Dr G.B. Chesher
Department of Pharmacology University of Sydney and National Drug and
Alcohol Research Centre University of New South Wales.
3. STUDIES USING THE TECHNIQUES OF EPIDEMIOLOGY
|These studies aim to determine whether or not a causal relationship
between drug use and a motor vehicle crash exists.
|I shall look at each of the above factors and will compare the two drugs
alcohol and cannabis in the light of current evidence. In interests of time and space I
have in this summary referred to reviews of the literature and have made only a brief
description of the studies themselves. A fuller description of these can of course be
sourced from the original literature of the cited reviews.
|First, the drugs themselves. With the increase in pharmacological
knowledge it is known that most drugs act upon specific receptors. A receptor is a
specific site in tissues, frequently on the cell membrane, which has a specific structural
affinity (shape) for a naturally occurring molecule. The interaction between receptor and
the endogenous molecule is part of the body's normal, physiological functioning. Most
drugs exert their activity by acting upon these receptors. Examples of such drug-receptor
interactions are the opioids (morphine etc) and the opioid receptors; the antihistamines
and the histamine receptors and the benzodiazepines which act on the benzodiazepine
receptors. The endogenous substances that physiologically act on these receptors are,
respectively, the endorphins and enkephalins on the opioid receptors; histamine on the
histamine receptors; however the identification of the physiological substance for the
benzodiazepine receptor has yet to be identified.
|Research within the last five years has revealed that the cannabinoids,
such as delta-9-tetrahydrocannabinol (THC) from the cannabis plant exert their effects on
specific receptors known as the cannabinoid receptors. To date two cannabinoid receptors
have been described and an endogenous (physiological) substance has been identified. This
has been given the name 'anandamide'. It is very likely that in the near future more
cannabinoid receptors will be described and more endogenous substances that act on these
receptors will be identified. An historical overview of these findings has recently been
|In contrast, the evidence strongly indicates that the drug alcohol does
not act on a specific receptor, but acts more widely in a non-specific manner on the cell
membranes themselves. This understanding is supported by the evidence that alcohol exerts
effects on most of the tissues of the body and in excess is toxic to most tissues. The
reader is referred to a recent review on this subject by Dufor and Caces.
|Drugs which act upon a specific receptor produce their effects in doses
measured usually as nanograms or micrograms per kilogram of body weight. Alcohol doses are
measured in grams per kilogram - many hundreds of thousands times greater than those of
most other drugs. Alcohol is a very non-specific drug.
|Another important factor is that receptor-specific drugs exert their
activity only on those cells which bear the specific receptor. In the case of the
cannabinoids these receptors are found only in the brain in the basal ganglia, the
cerebellum, the brain stem, thalamic nuclei, hypothalamus and corpus callosum. On the
other hand alcohol affects all nerve cells to which it is delivered by the circulating
|Consequently it is not surprising that differences in the action of
alcohol and the cannabinoids have been described in their effects on mood and behaviour.
These will be discussed below.
|The pharmacokinetics of alcohol and the cannabinoids could hardly be more
|The apparent volume of distribution of alcohol (the volume of fluid in
which the drug seems to be dissolved throughout the body) is quite low, consisting of the
41 litres of body water, providing a value of about 0.59 litres/kg. Cannabinoids, on
the other hand, are very fat soluble and have a high volume of distribution which has been
estimated to be about 10 litres/kg.
|The meaning of these values is that the concentration of alcohol in the
blood provides a reliable estimate of the concentration of the drug in the brain. This in
turn provides a reliable estimate of the degree of impairment of the drinker. In addition
to this, alcohol is excreted via the lungs to the breath and the blood : breath
ratio is such that the determination of the alcohol in breath provides a reliable estimate
of the blood alcohol concentration. It is because of these pharmacokinetic properties of
alcohol that it has been possible to accumulate the epidemiological data upon which our
drink-driving laws have been based.
|Cannabinoids, on the other hand are lipophilic (fat loving) and are
distributed in the fatty tissues of the body. When smoked, which is the most common route
of administration, the cannabinoids are rapidly absorbed from the lungs into the
bloodstream. Being so fat soluble the cannabinoids readily cross membranes, leave the
circulation and are rapidly 'dumped' into various tissues of the body, including the
brain. In this way the concentration of cannabinoid in the blood declines very rapidly as
indicated in Fig 1.
|As indicated in the Figure,
we can describe the concentration of cannabinoid across time in the blood in the three
phases: absorption, re-distribution and elimination. The steep upward curve of THC
represents the inhaled THC being absorbed into the blood through the lungs; the equally
sudden drop in the concentration of THC represents the drug being 'dumped' from the
bloodstream into fatty tissues. This redistribution phase 'flattens' out as the 'dumped'
THC re-enters the blood and is then metabolised in the liver-the
elimination phase. It is important to note that the sudden decline in the concentration of
THC (the psychologically active cannabinoid) in the blood does not represent drug
metabolism but rather the rapid re-distribution of the drug from the blood into other
tissues. The metabolism of the cannabinoids takes place when these 'dumped' cannabinoids
are released back into the bloodstream whence they pass through the liver and are very
rapidly metabolised and subsequently excreted.
1. The blood concentration of THC (squares) and its inactive metabolite, carboxy
THC (THC Acid; diamonds) after the smoking of a marijuana cigarette. Each point is the
mean of results from six volunteers, all of whom were free from cannabinoids before
smoking the drug. [The 925±7mg refers to the average weight of the cigarettes and
the 1.32% refers to the dry weight concentration of THC]
|Figure 1 also
shows the blood picture of the inactive metabolite, carboxy THC (or THC acid). It is
important to note several points about the pharmacokinetics of this substance. First, in
the study indicated here (Fig 1)
all of the volunteers had no cannabinoids in their blood before they began smoking.
Second, the THC acid is formed in the liver from the metabolism of THC, therefore its
appearance in blood follows that of the parent, THC. Third, the THC acid concentration
then increases and surpasses that of the parent molecule in the blood. At a time when the
parent THC is in the blood at only a very low concentration, that of the metabolite is
higher and exists in the blood for a longer time. Therefore, should the smoker smoke again
before the parent molecule and its metabolite have been eliminated, the ratio of the
concentrations of THC and of the THC acid will be different from that shown in Figure 1. This is because there
will exist a higher concentration of the metabolite than of the THC in blood at the time
when the next dose of cannabis is smoked.
|For this reason, analytical data that provides a value only for the
metabolite can only be validly interpreted as indicating recent consumption of cannabis;
however the time of this consumption could be a matter of hours or days. For this reason
the quantitative determination of only the metabolite is of no value to determine possible
|To assess possible impairment the analyst must provide data for the active
molecule, THC. And when this occurs, the only interpretation possible on present knowledge
is to infer the recent consumption of the drug by smoking. To date no meaningful
correlation between blood concentration of THC and impairment in laboratory tasks has been
established. This point will be clarified when the results of the recent epidemiological
studies are discussed below.
|Yet another problem arises in the interpretation of blood concentrations
of cannabinoids. The pharmacokinetics of the cannabinoids are quite different when the
drug is taken by mouth. Space in this discussion precludes further discussion of the
pharmacokinetics after oral administration, but suffice to say the absorption of
cannabinoids taken orally is slow and erratic. The absorbed THC passes through the liver
and is rapidly metabolised. This results in a different proportion of THC to the
metabolite, THC acid than encountered after smoking. There is a greater amount of
entero-hepatic 'recycling' as some of the cannabinoids are stored in the bile in the gall
bladder. These cannabinoids can later be 'recycled' and reabsorbed into the bloodstream
when the gall bladder empties. In this country, most who use cannabis, smoke it.
|It is also important to note that the detection of cannabinoids in a urine
sample provide evidence only that the donor of that urine has been exposed to cannabis at
some time in the past. It gives no indication at all of impairment or of intoxication. A
frequent, heavy cannabis user may be excreting cannabinoids in urine for some weeks or in
some cases, for more than a month. Those who take the drug by mouth also will be excreting
the drug for a longer period.