New Scientist Magazine:

Cannabis: Prescribing The Miracle Weed

Topic: Medical Marijuana

Issue 2485, 05 February 2005, page 38.                                                              www.newscientist.com


By Clare Wilson

The drug can be a lifeline, and a fortunate few may soon get it on prescription. But why has it taken so long?

I have had patients commit suicide because they said life had no meaning for them any more," says William Notcutt, an anaesthetist at James Paget Hospital in Great Yarmouth, Norfolk, on England's east coast. Notcutt specialises in treating patients in severe long-term pain. The causes are varied, ranging from spinal injuries to multiple sclerosis, but most of the patients have one thing in common: existing medicines don't help them.

"It's not just the pain, it's also what it does to your life," Notcutt says. "You've lost your job, you have financial problems, your spouse is fed up. I hear these heart-rending stories of people whose lives are crap."

If there is one thing more frustrating for a doctor than being unable to deal with a patient's problem, perhaps it is knowing that there is a drug that could help - but they are not allowed to prescribe it. For Notcutt that drug is cannabis. Many patients with difficult-to-treat conditions use cannabis to relieve their symptoms, but in most parts of the world that makes them criminals. Otherwise law-abiding citizens dislike having to get their treatments from drug dealers. And the quality of the medication they get that way is variable to say the least.

But in the next few weeks Canadian regulators will decide whether to approve an under-the-tongue cannabis spray called Sativex for multiple sclerosis (MS) patients. As the world's first prescription pharmaceutical made from marijuana, it would at last allow patients to get their therapy in a safe and consistent formulation. The product could become available in the UK in a year or so, and its British manufacturer, GW Pharmaceuticals, is expected to file for approval soon in Australia and New Zealand.

Sativex will not bring any miracle cures, and in countries like the US where official hostility to marijuana is ingrained, patients may have a longer wait for its benefits. All the same, the availability of a cannabis preparation as a prescription medicine will mark a milestone in a decades-long battle by doctors and patients for public acceptance of medical cannabis use.

Marijuana use has a long history. For thousands of years, people have been harvesting the seeds for food and oil, and making rope from the fibres.

The plant is used in traditional medicine all over the world to relieve pain and muscle spasms, to prevent seizures and to aid sleep. It may also alleviate nausea - though it can sometimes trigger nausea in new users - and it can boost appetite.

But the drug is best known for its effects on the mind: it is an intoxicant that makes people feel happy and relaxed, and over the past century its recreational use has become increasingly popular in the west. Cannabis is not very addictive and its harmful effects are mainly on the lungs, from smoking. In some users it can trigger delusions and hallucinations, and there is debate about whether it can cause longer-term psychiatric problems in a small minority. In the early 20th century, most western governments responded to what they saw as the growing menace of marijuana by outlawing it.

As for medicinal use, cannabis came to be seen as an obsolete herbal remedy with unpredictable potency. It disappeared from the US Pharmacopeia and National Formulary in 1941, and the British National Formulary in 1971.

Until the late 1980s, when Notcutt began investigating the medicinal use of cannabis, research on the drug was focused mainly on establishing its dangers to people who used it recreationally, or its effects on animals.

Notcutt's interest grew out of his wish to find something new to deal with his patients' chronic pain. He found repeated references to the drug in historical medical texts on pain relief, and a growing body of research on animals showed that the main active chemical of cannabis, tetrahydrocannabinol (THC), bound to specific receptors in the brain.

In 1982 a form of synthetic THC had been licensed for relieving nausea after cancer chemotherapy, so Notcutt's first step was to investigate this for pain.

He began a small trial in his worst-affected patients, mostly people with spinal injuries. Some of them said THC helped; some of them said it made them feel dreadful. Others said it wasn't as good as the "real stuff". Thus Notcutt was introduced to the underground world of medical marijuana use. Even in sleepy Norfolk he found a small subculture of people who were getting what they viewed as an essential medicine from their local drug dealers.

Notcutt began seeing growing number of MS patients, who said cannabis relieved their pain and muscle "spasticity" - spasms and stiffness - and helped them sleep. The next step, Notcutt says, was to find a better way to give the patients what they wanted. In the early 1990s he and his team began exploring how they might carry out a clinical trial of cannabis.

They immediately ran into difficulties, because of the drug's illegal status and the resulting haphazard supply chain. "Are you going to use any old thing that comes off the Felixstowe docks?" he asks. "What's the quality, how do you standardise it?" They also failed to come up with a safe and effective way to administer the drug. Taken orally, marijuana's potency varies markedly and it doesn't become effective for at least an hour.

Smoke it, and you inhale a bunch of cancer-causing chemicals just as you do when smoking tobacco.

In California, Donald Abrams, an HIV specialist at San Francisco General Hospital, was facing similar problems. He was interested in the possibility that cannabis could help people with AIDS stave off catastrophic weight loss. "They'd get loss of appetite and diarrhoea and just sort of waste away," Abrams says. "It was a terrible way to go." In 1992, synthetic THC was licensed for combating the nausea that is a symptom of AIDS, but, as with MS patients, many found marijuana more effective. Like the English patients, they faced supply problems. After a 70-year-old volunteer helper at his clinic was arrested for giving patients cannabis-laced brownies, Abrams decided to carry out a formal trial of marijuana.

If anything, he faced even stiffer opposition than Notcutt. In 1994 the team asked permission from the US Drug Enforcement Administration to obtain cannabis from a Dutch firm called Hortapharm but was turned down. They next approached the National Institute on Drug Abuse (NIDA), the only domestic body allowed to provide marijuana for research. Again they were rejected, partly because officials said they feared patients might sell their drugs on the street, and partly because the institute was more interested in investigating the harm from recreational cannabis use. A third proposal to NIDA, in 1996, was also turned down.

By then, official attitudes in the UK were showing signs of becoming more favourable to medicinal marijuana. Paradoxically, this stemmed partly from anti-drug sentiment. Increasing numbers of MS patients using marijuana were ending up in court, and many were given light sentences or effectively let off. Concerned that this was bringing drug laws into disrepute, the government started to make positive if cautious noises about legalising medicinal cannabis if a pharmaceutical form of it could be developed.

At the same time, medical research into cannabis was gaining respectability globally as details began to emerge about the cannabinoids our own bodies produce (see "Natural high"). But such research was almost entirely carried out by academics. What pharmaceutical firm would want to risk investing in such a politically controversial and financially uncertain field?

Enter Geoffrey Guy, a businessman with a background in pharmaceuticals who was looking for his next venture. Cannabis's long history ruled out the normal route for making money from a drug: by patenting it as a therapy. But Guy realised he could gain market exclusivity by developing a drug from cloned cannabis subspecies to which he owned the plant-breeders rights. Guy recalls that when he approached government officials for a licence to research his idea, they needed little convincing. "They were almost relieved that a company had turned up," he says. "I was pushing on a door that sprung open."

His new company, GW Pharmaceuticals, bought several strains of cannabis with consistent high drug yields from Hortapharm and by the late 1990s was growing and harvesting a crop of 5000 plants. To avoid the variable absorption of ingested cannabis, the firm decided to produce a spray to be applied under the tongue, where it would be quickly absorbed into the bloodstream. And so Sativex was born.

Notcutt agreed to carry out a clinical trial. But despite increasing public acceptance of the idea of using cannabis medicinally, he found it hard to get the study approved by his hospital.

It took about a year to get the go-ahead for a small three-month study in people, some with MS, for whom existing treatments were ineffective against chronic pain. The results, published last year (Anaesthesia, vol 59, p 440), showed that Sativex provided significant pain relief for 28 of the 34 patients in the study. GW began larger trials on people with MS or chronic pain, as well as pilot studies in people with cancer.

At this point GW began looking for a pharmaceutical company with the muscle and money to help market Sativex. Rumours circulating at the end of 2002 suggested that Guy was in talks with a major-league company, perhaps GlaxoSmithKline or AstraZeneca. Guy won't say, because before the deal was done, the firm got cold feet. They were spooked by the "c-word", Guy says. Cannabis was too controversial for the American board members. GW had to find another partner, and in May 2004 it finally struck a deal with the German-based multinational Bayer.

In the meantime, the larger clinical trials were starting to yield positive results. GW has applied for a licence from the Medicines and Healthcare Products Regulatory Agency (MHRA) to sell the drug in the UK. The MHRA has asked for a "confirmatory study", to prove that the reduction in muscle spasticity seen with Sativex brings meaningful benefits to patients. GW says this will take several months.

But it is in Canada, where patients can legally use cannabis for medicinal purposes, that Sativex is closest to being licensed. The preparation was given preliminary approval in December, and GW and the Canadian regulatory agency are now thrashing out exact terms for a licence to allow Sativex to be sold as a prescription drug. Assuming they reach agreement, Sativex could reach pharmacies within a couple of months. GW says it will be applying for licences in "other Commonwealth countries", probably Australia and New Zealand.

It may not be long before Sativex is joined by other cannabis preparations. A non-profit group, the Institute for Clinical Research in Berlin, Germany, is developing oral cannabis capsules, called Cannador. In November 2003 a study in 630 MS patients produced equivocal results (The Lancet, vol 362, p 1517). While the formal scoring system for measuring muscle spasticity indicated that Cannador performed no better than a placebo, the patients themselves felt it helped. Martin Schnelle, who conducted the trial, says that there are widely acknowledged problems with the formal scoring system used. "There are medicines that are already licensed for treating spasticity that have failed on this scale," he says. The group is planning a further study this year in which the patients' reports will be the main measure by which the drug's effectiveness is judged.

In the US, the NIDA has become more open to research on the benefits of cannabis, and Abrams is studying its ability to ease pain due to nerve damage in HIV, and nausea and vomiting after cancer chemotherapy. He is investigating a device called the Volcano, which heats cannabis to the point of vaporisation without burning it, which he says is less harmful than smoking it in a joint because it releases fewer carcinogens. While Abrams welcomes products like Sativex, he suggests that some people will always prefer marijuana to a commercial preparation - not least because they can grow it themselves.

But however cultural attitudes to street or home-grown cannabis change, its availability in standardised, licensed preparations such as Sativex and perhaps Cannador will be the key to its wider medical use. GW is planning studies of its possible benefits for people with a range of conditions from Crohn's disease to rheumatoid arthritis and heroin addiction. If positive, Canada's decision will signal a big change in the status of cannabis, says Philip Robson, the firm's medical director. "It's the dawning of a new clinical research era."

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