowiak et al., Alkaloids, 1991, 40, 189); for the concise large-scale synthesis of psilocin and psilocybin, see O. Shirota et al., J. Nat. Prod., 2003, 66, 885.

Puffballs

Species of Lycoperda contain constituents which produce auditory hallucinations and a state of half-sleep about half an hour after consumption. The effects are distinct from those caused by the mushrooms. Puffballs are used by the Mixtecs of Southern Oaxaca in Mexico.

Morning Glory seeds

In the sixteenth century the Spaniards in Mexico reported the use of sacred hallucinogenic seeds known as ‘ololiuqui’. The climbing plant from which they were obtained was subsequently identified as Rivea corymbosa. Closely related in constituents and action are the seeds of Ipomoea tricolor (I. violacea) and those of various species of Argyreia. The name ‘Morning Glory’ is applied to Ipomoea tricolor but also to a number of other species (e.g. to I. purpurea and to the Japanese Morning Glory, I. hederacea). The trade names of species of Ipomoea are endlessly mixed. The seeds of the above-mentioned Ipomoea hederacea have long been used in the East as a purgative and were formerly official in the British Pharmacopoeia under the name ‘kaladana’ or ‘pharbitis seeds’.

History

Hemp has been cultivated for its seeds and fibres from a very remote period, but the narcotic properties are usually not marked in plants grown in temperate regions, and even in India an active drug can only be grown in certain districts. The drug is mentioned in early Hindu and Chinese works on medicine, and its use slowly spread through Persia to the Arabs. It was used by the Mohammedan sect known as the Hashishin or Assassins, who came into contact with the Crusaders in the eleventh and twelfth centuries. The drug attracted the attention of Europeans at the time of Napoleon’s Egyptian expedition.

Production of ganja

This is legally only produced by a few licensed growers in Bengal, Mysore and Madras. The seed is sown in rows about 1.3 m apart and male plants are eliminated as soon as they can be recognized. The resinous tops, largely of unfertilized female plants, are cut about 5 months after sowing and pressed into cakes. The yield is about 120 kg per acre.

Macroscopical characters

The flat- or Bombay-ganja occurs in agglutinated flattened masses of a dull green or greenish-brown colour. The resin is no longer sticky but hard and brittle; the odour, which is very marked in the fresh drug, is faint. The drug has a slightly bitter taste. Here and there ovoid hemp seeds may be picked out. Before further examination the drug should be soaked in successive quantities of alcohol to remove the resin and then softened in water.

The lower digitate leaves of the plant are seldom found in the drug. The thin, longitudinally furrowed stems bear simple or lobed, stipulate bracts. These subtend the bracteoles, enclosing the pistillate flowers. The bracts are stipulate and the lamina may be simple or three-lobed. The bracteole enclosing each flower is simple. The perigone enveloping the lower part of the ovary and the two reddish-brown stigmas can be seen with a lens.

Microscopical characters

The resin is secreted by numerous glandular hairs, 130–250 μm long (see Figs 39.3; 42.5). The head is usually eight-celled and the pedicel multiseriate or unicellular. To differentiate these from similar trichomes (e.g. those of the Labiatae) specificstains can be used. These include Fast Blue Salt B and, as described by Corrigan and Lynch in 1978, a reagent consisting of vanillin in ethanolic sulphuric acid which stains the cannabis glands a deep reddish-purple. It is possible to analyse individual trichomes by GLC by which means it has been shown that the glands represent a dynamic system in the cannabinoid synthetic activity of the plant. In addition, sessile glands (Fig. 39.3), abundant conical, curved, unicellular hairs, are also found, many having cystoliths of calcium carbonate in their enlarged bases (see Figs 39.3; 42.3); however, these cystolith hairs are not confined solely to the genus Cannabis. Cluster crystals of calcium oxalate are abundant, particularly in the bracteoles.

Fig. 39.3 A, typical stalked glandular trichome from bracteole ×270. B, sessile glandular trichomes and covering trichomes, ×130. (J. W. Fairbairn.)

Constituents

The narcotic resin is a brown, amorphous semisolid; soluble in alcohol, ether and carbon disulphide. It contains over 60 compounds (cannabinoids) all composed of an aromatic portion (C₁₁ or C₁₂), theoretically derivable from six acetate units, and an isoprenoid component (C₁₀). They appear to form a natural group of C₂₁ terpenophenolics of unique occurrence. Some principal components are cannabinol, tetrahydrocannabinol (THC), cannabidiol (CBD), cannabidiol-carboxylic acid, cannabigerol and cannabichromene (Fig. 39.4). Cannabinodiol is the aromatic analogue of cannabidiol. Cannabigerol precedes Δ⁹-THC in the biosynthetic pathway and is incorporated, by the plant, into the latter and other neutral cannabinoids. The identification of phloroglucinol β-D-glucoside in the shoot laticifer exudate of C. sativa, and phloroglucinol as a prominent component, and the only phenol, in the glandular trichomes suggests that it may have an important role in the in vivo enzymatically regulated biosynthesis of the cannabinoids (C. T. Hammond and P. G. Mahlberg, Phytochemistry, 1994, 37, 755).

Fig. 39.4 Principal cannabinoids of Cannabis sativa and synthetic analogue.

Cannabipinol, isolated in 1967, contains a bicyclic monoterpene moiety in addition to the acetate-derived portion. Cannabidivarin, described in 1969, is a cannabidiol homologue with a 5-propyl-resorcinol moiety. In view of the importance of the detection of Indian hemp, a number of gas and thin-layer chromatographic techniques coupled with mass spectrometry have been developed for the separation of these substances.

Δ⁹-THC is the principal psychoactive constituent; Δ⁸-THC is almost as active but is only present in the plant in small amounts; cannabinol is less potent; although lacking psychotropic properties cannabidiol has anticonvulsant and possible analgesic effects. Cannabichromene may enhance THC activity and has antifungal, antimicrobial and anti-inflammatory activity; for enzyme studies related to its formation see S. Morimoto et al., Phytochemistry, 1998, 49, 1525.

The plant also contains a small quantity of laevorotatory volatile oil (about 30 components) containing terpenes and a sesquiterpene (cannibene); the bases choline, trigonelline, spermidine and an alkaloid cannabisativine; flavonoid O-glycosides of both vitexin and orientin; and calcium carbonate. It yields about 15% of ash and 10–18% of alcoholic extract.