THE CANNABIS REMEDYWONDER 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
weedCannabis 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]
9tetrahydroacannabinol (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, antiemetics, 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
receptorselective 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
shortterm memory", suggests Pertwee, an idea that is reinforced by
invitro work showing that CB1 agonists can prevent longterm
potentiationa 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. CB2selective 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
socalled 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 10·1 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
harmreduction strategy.

Copyright © 1997, The Lancet Ltd.

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