Endogenous cannabinoids could treat multiple sclerosis

As Britain continues to agonise over the politics of treatment for multiple sclerosis, more sophisticated approaches to combat the disease have been developed that could leave today's debates over the cost-effectiveness of some licensed drugs far behind. The new approaches could also overcome worries about the ethics of using cannabis as a treatment for the disease. In the foreseeable future it should be possible to assess an individuals' genetic makeup to target MS therapies for maximum benefit. "We don't know enough yet, but with all the tools becoming available, it is just a matter of time," said Roland Martin, a neuro-immunologist at the US National Institutes of Health, Bethesda, Maryland. Eventually, researchers believe they may also be able to exploit the body's own cannabis-like compounds to help treat the symptoms of MS without the unwanted psychological disturbances associated with cannabis.Multiple sclerosis sufferers in Britain have spent the past few weeks on a roller coaster. After a protracted review process, the National Institute for Clinical Excellence (NICE) — which advises the NHS on best practice for England and Wales — concluded at the end of October 2001 that two licensed immunotherapies, beta interferon and glatiramer acetate, should not be recommended for treatment of the disease. The decision centres on doubts about the cost-effectiveness of the treatments in the long term and what NICE calls their 'modest' benefit to patients. While NICE accepts that patients already receiving the treatments should be allowed to continue, new patients will not be entitled to receive them on the NHS. The Multiple Sclerosis Society, which represents patients, said last week that it would appeal. "While NICE has muddled its way through more than two years of appraisal, hundreds of people have become too disabled to qualify for the drugs," the society said. NICE said it has not yet issued any formal guidance to the NHS on the basis of its decision, but will do so in December 2001, depending on the appeal process.But the Department of Health also threw out a crumb of comfort to patients, confirming that it was in confidential discussions with four manufacturers of beta interferon and glatiramer acetate about ways to provide the drugs affordably to all patients while monitoring effectiveness over a longer period than the two or three years typical of conventional clinical trials. "Our discussions are looking at a range of options, including the possibility of a 'risk-sharing' scheme," said the DOH. Under such a scheme, all patients would be monitored and if the drugs worked, the NHS would continue to pay for them; if the drugs failed, the payments to manufacturers would be reduced on a sliding scale. Patients' groups welcomed the proposals.There was one more piece of good news. David Blunkett, the UK Home Secretary, said that the law could be changed to allow the legal prescribing of cannabis for the treatment of the certain diseases, including MS, if ongoing trials prove the drug is effective. Researchers involved in the trials, such as John Zajicek of Derriford Hospital, Plymouth, who heads a major trial for the Medical Research Council, have welcomed the announcement, saying that patients who might be deterred from using cannabis because of its stigma would now be able to participate in trials. Certain other countries, including Canada and Belgium, have already licensed cannabis for trials for medicinal purposes.Britain's reluctance to use beta interferon and glatiramer has raised the eyebrows of some researchers and clinicians in other industrialized countries. "I can definitely see the argument that there are limited resources and that they should be used to give equal access to health," said Martin at NIH. "But I think the evidence that these drugs really do something beneficial is now firm enough to justify their use." The MS Society estimates that about 2% of Britain's 85,000 MS patients currently receive the drugs, compared with 12 to 15% in northern European countries and the United States. Treatment costs have been estimated at around $10,000 a year but advocates argue that these costs should be set against the lost productivity of working adults and parents disabled by the disease.Few claim that either beta interferon or glatiramer acetate have a spectacular effect on the course of MS; the available data from large trials suggest that they both reduce the number of exacerbations of the disease by about 30% and may delay the progression of disease. But Martin argues that the efficacy of the treatments may appear weak in trials in part because multiple sclerosis patients are a heterogeneous group, some of whom may be genetically predisposed to benefit from certain treatments, others not. As a result, 'responders' and 'nonresponders' are lumped together and any effect on responders is diluted in the overall data. "This disease is genetically very complex and there are maybe 50 or 100 genes that contribute to susceptibility," said Martin. It is too simplistic to assume that one drug fits all, he argued. Instead, tools should be used to tease out differences between individuals, such as gene expression profiling, using new tools such as cDNA microarrays, combined with the use of magnetic resonance imaging to study the disease process as it happens. The resulting knowledge should enable the targeting of combination therapies in the foreseeable future. "When you look at cancer treatments, this approach has been studied much more," Martin continued. "I think auto-immune diseases will be considered in the same way very soon."Back in Britain, researchers are refining the idea of using cannabis to treat multiple sclerosis — and coming up with some intriguing new findings. David Baker and colleagues at the Institute of Neurology, University College London, have found that the body's endogenous cannabis-like substances such as anandamide — meaning 'inner bliss' in Sanskrit — can help to reduce muscle spasticity and tremor when administered to mice with an MS-like condition called chronic relapsing experimental allergic encephalomyelitis (CREAE). Unlike exogenous cannabinoids, such as delta 9 tetra-hydrocannabinol (THC), these endocannabinoids do not seem to produce psychological effects.Equally interesting, Baker's group find that they can reduce tremor and spasticity by using other compounds to stop the normal breakdown and removal of anandamide and other endocannabinoids in the areas where nerve tissues are being damaged. These compounds, synthetic fatty acids, — such as AM404 — selectively block the reuptake of the endocannabinoids, rather as Prozac and similar drugs block the reuptake of serotonin in the brain. "We get the same results as with strong cannabinoid agonists, but without the side effect profile," said Baker. He warns that the approach is still experimental, but believes that pharmaceutical companies are likely to be more interested in this approach than using cannabis itself, even in the light of recent announcements of a relaxation in the law concerning cannabis possession and use.In 2000, Baker's group provided the first solid evidence that cannabinoids can reduce muscle tremor and spasticity in mice with CREAE. The findings strengthened the case for the current trials of cannabis itself as an MS therapy.

Endogenous cannabinoids could treat multiple sclerosis

Cannabinoid research could circumvent the economic debate over the use of beta interferon in the treatment of MS.

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