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     The Lancet
Volume 350, Number 9094 - Saturday 20 December 1997

Larry Husten

The cannabis remedy--wonder worker or evil weed?

To many physicians, the opium poppy conjures up images of illicit drug use, yet morphine and other poppy products are regarded as effective therapeutics. Matters are not as clear cut for a similarly cultivated weed--Cannabis sativa.

Interest in cannabis and its active constituents, cannabinoids, as therapeutic agents has increased recently. Of the 60 or so cannabinoids, only the main psychoactive component, delta-9-tetrahydroacannabinol (THC), is commercially available (dronabinol). This drug and the THC analogue nabilone are licensed for a few indications only.

This year, both the US National Institutes of Health and the British Medical Association released reports on the potential therapeutic uses of cannabis and cannabinoids. Each report concluded that cannabinoids may be potentially useful as analgesics, anti-emetics, antispasmodics, appetite stimulants, and in treatment of glaucoma and epilepsy. Much of the evidence is anecdotal, or from small controlled trials of oral dronabinol or nabilone. The potential medical utility of cannabis cannot be gauged by studying only these drugs, says NIH. Other cannabinoids could have important actions, or could modulate THC's effects. And, THC pharmacokinetics differ between oral THC and smoked cannabis products.

Interest in therapeutic uses for cannabinoids increased after the discovery of a human cannabinoid receptor (CB1) and the first endogenous ligand, anandamide. Now, several other endogenous agonists have been identified that activate CB1 or a second receptor, CB2. Early data suggest that more receptors exist. These results support a call for more basic research on "the functional roles of cannabinoid receptors as a key underpinning for possible therapeutic applications", asserts NIH.

President of the International Cannabinoid Research Society, Roger Pertwee (University of Aberdeen, UK) agrees. If little is known about the pharmacological effect of exogenous cannabinoids, even less is known about the role of the endogenous cannabinoid system in health and disease. But, he says, the distribution of receptors and the actions of synthetic receptor-selective agonists and antagonists tell us something about cannabinoid functions, and is leading to potential new drugs.

CB1 receptors are mainly found in specific areas of the brain, spinal cord, and peripheral nervous system. Their location on nerve terminals implies that CB1 activation may modulate neurotransmitter release, for which there is some experimental evidence. High CB1 density in the basal ganglia could be the basis of antispasmodic effects of agonists, while CB1 binding in the substantia gelatinosa could mediate analgesia.

"Hippocampal binding fits in with the ability of cannabis to affect short-term memory", suggests Pertwee, an idea that is reinforced by in-vitro work showing that CB1 agonists can prevent long-term potentiation--a model of memory. SR141716A, a synthetic CB1 antagonist, improves memory in rats, raising the possibility that this drug could improve memory in cognitive disorders, even ageing.

CB2 receptors are found mainly on immune cells, especially B cells. CB2 activation may cause the alleged immunosuppressant effects of cannabis, but THC alone is unlikely to have a marked effect given that it seems to have low efficacy at CB2. CB2-selective agonists, and more recently, an antagonist, are available, which will help to further investigate the consequences of activating CB2.

Much more remains to be worked out. The effect of whole cannabis is mainly attributed to THC. But, cannabinol and cannabidiol may modulate THC's effects. And cannabidiol, which does not act through CB receptors, has potentially useful anticonvulsant properties. Other exogenous cannabinoids have been "more or less totally ignored", says Pertwee. The function of endogenous cannabinoids also remains a mystery. However, potent inhibitors of anandamide's breakdown and uptake are now available so it may be possible to develop drugs to alter the metabolism or neuronal uptake of endogenous cannabinoids.

So, why is the controversy still raging? "A rational appraisal of therapeutic cannabinoid use has become a casualty of the debate about the legal status of its recreational use", says Wayne Hall, executive director of the Australian National Drug and Alcohol Research Centre in Sydney. "Among supporters of its therapeutic use are some who favour legalisation for recreational purposes. This has led those opposed to its legalisation to deny its therapeutic potential and to block attempts to study it." Hall says that treating cannabis as a special case, either as a benign "wonder drug" or as an inherently evil weed, "makes for uninformed and irrational public policy". Concerns about dependence should be put into perspective with therapeutic opiate use, which rarely results in dependence. And, the so-called gateway effect, in which cannabis is purported to lead on to other illicit drug use, is not supported by the statistics: the 1996 US National Household Survey on Drug Abuse estimated that 101 million Americans used cannabis in the month before the survey.

For groups genuinely interested in therapeutic uses, the position is clear. They are advocating proper trials of individual cannabinoids for specific disorders. Some practical issues remain, such as how to give cannabinoids effectively while removing the risks of smoking cannabis. Pertwee is planning a trial of THC suppositories in multiple sclerosis. Other proposed delivery systems include nasal sprays, skin patches, and inhalers. And, says the BMA, it is important that the medical establishment is enabled by law to carry out these trials. For now, legal systems should act with compassion, sympathy, and understanding when dealing with the thousands of people who "resort to taking cannabis illegally in an attempt to ease their distressing symptoms". But without a legal framework, such court decisions remain controversial (see p 1832).

Ultimately, says Hall, "it becomes a simple matter of weighing the benefits and costs of use". Perhaps once the debate on therapeutic uses has been resolved, the debate on recreational use can then proceed in a similarly rational way, by weighing the benefits and costs of prohibition as a harm-reduction strategy.

Anderson Wachira Kigotho

Tobacco-promotion bans will work

Banning the distribution of cigarette promotional items (CPIs), such as T-shirts, lighters, backpacks, and electronic equipment, would help to dissuade American youths from smoking, say US researchers.

The researchers, from Dartmouth-Hitchcock Medical Center (Lebanon, NH, USA), interviewed more than 1200 students in five rural schools and found that one-third owned a CPI. After control for confounders, such as having family and friends who smoked, students who owned CPIs were more than four times as likely to be smokers as those who did not own CPIs (Arch Pediatr Adolesc Med 1997; 151: 1189-96). Never smokers and experimental smokers who owned CPIs were more likely than non-owners to start smoking in school grades 6-9, a period when children are most vulnerable to starting smoking.

The sale of CPIs in the USA has risen massively, the authors note. Money spent by the tobacco industry on CPIs increased from 77% of its advertising budget in 1990 to 258% in 1994. "It is difficult to conceive of alternatives for limiting the impact of CPIs on children short of an outright ban", say the authors, who support the inclusion of CPIs in US Food and Drug Administration restrictions on cigarette promotion to minors. The tobacco industry is challenging these restrictions in federal court.

In the UK, smoking is increased in boys whose favourite television sport is motor racing (see Lancet Nov 15, p 1474). Conversely, countries such as Finland and New Zealand that have banned tobacco advertising have seen smoking rates fall substantially. Earlier this month, European Union health ministers agreed to phase in a total ban on tobacco advertising and sponsorship by 2006.

Meanwhile, in Massachusetts, USA, where 78% of adults who frequent bars are non-smokers, bar owners could get more customers if smoking were banned. A team from Boston University found that, if bars were smoke-free, 20% of survey respondents said they would go to bars more often, and 10% of people who did not go to bars would start going (Am J Publ Hlth 1997; 87: 2042-44). This could mean 120 000 more customers for bars and clubs in Massachusetts, say the authors.

Karen Birchard

Canadian judge allows marijuana as therapy

A Toronto man is flying high after a judge ruled that it was unconstitutional for police to deprive him of the right to cultivate, possess, and smoke marijuana to alleviate the symptoms of epilepsy.

"I'm sort of overawed by the decision. It hasn't sunk in yet", said an elated Terry Parker on Dec 10. Ontario provincial-court judge Patrick Sheppard ruled that sections of the Controlled Drug and Substance Act were unconstitutional because they deprive Parker of his "right to life, liberty and security of the person" under the Canadian Charter of Rights and Freedoms. "Health is fundamental to the life and security of each person", wrote Sheppard. "It does not accord with fundamental justice to criminalize a person suffering a serious chronic medical disability for possessing a vitally helpful substance not legally available to him."

Evidence indicated that Parker had no major epileptic seizures while taking marijuana in addition to conventional drugs. Without marijuana, he had three to five grand mal and 15-80 petit mal seizures weekly. Sheppard said Parker had to grow the marijuana because it would cost Can$5000 a year to buy, leaving him little money from his disability pension. However, Parker was sentenced to 12 months probation for trafficking, because he admitted to giving marijuana to friends with epilepsy.

The federal Justice minister, who has been under increasing pressure to decriminalise the medicinal use of marijuana, said Sheppard's ruling will be taken under advisement.

Wayne Kondro
From The Lancet WWW site: http://www.thelancet.com/
Copyright 1997, The Lancet Ltd. All rights reserved.