2. CANNABIS : BROAD PERSPECTIVES

2.1 The substance
Cannabis sativa L. is an annual plant normally occurring in male and female forms. It often grows to a height of about six feet, but under optimum conditions may reach 20 feet. It is probably indigenous to Central Asia (Bouquet, 1950) but now grows wild in most temperate to tropical areas; it is produced commercially in some places. It has a long history of cultivation, as a source both of fibre (hemp) and of psychoactive substances contained in its leaves and flowering tops. In the past, it was very often grown for fibre with apparently no local awareness of its psycho-active properties.

Botanically, only one species of cannabis is now recognized (C. sativa L.), but in the past other designations were sometimes applied to plants found in different parts of the world (e.g., C. indica and C. americana).

There are, however, substantial differences in the amount of psycho-active material contained in what may be different varieties of C. sativa L. The amount is also influenced by variations in climate, weather, soil, time of harvest, and conditions and length of storage (Davis et al., 1963; Lerner & Zeffert, 1968; Joyce & Curry, 1970).

C. sativa L. produces a resinous substance which contains the major part of the psychoactive and intoxicating ingredients. It occurs primarily in the flowering tops and upper leaves and is sometimes separated from the rest of the plant for use as hashish. In a given plant the lower leaves contain less of these ingredients than do those at the top of the plant; the flowering tops contain the highest concentration. The stalk and seeds contain a negligible amount of psychoactive ingredients (Fetterman et al., in press; Valle, 1969).

Contrary to the widely held belief that only the female plant contains psychoactive substances, there is convincing evidence that the male plant also does (Fetterman et al., in press; Valle et al., 1968). However, the upper portions of the male plants tend to be smaller than those of the female plants and to wither after pollination. Thus the male plants are usually not reaped when the female plant is later harvested (Bouquet, 1950).

Materials from the cannabis plant are prepared for human consumption in many different ways. Known by hundreds of different local and more general names (United Nations, 1968), they may be classified according to the nature of the plant material contained. For the purposes of this report, preparations mostly containing leaves and flowering tops (with or without the inclusion of large stems and seeds) will be referred to as marihuana, preparations containing flowering tops but no leaves as ganja, and preparations containing primarily resin as hashish.'

2.1.1 Recent advances in cannabinoid chemistry and measurement

The chemical constituents of C. sativa L. are quite complex. They include a unique group of chemicals called cannabinoids (Mechoulam, 1970) together with waxes, starches, terpenes, oils, and trace amounts of other as yet unidentified substances. The five most important cannabinoids, as far as the biological potency of cannabis is concerned, are the (—)-A9-trans-tetrahydrocannabinol (A9-THC),1 (—)-A8-trans-tetrahydro-cannabinol (A8-THC),2 A9-trans-tetrahydrocannabinolic acid (THC-acid), cannabinol (CBN), and cannabidiol (CBD). The first two are psycho-active when taken orally or by smoking. THC-acid is not active when taken orally, but is partly converted to the active A9 or A8 when smoked (Mechoulana, 1970). Knowledge of the extent of this conversion is in-complete. CBN and CBD have very little psychoactivity but are present in fairly large amounts. They appear to have an inverse quantitative relationship to the highly active A9-THC and A8-THC. A8-THC, discovered by Hively et al. (1966), occurs in very small amounts as compared to A9-THC, except in aged hashish (Lerner & Zeffert, 1968).
A9-THC produces most of the effects of cannabis or extracts of cannabis in both animals and man. It is therefore believed, but not entirely proved, that A9-THC accounts for most of the pharmacological activity of cannabis. At least thirty other cannabinoids have been isolated from cannabis (Mechoulam, 1970), but relatively little information about their biological activity is available. In addition, trace amounts have been reported of an alkaloid or alkaloids as yet chemically uncharacterized. The presence of an atropine-like substance and trigonelline in a commercial preparation of cannabis has been reported (Gill et al., 1970).
A9-THC and A8-THC volatilize readily when smoked (Manno et al., 1970) and are rapidly absorbed from human lungs. They are also absorbed, but more slowly, from the gastrointestinal tract.
In animals, both A9-THC and A8-THC are bound to serum protein. Only small amounts are found in the brain. They are metabolized in the liver, and the metabolites are excreted in the bile 3 and re-absorbed from the gastrointestinal tract; an enterohepatic circulation therefore exists. The metabolites of A9-THC and A8-THC first formed in the liver are 11-hydroxyl derivatives (11-0H-A9-THC and 11-0H-A8-THC). In later steps additional hydroxylations occur on the rings. The 11-hydroxyl derivatives of A9-THC and A8-THC possess pharmacological activity (Mechoulam, 1970), and it has been postulated, but not proved, that they, rather than the THCs themselves, are the compounds responsible for the pharmacological activity. The metabolites of the THCs persist in the bodies of animals for long periods of time. A8-THC and A9-THC disappear from blood rapidly, so that neither can be found in blood 15 minutes after intravenous injection (Klausner & Dingell, 1970). A8-THC and A9-THC are not excreted as such in the urine. These phenomena mean that present chemical methods for the detection of these THCs will not be useful for determining the presence of cannabis in man. Attention must therefore be turned to methods for detecting the metabolites rather than the THCs themselves. Radioimmune assays may prove useful.
For purposes of comparison, three of the older synthetic tetrahydro-(±)_A6a,10a_    (±)_A6a,10a_ cannabinols deserve mention :    THC;    5-n-hexyl-(±) A6a,10a_ tetrahydrocannabinol (called synhexyl or parahexyl); and 5-dimethyl-octylheptyl-tetrahydrocannabinol (DHMP). The first is a synthetic tetrahydrocannabinol but possesses only about one-fourteenth of the biological activity of the natural A9-THC (Loewe, 1950). The second (synhexyl) possesses marihuana-like activity (Loewe, 1950) and underwent a limited clinical trial as an antidepressant (Parker & Wrigley, 1950). The third (DHMP) is a very potent drug which, in doses of 1-2 mg orally in man, produces cannabis-like subjective effects, marked sedation, and profound postural hypotension (Isbell, unpublished data).
The chemistry of the major cannabinoids was investigated extensively from about 1936 to 1941 by Adams and co-workers in the USA (Adams, 1942) and by Todd and co-workers in the United Kingdom (Todd, 1940). These two groups of workers determined the chemical structure of cannabinol, cannabidiol, and tetrahydrocannabinol, except that neither group was able to establish the position of the double bond in the non-phenolic ring of either cannabidiol or tetrahydrocannabinol. Mechoulam & Shvo (1963) identified the position of the double bond in natural cannabidiol as being located in the A9 position, and Mechoulam et al. (1967) and Petrzilka et al. (1967) developed two different methods for the synthesis of A8-THC and A9-THC.
It is now possible to determine the amount of A9-THC, A8-THC, CBD, and CBN in the cannabis plant by gas-liquid chromatography (Lerner & Zeffert, 1968; Lerner, 1969). Cannabis grown in the same soil and the same climate from authenticated samples of seed collected in Canada, the USA, and Western Europe have produced plants that, as a group, contain a low A9-THC content (average 0.2 % bY weight) but a high cannabidiol content (Fetterman et al., in press). Seed from Mexico and Thailand, on the other hand, produced plants with a high content (1.5-2.0 %) of A9-THC.1 Some samples of naturalized or wild cannabis growing in the USA contain as little as 0.09 % of A9-THC, while a sample from Thailand contained 4.89 % (Turk, 1970).
The A9-THC content of cannabis preparations is influenced not only by the characteristics of the plant and the place and circumstances of its growth but also by such factors as the age and methods of storage of the harvested materials. All active substances contained in preparations of cannabis deteriorate with time, the A9-THC being converted to cannabinol. Inactivation of A9-THC is particularly rapid if the herbal material is exposed to or stored at high temperatures (Lerner, 1969). If cannabis preparations are stored at —10° C, the A9-THC content remains much the same for periods of at least two years (Isbell, unpublished data). It follows that the A9-THC content of preparations in use in experimental work must be carefully and frequently monitored.
The average A9-THC content of marihuana believed to be of Mexican origin and obtained from the illicit market is around 1 %, although it varies widely (Lerner & Zeffert, 1968). The A9-THC content of samples of hashish has ranged from 1 % to 15 %, with an average of about 5 % (Lerner & Zeffert, 1968; Mechoulam, 1970; Turk, 1970). Very little information is available about the THC content of marihuana-type preparations available in many parts of the world or about ganja in India.
With the data available, however, it is possible to establish a rough scale of relative potency for the purpose of making broad or order-of-magnitude comparisons of the amounts of A9-THC contained in the cannabis preparations commonly consumed. For this purpose, marihuana (bhang, kif, etc.), ganja, and hashish (charas) are assumed to average respectively about 1 %, 3 % and 5 % by weight of A9-THC.

2.2 Historical trends

Only the use of cannabis preparations for intoxicant, medical, and religious purposes is considered here. The only comment on the cultivation of cannabis for the production of fibre is that such cultivation was at one time or another very widespread and doubtless contributed to the existence of naturalized or wild cannabis plants in many parts of the world.
The intoxicating properties of certain cannabis preparations were probably known in India before the Christian era; however, a direct reference to their use in ayurveda, the traditional Hindu system of medicine, does not appear until the eighth century A.D.1 Since antiquity it has been used quite widely by religious mendicants, mystics, and others. Bhang has been and still is widely taken as a drink or eaten as an ingredient in a confection or other foods among all social classes in certain parts of India, particularly on festivals and in the worship of the Lord Shiva (Chopra & Chopra, 1939; Wig, unpublished data). In some sections of the country, ganja is smoked fairly commonly by men of certain lower socio-economic groups. Women are said to smoke it only rarely. Only very recently has the smoking of cannabis preparations by students and other young people from a wide range of social classes become noticeable, and it is still apparently much less widespread than in some Western countries. Cannabis has been used in indigenous systems of medicine in India for many centuries (Chopra & Chopra, 1957; Dwarakanath, 1965) because of its sedative, mild analgesic, and other alleged properties (Chopra & Chopra, 1939).
The area west of India and the Eastern Mediterranean region apparently became acquainted with cannabis preparations around the seventh century A.D. (Bouquet, 1950). The preparations were both taken orally and smoked.
In North Africa cannabis was and still is taken chiefly by smoking marihuana (kif) and hashish. In most North African countries the practice was perhaps more prevalent among males of the lower socio-economic classes, although in some areas it was adopted by significant numbers of persons from other classes (Roland & Teste, 1958; Soueif, 1967). It is quite widespread in some North African countries in spite of strong legal sanctions against it. Those who take cannabis preparations once or several times a day usually form a minority of cannabis-users in both India and North Africa, but they tend to consume larger amounts than regular users do in most countries of Europe and the Western Hemisphere. Cannabis is also taken in the southern (Watt, 1961), eastern (Tanner, 1966), and western (Asuni, 1964) parts of Africa south of the Sahara. It is taken by some adults and more recently by young people who are said to be oriented towards Western culture. As in India, cannabis preparations are frequently used in local traditional systems of medicine in southern Africa (United Nations Economic and Social Council, 1955).
Cannabis preparations were introduced into central Europe, probably from North Africa, around 1800, but they generated little interest in the general population at that time, despite the publication of very detailed studies by Moreau de Tours (1845) and some colourful accounts of their effects by such literary figures as Baudelaire (1858) and Gautier (1843). The history of cannabis in Greece is more closely related to that of the Eastern Mediterranean region than to that of Europe. Cannabis prep-arations began to be widely used in Western European countries in the 1960s, as in many other countries of the world. Young people of all socio-economic classes have tried them in recent years, and in many countries adults have joined their ranks (Binnie, 1969; United Kingdom, Advisory Committee on Drug Dependence, 1968).
In Latin America, marihuana (maconha) has been utilized for its psychoactive properties for many years in some countries (Dewey, 1913), but in other countries scarcely at all. Its use was largely associated with men of the lower socio-economic classes until the quite recent upsurge in its use by young people of all classes. This upsurge has occurred both in countries where cannabis had been used for some time and in those where its use was formerly almost non-existent.1-
Although cultivated for fibre for some 300 years in the area that is now the USA and southern Canada, cannabis was rarely used for its psychoactive properties in the USA until around the turn of the last century. It was at first largely restricted to lower socio-economic minority groups, especially in the south-western part of the country. It then spread in the 1920s to some jazz musicians and limited numbers of other persons. Only in the 1950s did its use begin to appear among all classes of youth, a trend that has accelerated rapidly in the last few years and is now to be found in Canada as wel1.2 The groups now taking cannabis in North America are composed largely of middle-class and upper-class young persons of second-ary-school and college age. The percentage is higher in selected popula-tions and in the north-east and west coast areas. A recent sample survey of USA college students indicated that one-third has tried cannabis at some time (Berg, 1969). Among infrequent users, males outnumber females only slightly. However, among those who use cannabis at least two or three times a week, males outnumber females by two or three to one (Blum & Associates, 1969b).
Recent use among young people has been reported for certain South American countries. For example, about 1 % of college and university students in the State of Sao Paulo, Brazil, are estimated to have tried cannabis at least once (Valle, unpublished data). Widespread recent use by young persons has been noted in several Western European countries 3 and reports from some African countries indicate that young people are beginning to use cannabis there.4 In the United Kingdom, one small sample survey of a school population indicated that 2.5 % had taken the drug at least once (Weiner, 1970). Larger surveys of university students showed that 4-10 % had tried cannabis (Binnie, 1969; Lewis, 1968). On the other hand, there is no evidence of more than very occasional use in most Eastern European countries. In some North African countries with a long-established pattern of use among lower-class males, there appears to be no upsurge among youth or middle-class groups. In Morocco there are indications of an overall decline in cannabis use, associated with an increase in the use of alcohol (Defer, 1968).

2.3 Relation to use of other drugs

Very broadly, there has been a tendency to use cannabis as the principal intoxicant in some regions (e.g., the Indo-Pakistan subcontinent and North Africa), and alcohol in others (e.g., North America, Europe, and many areas of South America). In many countries the current trend appears to be towards using both alcohol and cannabis preparations, although in only a very few countries is there anything approaching the use of both to an equal extent.
A large proportion of cannabis users frequently take in addition psychoactive dependence-producing drugs of the alcohol, amphetamine, barbiturate, hallucinogen, and morphine types (Eddy et al., 1965), either at the same time or consecutively.' This greatly complicates the task of attributing drug effects to a single substance. Multiple drug use is perhaps more frequent in parts of Europe and North America than in the Indo-Pakistan subcontinent and Africa. In nearly all areas where cannabis is used, however, numerous other factors complicate the identification of individual drug effects.

2.3.1 Progression to the use of other drugs

The assertion is commonly made that the use of cannabis leads to the use of other drugs. This " stepping-stone " theory holds that adolescents begin with marihuana and later proceed to other drugs, often including heroin, in search of greater thrills. Most observers discount any phar-macological action disposing the cannabis user to resort to other drugs. In some countries most heroin users have taken cannabis preparations before trying heroin (Ball et al., 1968; United Kingdom, Advisory Com-mittee on Drug Dependence, 1968), but the great majority of cannabis users never proceed to the use of morphine-type drugs. However, it is well established that marihuana use is positively correlated with at least experimental use of other drugs (Blum & Associates, 1969b). The prob-ability in some countries of people taking strong hallucinogens such as lysergide (LSD) and other drugs increases greatly with increase in their use of marihuana (Goode, 1969). The longer cannabis is used, too, the greater the probability that opium will be used as well (Soueif, unpublished data). These associations are, of course, not sufficient to establish causal relationships between the use of one drug and another. It appears likely that important sociocultural and personal factors contribute to any apparent progression from cannabis preparations to other dependence-producing drugs. For example, many people who take marihuana fre-quently tend to limit their social life to the circle of drug-takers, particularly in areas where drug-taking is not socially acceptable. They are thus frequently given the opportunity to try other drugs (Goode, 1969). It is also possible that certain individuals have a greater personal need than others to experience the effects of drugs, and/or that chronic intoxication with cannabis contributes to a generally poor orientation to reality, especially among adolescents.

1 In the literature and among users, marihuana usually refers to a mixture of leaves and flowering tops. Other terms often applied to such a mixture are : bhang (India, often only leaves); maconha (Brazil); kif (Morocco); and dagga (South Africa). The term and preparation ganja are used chiefly in India. Hashish is widely used as the designation for the resin, but in some countries, such as Egypt, it may apply to any cannabis preparation. Charas is the term most commonly used in India to des-ignate a primarily resinous preparation.

1 Also known as (—)41-trans-tetrahydrocannabinol W-THC).

2 Also known as (—)-A1(6)-trans-tetrahydrocannabinol (A6-THC).

3 Ben-Zvi et al., 1970; Burstein et al., 1970; Foltz et al., 1970; Nilsson et al., 1970.

4 The cannabis preparations analysed were marihuana without seeds, stalks, and main stems.

5 Bouquet, 1950 & 1951; Dwarakanath, 1965; Walton, 1938.

1 Dewey, 1913; El Mercurio, 1970; Valle, unpublished data.

2 Addiction Research Foundation, 1970; Blum & Associates, 1969b; Smart et al., 1970a & b.

3 Booij, 1966 & 1971; Bschor, 1970; Builchuisen, 1970; van Dijk et al., 1970; Kielholz & Ladewig, 1970.

4 Asuni, 1964; Lambo, 1965; Tanner, 1966; Watt, 1961.

5 Goode, 1969; Kielholz & Ladewig, 1970; Popham, 1970; United Kingdom, Advisory Committee on Drug Dependence, 1968.