David Watson, the Director of HartaPharm, a small company in the Netherlands, is standing in the company's small laboratory on the banks of a quiet canal in Amsterdam. It looks like a school science lab, but one thing betrays the illusion - the sweet aroma of cannabis in the air.

Watson's dream, first conceived on a trip to India many years ago, is to make medicines from the cannabis plant. "I saw how it was widely used in Ayurvedic medicine to treat diarrhoea and vomiting, and I became convinced that it could be of use in the Western world." Watson moved to the Netherlands ten years ago to set up HortaPharm, one of the few companies in the world working to develop cannabis therapeutics. He chose the country because "it was more open to the idea that cannabis could have medicinal purposes". (The Netherlands decriminilised cannabis for recreational use in 1976.)

The medicinal use of the cannabis plant is contraversial - particularly when it is smoked - but the development of its constituents, known as cannabinoids, into licensed pharmaceuticals should not be. Watson is keen to stress that the goal of his company is to achieve the latter, but he believes the recreational use of cannabis has obscured its medical benifits to such an extent that the pharmaceutical industry is afraid to touch it. He says: "The pharmaceutical industry can smell the profits - they want to make the money but they don't want the baggage that comes with it."

For many years, most of the people doing research in this field have been academics who have difficulty getting funds, or permission to grow cannabis, for their research. But now, albeit slowly, there are some signs that things may be beginning to change.

"Ten years ago, this idea was pie in the sky," Watson says, but two important things have happened in the past decade which may just herald a turning point.

First came AIDS, and a group of patients who demanded that new drugs be developed to tackle their disease. When AIDS patients with wasting disease discovered that smoking cannabis stimulated their appetite and helped them put on weight, they didn't care whether society approved or not. Anecdotal evidence began to emerge of the benifits of smoking cannabis in a number of other conditions: for the prevention of nausea and vomiting associated with cancer chemotherapy; in the eye disease, glaucoma; as a pain reliever; and for neurological disorders such as multiple scelrosis (MS). Later on came suggestions that at least some constituents of cannabis could be of use in epilepsy, anorexia, asthma, hypertension and various mood disorders.

The second important event was the discovery of endogenous cannabis receptors and an endogenous cannabis-like compound - anandamide - in the human body. These findings gave credibility to the concept of cannabis as a medicine, which had always been treated with some scepticism by mainstream science. However, as yet, large pharmaceutical companies have still not dared to venture into cannabis territory - bar a very few attempts - for fear of tarnishing their corporate images. But are they missing out on a huge marketing opportunity - trawling the world's oceans and combing its rainforests for new drug sources, when all the time cannabis is staring them in the face?

The botany

The Cannabis sativa plant contains over 400 chemical compounds and more than 60 cannabinoids. However, Dave Pate, a botanist/chemist and Senior Technical Officer at HortaPharm, says "in reality, there are only small quantities of, at most, a few dozen terpenes and only three or four cannabinoids present in significant quantities in any one plant". He calls these "the big four": delta-9-tetrahydrocannabinol (THC), the most potent psychoactive agent in the plant, which is usually dominant in the C sativa species from tropical countries; cannabidiol (CBD), which is found in greater quantities in plants grown in temperate regions, lacks the psychotropic properties of THC and may have anticonvulsant, anxiolytic and analgesic effects; cannabichromene (CBC); and cannabigerol (CBG). The last two are found in small quantities and are thought to have antibacterial and fungicidal properties, Pate says. THC, as well as being the most psychoactive component of the plant, is also responsible for many of the other pharmacological actions of cannabis.

One of the physical properties of cannabinoids - their lipophilicity - may have worked against them when it comes to medicinal use - because of their insolubility in water it has been difficult to formulate pharmaceutical preparations. An oral preparation of THC, formulated in sesame oil, is licensed in the US and some other countries, as dronabinol (Marinol; marketed by Unimed), for use as an anti-emetic and appetite stimulant. But the problem with an oral preparation of THC is that absorption of the drug varies greatly between individuals and it undergoes first metabolism in the liver. Patients say they get a much quicker and more effective reponse, with fewer unwanted side effects, from smoking herbal cannabis. Therefore the way ahead probably lies in developing other methods of administration, such as cannabis aerosols and pure cannabinoid metered-dose inhalers.

The history

The use of cannabis as a medicine dates back to ancient times - there are written records of it being used in China as far bask as 2700 BC. It is mentioned in the 8th Century Hindu Medical Text, The Sucrutu, and the Romans introduced it into Europe, where it was widely used until the beginning of this century. Quenn Victoria's personal physician prescribed it for her menstrual cramps, and wrote in the first issue of The Lancet that 'when pure...it is one of the most valuable medicines we possess'.

Yet early in this century, cannabis started to cross a psychological barrier in people's minds, from being a drug of use to a drug of abuse. In 1924, at the second International Opiates Conference, cannabis was declared a narcotic and strict international control was recommended. Cannabis was dropped from the American Pharmacopoeia in 1941, and in 1961, the narcotics division of the United Nations called it "a drug of misuse with no therapeutic benifit".

During the flower power decade of the 1960s, smoking cannabis became a way of making a political statement, and it was the backlash against this which resulted in the harshest government controls. In 1971, the UK Misuse of Drugs Act listed cannabis as a Schedule 1 drug (ie a compound having no therapeutic benifit), despite the recommendations of an earlier report that it should continue to be available on prescription for "purposes of medical treatment and research". In the same year, President Nixon also put cannabis in Schedule 1 and declared drugs "America's public enemy number one". (In the US, cannabis is more commonly known as marijuana, and the two terms will be used interchangeably throughout this article.)

The scientific evidence

The discovery of endogenous cannabinoid receptors in 1988 - termed CB1 and CB2 - showed the way in which cannabis and its constituents exert their pharmacological effects in the body. CB1 is found primarily in the central nervous system but also in peripheral nerves, while the CB2 receptor has been detected in organs such as the tonsils and spleen and immune cells, such as macrophages. This discovery raises the possibility of developing selective cannabinoid agonists and antagonists, for use as either pharmacological tools or therapeutic agents. Dr Roger Pertwee of the University of Aberdeen, UK - a prominent cannabis researcher speaking at a Royal Pharmaceutical Society of Great Britain (RPSGB) Conference on the therapeutinc applications of cannabinoids held this summer - said that, "for drug companies the CB2 receptor is perhaps the more attractive", because compounds interacting with it would not be expected to exert any CNS activity.

Shortly after the identification of the cannabinoid receptors, the first endogenous sunstance shown to bind with them was discovered in Jerusalem. Secreted from neurones, it was called anandamide, after the Sanskrit word word for 'bliss'. This summer, two more advances were made by a team at the Scripps Research Institute in La Jolla, California. Firstly they idnetified a second endogenous cannabinoid, called 2AG, which is present in about 175-fold greater amounts than anandamide. Stimulation of the hippocampus region of the rat brain resulted n large amounts of 2AG with no change in the concentration of anandamide.

Secondly they were able to synthesise a compound which inhibited anandamide transport into neurones and glial cells in the brains of mice, in much the same way that serotonin-reuptake inhibitors prevent serotonin from being broken down. The compound, given alone, had no affect but when administered with anandamide it potentiated the latter's effects. All of this work shows that the tools to respond to cannanbis are undoubtedly present within the human body, and it is likely that a whole system of yet unidentified cannabinoid receptors and anandamide-related substances will be discovered in years to come.

Cannabis vs cannabinoids

Although everyone in the field agrees that the ideal answer is to develop individual cannabinoids into medicines, or make synthetic cannabinoids or related compounds (eg agonists, cannabinoid reuptake inhibitors), in the meantime there is still a need to examine the value of smoking marijuana as a medicinal aid for the patients who do not have time to wait for cannabinoid phearmaceuticals.

Andrew Coldwell, a 50-year-old British man, who has multiple sclerosis and smokes about ten 'joints' (cannabis rolled up in cigarette paper with tobacco) every week to relieve his muscle spasms, at a cost of around £30. "I was diagnosed with MS about 14 years ago, and five years ago I was in a conversation with some friends at a local club. A couple of them said that they have heard that cannabis was good for MS, and suggested that I try it." One of them smoked cannabis recreationally and gave Coldwell a joint, which he kept for a while because, he recalls, "I was rather sceptical about the whole thing."

Then one day he had a severe attack of muscle spasms, "like the twisting of a metal bar in my calf muscle...it was excruciating." He had tried all the conventional therapies, including the muscle relaxant baclofen, and his doctor at the time had even given him an injection of morphine. In desperation he decided to smoke the joint. "Within ten minutes my muscle spasms had stopped. For the first time in four days I had a good nights sleep and, ever since then, I've smoked cannabis whenever I nedd it."

Coldwell is well aware of the problems surrounding his cannabis use, which is illegal in the UK. His biggest problem is getting hold of the drug. Because it is illegal, he must go to a dealer to get his supplies and cannot always be sure of the quality of cannabis he gets. "I don't want to be buying my drugs from an illegal peddler," he says, "I've been offered cocaine and heroin from such people in the past." Also, because Coldwell adds tobacco to his joints, he has started smoking cigarettes again, something he regrets. For these reasons he supports the UK organisation ACT - Allinace for Cannabis Therapeutics.

ACT is a pressure group lobbying for a change in the UK law to allow patients to receive cannabis on prescription; they want it to be moved from Schedule 1 to Schedule 2. They also want to see pharmaceutical companies doing research into cannabinoids and developing delivery devices whereby patients could use cannabis plants material for therapeutic purposes without having to smoke it.

The people at HortaPharm say they may be able to help patients like Coldwell, if they can get ther backing they need. Pate says there are three reasons why medical science doesn't like cannabis as a medicine. "Firstly, it likes single component medicines, secondly it wants reproducibility in any drug source rather than variablility, and lastly it doesn't like smoke in people's lungs. We've answered all three questions," he says. By cross-breeding different species of C sativa, HortaPharm has managed to produce plants which have a ratio of THC to all the other cannabinoids of over 95-1. In this way they can more easily extract and purify THC, which is actually the main aspect of their business at present (they have a 20-year contract to supply raw THC to a large, unnamed pharmaceutical company). In the same way they can also breed plants expressing high quantities of the other cannabinoids, and very low quantities of THC, for example.

Some of our specimens are, for all practical purposes, single component plants," Pare maintains. Using analytical techniques, they can show the reproducibility of their crops - acres of cannabis plants with the same chemical profiles. Furthermore they have developed a vapourisation device which volatises nearly pure THC from this plant material, which people can then inhale without the smoke (a patent is pending on the device). Pure THC, Pate claims, "is harmless to human cells - it is the combustion artefacts from smoking cannabis which confuse the picture".

In fact, the relevance of Pate's last point depends on the type of patient using cannabis. If, for example, they are using it for six weeks to prevent nausea and vomiting during a course of chemotherapy, smoking joints and inhaling smoke may be acceptable; they are not likely to get lung cancer from this short-term exposure. But if the patient is someone like Coldwell, who may well be smoking cannabis for decades, then the issue of lung damage becomes more important.

The patients' argument, however, is that each person should be able to make up his or her own mind, based on a balanced assessment of the risks and benefits, without having to worry about breaking the law. After all, they are the ones suffering and, for the most part, they have usually tried every pharmaceutical on the market before they resort to smoking cannabis. Although they want to see a properly formulated, effective cannabis pharmaceutical, they know this will take time to develop and they want the right to smoke cannabis in the meantime.

Elsewhere around the world, patients feel similarly but the law, with a few exceptions, is the same is as in the UK. In Italy, those who need canabis for therapeutic purposes are allowed to grow their own supply once they have a certificate from the local authority. However in the Netherlands - where smoking cannabis recreationally is not illegal - an ironic situation now exists. The Health Inspectorate this summer banned the prescription of cannabis on the basis of a 1996 report from the Dutch Health Council which concluded that cannabis did not have any medicanla benefit. Dutch patients now have to got to the famous 'coffee shops' and purchase their supples in the same way as anyone who wants to smoke cannabis for pleasure. This example, perhaps, more than any other, illustrates the hypocrisy and confusion which reigns on medicinal cannabis the world over.

Last year, the US state of Arizona passed a law allowing doctors to prescribe any drug in Scedule 1, and Californian voters approved a state law eliminating criminal penalties for those who grow or use small amounts of cannabis for medical purposes, and permitting doctors to prescribe cannabis.

But under US Federal Law, marijuana is still an illegal narcotic, and the Clinton Administration is unhappy with the situation in California and Arizona; in December last year four high ranking US officials - including the US 'Drug Csar' General Barry McCaffrey, Attorney General Janet Reno and Secretary of Health and Human Services, Donna Shalala - stood before television cameras threatening doctors who recommend or prescribe Schedule 1 substances with "administrative action by the Drug Enforcement Agency to revoke the practioner's registration".

McCaffrey argues that the acceptance of medicinal marijuana use will encourage teenagers to experiment with the drug, which he believes is a "gateway drug" to hard drugs such as heroin. His arguement is that if people, particularly children, believe marijuana is a medicine, they will naturally assume it's safe to use recreationally and marijuana use will go up. This will then lead on to greater use of, and addiction to, hard drugs and so forth.

Although there are some data to support this - a paper in the journal, Science, this summer showed that the long-term administration of a cannabinoid, followed by subsequent withdrawal, stimulated corticotrophin-releasing factor in the brain in a manner similar to that seen with other 'hard' drugs of abuse - most evidence points to the contrary. In the Netherlands, for example, where recreational cannabis use has been tolerated since 1976, there are fewer heroin addicts per capita than most other countries where cannabis use is illegal. HortaPharm's Watson sys, "if marijuana is a gateway drug, show me the 70 million heroin or cocaine addicts in the US" - there are thought to be this number of recreational cannabis users in that country. (In reality, there are estimated to be about two million regular heroin and cocaine users in the US.)

In April this year, however, a Federal Judge issued a preliminary injunction barring the US government from threatening or taking any action against doctors who recommend marijuana to their patients. And an editorial in the prestigious medical journal, the New England Journal of Medicine, sprang to the Californian doctors' defence, calling the government's policy 'misguided, heavy-handed and inhumane'. The government suddenly realised it must tread very carefully, or it would look like it was targetting firstly, a group of patients, many of whom were terminally ill, and secondly, doctors, who are generally held in high esteem by the general public.

In February, the US National Institutes of Health (NIH) convened an expert panel to discuss the possible medical uses of marijuana. At the meeting, AIDS activists said the discussion was little more than a stalling tactic to keep the initiatives in Arizona and California "in limbo". Patients gave testimony on their experiences with marijuana and asked the Federal government to expedite research by moving the drug from Schedule 1 to Schedule 2 of the Controlled Substances Act. The panel eventually concluded that marijuana warrants further study in the treatment of AIDS wasting syndrome, glaucoma, neuropathic pain and nausea from cancer chemotherapy; its full report was published in August.

The report made three major recommendations: that the NIH make marijuana easily accessible to researchers, that a pure form of it be used for human clinical trials; and that marijuana should be used as 'add-on' therapy and not a primary medication. It also noted that, 'The scientific process should be allowed to evaluate the potential therapeutic effects of marijuana for certain disorders, dissociated from the social debate over the potential harmful effects of non-medical marijuana use.' In October, a further suprise came. The NIH announced it would provide almost US$1 million in funding for a study of smoked marijuana.

Does this represent a U-turn in US policy? It is unlikely that the report would have been published without the blessing of federal government, but only time will tell whether the tide really has turned. At the very least, the report has enabled much needed research to begin. Donald Abrams, University of California San Fransisco Professor of Medicine at the UCSF AIDS Program, and his team are the recipients of the US$1 million to study the effects of marijuana in HIV-infected patients, after a five-year struggle to get their work off the ground.

Just as important as the money is the supply of marijuana needed for the study; in the US, the latter is exclusively controlled by the NIH. Abrams will compare HIV-infected patients who smoke marijuana, with patients taking an oral tanlet of Marinol (THC in sesame oil), with a control group taking neither. All the patients will also be taking Merck & Co's indinavir (Crixivan), and one of the aims of the study is to see whther smoking marijuana or taking Marinol alters the safety or activity of the protease inhibitor.

Abrams says that the most important factor in getting his work approved was public opinion: "Barry McCaffrey's fiasco [last year] did more to get this study funded than anything else [and] there was a lot of pressure from medicine to figure this out."

UK doctors

Meanwhile, the UK doctors' union, the British Medical Association (BMA), last month issued an in-depth report on the therapeutic uses of cannabis. The BMA stopped short of recommending the smoking of herbal cannabis with 'unkown concentrations of cannabinoids or other chemicals'. But it did note that 'while research is underway...prosecuting authorities should be aware of the medicinal reasons for the unlawful use of cannabis by those suffering from certain medical conditions for whom other drugs have proved inneffective' - in effect a call for the authorities to 'look the other way' on the issue of smoking cannabis for therapeutic purposes.

Among the BMA's other recommendations were: that the regulation of cannabis and cannabinoids should be sufficiently flexible to allow such compounds to be researched without a Misuse of Drugs Act licence needing to be issued by the UK Home Office; that the World Health Organisation, should advise the UN Commission on Narcotic Drugs to reschedule certain cannabinoids under the UN convention on Psychotropic Substances; that pharmaceutical companies should undertake research and develop novel cannabinoid analogues which may lead to new clinical uses; and that the industry, together with patient groups, the Clinical Cannabinoid Group chaired by Dr Pertwee, and the Department of Health, should work together to encourage properly conducted clinical trials.

The BMA's report also includes moving accounts of how cannabis has helped a number of patients suffering from such diverse conditions as cancer, migraine, epilepsy, depression and rheumatoid arthritis. One of these is actually an extract from a patient's testimony when she was tried in court for growing cannabis for her own medical use. Without exception, all the patients describe how the drug had a profound effect, for the better, on their varying symptoms.

Industry's role

So, the patients are calling for research into cannabis, the doctors are calling for it, the media is interested and governments appear to be softening on the issue. Is it time for a big pharma to dip its toes into the water?

The first, and quickest way, of making cannabis available to patients in an acceptable form will be to develop alternative delivery devices for the herbal plant material, as HortaPharm has done. By using its specially bred plants it can ensure reproducibility in its source material. Other possible ways of delivering THC without it undergoing first pass metabolism in the liver (as is in the case with oral preparations), are rectal suppositories and skin patches. In its November report the BMA says that "research in this area is badly needed...[otherwise] patients will resort to illegally smoking cannabis."

But another concern is the possible infection of C sativa plants by pathogenic fungi such as Aspergillus species. This should not pose a threat to immunologically competent patients but could certainly be a risk for late-stage AIDS patients or those on chemotherapy. HortaPharm believes it has circumvented this issue by developing an effective method for sterilising its plant material.

The company is working on anandamide, the endogenous cannabinoid found in man. It had patents issued in the US in May of this year for the use of anandamide for glaucoma, and a means to solubilise this lipophilic compound in aqueous solutions. It has also developed analogues of anandamide which appear to be even better at controlling intra-ocular pressure, but it needs a partner to be able to take this work forward. "We're flirting with a couple of companies...but that's all it is at this stage," says Pate.

The extend to which industry at large is interested in cannabis is very hard to ascertain. At the RPSGB meeting in July, there were delegates from a range of companies, from bug firms like Merck Sharp & Dohme, Glaxo Wellcome, Rhone-Poulenc and Organon, to smaller ones such as Cephalon, Phytopharm and HortaPharm. But if big pharma is doing any research in the are it is keeping very quiet about it. A search on PJB Publications drug database, Pharmaprojects, reveals only a few compounds in development based on cannabis.

As well as Unimed's formulation of THC, Marinol, a synthetic analogue of THC, nabilone (Cesamet) is available in some markets as an anti-emetic. Originally developed by Lilly, the product is now marketed by Cambridge Laboratories.

The Israeli company, Yissum, also appears to be working on the endogenous compound, anandamide, for a number of indications, and says it has Israeli patents pending on a number of uses.

Moving on to cannabinoid receptor modulators, the most advanced seems to be an antagonist, SR-141716A, from the French company, Sanofi, which is in Phase I trials as a neuroleptic and for dependence treatment. Lilly was also working on a similar compound for dependence treatment but no development has been reported on this compound since last year, when it was in preclinical trials.

Cannabis receptor agonists do not fare much better. The US company, Pharmos, is developing dexabinol (HU-210(, a synthetic cannabinoid with NMDA receptor antagonist activity, for stroke, head trauma, spinal cord injury and glaucoma. Some Phase II trials are underway with the compound but the company needs commercial partners to continue development. Merck & Co is investigating a series of indole derivatives as cannabinoid agonists for glaucoma, but this is at an early stage.

All in all, there's very little activity in this area but, hopefully, pharmaceutical companies are now beginning to come around to the idea that cannabis-derived therapeutics, and their analogues, could be big business. Watson believes that governments will never condone the use of smoked cannabis and that the way forward unquestionably lies in the development of cannabinoid-based pharmaceuticals.

From his small base in the Netherlands he sees the challenge in "David versus Goliath" terms. "We're trying to set the groundwork," he says, "but think about it...if only one application [of THC] could be as an appetite stimulant for anorexics...we're talking baout a market worth hundreds of million of dollars." For any smart pharmaceutical company executive, his words are food for thought.

Lisa Nainggolan is Products Editor of Scrip World Pharmaceutical News.