Science Spin November 2008

Synthetic cannabis; a wonder drug for MS?

The notion of using cannabis as a therapeutic agent is nothing new. It has been used for centuries as an agent for symptom relief in inflammatory and neuropathic (central nervous system) disorders. Even as early as the 1840s, European and US medical journals had published more than 100 articles on the therapeutic use of cannabis.

People with MS have known about the benefits of cannabis, and have been taking cannabis for many years. In fact, the history of the medical use of cannabis, remarkably, dates back to 2,700 BC. However, the illegal status of cannabis in the US and elsewhere means that clinical research into its positive effects has been limited - to the detriment of medical science and the wellness of patients. However, in some countries, there is a more liberal approach and cannabis today is available by prescription in The Netherlands and in Canada.

Several new studies have been published in recent years in peer-reviewed journals that demonstrate cannabis has medical value in treating patients with serious illnesses such as AIDS, cancer, MS and epilepsy. The focus of my work is in the area of multiple sclerosis, and research here carried out with MS patients has shown that cannabis can alleviate symptoms including pain, blindness, muscle spasms, muscle stiffness and the disabling fatigue that MS patients frequently experience.

MS

Over 7,000 people in Ireland are affected by MS and sadly this number is increasing annually. It is an autoimmune disease of the central nervous system (CNS), which means it is a disease characterised by the body's own immune system attacking the CNS. The CNS is made up of the brain and spinal cord, and this is where many nerves are found. In a healthy person, nerves function to transmit signals or nerve impulses to particular 'target' cells around the body. These signals enable use to move our body parts. However, in a person with MS, the nerves are damaged and this means that the transmission of nerve impulses, or signals, is either stopped, staggered or delayed.

The question that researchers want to answer is what exactly triggers the nerve damage in people with MS? An axon is a slender projection or a nerve cell - a neuron. Surrounding the axons there is a smooth insulating material called the myelin sheath.

Nerves are like an electric cord. An electric cord contains wires and surrounding the wires is the plastic insulation material. The plastic contains the transmission of electrical impulses through the wires. Similarly, with nerve cells, the 'wires' are the axon, and the plastic is the myelin sheath. The sheath, like the plastic of the electric cord, functions to contain the transmission of nerve impulses to target cells around the body.

MS, as already stated, is an autoimmune disease. In people with MS, the body's own white blood cells - the cells that are normally in the front line fighting disease - begin to attack the myelin sheath. When that starts to happen, holes soon appear in the myelin sheath, the layer protecting the axons. The axons are, thus, exposed, and begin to suffer damage. The attack on the myelin sheath is called an 'MS attack'.

Impact

This attack will start to have an impact on the brain. The human brain is divided, roughly, into four lobes; the frontal lobe, the parietal lobe, the occipital lobe and the temporal lobe. Each lobe has different functions. For example, the frontal lobe is involved with speech and muscle activity, and the occipital lobe's function is to provide us with the ability to see. If the white blood cells attack the nerves of the frontal lobe, the person with MS will begin to experience problems with their speech and muscle functions. The nature of the MS, thus, is determined by the nature of the MS attack.

MS is a progressive disease consisting of four main stages, where each stage is characterised by periods of relapses, where symptoms appear, and remissions, where symptoms disappear. The severity of the disease and a person's progression into the more chronic stage depends on the intensity of the attack on the myelin sheath. This means that those unfortunate people who experience several intense MS attacks, can rapidly progress from stage one to stage four of the disease within a few years.

There is no cure, at the moment, for MS. The majority of treatments that are out there at the moment work by decreasing the intensity of the attack on the myelin sheath, and, thus, can reduce a person's progression into a more chronic relapsing stage. There are also treatments available to target the specific symptoms experienced by people with MS. But, there is nothing to inhibit disease progression that also targets MS symptoms.

Cannabis

In the 1960s, the active ingredient of the cannabis plant was discovered, and named delta9-tetrahydrocannabinol, or ∆9-THC. This is what gives cannabis users the 'high' associated with inhaling cannabis smoke. Later, other active substances were found in the cannabis plant. These included cannabidiol (CBD) and cannabinol (CBN). These two active substances belong to a group of lipid soluble chemical messengers called cannabinoids.

Scientists then discovered that cannabinoids bind to receptors in the brain which are called cannabinoid receptors (CB). This binding induces a signalling cascade in the brain, which ultimately leads to the 'high' sensation and the enhancement of appetite that cannabis users often experience after ingesting cannabis.

It was presumed that these receptors didn't just exist for providing people with a 'high' and so scientists went about searching for the real function of CB. These investigations in turn led to the discovery of two cannabinoid receptors called CB1 and CB2 in the early 1990s. CB1, it was found, is predominantly expressed in brain cells, while CB2 is mainly expressed in cells of the immune system, for example the white blood cells.

Benefits

Research has shown that MS patients who smoke or ingest cannabis orally have reduced muscle spasms, sleep better, therefore have less fatigue, have an increased appetite and also a reduction in their joint pain due to lack of mobility. In mouse models, it has also been shown that t ∆9-THC exerts anti-inflammatory effects.

Against this, there are side effects to ingesting cannabis that must be taken into account, and people with MS need to weigh these against the proven benefits. The side effects include dizziness and paranoia, and there is some evidence that people with a history of schizophrenia might experience a worsening of their symptoms. There is also a high risk of cancer from smoking cannabis. This is not due to the presence of cannabinoids, but because cannabis cigarettes are smoked without filters, and thus carcinogenic chemicals are not being filtered out at all during the smoking process.

Researchers have wondered, whether, given the many positive effects of taking cannabis, could the negative side effects be eliminated? The other thing to consider was the legal issues related to acquiring cannabis. Would this be a barrier that would prevent scientists investigating the therapeutic effects of cannabis in MS patients?

Synthetic

Cannabinoid researchers at the Institute of Immunology at NUIM got around the issue of acquiring cannabis by producing synthetic cannabinoids that would form the basis of research. Synthetic cannabinoids are structurally similar to herbal cannabinoids, and the synthetic cannabinoids have been found to possess many of the same therapeutic properties as herbal cannabinoids.

But, and this is the key, the structure of the synthetic cannabinoids can be changed to eliminate the side effects that are associated with herbal cannabis. It is possible for researchers to design a synthetic cannabinoid where none of the negative side-effects caused by the herbal cannabinoid are displayed.

A team of researchers, including this author and led by Professor Paul Moynagh have demonstrated that a synthetic form of cannabinoids, namely R(+)WIN55,212 can decrease the levels of certain proteins involved in the migration of the white blood cells into the CNS. Blocking the migration of the white blood cells ultimately leads to a reduction in the MS attack on the myelin sheath.

It has also been shown that the drug can decrease the activation of various transcription factors (these factors are proteins that regulate gene expression) that are involved in the production of proteins that contribute to an MS attack.

Ultimately, the goal of researchers would be to carry out similar research in humans. Numerous groups at this point have demonstrated the beneficial value of cannabinoids in the treatment of MS patients, including those who have failed to improve on current treatments.