Miracles from the herb that heals?
Outlawed in modern times because of its intoxicant properties, cannabis used to be valued for its medicinal benefits. Dr Sarah Houlton looks at the potential uses for the plant, should its legal status change
Outlawed in modern times because of its intoxicant properties, cannabis used to be valued for its medicinal benefits. Dr Sarah Houlton looks at the potential uses for the plant, should its legal status change
Modern medicine has provided many minor miracles - from antibiotics to antiulcerants. But a single drug that could treat conditions as diverse as glaucoma, multiple sclerosis, AIDS wasting syndrome, stroke, nausea, migraine and colitis would surely be a true miracle drug. Yet these are precisely the claims that are being made for cannabis.
Cannabis has been known for thousands of years, having been mentioned in Assyrian tablets as far back as the seventh century BC. It induces a mild euphoria, hence its popularity as an intoxicant drug, usually in the form of dried leaves and female flower heads (often referred to as marijuana), or hashish, which is the resin the plant secretes.
In addition to its use for intoxication, cannabis has been exploited for medicinal purposes for centuries. Historically used in the Middle East and Asia, it featured in Dioscorides' Herbal in around 60AD. It became increasingly popular in the West from the 16th century, appearing in the English John Gerard's Herbal of 1597 as a treatment for earache and jaundice. Nicholas Culpeper's 1653 Herbal also suggests a decoction of cannabis roots for inflammation, and easing pain from gout, tumours, joints and hips.
composition changes
The army surgeon Dr O'Shaughnessy was responsible for the reintroduction of cannabis into British medicine in 1842. Tincture of cannabis was a common Victorian treatment for numerous conditions, including convulsions, rheumatism, muscle spasms and menstrual pain, and as a sedative. Queen Victoria is rumoured to have taken cannabis for period pains.
However, along with many ancient herbal remedies, it fell into disuse in the past century as modern synthetic drugs were discovered and developed, and by the time the 1932 edition of the British Pharmacopoeia was published, cannabis had vanished from its pages. Cannabis, cannabis resin, and cannabinol and its derivatives are now listed in the UK misuse of drugs regulations, and are illegal for any purpose, including medical. This is in sharp contrast to a number of other illegal drugs, such as heroin and cocaine, which can be used medicinally.
Cannabis sativa contains more than 60 different cannabinoid alkaloids. The most abundant of these, Δ9-tetrahydrocannabinol, or THC, is also responsible for most of the drug's intoxicating properties. Several others, such as cannabinol and cannabidiol, are not intoxicants, but are thought to modify the action of THC. The precise composition of cannabinoids varies from strain to strain, and cross-breeding can alter the proportions. Cannabinoids are lipophilic, giving them a relatively low oral availability. However, they are absorbed extremely rapidly by the lungs after inhalation, and the onset of action is very rapid. The effects wear off within four to six hours, but residual quantities of THC can remain in the body's fatty tissues for several weeks.
THC acts on the cannabinoid receptors, and two subtypes of these have now been identified. CB1 receptors are concentrated in the brain and spinal cord, with some found in peripheral tissue. The CB2 receptors are largely present in the immune system, and are not found in the central nervous system. CB1 receptors are implicated in pain relief, movement control and memory impairment, plus a lowering of body temperature and a reduction in activity in the gut.
modulating activity
The body naturally contains endogenous compounds that act at the cannabinoid receptors, notably arachidonylethanol- amide, also called anandamide, and 2-arachidonyl glycerol, or 2-AG. The discovery of these endogenous compounds has led to the realisation that the cannabinoid receptors are a part of an important physiological control system. Endogenous cannabinoids appear to modulate neural activity by regulating the quantity of chemical messenger compounds released by the nerves within the brain.
This discovery has great implications for the potential of developing novel drugs that act at the cannabinoid receptors, and several synthetic selective agonists and antagonists of the CB1 and CB2 receptors have already been developed.
Until recently, the only adequate clinical data on cannabis as a medicine was from trials on THC and its analogue nabilone as a nausea suppressant in the 1970s. Nabilone is licensed in the UK for this indication, but it is not widely used, largely as a result of more effective drugs: the serotonin antagonists granisetron (Kytril), ondansetron (Zofran) and tropisetron (Navoban). These were introduced in the 1980s, and can be administered intravenously as they are water-soluble. THC itself is licensed in the US as an antiemetic, under the generic name dronabinol and the trade name Marinol.
Of all the potential uses proposed for cannabis in medicine in recent years, the application that has received most attention is in multiple sclerosis. MS is the commonest neurological disabling condition to affect the young and middle-aged, but its precise cause has yet to be established, and it is difficult to treat. It is an autoimmune condition, in which the myelin sheath that protects nerve fibres in the brain, brain stem and spinal cord is destroyed. Disease progression varies dramatically from patient to patient, and common symptoms include muscle spasm, incontinence or urinary retention, and depression.
Because the cannabinoid receptors are implicated in movement control as well as pain, it is possible that drugs that act at these receptors could be of value in the treatment of patients with MS. Reports commissioned by the UK House of Lords and the National Institute of Health in the US have both suggested that formal investigation of the utility of cannabinoid derivatives in relieving the symptoms of MS would be worthwhile.
Several limited clinical observations on the effects of cannabinoids in MS patients have been reported. In 1981, Petro published a study which showed that two patients with MS-related muscle spasms gained symptomatic relief after smoking cannabis.1 A further study a couple of years later showed subjective improvements in five patients, and two experienced improved motor control.2
A double blind placebo controlled crossover study of THC in 13 patients with MS and spasticity showed that doses over 7.5mg gave a significant improvement in the spasticity.3
alleviating pain
“If the full-scale trials are as positive as initial indications imply, then cannabis-based medicines could be available legally for several difficult-to-treat conditions, and our ancestors would be correct in their belief that Cannabis sativa is highly beneficial |
Various different types of pain are thought to be alleviated by cannabinoids. Cannabis was used historically as an analgesic, and it is believed to improve somatic pain, visceral pain and neuropathic pain. It is the last of these that is receiving most attention because it is frequently unresponsive to more standard painkillers like opioids.
Until recently, there had been little clinical research into the use of cannabis in treating pain, but some work has been done on its use in cancer pain. Noyes carried out a double blind controlled crossover study into THC in cancer pain, and found it to have an effect similar to codeine.4 A further study on an analogous compound gave similar results.5
The way in which cannabis functions as an analgesic is now beginning to be understood. The endogenous cannabinoid anandamide has also been shown to control pain, and rats in a study at the university of Naples indicated that the animals released anandamide when cells are damaged, and if given a synthetic compound that blocked the action of anandamide, their reaction to pain was increased and lasted for longer.6 A study in rats at the University of California in San Francisco in 1998 showed that it interacts with the base of the brain, leading to a modulation in pain signals similar to that caused by opiates, implying that, like the opiates, it is a centrally acting analgesic.7
disease response
Recent reports have highlighted the possibility that cannabis may prevent various forms of tumour from developing. Synthetic THC has been shown to eradicate malignant brain tumours in a third of a group of treated rats, and extended the life of another third by as much as six weeks.8 Other studies suggest that it can shrink cancer cells in mouse lungs,9 and that anandamide can affect the DNA proliferation cycle and hence inhibit the growth of human breast cancer cells in vitro.10
Various forms of inflammatory disease may also respond to cannabis treatment. A good example is asthma, which is normally treated with anti-inflammatory steroids that reduce swelling, or bronchodilators that relax the bronchioles. Smoked cannabis (and, though less effective, oral THC) acts as an acute bronchodilator.11 In the inflammatory bowel disorders Crohn's disease and ulcerative colitis, which are generally treated with anti-inflammatory drugs, reports indicate that cannabis can ameliorate symptoms.12
Many other conditions have been reported to respond to cannabis as a medicine. It reduces intraocular pressure in glaucoma patients.13 Anandamide has been shown to relax blood vessels, which may be of use in hypertension.14 Cannabis was historically popular as a treatment for depression, but results from the early, limited trials that have been carried out are mixed, not least because of the known side-effects of cannabis, including, occasionally, paranoia. It appears to increase appetite, and hence may well be useful in treating patients with eating disorders,15 or AIDS wasting syndrome.
The increasing amount of evidence, anecdotal and otherwise, led to the UK government licensing a range of clinical trials on cannabis, and saying that any effective medicines that may result would be legal, subject to the normal licensing laws and procedures.
Leading the way in the clinical study of cannabis is UK company GW Pharmaceuticals. Established in December 1997, it is licensed by the UK Home Office to cultivate, possess and supply cannabis for medical research purposes. It is focusing on several of the cannabinoids, including THC, D9-THC propyl analogue, cannabidiol (CBD) and its propyl analogue, cannabinol, cannabichromene and its propyl analogue, and cannabigerol. Most of GW's research thus far has been directed towards the two most abundant substances, THC and CBD. Because the different compounds interact to modify the therapeutic effect, GW Pharmaceutical's product portfolio consists of a range of cannabinoids in different ratios.
The company's medicines are derived from whole extracts of a selection of varieties of cannabis plants. A big advantage of this approach is that it is relatively fast to implement clinical trials: the first Phase II trial started 20 months after the first crop was planted, and just over a year later the first Phase III trial was initiated. It has already established that a therapeutic benefit can be achieved from a dose too low to induce a 'high'.
clinical trials
Phase III trials are under way for the treatment of the symptoms of multiple sclerosis; cancer pain; and brachial plexus injury, a severe form of neuropathy. GW has recently announced the commencement of four further Phase III trials, looking at pain in spinal cord injury; pain and sleep in MS and spinal cord injury; neuropathic pain in MS; and general neuropathic pain. Further Phase III trials are expected to be initiated later on in the year. The company hopes to be able to apply for regulatory approval in 2003, with the aim of a product being on the market by 2004.
GW is administering the cannabis-based medicine in these Phase III trials using a sublingual spray device. It is also developing a sublingual tablet formulation in-house. The tablets dissolve under the tongue rather than being swallowed, and have already been used in a Phase II trial. A third delivery option is an inhalation device that GW is developing. Inhaled delivery provides extremely fast relief, but the carcinogens associated with smoke pose a problem. This novel device will allow the medicine to be inhaled without the smoke, and GW intends to explore its commercial use in other applications.
A second study being carried out in the UK is being funded by the Medical Research Council. Led by Dr John Zajicek, a consultant neurologist in Plymouth, the three year double blind randomised trial is looking at the effects of THC and cannabis extract in multiple sclerosis patients with significant spasticity in some of their leg muscles. Over a 15-week period, patients are given capsules containing Cannador, Marinol or a vegetable oil placebo, and if they derive benefit from it, they will be able to continue treatment for a further nine months. The Cannador capsules contain cannabis extract, standardised to contain 2.5mg of THC, grown in Switzerland and encapsulated in Germany. The Marinol capsules are the commercially available product from the US, made by Unimed Pharmaceuticals.
The trial hopes to look at 660 patients, and at least two thirds of these have already been recruited since it began in June 2001. If all goes to plan, the results should be published by the middle of 2003.
If the final results of the full-scale trials that have been carried out so far are as positive as initial indications imply, then within the next couple of years we may well see cannabis-based medicines available legally for several difficult-to-treat conditions, such as multiple sclerosis. Our ancestors would be vindicated in their belief that Cannabis sativa is highly beneficial as a medicine.