Cannabinoid agonists may provide new strategies for treating malignant glioma, a fatal form of brain tumour. In addition, a rationale for their use to treat muscle spasticity and tremor in patients with multiple sclerosis (MS) may have been found.
The potential use of cannabinoids for glioma is indicated by results of a study by Dr Ismael Galve-Roperh (department of biochemistry and molecular biology, Complutense university, Madrid) and colleagues (Nature Medicine 2000;6:313).
Tumours were induced in 45 rats by direct injection of glioma cells into the right hemisphere of the brain. Of the 45 rats, 15 were left untreated, 15 were given tetrahydrocannabinol (THC) and 15 received WIN-55,212-2, a potent synthetic cannabinoid agonist, both of which were infused into the location of the tumour. All of the rats that were untreated died within 18 days after inoculation with glioma cells. Nine of the THC group survived for up to 35 days and there was complete tumour eradication in another three. In the WIN-55,212-2 group, four rats survived for up to 43 days and there was complete eradication in five.
The authors found that cannabinoids have a direct antitumour action and a competent immune system is likely to favour complete eradication. THC induces apoptosis (programmed cell death) of transformed neural cells, possibly through sustained accumulation of ceramide and activation of extracellular kinase cascades, they say. THC and other cannabinoids are thought to exert their effects through two receptors, CB1 and CB2, both of which are involved in the antitumour effect of cannabinoids. The researchers suggest that CB2 agonists might be of particular interest as they are less likely to produce psychotropic effects than CB1 agonists.
Commenting in an accompanying editorial (ibid, p255), Dr Daniele Piomelli (department of pharmacology, University of California, US) says that, although incomplete, the findings must be "seriously considered", as glial tumours are "peculiarly resistant" to traditional therapy. The risk of typical cannabinoid side effects may be outweighed by therapeutic advantages and eventually be overcome through the development of CB2-selective agonists. The bleak outlook for glioma patients at present, he says, "should provide sufficient motivation to continue the studies".
Dr David Baker (Institute of Neurology, London) and colleagues report in Nature (2000;404:84) that data from a study on mice "provide compelling evidence" that cannabinoid receptors are involved in the control of spasticity, and that receptor agonists may be beneficial in patients with MS.
They describe how cannabinoid agonists, including THC, ameliorated both frequency and amplitude of tremor in a mouse model of MS. However, this effect was eliminated if the animals were pre-treated with selective CB1 and CB2 antagonists. When mildly spastic mice, which had no tremor, were given a CB1 antagonist, significant spasticity and tremor developed. If they were then given a CB2 antagonist, spasticity increased further. This suggests that both CB receptors control spasticity, they say.
Dr Baker and colleagues conclude that the data "provide evidence for the rational assessment of cannabinoid derivatives in the control of spasticity and tremor in multiple sclerosis, in placebo-controlled trials". They add that it may be difficult to dissociate the beneficial effects of CB1 agonists from their less desirable effects but that selective CB2 agonists may provide some benefit, without significant psychoactive effects.