The health and psychological consequences of cannabis use chapter 4
4. Cannabis the drug 4.1 Cannabis the drug Cannabis is the material derived from the herbaceous plant Cannabis sativa, which grows vigorously throughout many regions of the world. It occurs in male and female forms, with both sexes having large leaves which consist of five to 11 leaflets with serrated margins. A sticky resin which covers the flowering tops and upper leaves is secreted most abundantly by the female plant and this resin contains the active agents of the plant. While the cannabis plant contains more than 60 cannabinoid compounds, such as cannabidiol and cannabinol, the primary psychoactive constituent is delta-9-tetrahydrocannabinol or THC (Gaoni and Mechoulam, 1964), the concentration of which largely determines the potency of the cannabis preparation. Most of the other cannabinoids are either inactive or only weakly active, although they may increase or decrease potency by interacting with THC (Abood and Martin, 1992). Cannabis has been erroneously classified as a narcotic, as a sedative and most recently as an hallucinogen. While the cannabinoids do possess hallucinogenic properties, together with stimulant and sedative effects, they in fact represent a unique pharmacological class of compounds. Unlike many other drugs of abuse, cannabis acts upon specific receptors in the brain and periphery. The discovery of the receptors and the naturally occurring substances in the brain that bind to these receptors is of great importance, in that it signifies an entirely new pathway system in the brain. 4.2 The cannabinoid receptor The desire to identify a specific biochemical pathway responsible for the expression of the psychoactive effects of cannabis has prompted a prodigious amount of cannabinoid research (Martin, 1986). Early studies found that radioactively labelled THC would non-specifically attach to all neural surfaces, suggesting that it produced its effects by perturbing cell membranes (Martin, 1986). However, the work of Howlett and colleagues (Howlett et al 1986; 1987; 1988) showed that cannabinoids inhibit the enzyme that synthesizes cyclic AMP in cultured nerve cells, and that the degree of inhibition was correlated with the potency of the cannabinoid. Since many receptors relay their signals to the cell interior by changing cellular cyclic AMP, this finding strongly suggested that cannabinoids were not just dissolving non-specifically in membranes. After eliminating all the known receptors that act by inhibiting adenylate cyclase, it was concluded that cannabinoids acted through their own receptor. The determination and characterisation of a specific cannabinoid receptor in brain followed soon after (Devane et al, 1988), paving the way for its distribution in brain to be mapped (Bidaut-Russell et al, 1990; Herkenham et al, 1990). It is now accepted that cannabis acts on specific cannabinoid receptors in the brain, conclusive evidence for which was provided by the cloning of the gene for the cannabinoid receptor in rat brain (Matsuda et al, 1990). A cDNA which encodes the human cannabinoid receptor was also cloned (Gerard et al, 1991) and the human receptor was found to exhibit more than 97 per cent identity with the rat receptor. Cannabinoid receptors have also been found in the nervous system of lower vertebrates, including chickens, turtles and trout (Howlett et al, 1990) and there is preliminary evidence that they exist in low concentration in fruit flies (Bonner quoted in Abbott, 1990; Howlett, Evans and Houston, 1992). This phylogenetic distribution suggests that the gene must have been present early in evolution, and its conservation implies that the receptor serves an important biological function. The localisation of cannabinoid receptors in the brain has elucidated the pharmacology of the cannabinoids. Herkenham and colleagues (Herkenham, et al 1990; 1991a; 1991b; 1992) used autoradiography to localise receptors in fresh cut brain sections of a number of species, including humans. Dense binding was detected in the cerebral cortex, hippocampus, cerebellum and in outflow nuclei of the basal ganglia, particularly the substantia nigra pars reticulata and globus pallidus. Few receptors were present in the brainstem and spinal cord. Bidaut-Russell and colleagues (Bidaut-Russell et al, 1990) located cannabinoid receptors in greatest abundance in the rat cortex, cerebellum, hippocampus and striatum, with smaller but significant binding in the hypothalamus, brainstem and spinal cord. High densities of receptors in the hippocampus and cortex suggest roles for the cannabinoid receptor in cognitive functions. This is consistent with evidence in humans that the dominant effects of cannabis are cognitive: loosening of associations, fragmentation of thought, and confusion on attempting to remember recent occurrences (Hollister, 1986; Miller and Branconnier, 1983). High densities of receptors in the basal ganglia and cerebellum suggested a role for the cannabinoid receptor in movement control, a finding which is also consistent with the ability of cannabinoids to interfere with coordinated movements. Cannabis has a mild effect on cardiovascular and respiratory function in humans (Hollister, 1986) which is consistent with the observation that the lower brainstem area has few cannabinoid receptors. The absence of sites in the lower brainstem may in fact explain why high doses of THC are not lethal. Cannabinoid receptors do not appear to reside in the dopaminergic neurons or the mesolimbic dopamine cells that have been suggested as a possible "reward" system in the brain. These mappings of receptors have been broadly confirmed in recent work by Matsuda and colleagues (1992, 1993) using a histochemistry technique to neuroanatomically localise cannabinoid receptor mRNA. Labelling intensities were highest in forebrain regions (olfactory areas, caudate nucleus, hippocampus) and in the cerebellar cortex. Clear labelling observed in the rat forebrain suggests several potential sites in the human brain that could mediate an impairment of memory function (Miller and Branconnier, 1983), such as the hippocampus, medial septal complex, lateral nucleus of the mamillary body, and the amygdaloid complex. Similarly, labelling was detected clearly in rat forebrain regions that correspond to those that could mediate cannabis-induced effects on human appetite and mood (namely, the hypothalamus, amygdaloid complex, and anterior cingulate cortex). It should be borne in mind that the regions where cannabinoid receptors occur may have long projections to other areas, contributing to the multiplicity of effects of the cannabinoids. Since THC is not a naturally occurring substance within the brain, the existence of a cannabinoid receptor implied the existence of a naturally occurring or "endogenous" cannabinoid-like substance. Devane and colleagues (1992) recently identified a brain molecule which binds to the receptor and mimics the action of cannabinoids. The molecule, arachidonylethanolamide, which is fat soluble like THC, has been named "anandamide" from a Sanskrit word meaning "bliss". Anandamide has been found to act on cells that express the cannabinoid receptor, but it has no effect on identical cells which lack the receptor. Further research is necessary to determine which neurons are responsible for producing anandamide molecules and to determine what their role is. The unique psychoactivity of cannabinoids may be described as a composite of numerous effects which would not arise from a single biochemical alteration, but rather from multiple actions (Martin, 1986). Thus, the diverse pharmacological actions of the various cannabinoids implies the existence of receptor subtypes. Cannabinoid receptor cDNA can be used to search for other members of the hypothesised receptor family (Snyder, 1990). If the receptors with the potential for mediating the therapeutic uses of cannabis are different from those responsible for their psychoactive effects, cannabinoid receptor cDNA cloning and new synthetic cannabinoids modelled on anandamide may help to uncover the receptor subtypes and develop drugs to target them, thus fulfilling the ancient promise of "marijuana as medicine". If, however, it were the case that there was only one type of cannabinoid receptor, then the psychoactive and therapeutic effects would be inseparable. The evidence against this proposition mounts with the recent cloning of a cannabinoid receptor in spleen that does not exist in brain (Munro et al, 1993). 4.3 Forms of cannabis The concentration of THC varies with the forms in which cannabis is prepared for ingestion, the most common of which are marijuana, hashish and hash oil. Marijuana is prepared from the dried flowering tops and leaves of the harvested plant. Its potency depends upon the growing conditions, the genetic characteristics of the plant and the proportions of plant matter. The flowering tops and bracts (known as "heads") are highest in THC concentration, with potency descending through the upper leaves, lower leaves, stems and seeds. Some varieties of the cannabis plant contain little or no THC, such as the hemp varieties used for making rope, while others have been specifically cultivated for their high THC content, such as "sinsemilla". Marijuana may range in colour from green to grey or brown, depending on the variety and where it was grown, and in texture from a dry powder or finely divided tea-like substance to a dry leafy material. The concentration of THC in a batch of marijuana containing mostly leaves and stems may range from 0.5-5 per cent, while the "sinsemilla" variety with "heads" may result in concentrations from 7-14 per cent. The potency of marijuana preparations being sold has probably increased in the past decade (Jones, 1987), although the evidence for this has been contested (Mikuriya and Aldrich, 1988). Hashish or hash consists of dried cannabis resin and compressed flowers. It ranges in colour from light blonde/brown to almost black, and is usually sold in the form of hard chunks or cubes. The concentration of THC in hashish generally ranges from 2-8 per cent, although it can be as high as 10-20 per cent. Hash oil is a highly potent and viscous substance obtained by using an organic solvent to extract THC from hashish (or marijuana), concentrating the filtered extract, and, in some cases, subjecting it to further purification. The colour may range from clear to pale yellow/green, through brown to black. The concentration of the THC in hash oil is generally between 15 per cent and 50 per cent, although samples as high as 70 per cent have been detected. 4.4 Routes of administration Almost all possible routes of administration have been used, but by far the most common method is smoking (inhaling). Marijuana is most often smoked as a hand-rolled "joint" the size of a cigarette or larger, and usually thicker. Tobacco is often added to marijuana to assist burning and "make it go further", and a filter may be inserted. Hashish may be mixed with tobacco and smoked as a joint, but is more often smoked through a pipe, either with or without tobacco. A water pipe known as "bong" is a popular implement for all cannabis preparations, because the water cools the hot smoke before it is inhaled and there is little loss of the drug through sidestream smoke. Hash oil is used sparingly because of its extremely high psychoactive potency; a few drops may be applied to a cigarette or a joint, to the mixture in the pipe, or the oil may be heated and the vapours inhaled. Whatever method is used, smokers usually inhale deeply and hold their breath for several seconds in order to ensure maximum absorption of THC by the lungs. Hashish may also be cooked or baked in foods and eaten. When ingested orally the onset of the psychoactive effects is delayed by about an hour. In clinical and experimental research, THC has often been prepared in gelatine capsules and administered orally. In India, a popular method of ingestion is in the form of a tea-like brew of the leaves and stems, known as "bhang". The "high" is of lesser intensity but the duration of intoxication is longer by several hours. It is easier to titrate the dose and achieve the desired level of intoxication by smoking than by oral ingestion since the effects are more immediate. Crude aqueous extracts of cannabis have on very rare occasions been injected intravenously. THC is insoluble in water, so little or no drug is actually present in these extracts, and the injection of tiny undissolved particles may cause severe pain and inflammation at the site of injection and a variety of toxic systemic effects. Injection should not be considered as a route of cannabis administration, but has been used in research to investigate pharmacokinetics. Since different routes of administration give rise to differing pharmacokinetics (see below), the reader should assume for the remainder of this document that the method of ingestion is smoking unless stated otherwise. 4.5 Dosage A typical joint contains between 0.5g and 1.0g of cannabis plant matter, which varies in THC content between 5mg and 150mg (i.e. typically between 1 per cent and 15 per cent THC). Not all of the available THC is ingested; the actual amount of THC delivered in the smoke has been estimated at 20 per cent to 70 per cent of that in the cigarette (Hawks, 1982), with the rest being lost through combustion or escaping in sidestream smoke. The bioavailability of THC from marijuana cigarettes (the fraction of THC in the cigarette which reaches the bloodstream) has been reported to range between 5 per cent and 24 per cent (mean 18.6 per cent) (Ohlsson et al, 1980). For all these reasons, the actual dose of THC that is absorbed when cannabis is smoked is not easily estimated. In general, only a small amount of smoked cannabis (e.g. 2mg to 3mg of available THC) is required to produce a brief pleasurable high for the occasional user, and a single joint may be sufficient for two or three individuals. A heavy smoker may consume five or more joints per day, while heavy users in Jamaica, for example, may consume up to 420mg THC per day (Ghodse, 1986). In clinical trials designed to assess the therapeutic potential of THC, single doses have ranged up to 20mg in capsule form. In human experimental research, THC doses of 10mg, 20mg and 25mg have been administered as low, medium and high doses (Barnett et al 1985; Perez-Reyes et al 1982). Perez-Reyes et al (1974) determined the amount of THC required to produce the desired effects by slow intravenous administration. They estimated that the threshold for perception of an effect was 1.5mg while a peak social "high" required 2-3mg THC. These levels did not differ between frequent and infrequent users, so Perez-Reyes et al concluded that tolerance or sensitivity to the perceived high does not develop. 4.6 Patterns of use Cannabis is the most widely used illicit drug in Australia, having been tried by a third of the adult population, and by the majority of young adults between the ages of 18 and 25 (see Donnelly and Hall, 1994). The most common route of administration is by smoking, and the most widely used form of the drug is marijuana. The majority of cannabis use in Australia and elsewhere is "recreational". That is, most users use the drug to experience its euphoric and relaxing effects rather than for its recognised therapeutic effects. Unless explicitly stated to the contrary (as in chapter 8) it should be assumed that the phrase "cannabis use" is a short-hand term for the recreational use of cannabis products. The majority of cannabis use is also "experimental" in that most of those who have ever used cannabis either discontinue their use after a number of uses, or if they continue to use, do so intermittently and episodically whenever the drug is available. Only a small proportion of those who ever use cannabis become regular cannabis users. The best estimate from the available survey data is that about 10 per cent of those who ever use cannabis become daily users, and a further 20-30 per cent use on a weekly basis (see Queensland Criminal Justice Commission, 1993; Donnelly and Hall, 1994). Among those who continue to use cannabis, the majority discontinue their use in their mid to late 20s. Because of uncertainties about the dose of THC contained in illicit marijuana, there is no information on the amount of THC ingested by regular Australian cannabis users. "Heavy" cannabis use is typically defined in terms of the frequency of use rather than average dose of THC received. Although it is possible that daily users could use small quantities per day, this is unlikely to be true of the majority of regular users because of the tolerance to drug effects which develops with regular use. Evidence collected on chronic long-term users at the National Drug and Alcohol Research Centre (Solowij, 1994), indicated that they typically used more potent forms of cannabis (namely, "heads" and hashish). The daily or near daily use pattern is the pattern that probably places users at greatest risk of experiencing long-term health and psychological consequences of use. Such users are more likely to be male and less well educated, and are more likely to regularly use alcohol, and to have experimented with a variety of other illicit drugs, such as amphetamines, hallucinogens, psychostimulants, sedatives and opioids. 4.7 Metabolism of cannabinoids "Cannabinoids" is the collective term for a variety of compounds which can be extracted from the cannabis plant or are produced within the body after ingestion and metabolism of cannabis. Some of these compounds are psychoactive, that is, they have an effect upon the mind of the users; others are pharmacologically or biologically active, that is, have an effect upon cells or the function of other bodily tissues and organs, but are not psychoactive. Animal and human experimentation indicates that delta-9-tetrahydrocannabinol (THC) is the major psychoactive constituent of cannabis. THC is rapidly and extensively metabolised in humans. Different methods of ingesting cannabis give rise to different patterns of absorption, metabolism and excretion of THC. Upon inhalation, THC is absorbed within minutes from the lungs into the bloodstream. Absorption of THC is much slower after oral administration, entering the bloodstream within one to three hours, and delaying the onset of psychoactive effects. After smoking, the initial metabolism of THC takes place in the lungs, followed by more extensive metabolism by liver enzymes which transform THC to a number of metabolites. The most rapidly produced metabolite is 9-carboxy-THC (or THC-COOH) which is detectable in blood within minutes of smoking cannabis. It is not psychoactive. Another major metabolite of THC is 11-hydroxy-THC, which is approximately 20 per cent more potent than THC, and which penetrates the blood-brain barrier more rapidly than THC. 11-hydroxy-THC is only present at very low concentrations in the blood after smoking, but at high concentrations after the oral route (Hawks, 1982). THC and its hydroxylated metabolites account for most of the psychoactive effects of the cannabinoids. Peak blood levels of THC are reached very rapidly, usually within 10 minutes of smoking and before a joint is fully smoked, and decline rapidly to about 5-10 per cent of their initial level within the first hour. This initial rapid decline reflects the rapid conversion of THC to its metabolites, as well as the distribution of THC to lipid-rich tissues, including the brain (Fehr and Kalant, 1983; Jones, 1980; 1987). THC and its metabolites are highly fat soluble and may remain for long periods of time in the fatty tissues of the body, from which they are slowly released back into the bloodstream. This phenomenon slows the elimination of cannabinoids from the body. The time required to clear half of the administered dose of THC from the body has been found to be shorter for experienced or daily users (19-27 hours) than for inexperienced users (50-57 hours) (Agurell, et al 1986; Hunt and Jones, 1980; Lemberger et al, 1970; 1978; Ohlsson, et al, 1980). Recent research using more sensitive detection techniques suggests that the half-life in chronic users may be closer to three to five days (Johansson et al, 1988). It is the immediate and subsequent metabolism of THC that occurs more rapidly in experienced users (Blum, 1984). Given the slow clearance, repeated administration of cannabis results in the accumulation of THC and its metabolites in the body. Because of its slow release from fatty tissues into the bloodstream, THC and its metabolites may be detectable in blood for several days, and traces may persist for several weeks. While blood levels of THC peak within a few minutes, 9-carboxy-THC levels peak approximately 20 minutes after commencing smoking and then decline slowly. The elimination curve for THC crosses the 9-carboxy-THC curve around the time of the peak of the latter and subjective intoxication also peaks around this time (i.e., 20-30 minutes later than peak THC blood levels), with acute effects persisting for approximately two to three hours. 4.8 Detection of cannabinoids in body fluids Cannabinoid levels in the body, which depend on both the dose given and the smoking history of the individual, are subject to substantial individual variability. Plasma levels of THC in man may range between 0-500ng/ml, depending on the potency of the cannabis ingested and the time since smoking. For example, blood levels of THC may decline to 2ng/ml one hour after smoking a low potency cannabis cigarette, a level that may be achieved only nine hours after smoking a high potency cannabis cigarette. In habitual and chronic users such levels may persist for several days after use because of the slow release of accumulated THC. The detection of THC in blood above 10-15ng/ml provides presumptive evidence of "recent" consumption of cannabis, but it is not possible to determine how recently it was consumed. A somewhat more precise estimate of the time of consumption may be obtained from the ratio of THC to 9-carboxy-THC: similar concentrations of each in blood could be an indication of use within the last 20-40 minutes, and would predict a high probability of the user being intoxicated. When the levels of 9-carboxy-THC are substantially higher than those of THC, ingestion can be estimated to have occurred more than half an hour ago (Hawks, 1982; Perez-Reyes et al, 1982). However, such an interpretation probably applies only to the naive users who have resting levels of zero. Background levels of cannabinoids (particularly 9-carboxy-THC) in habitual users make the estimation of time of ingestion almost impossible. It is very difficult to determine the time of administration from blood concentrations of THC and its metabolites, even if the smoking habits of the individual and the exact dose consumed are known. The results of blood analyses indicate, at best, the "recent" use of cannabis. Urinary cannabinoid levels provide an even weaker indicator of current cannabis intake. In general, the greater the level of cannabinoid metabolites in urine, the greater the possibility of recent use, but it is impossible to be precise about how "recent" use has been (Hawks, 1982). Only minute traces of THC itself appear in the urine due to its extensive metabolism, and most of the administered dose is excreted in the form of metabolites in faeces and urine (Hunt and Jones, 1980). 9-carboxy-THC is detectable in urine within 30 minutes of smoking. This and other metabolites may be present for several days in first time or irregular cannabis users, while frequent users may continue to excrete metabolites for weeks or months after last use because of the accumulation and slow elimination of these compounds (Dackis et al, 1982; Ellis et al, 1985). As with blood levels, there is substantial human variability in the metabolism of THC, and no simple relationship between urinary levels of THC metabolites and time of consumption. Hence, urinalyses results cannot be used to distinguish between use within the last 24 hours and use more than a month ago. Several studies have examined measures of cannabinoids in fat and saliva. Analyses of human fat biopsies confirm storage of the drug for at least 28 days (Johansson, et al, 1987). Detection of cannabinoids in saliva holds more promise for forensic purposes, since it has the capacity to reduce the time frame of "recent" use from days and weeks to hours (Hawks, 1982; Gross et al 1985; Thompson and Cone, 1987). Salivary THC levels have also been shown to correlate with subjective intoxication and heart rate changes (Menkes et al, 1991). 4.9 Intoxication and levels of cannabinoids Ingestion of cannabis produces a dose related impairment of a wide range of cognitive and behavioural functions. Since there is evidence that cannabis intoxication adversely affects skills required to drive a motor vehicle (see below), it would be desirable to have a reliable measure of impairment due to cannabis intoxication that was comparable to the breath test of alcohol intoxication. For this reason, a reliable measure for determining the degree of impairment due to cannabis has been particularly sought after. While the degree of impairment from alcohol can be determined from a single blood alcohol estimate, a clear relationship between blood levels of THC or its metabolites and degree of either impairment or subjective intoxication has not been demonstrated (Agurell et al, 1986). The estimation of the degree of intoxication from a single value of blood THC level is difficult, not only because of the time delay between subjective high and blood THC, but also because of large individual variations in the effects experienced at the same blood levels. The difficulty is compounded by the distribution of THC to body tissues, and its metabolism to other psychoactive compounds. Blood levels of THC metabolites, such as 11-hydroxy-THC, correlate temporally with subjective effects but are not readily detectable in blood after smoking cannabis, while blood levels of THC correlate only modestly with cannabis intoxication, in part because of its lipid solubility (Barnett et al, 1985; McBay 1988; Ohlsson et al 1980). The level of intoxication could only realistically be related to the total sum of all the psychoactive cannabinoids present in body fluids and in the brain and various tissues. Due to large human variability, no realistic limit of cannabinoid levels in blood has been set which can be related to an undesirable level of intoxication. Tolerance also develops to many of the effects of cannabis. Hence, a given dose consumed by a naive individual may produce greater impairment on a task than the same dose consumed by a chronic heavy user. THC may also be active in the nervous system long after it is no longer detectable in the blood, so there may be long-term subtle effects of cannabis on the cognitive functioning of chronic users even in the unintoxicated state. To date, there is no consistently demonstrated correlation between blood levels of THC and its effect on human mind and performance. Thus, no practical method has been developed as a forensic tool for determining levels of intoxication based on detectable cannabinoids. A consensus conference of forensic toxicologists has concluded that blood concentrations of THC which cause impairment have not been sufficiently established to provide a basis for legal testimony in cases concerning driving a motor vehicle while under the influence of cannabis (Consensus Report, 1985). 4.10 Passive inhalation In the United States, urine testing for drug traces and metabolites is increasingly used to identify illicit drug users in the workplace (Hayden, 1991). A technical concern raised by the opponents of this practice has been the possibility of a person having a urine positive for cannabinoids as the result of the passive inhalation of marijuana smoke at a social event immediately prior to the provision of the urine sample. A number of research studies have attempted to determine the relationship between passive inhalation of marijuana smoke and consequent production of urinary cannabinoids (Hayden, 1991). In one of the first studies on passive inhalation, Perez-Reyes and colleagues (1983) found that non-smokers who had been confined for over an hour in a very small unventilated space containing the smoke of at least eight cannabis cigarettes over three consecutive days had insignificant amounts of urinary cannabinoids. Law and colleagues (1984) and Mule et al (1988) also showed that passive inhalation produced urinary cannabinoid concentrations well below the detection limit of 20ng/ml 9-carboxy-THC used in workplace drug screens. 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