APPENDIX 4
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).
Endogenous cannabinoids
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.
Cannabinoid receptors
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.
Adverse effects
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.
Miscellaneous
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.
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