Notes on the International Cannabinoid Research Society 1998 Symposium on Cannabinoids, La Grande Motte, France, 23-25 July 1998
by Professor Leslie Iversen FRS, Specialist Adviser
1. The annual meeting of this group of research scientists was held for the first time outside North America and was attended by about 150 scientists, largely from academia. Of the 135 papers presented 73 originated from the United States and 50 from Europe (including 12 from Britain, 5 of which were from Dr Pertwee's group in Aberdeen).
2. A substantial number of papers focused on the naturally occurring cannabinoids in the brain and in peripheral tissues. At least two lipid derivatives are now recognised: anandamide (arichidonylethanolamide) and an arichidonic acid ester, 2arachidonylglycerol (2AG). The latter substance is as potent as anandamide and is present in much larger quantities than anandamide in the brain. Several papers focused on the biochemical mechanisms involved in the synthesis and degradation of these lipids in the brain, and progress has been made in defining the biochemical mechanisms involved. Attention has also focused on the development of metabolically more stable chemical analogues of anandamide and 2AG with improved activity in whole animal studies: the naturally occurring compounds are rapidly degraded and are thus not very active in vivo. Another lipid, palmitoylethanolamide, may represent the natural activator of CB2 receptors, although there was some disagreement about its pharmacological activity and selectivity.
3. Several groups are studying the detailed molecular architecture of the CB1 and CB2 receptors and beginning to identify the precise sites at which the cannabinoids bind to these proteins. Studies of the receptors in in vitro model systems have revealed some interesting differences between the effectiveness of various cannabinoids in activating the receptors. In particular Ä9THC appears to act as only a partial agonist at the CB1 receptor (i.e. it cannot elicit a maximum response). Cannabidiol, one of the most abundant plant alkaloids, on the other hand appears to act as an antagonist at the CB1 receptor.
4. The CB1selective antagonist drug SR141716A and the related CB2selective antagonist SR144528 from the French pharmaceutical company Sanofi were the subject of many papers, and these compounds have proved to be important new research tools for probing cannabinoid functions. Scientists from Sanofi revealed that they are developing SR141716A for clinical trials, with schizophrenia as their first target (on the rationale that high doses of THC can cause a schizophrenialike psychosis). A novel CB1 antagonist CP272871 from Pfizer was described for the first time; it has properties similar to those of SR141716A.
5. The CB2 receptor, located principally on cells in the immune system, has attracted attention from a number of major pharmaceutical companies as a potential target for discovering novel antiinflammatory or immuno-suppressant drugs. There has been progress in identifying CB2selective drugs (by Merck Frosst, GlaxoWellcome, and Smith Kline Beecham) but so far there is little confidence that this target will prove useful. Dr Nancy Buckley (US National Institutes of Health) described the "CB2 knockout mouse" in which as a result of genetic engineering the CB2 receptor is no longer expressed. These mice seem remarkably normal in their immune cell population and in immune function and have not so far assisted in understanding the role normally played by the CB2 receptors.
6. D. Tashkin (UCLA) reported that treatment of mice with THC (5 mg/kg four times a week) led to more rapid growth of implanted lung cancer cells and decreased survival. He suggests that THC may suppress immunemediated eradication of tumour cells.
7. A session sponsored by the US National Institute on Drug Abuse focused on the effects of long-term cannabis use on frontal lobe function in man. A series of studies using imaging, cerebral blood flow and electroencephalographic measurements indicated depressed frontal lobe function in long-term cannabis users, and there were accompanying subtle deficits in sensory and cognitive processing, the so-called "executive functions" of the brain. There was little evidence that any of these effects persisted after cessation of drug intake.
8. Billy Martin et al (Virginia, USA) described an animal model of cannabis dependence. When dogs were treated with high doses of THC for 714 days and then challenged with the CB1 antagonist SR141716A clear physical signs of withdrawal became apparent; these included trembling, shaking, restlessness, vomiting and diarrhoea. By using the antagonist challenge model it has become much clearer that physical dependence and withdrawal can occur with THC, at least in animals. Furthermore, de Fonseca et al (Madrid) reported that the administration of SR141716A to morphinedependent animals elicited a behavioural and endocrine syndrome similar to that seen in opiate withdrawal, although considerably milder. Conversely some withdrawal signs could be elicited in cannabinoid-dependent animals when challenged with the opiate receptor antagonist naloxone, suggesting an interaction between the opioid and cannabinoid systems in the brain.
Possible applications of cannabinoids
9. The interaction of opiate and cannabinoid mechanisms was also highlighted by Sandra Welch (Medical College of Virginia, USA) who reported that low doses of THC significantly potentiated the painrelieving effects of morphine and other opiates in a mouse model of arthritislike pain. Higher doses of THC were also by themselves fully effective in causing analgesia in this model. She is planning a clinical trial (with the approval of the US Food & Drug Administration) of low doses of THC (dronabinol) in conjunction with selfadministered morphine in patients suffering from cancer pain, in the hope that the drug combination may make morphine more effective in such patients.
10. D. Piomelli ( San Diego, USA) described powerful analgesic effects of anandamide when injected directly into the rat paw in an inflamed paw model of inflammatory pain. The mechanism appeared to involve both CB1 and CB2 receptors located on sensory nerve fibres in the skin, and when a combination of CB1selective and CB2selective compounds was injected there was synergy between them. Experiments using radiolabelled anandamide showed that >90 per cent of the injected dose remained in the paw, and very little entered the brain or spinal cord. These results are highly original and suggest the possibility that cannabinoids can exert painrelieving actions without having to penetrate into the central nervous system.
11. P. Consroe and R. Musty (University of Arizona, USA) described the results of an anonymous survey of 106 patients with spinal cord injuries who were selfmedicating with smoked marijuana. Patients smoked an average of 4 joints a day, 6 days a week and had been doing so for >10 years. More than 90 per cent reported that cannabis helped improve symptoms of muscle spasms of arms or legs, and improved urinary control and function. Around 70 per cent reported pain relief. The results of this survey and a similar one conducted with R. Pertwee in MS patients may help to pinpoint the relevant symptoms to focus on as outcome measures in future clinical trials of cannabis or cannabinoids.
12. D. Pate (University of Kuopio, Finland) described promising results in the reduction of intraocular pressure when a metabolically stable anandamide analogue was applied topically to normal rabbit eye. This effect appeared to involve a local CB1 receptor mechanism as it could be blocked by pretreating the animals with the antagonist SR141716A. In order to deliver the waterinsoluble lipid derivative to the eye it was dispersed in an aqueous solution containing a betacyclodextrin carrier.
13. M. El Sohly (University of Mississippi, USA) summarised results obtained from the analysis of confiscated marijuana samples, a service which has been running since 1980 and which involves the analysis of samples from all regions of the United States. Data from 35,312 samples were available. The potency of marijuana leaf samples (the commonest in US seizures) rose from around 1.5 per cent THC content in 1980 to around 3 per cent in the 1980s and most recently to 3.87 per cent in 1996 and 4.15 per cent in 1997. The THC content of sinsemilla (the female plant flower head) rose from around 6.5 per cent in 1980 to 9.22 per cent (1996) and 11.53 per cent (1997). The increases are thought to be due to improved culture conditions rather than to any genetic improvements. Analysis of samples of cannabis resin or oil revealed few discernible trends, with figures ranging from 3 per cent to 19 per cent THC content.
14. J. Khodabaks and O. Engelsma (Maripharm, Netherlands) described their development of "The standardised medical grade marihuana plant". Until recently this group has been supplying Dutch pharmacists with medical grade marijuana, but its legal status has recently been questioned. The laboratory cultivates standard cannabis plants selected for a high yield of THC and low content of other cannabinoids; these are cloned by propagating (by cuttings) from female plants. The plants are grown under standard conditions and the female flower heads harvested and vacuum-sealed for storage and then gammairradiated to sterilise the preparations. Samples are routinely checked for THC and other cannabinoids and to ensure that they are free of pesticides. The THC content in different batches was highly consistent at 10.7 ± 0.1 per cent (standard deviation). Interestingly, in the light of discussions about the relevance of other cannabinoids in herbal cannabis, cannabidiol and cannabinol were present in only minor amounts (<0.1 per cent) in these samples.