"Therapeutic Applications of Cannabinoids"

        On July 8, 1997 a historic one-day symposium on the therapeutic applications of cannabinoids was held at the Royal Pharmaceutical Society of Great Britain. The symposium was organized by the Society’s Pharmaceutical Sciences Group and the Multiple Sclerosis Society of Great Britain and Northern Ireland, and was supported by the British Medical Association.
     The historical nature of the meeting was enhanced by the recent vote of approval by the British medical Association delegates for the medical use of cannabis and the British Home Office willingness to issue licenses for research into cannabis and cannabinoids.
     The meeting was chaired by Professor Patrick D Wall, FRS, St. Thomas’ Hospital, London and focused on the following objectives: to survey the evidence for the medicinal use of cannabinoids; to review the history, chemistry and pharmacology of cannabinoids; and to clarify the legal position on using cannabinoids therapeutically.
     Professor Wall discussed the significance of this historical meeting which until recently would not have been possible. He proposed that a research working party would be set up to facilitate future research into the medicinal use of cannabis and the cannabinoids.
     Mr. Peter Cardy, chief executive of the MS Society, in his welcoming speech said that in his view it was not to be expected that cannabis in its entirety would be licensed in the current regulatory framework, but he was hopeful that the conference would lead to clinical trials with its active ingredients, the cannabinoids.

Evidence for the medicinal use of cannabinoids
     The eight speakers at the conference discussed the promising results achieved in relieving the chronic pain and discomfort of multiple sclerosis (MS) and the easing of physical symptoms (e.g., nausea and vomiting, anorexia, weight loss, pain) and psychological symptoms (e.g., anxiety) of HIV/AIDS.
     Dr. Christopher Martyn, Southampton General hospital, presented his findings resulting from a double blind crossover trial (n=1) conducted with nabilone (a synthetic cannabinoid analog) in a patient with MS.1 Dr. Martyn concluded that the initial evidence suggested a useful effect for nabilone (cannabinoids) in neurological disease, over a placebo response, as well as showing effects in reducing spasticity and pain. However, he cautioned against the danger of to much optimism concerning the usefulness of cannabis or cannabinoids.
     Dr. William Notcutt from James Paget Hospital in Great Yarmouth, described his experiences with nabilone in 43 patients with chronic pain of various etiologies, such as MS, peripheral neuropathy, and spinal injuries. Nabilone was found to be effective for controlling pain in nine patients, where six patients preferred self-medicating with cannabis. The other 28 patients experienced either no benefit (18) or, due to adverse effects or other reasons, stopped the treatment (10). Dr. Notcutt emphasized that the use of cannabis can reduce the use of morphine up to 90 percent.
     Dr. Anita Holdcroft of Hammersmith Hospital in London, presented her findings resulting from a crossover trial (n=1) in a patient diagnosed with familial Mediterranean fever, presenting itself with symptoms of relapsing chronic pain and inflammation. The study was conducted with capsules containing oil of cannabis (containing 5.75 per cent delta-9-tetrahydrocannabinol [THC], 4.73 per cent cannabidiol [CBD], and 2.42 per cent cannabidiol [CBD]) or placebo (virgin olive oil), in addition to regular morphine sulfate (MST) 30 mg daily, for one week at the time over a six week period. While using a daily dose of 50 mg of THC the patient saw a reduction of needed MST where while on the placebo an increase in MST was required (respectively 17 and 41 tablets of morphine).
     Dr. Kathy Pickhanes of Chelsea and Westminster Hospital in London, focused on the use of cannabinoids in HIV/AIDS. She stated that, in her opinion, smoking cannabis has advantages over taking oral THC (dronabinol; Marinol®); showing a more rapid onset of action, less difficulties in administration for patients suffering from nausea, and is cheaper than the cost of dronabinol. Dr. Pickhanes did see possible hazards of smoking cannabis, in particular in immunocompromised patients suffering from HIV/AIDS being the possible exposure to Aspergillus spp., sometimes present in marijuana. Dr. Pickhanes also discussed the results of a multi-center, randomized, double blind, placebo-controlled trial of dronabinol for anorexia and weight-loss involving 139 patients with AIDS2. Patients treated with dronabinol experienced, compared to the placebo control group, a significant improvement in appetite (38 and 8 % respectively; P=0.015).

Review the history, chemistry and pharmacology of cannabinoids
        Professor Fred Evens, School of Pharmacy, University of London, discussed the research done by his group into those cannabinoids which seemed to be most likely to have a medical use; delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), and cannabigerol (CBG) and the terpenoid olivetol (OL). Studies done by the group had shown that cannabinoids had peripheral analgesic effects and were potent anti-inflammatory agents. Experiments in isolated enzyme systems had indicated that cannabinoids acted as free radical scavengers and could inhibit several enzymes, such as cyclogenase, lipoxygenase and protein kinase C. THC and CBD were also shown to inhibit lipoxygenase in studies using human polymorphonuclear cells.
     Dr. Rodger Pertwee from the department of Biomedical Sciences of the University of Aberdeen, discussed that cannabinoids act very specifically through receptors and not, as previously thought, by disturbing cell-membrane phospholipids in a non-specific manner. There are at least two types of cannabinoids receptor, namely CB1 and CB2. The strongest evidence for this came from the cloning of the receptor. This identified the genetic material responsible for expressing the receptor protein. CB1 receptors are found in brain neurons, spinal neurons and some peripheral neurons, as well as in nerve terminals where they might serve to modulate transmitter release. CB2 receptors are not found in neuronal tissue and thus do not mediate psychotropic effects. Dr. Pertwee believes that cannabinoid receptors could have important physiological, pathophysiological, pharmacological and clinical implications.
     Furthermore, Dr. Pertwee discussed cannabinoids and MS. He emphasized that cannabinoids do not present us with a cure for MS, but might relieve some of its signs and symptoms. The most convincing evidence for the use of cannabinoids in MS has been anecdotal and the result of small trials which show encouraging results. A recent open-label pilot study in two patients, using a suppository formulation of THC hemisuccinate (a pro-drug, converted to THC in the body), showed that the rectal route of administration of cannabinoids has fewer adverse side effects than other routes. Studies in the animal model of MS, Experimental Autoimmune Encephalitis (EAE), has shown a delayed onset and reduced intensity of clinical signs when THC is administered. Dr. Pertwee said that he believes there is a strong case for clinical trials with cannabinoids both on the basis of the above mentioned evidence and the fact that the adverse effects of cannabis and cannabinoids are no worse than many of the drugs already available. In closing, he expressed his concern about the possible hazards of self-medicating as is done by many patients. Due to the lack of clinical trials this is done without medical supervision.

The legal position on using cannabinoids therapeutically
         Mr. Alan McFarlane, British Home Office, discussed both the historical and current position of the British Home Office towards the therapeutic use of cannabinoids.
     In 1961 the United Nations classified cannabis, cannabis resin, cannabinol and its derivatives to be Schedule 1 drugs (no recognized medical use). In 1995 on the advice of the World Health Organization the United Nations and subsequently the United Kingdom, rescheduled dronabinol (THC) to a Schedule 2 drug classification allowing it to be prescribed on a ‘named patient’ basis only. The reason for the rescheduling was said to be the availability of evidence supporting the benefit for patients suffering from nausea and vomiting induced by cancer chemotherapy. This leaves cannabis and cannabinoids with the exemption of dronabinol still to be a Schedule 1 drug. Mr. McFarlane did emphasize that the British Home Office is not opposed to scientific research. If a cannabis-based product gained a product license, the Home Office would reschedule it.
        Dr. Brian Davies, clinical trials unit, Medicines Control Agency (MCA), said that studies conducted with cannabis substances would most likely take place under the doctor’s and dentist’s exemption scheme. This scheme allows these professionals to conduct small trials involving their patients. Doctors are also given the freedom, under the Medicines Act 1968, to prescribe unlicensed drugs, or licensed drugs for unlicensed indications, for a ‘named patient’, under the condition that the doctor takes
responsibility for the prescription. Dr. Davies made it clear the there is no legal barrier to conducting clinical trials and that the MCA recognizes that medicinal products could be derived from cannabinoids.

1Lancet 1995;345:579
2J Pain Symptom Manage 1995;10:89-97