24 June 2002 15:55
by Jo Whelan, BioMedNet News
A new synthetic cannabinoid could provide symptomatic relief from muscle spasticity and tremor in people with multiple sclerosis (MS), without psychoactive side effects. Ajulemic acid (CT-3) has already completed Phase I clinical trials to determine its safety and tolerability, and has recently demonstrated anti-spastic activity in a mouse model of MS.
Multiple sclerosis is an autoimmune disease in which the myelin sheath surrounding motor and sensory neurones is progressively destroyed. It is the commonest neurological condition in young adults in the developed world. Symptoms result from reduced signal conductivity and vary in type and severity depending on the location and extent of myelin loss.
Muscle spasticity affects about 90% of MS patients at some time and can be extremely painful. Debilitating tremor is also common. Controlling these symptoms is difficult: Drugs used include baclofen, dantrolene, diazepam and tizanidine, but they are unsatisfactory for many patients because of dose-limiting side effects.
Many sufferers find that smoking cannabis provides the best relief. Anecdotal evidence for the anti-spastic and anti-tremor effects of cannabinoids has been backed up by experiments with mouse models of MS. These provided strong evidence that cannabinoid (CB) receptors are involved in the control of spasticity where there is neurological damage.
CB receptors are thought to have a regulatory role in nerve signal transmission at the synapse. Blocking them makes tremor and spasticity worse, although the mechanism for this is not yet fully understood. Research has thus concentrated on developing selective CB receptor agonists that have therapeutic but not psychoactive effects.
Several Phase III clinical trials are under way in the UK using natural cannabis extracts, both in MS and in other indications such a neuropathic pain and appetite enhancement. The main active ingredients in natural cannabis are tetrahydrocannabinol (THC) and cannabidiol. Other researchers are working on synthetic cannabinoids.
Atlantic Technology Ventures (ATV), based in New York City, has developed CT-3, a proprietary synthetic analogue of the THC metabolite, THC-11-oic acid. Initially developed as an alternative to non-steroidal anti-inflammatory drugs (NSAIDs), it inhibits prostaglandin synthesis and has shown analgesic and anti-inflammatory activity in animal studies. In a Phase I clinical trial it produced no clinically relevant adverse events, and no cannabis-like psychoactivity at the doses used.
David Baker and colleagues at University College London's Institute of Neurology have now demonstrated that intravenous CT-3 inhibits spasticity in the chronic relapsing experimental allergic encephalomyelitis model of MS in mice.
"CT-3 produced drastic inhibition of spasticity and limb stiffness at microgram doses, with a very rapid onset of action," said Michael Ferrari of ATV. "The inhibition was relatively long-lived. The mice tolerated very high doses of up to 50mg/kg intravenously, without evidence of psychotropic side effects typical of CB-1 agonists. If you give mice THC at high doses they fall over."
The mechanism of action of CT-3 is unknown, but unpublished research by ATV has shown that, despite its lack of psychoactivity, CT-3 does cross the blood-brain barrier. It does not have a high affinity for either of the known CB receptors, but appears to antagonize some of the actions of THC. "It is a partial CB1/CB2 agonist," says Ferrari, "but we think it might also be acting on a third cannabinoid receptor that has not been cloned yet."
CT-3's analgesic and anti-inflammatory profile is similar to that of NSAIDs, but animal studies suggest it might lack their characteristic side effects. In contrast to NSAIDs, CT-3 caused no gastrointestinal ulceration in mice at therapeutically relevant doses. One potential indication is rheumatoid arthritis, where CT-3 appears superior to other NSAIDs in preventing joint destruction in a rat model.
The development of CT-3 is going ahead on several fronts. A pilot Phase I/II study has just begun in Germany to test its analgesic properties in patients with neuropathic pain. Upon completion of further safety studies to test the higher dose limits of CT-3, a Phase II study will be carried out in tremor and spasticity in MS. The US Army Medical Research Institute for Chemical Defense is also testing CT-3 as a possible treatment for the chemical warfare blister agent sulphur mustard.
"Route of administration is a big issue with cannabinoids, and no one has really cracked it yet," says John Zajicek, a principal investigator in the UK Medical Research Council's Cannabis in MS study, who is consultant neurologist at the Derriford Hospital in Plymouth. "It is difficult to get a consistent dose orally because the high lipophilicity [of cannabinoids] leads to individual variations in absorption, and there is a lot of first-pass metabolism in the liver. Inhalation avoids that, but the technology is difficult and in some studies there has been irritation of the airways."
However, he is optimistic that cannabinoids have a therapeutic role. "I predict that there will be a whole family of synthetic cannabinoids that will be effective in different indications, and hopefully these will have very few psychoactive effects."
Cannabinoids control spasticity and tremor in a multiple sclerosis model
D. Baker, G. Pryce, J.L. Croxford, et al.
Nature, 2000 Mar 404:84-7
acid (CT3): a potent analog of the acid metabolites of THC
Curr Pharm Des, 2000 Sep 6:1339-45
and multiple sclerosis: a blessing from the 'inner bliss'?
Vincenzo Di Marzo, Maurizio Bifulco and Luciano De Petrocellis
Trends in Pharmacological Sciences, 2000, 21:6:195-197
receptors and pain
Roger G. Pertwee
Progress in Neurobiology, 2001, 63:5:569 - 611
receptors and the regulation of immune response
Chemistry and Physics of Lipids, 2000, 108:1-2:169 - 190
© Elsevier Science Limited 2002