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"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