 | NORML News: Cannabinoids and Cannabis: From The Bench To The Clinic |
 The pharmacology of cannabinoids and cannabis at Otago University
By Geoff Noller, NORML News Summer 2003-4
This article draws its title from the 4th year Otago University pharmacology paper it describes. After teaching the pharmacology of cannabis and cannabinoids as parts of other papers for a number of years Professor Paul Smith decided there was enough interest in the subject to warrant an entire paper on it. He was not wrong; for a first-time 4th year class the numbers are high and every Monday for the first half of 2003 an enthusiastic group of students crams into a small room on the 3rd floor of the pharmacology building close to the university campus on Dunedin's Albany Street. Smith, an ex-pat Australian and author of the recently published Cannabis on the Brain (see review), is no less enthusiastic than his students, and has constructed a 14 week paper based around his book which examines in varying complexity many facets of cannabis and cannabinoids.
Obviously, a pharmacology paper is principally concerned with the biochemical processes, structure, neurophysiology and consequences of the effects of, in this case, cannabinoids, in the human brain and on the body. To his credit, however, Smith has designed a paper which extends beyond the bounds of this narrow though highly complex discipline to encompass issues relating to epidemiology, adverse effects, evidence for tolerance and dependence, therapeutic applications of cannabinoid drugs (including cannabis) and the social and legal issues relating to cannabis use. Having noted this, unlike the book, the paper is less a challenging walk through the pharmacological and related social issues of cannabis and its relatives, than an immersion in their complexity. For science dummies such as this writer (doing the paper due to related studies), there is the danger of being swept rapidly out of depth. This is compounded by the requirement that participating students present a seminar on the subject of their choice. (I got in early and did one on cannabis botany - which was lucky, as it turned out many of the class knew no more than I did.) Most student seminars, however, engage with more specialized pharmacological issues, although not always as critically as they might.
The first couple of weeks set the scene: we get to sort out important stuff like what cannabis actually is (the substance contains over 400 different chemicals), what are cannabinoids (the 60+ chemicals unique to cannabis plus those the body produces that act on receptors) and briefly discuss that well-travelled trail, the history of cannabis use. Smith is keen to note that since the discovery of cannabis receptors in the brain in 1988 and the subsequent identification in the early 1990's of endogenous cannabinoids (naturally occurring within our own bodies) such as anandamide (1992), pharmacological interest in cannabinoids has really taken off. By identifying the presence of cannabinoid receptors and the existence of a cannabinoid 'system' in the human body a huge range of options for treatment of illnesses and diseases, and for the development of synthetic cannabinoids beckons. Depending on how one looks at it this may be good or bad for those interested in recreational cannabis use, with the possibility that future developments of synthetic drugs might undermine the medicinal use of natural cannabis. However, sufferers of diseases treatable by cannabinoids may well benefit from the impetus this area has received by the massive increase in interest from pharmacologists. A side effect of this research is an increased critical awareness of the negative consequences of cannabis use. Whereas in the past, users may have thought the substance was totally benign, or propagandarists were able to disguise nonsense as fact or pseudoscience, emerging research can both educate users about real dangers and undermine the manufactured 'truths' of those opposed to cannabis use in any form. This critical appraisal of cannabis use and cannabinoids is at the core of the Otago paper.
Cannabinoids, including those 'active' metabolites produced by the body breaking down cannabis (that's right, our bodies produce other psychoactive cannbainoids from what we ingest) are the paper's first port of call. For example, delta-9-THC's major metabolite, is 11- hydroxy-delta-9-THC. It could be as potent as THC itself and might be responsible for the continuation of some psychotropic effects, especially with body stones.
Having noted the extensive cannabinoid family, Smith focuses much of the paper on delta-9-THC, cannabis' principal psychoactive. There are advantages and disadvantages of this, such as considering THC in isolation. In nature, of course, it occurs within a very complex substance, which in synergy with other chemicals in cannabis, may produce different effects. He considers the importance of dose or concentration of THC as opposed to how much cannabis a person might consume and debunks (through authors such as Zimmer & Morgan's Marijuana Myths, Marijuana Facts, 1997) the notion of a massive increase in general THC strength over the last 20 years.
Weeks 2-4 of the paper consider, respectively, the epidemiology of cannabis use (i.e. who, how, why, when, where), kinetics (how cannabis gets into the body) and cannabis receptors. As with Smith's book, one of the paper's strengths is its critical focus on New Zealand cannabis data. Detailed evidence of use, prevalency and demographics in Aotearoa is contrasted with, for example, Australian data. A picture of significant and widespread use emerges, with more Australians using ever/ and in the last year than Kiwis (45% vs. 35%, and 35% vs. 29%; 14-19 age group) respectively as at 2000. Female smokers are shown to be catching up in both countries and use in general seems to be slowly increasing. Coming in for heavy criticism is the gateway theory, suggesting that cannabis use leads to use of other 'harder' drugs. An acknowledged positive correlation, however, does exist between heavy cannabis use and other drugs although Smith follows Zimmer & Morgan in noting this is a descriptive correlation, not a causative one.
In examining cannabis pharmacokinetics, how much THC gets into the blood is crucial, and this depends on absorption, distribution, metabolism and excretion. Also important are tolerance and dependence, especially for the development of therapeutic cannabinoids. With cannabis being mostly smoked, peak blood levels are achieved within about 15 minutes, which is similar to i.v. administration. Blood concentrations are 70%-75% higher than after eating cannabis, although still only 10%-25% of the available THC reaches the bloodstream. For smoking, bioavailability (how much the body can access) is higher than for eating due to latter involving the 1st pass process, whereby before being absorbed by the stomach and gut, chemicals within eaten cannabis first pass through the liver, where a portion of these are broken down and excreted. 11-hydroxy-delta-9-THC, the most active of the approximately 80 identified THC metabolites, is ultimately converted into, amongst others, 11-nor-9-carboxy-delta-9-THC, which can be detected in urine for several days after smoking. THC has a long and variable half-life of between 18.7 hours and 4 1/2 days, with its fat-solubility contributing to this. There is some evidence that heavy users take longer to eliminate THC. Four to five 'half lives' are required to eliminate traces of one dose of cannabis from the body (i.e. up to about 20 days).
A significant portion of Smith's paper deals with cannabinoid receptors and their implications for research, therapy and drug synthesis, subjects which readers with a specialised science background would find fascinating, but which many of us (including this writer) would struggle with. What follows is a necessarily brief and 'science-lite' description of some relevant details. For those interested, Smith's book provides a far more detailed and accessible explanation.
Receptors are proteins allowing chemicals to 'bind' to them, like a key fitting a lock. They can be found in parts of the central nervous system (CNS, i.e. brain, optic nerve / retina and spinal cord) and in other parts of the body, i.e. in the testes in males and the uterus in females. They are concentrated in certain parts of the brain more than others, i.e. in the hippocampus, a structure associated with memory.
Currently there are two known cannabis receptors, CB1 (discovered in 1988), found principally in the CNS, and CB2 (1993), a peripheral receptor found in other parts of the body including the immune system and gonads, which is about 44% identical to CB1. The location of these receptors, how they respond to cannabinoids, especially delta-9-THC, and how their responses mediate the activities of associated brain and neural structures has implications for the consequences of cannabis use, cannabinoid therapy and the development of synthetic cannabinoids. For example, receptors are responsive to over-stimulation by THC, with some of them being absorbed back into the cell on which they are located if constantly exposed to THC, i.e. heavy smoking. Thus absorption of THC, and therefore the stone, is reduced. If exposure reduces, receptors re-emerge from the cell. They also appear to have the ability to 'sequester' pooled proteins commonly used by several receptors, thus reducing the effectiveness of other unrelated receptors. In this way, for example, stimulated cannabinoid receptors reduce opioid receptor plasticity and prevent desensitisation to opioids.
At the molecular level, this is where arguments about the effect of THC on the potentiation of schizophrenia are based.
Similarly for CB2 receptors' association with the immune system. Here Smith's paper assess evidence claiming that THC negatively impacts on the immune system and that consequently its use as an anti-nausea drug for HIV and cancer suffers is problematic or that there might be implications for the general population. Smith concludes that there are some limited negative consequences for the immune system but that these are not clinically significant and that there might also be questions about the extreme dosages used by experimenters to generate these findings.
CB receptors are found in many animals, including mammals and the chicken, frog, turtle and trout. For this reason, much of the clinical research on CB receptors has been carried out on mammals such as rats. Again, there are issues here that require critical assessment, particularly in relation to differences between other animals and humans where the use of a drug is so involved with meaning and the implications for how the human use of cannabinoids affects the human brain. Antivivisectionists would also have problems with many of the studies discussed.
A section of the course particularly relevant to recreational cannabis users examines the behavioural and negative health consequences of use. The usual suspects are trotted out: euphoria, sedation, altered perception and memory, enhanced sound and colour sensitivity, analgesia (pain relief), loss of motor control, appetite stimulation, increased heart rate and reduced blood pressure. These are given a balanced treatment, with aspects of pleasure considered and a critical assessment of some of the studies showing negative consequences for memory and learning. Experimental design is often problematic due to small numbers of both experiments and subjects, and lack of 'double-blind' structure, i.e. subjects need to NOT KNOW that they are getting either real cannabis or a non-psychoactive 'placebo'. There are undoubtedly negative consequences of use, particularly if this is heavy and it is good to see these aspects of cannabis use presented clearly and honestly and linked to the pharmacological processes described above.
Similarly with adverse effects on lung function, memory and foetal development impairment and toxicity. In the battle for the medicinal use of natural cannabis these issues loom large. It is difficult to deny the negative consequences of smoking cannabis for the lungs with levels of certain carcinogens significantly higher in cannabis than tobacco, i.e. benz(a)anthracene and benzo(a)pyrene. Other carcinogens produced by burning cannabis include vinyl chloride, dimethylnitrosamine and methylthylnitrosamine. Compared to tobacco, there is also a five-fold increase in carboxyhaemoglobin, which reduces the blood's effectiveness in carrying oxygen to the tissues, and a three-fold increase in the tar inhaled, with one third more tar retained in the respiratory tract. Interestingly, despite these concerning facts, Smith was determined to note that there is no causative link between smoking cannabis and lung cancer, although with exposure to smoke, there is a latency period of 15-30 years before effects may show. Certainly there is a very strong genetic component in the development of cancer. Aside from initiation by myself, there was no discussion of vaporisers and little regarding the possibilities associated with smoking stronger cannabis less frequently. These issues are potentially important as a major barrier to the use of whole cannabis for medicinal purposes concerns damage to lung function. A similar argument could be made regarding concerns over the psychotropic effects of THC, with issues relating to working while stoned. This 'effect' of cannabis is considered another barrier to the substance being used medicinally although discussion about how cannabis users compensate for the effects was not broached.
Following from the above, a similarly detailed and balanced assessment of tolerance and dependence was explored, along with a healthy discussion on legal and social issues including prohibition.
For those wanting to increase the depth of their cannabis knowledge, fortunate to be in the right place at the right time and at the business end of their degree at Otago University, this is an excellent paper.
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