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The health and psychological consequences of cannabis use chapter 4

National Drug Strategy
Monograph Series No. 25

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

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

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,

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.

Morland et al (1985) produced urinary cannabinoid levels above 20ng/ml
in non-smokers but the conditions were extreme, namely, confinement in
a space the size of a packing box with exposure to the smoke of six
cannabis cigarettes. The studies of Cone and colleagues (1986; 1987a,
1987b) confirmed the necessity to apply extreme experimental
conditions, which they claimed non-smokers were unlikely to submit
themselves to for the long periods of time required to produce urinary
metabolites above 20ng/ml. They also showed that non-smokers with
significant amounts of cannabinoids in their urine experienced the
subjective effects of intoxication.


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