APPENDIX 3
Notes on Conference "Marihuana and Medicine"
at New York University Medical Center, New York, 20-21 March 1998
by Professor Leslie Iversen FRS, Specialist Adviser
1. The conference, organised by Professor G.
Nahas and colleagues, gave an overview of the current position
in the USA. A topical issue there is whether smoked marijuana
should be permitted for medical use, since oral formulations of
tetrahydrocannabinol (THC) and nabilone are already available
medically.
2. M. Huestis (National Institute on Drug Abuse)
reviewed new information on the disposition and metabolism
of cannabis in human subjects, using sensitive analytical
techniques to measure THC and some of the major metabolites. Because
a substantial proportion of the absorbed THC is sequestered in
fat tissues, the half life of the drug in blood is > 4 days
and the half life of the major urinary metabolite 11carboxylic
acid THC is > 30 hours. By measuring the ratio of unchanged
THC to this metabolite in samples of blood or urine it may be
possible to calculate when the last dose of THC was taken-information
that could be of importance forensically. An unexpected finding
was the large variability between subjects in the amount of THC
absorbed by smoking a standard marijuana cigarette under laboratory
conditions; even though the number and frequency of puffs was
controlled there was a 3fold range. For the same subject
tested on different occasions there was also a considerable variability
in the amount of THC absorbed (17 per cent on average).
3. M. El Sohly (University of Mississippi) described
the development of a rectal suppository formulation for
delivery of THC in the form of a "prodrug" (the
hemisuccinate ester) dissolved in a lipid base. Absorption of
THC increased in a dosedependent manner and was prolonged
(THC was measurable in blood for up to 8 hours). Because this
route of absorption avoids first pass metabolism in the liver,
the amount of THC absorbed into circulation was more than twice
as great as after oral dosage. Unfortunately there was a high
variability between subjects in the amount of THC absorbed (about
3fold). The advantages of this route of administration seem
clear, but it was thought unlikely to be popular in the United
States where suppository formulations have never been widely accepted.
4. B. Thomas (Research Triangle Institute) reviewed
the operation of his laboratory which supplies standard marijuana
cigarettes to the 8 individual glaucoma patients licensed
in the US to receive this medication, and to research groups in
the US and elsewhere. By using standard growing conditions (at
the University of Mississippi) and different strains of cannabis
plant they are able to generate marijuana cigarettes of consistent
quality and standard THC content (standard = 1.8 per cent
THC; strong = 4.0 per cent THC) free of microbial or insect
contamination. Placebo cigarettes are prepared using leaf material
extracted with alcohol to remove THC.
5. Roger Pertwee (University of Aberdeen) reviewed
current knowledge of the two cannabinoid receptors CB1
(found in the brain and some peripheral organs) and CB2 (peripheral
only). The presence of CB2 receptors on cells in the immune system
has prompted some pharmaceutical companies to become interested
in this as a possible target for the discovery of novel immunesuppressant
or antiinflammatory drugs. The French company Sanofi and
the Canadian company MerckFrosst have reported novel synthetic
antagonists/agonists acting selectively at these sites. The availability
of novel synthetic antagonists acting at the CB1 receptors (eg
SR141716A (Sanofi), LY 320135 (Eli Lilly)) has provided valuable
new research tools. New drugs are also being designed based on
the structure of the endogenous cannabinoid anandamide.
6. R. Mechoulam (Hebrew University, Israel) described
his identification of Ä9THC
as the principal psychoactive compound in cannabis extracts, and
his subsequent discovery of anandamide as the naturally
occurring cannabislike compound in the brain. Other naturally
occurring fatty acid derivatives also interact with cannabis receptors,
and one of these, 2arachidonylglycerol, may act selectively
at CB2 receptors.
7. E. Gardner (Albert Einstein College of Medicine,
New York) described studies of the interaction of THC with reward
pathways in rat brain. He confirmed earlier work from an Italian
laboratory (Tanda et al, 1997, Science, 276:20482050)
that administration of THC (0.5 mg/kg) to rats caused an increase
in dopamine release in the nucleus accumbens region of the brain
and, furthermore, that this release could be blocked by coadministration
of the drug naloxone, which blocks opiate receptors in the brain.
He also found that THC sensitised rats to the rewarding effects
of intracranial selfstimulation and that this effect was
also blocked by naloxone. These results are potentially important
as they indicate that THC stimulates dopamine pathways in the
brain known to be activated by various addictive drugs—nicotine,
amphetamine, heroin and cocaine. The blocking effects of naloxone
suggest that THC may exert at least part of its rewarding effects
indirectly by promoting a release of opiatelike chemicals
in the brain.
8. D. Tashkin (University of California Los Angeles)
surveyed the effects on the lung of long-term marijuana
use. He conducted large scale studies in the 1980s in heavy marijuana
smokers and compared them with subjects who smoked tobacco. Marijuana
smokers showed some bronchial symptoms (cough, wheeze and bronchitis),
but there was no evidence for any significant reduction in overall
respiratory function. When data were collected annually for a
further 8 years, the marijuana smokers did not show the agerelated
decline in respiratory function seen in tobacco smokers. Nevertheless,
there was concern about the longer-term effects of marijuana smoking.
Examination of the lining of the airways revealed inflammatory
changes in chronic marijuana smokers, with an increase in the
number of mucussecreting cells and sometimes what appeared
to be precancerous alterations in cells lining the lungs.
Examination of lung biopsy specimens showed an increased expression
of certain genes that are markers of lung tumours. In addition
the immune defence system appears to be depressed in the lungs
of marijuana smokers. The defending white cells (macrophages),
although present in increased numbers, had a decreased ability
to kill bacteria or fungi and produced reduced amounts of nitric
oxide and cytokines, the normal defence chemicals. Suppression
of immune system function may be related to a direct effect of
cannabis on receptors on the macrophages and other immune system
cells. Although there was no evidence for increases in lung cancers
in marijuana smokers, there were some reports of increases in
cancers of mouth and throat. The reduction in immune system function
could make marijuana smokers especially vulnerable to lung infections.
9. K. Coe (formerly at Pfizer Research) and L.
Lemberger (formerly at Eli Lilly Research) gave historical reviews
of the development of novel drugs for the treatment of
pain and prevention of nausea based on cannabinoid chemical structures.
A project at Pfizer in the 1970s led to the discovery of the synthetic
compound levonantradol and the related compound CP55,940.
These compounds had a much greater water solubility than THC and
proved to be up to 100 times more potent than morphine in some
animal tests of pain. Levonantrodol entered pilot scale clinical
trials and was effective in suppressing postoperative pain
and in preventing nausea and vomiting associated with cancer chemotherapy.
It was evident, however, that the drug did not separate the beneficial
clinical effects from intoxicant effects, and the company abandoned
the project in 1980. CP55,940 proved valuable, however,
in radioactively labelled form as a probe which led to the identification
of the cannabis CB1 receptor in the brain.
10. At Eli Lilly during the same period there
was also a hope that the beneficial effects of cannabinoids could
be separated from unwanted psychoactivity, and this led to the
discovery and development of nabilone. Clinical trials
established the effectiveness of this drug in the treatment of
the nausea and vomiting associated with cancer chemotherapy. Although
some patients complained of the druginduced "high",
this appeared milder than that associated with THC. However, although
nabilone was approved for medical use by the Food and Drug Administration,
the US Drug Enforcement Agency insisted that it be given a "Schedule
II" classification [i.e. a compound with some medical use
but a high abuse potential, so doctors using it have to keep detailed
records]. This led to the company withdrawing from the project
and also failing to give any substantial marketing support to
the compound. Postmarketing surveillance reports in the
UK, where the compound has some limited use, have not shown any
danger of abuse.
11. W. Notcutt (Great Yarmouth), a consultant
in a pain clinic, reported on the positive effects of nabilone
in the relief of pain in some of his patients who were
suffering from chronic pain and not responding to other medications.
In a total of 55 patients he observed beneficial effects of nabilone
(improved sleep, reduced pain) in about one third.
12. K. Green (Medical College of Georgia) and
M. Forbes (Columbia University College, NY) discussed the possible
use of cannabis in the treatment of glaucoma. There are
more than 2 million glaucoma patients in the USA alone, and glaucoma
is a major cause of blindness. THC or smoked marijuana does cause
a marked fall in intraocular pressure in both normal subjects
and patients with glaucoma (up to 45 per cent reduction),
but the effect is transient and returns to baseline within 34
hours. It is difficult to achieve longer-term control of intraocular
pressure as this would require frequent repeat dosing. THC cannot
be delivered topically to the eye (the preferred route for antiglaucoma
medications) because of its low water solubility. It is possible
that an improved topical delivery formulation, or topical use
of a more water soluble synthetic cannabinoid, could be developed
in the future. In the USA a small group of patients (8) have individual
permission to use smoked marijuana to treat their glaucoma.
13. R. Graller (New Orleans) reviewed the use
of cannabis in the treatment of nausea and vomiting. Although
there have been several controlled clinical trials showing the
effectiveness of orally administered THC and nabilone in patients
receiving cancer chemotherapy, there are few data on smoked marijuana.
In recent years a new class of antinausea drugs, the 5HT3
antagonists (e.g. ondansetron, granisetron) have radically improved
the treatment of nausea and vomiting in cancer patients. He found
that a combination of granisetron and the steroid dexamethasone
controlled the symptoms in more than 90 per cent of patients.
Unlike THC which cannot be given intravenously, granisetron can
be given by this route as well as by mouth.
14. G. Francis (McGill University, Montreal)
discussed the use of cannabis in the treatment of multiple
sclerosis. There are few effective treatments for this disease,
and more than 250,000 patients in the USA. Some symptoms are particularly
poorly controlled by existing medicines, notably tremor, pain
and spasticity. There are many anecdotal reports that these symptoms
are eased by smoked marijuana, but so far there have been few
controlled clinical trials. A currently ongoing study with 600
subjects aims to compare smoked marijuana with a placebo (cigarettes
with THC removed). Results available so far suggest that the subjective
reports of improvement by patients are not always accompanied
by improvement in objective measures of performance.
|
|
