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Hallucinogenic Sage

Posted on 20. May, 2010.

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There are over 900 species of sage found in countries as widespread as China, Brazil and Mexico, as well as in many European countries particularly those around the Mediterannean. The common garden sage is used today as a culinary herb. However, it and its relatives have a long history as medicinal plants.

Salvinorin A, for example,  is a powerful hallucinogenic substance and in the search for novel non-addictive analgesics it has provided the starting point for structure:activity studies. 

The isolation, structures and biological activity of the neoclerodane and other natural products obtained from the Mexican hallucinogenic sage, Salvia divinorium are reviewed. 

There are reports in herbals from the sixteenth century of its use as a tonic and for the treatment of various infections. There is an old saying ‘He that would live for aye, must eat Sage in May’. 

The Roman writer, Pliny used the Latin name Salvia derived from salvere, to heal, to describe these beneficial plants. Indeed, the word ‘sage’ may have arisen as a corruption of this. Salvias, along with other members of the Lamiaceae, are noted for the terpenoid natural products which they contain. 

The volatile monoterpenoid essential oils are responsible for their use as aromatic herbs and some of their monoterpenoids may also contribute to the beneficial properties of the plants. 

In other cases, it is their diterpenoid content which is of value. A number of members of this genus have attracted attention. Thus the roots of the Chinese species, S. miltiorrhiza, are the source of the Chinese traditional medicine, Tan-shen. This contains a series of biologically-active diterpenoid quinones. A recent study of Turkish Salvia species has also revealed the presence of antibacterial diterpenoids some of which also possess cardiovascular activity. 

The Clary Sage, S. sclarea, has medicinal properties and also produces the diterpenoid, sclareol, which is used in the perfumery industry. 

A number of Salvia species are grown as ornamental plants. These include the delicate blue, S. farinacea and the bright red S. splendens beloved of the Parks and Gardens Departments of many local authorities. Examination of these plants has revealed the presence of diterpenoids amongst their natural product constituents. 

Salvia species are particularly well-represented in Mexico where over 270 species have been recorded. In recent years,  a relatively rare Mexican member of this genus, S. divinorum, has attracted interest because a biologically-active diterpenoid component binds selectively to the k-opioid receptors in the brain4. The constituents of this species are the subject of this review. Unlike other Salvia species, S. divinorum, which grows in the Oaxaca region of Mexico, is used as a hallucinogenic plant5. It is known to the Mazatec people by the folk names of ‘hojas or ska de la Pastora’ or ‘hojas de la Maria Pastora’. It may also be the plant known to the Aztecs as ‘pipiltzintzintli’. 

As the name ‘hojas’ suggests the activity resides in the leaves. These are chewed or the dried leaves are smoked to induce hallucinations and a trance-like state. The effect has a relatively short time scale, reportedly up to an hour, but this was sufficiently long for the plant to be used in ritual divinations. 

In the last 10 to 15 years, this plant has begun to enter the so-called ‘drug culture’ as a recreational drug and substance of abuse. Its use is now illegal in some parts of the world. 

Successful investigations into the structures of the bio-active components of the plant were first reported in 1982. A diterpenoid neoclerodane structure was assigned to salvinorin A on the basis of X-ray crystallographic and spectroscopic measurements. Its absolute stereochemistry was established in 1990. 

An independent study of the plant was also reported in 1984 and in which the major components were described as divinorin A and B. These compounds were shown to be the same as salvinorins A and B and hence the divinorin name for them was dropped. 

Salvinorin A is a very powerful hallucinogenic substance. It has been estimated that a human response is observed with between 200 mg and 1mg of material. A major stimulus to the work on salvinorin A came from the demonstration that it selectively binds to the k-opioid receptor in the brain. 

A consequence of the interest in the biological activity of salvinorin A has been its total synthesis. The structure with its multiplicity of adjacent chiral centres represents a serious challenge. In one asymmetric synthesis, the creation of the tricyclic core of salvinorin A was achieved by a transannular Michael reaction of a macrocyclic bisenone. 

A number of approaches to the carbon skeleton have also been reported. Studies on the biosynthesis of salvinorin A have also commenced. 

There are two main pathways leading to the biosynthesis of the isoprene unit of the terpenoids. The best known of these utilises mevalonic acid and has been found in animals, fungi and some plants. More recently another pathway based on 1-deoxyxylulose has been identified in higher plants. It has been shown that the isoprene units of salvinorin A are formed by this pathway. 

Salvinorin A joins a growing list of biologically interesting diterpenoid natural products. This list includes compounds such as vitamin A, the gibberellin plant hormones, tumour inhibitory substances such as taxol_ and aphidicolin, the anti-AIDS compound prostatin, the cardioactive forskolin and many others. It suggests that this family of natural products are worthy of more thorough evaluation.

This article features in the next issue of Science Progress.

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