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 (0.5mg/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.