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Medical Cannabis Is A Blunt Tool
Medical News Today | 07/28/2006

If anecdotes and ancient medicine are to be trusted, cannabis is a wonder drug. Yet results of clinical trials have been mixed and its use in modern medicine remains limited. Now it seems the reasons may be practical as much as political and cultural: there are fundamental problems with how our bodies respond to the stuff.

Some compounds in cannabis, including THC and cannabidiol, interfere with a natural signalling system throughout our brains, nerves and immune system. This system, which produces its own cannabis-like compounds called endocannabinoids, plays a role in many medical conditions including pain, epilepsy, multiple sclerosis, Parkinson's disease, depression and schizophrenia.

Because the system is so widespread, smoking or ingesting cannabis is bound to have varied effects, including its influence on the mind. Now it seems that even with purified cannabis extracts, changing the amount, time or place of a dose could produce completely opposite effects on the body, according to evidence presented at the Federation of European Neuroscience Societies (FENS) meeting in Vienna earlier this month. This could explain why the medical benefits have proved so difficult to harness.

In one study, Vincenzo Di Marzo of the National Research Council in Pozzuoli, Italy, boosted levels of an endocannabinoid called andandamide in rats engineered to develop an Alzheimer's-like disease. This appeared to protect the rats from memory loss and nerve degeneration. But if the rise was prolonged, cannabinoids became ineffective or even damaging.

Beat Lutz of the University of Mainz in Germany found a similar paradox in models of epilepsy in mice. Anandamide is synthesised during epileptic fits, providing a natural calming effect. “If we apply cannabinoids we should protect from seizures,” says Lutz. “But no, we actually get worsening of seizures in mice.”

He believes he has found the reason. The main class of cannabinoid receptor, called CB1 receptors, occurs in two distinct populations of neurons, those that excite neighbouring neurons and those that inhibit them - so cannabinoids can have opposite effects depending on which neurons they hit. David Baker, a multiple sclerosis expert at University College London has found the same problem in MS. Mice that have been engineered to have a condition like MS and no CB1 receptors suffer much worse nerve damage than those with normal CB1 receptors, suggesting that cannabinoids are involved in protecting against the nerve damage seen in MS. But other experiments in mice have shown that cannabinoid signalling also prompts release of stress hormones called glucocorticoids that can kill neurons.

The greatest anecdotal evidence for the medical benefits of cannabis comes from its painkilling properties, and animal models have produced promising results. Yet even here new evidence suggests that an endocannabinoid called NADA binds not only to cannabinoid receptors but to a completely different class of receptor as well, where it mimicks the effect of a pain-producing chemical called capsaicin, says J. Michael Walker of Indiana University in Bloomington, who also presented his research at FENS. This may explain why human trials of cannabis for the treatment of pain have produced mixed results.

“The problem with cannabis is that there's no way of targeting the drug to any particular place,” says Baker.

The answer will be to manipulate the system from within, he says. New ways of amplifying natural cannabinoid release include reuptake inhibitors that prolong this release just as Prozac does for serotonin. Such methods look promising for a range of conditions from pain and cancer to nerve degeneration and MS.

Other methods now being tried in the lab include the manipulation of enzymes that make and deliver endocannabinoids, as well as compounds that stimulate and block them. Drugs that bind to CB1 receptors and alter their efficiency are also being discovered, says Roger Pertwee, director of pharmacology at GW Pharmaceuticals, based in Porton Down Science Park, Wiltshire, UK. His company developed Sativex, the first pharmaceutical cannabis extract to gain clinical approval.

Ironically, the first offshoot of endocannabinoid research to gain clinical approval, last month, has the opposite effect to cannabis: Acomplia (rimonabant), an appetite suppressant, works by blocking CB1 receptors (New Scientist, 8 July, p 5).