CHAPTER 5 MEDICAL USE OF CANNABIS
AND CANNABINOIDS: REVIEW OF THE EVIDENCE
Pain
5.26 Besides MS, the
other main indication claimed for cannabis-based medicines is
the control of pain (analgesia). The BMA report says, "The
prescription of nabilone, THC and other cannabinoids...should
be permitted for patients with intractable pain", especially
in terminal illness.
5.27 Professor Wall
told us that there is clear evidence of analgesic effects of cannabis
and cannabinoids from animal experiments. Some of the results
suggest that pain which originates from damaged nerves might respond
to cannabinoids; this could be of medical value as this type of
pain does not respond well to treatment with morphine and related
narcotics (Q 99). An example of such pain is phantom limb
pain following amputation (Q 100). As many as 30 per cent
of amputees suffer from this distressing condition, for which
there is currently no satisfactory treatment. Dr Colin Stewart,
who works in the field of major limb amputation in Dundee, reports
anecdotal evidence that cannabis can relieve this pain; he recommends
that trials of cannabis be undertaken in such patients (p 304).
5.28 Dr David Lambert,
of the University of Leicester, confirmed that there is evidence
for analgesic actions of cannabinoids acting on both the spinal
cord and higher brain centres. He and Dr Notcutt suggested
that one way of dissociating the painrelieving actions of
cannabinoids from their psychoactive effects might be to deliver
the cannabinoid locally to the spinal cord via the cerebrospinal
fluid, as has been done with opiate analgesics (QQ 440-6).
5.29 Dr Anita Holdcroft
of Hammersmith Hospital, a contributing author to the BMA report,
has reported the results of a placebo-controlled trial of cannabis
in a patient with severe chronic pain of gastrointestinal origin
(diagnosed as familial Mediterranean fever)[21].
Treatment was with capsules of cannabis oil, standardised for
THC content. The patient's demand for morphine was substantially
lower during treatment with cannabis than during a period of placebo
treatment (p 224).
5.30 In short, there
is scientific evidence that cannabinoids possess painrelieving
properties, and some clinical evidence to support their medical
use in this indication. Many of our witnesses consider that high
priority should be given to further research in this area.
Epilepsy
5.31 There is some
anecdotal evidence to support the possible use of cannabis or
cannabinoids in the treatment of epilepsy, but little more. Cannabinoids
can exert both convulsant and anticonvulsant effects in various
animal tests. Of greatest interest are the anticonvulsant properties
of the naturally occurring cannabinoid cannabidiol; this compound
is essentially devoid of the psychoactive effects of THC. The
limited clinical data available on the use of cannabidiol in the
treatment of epilepsy are, however, equivocal and based on very
small numbers of patients. The BMA report concludes, "It
could possibly provide a useful adjunctive therapy for patients
poorly controlled on presently available drugs. THC and other
psychoactive cannabinoids are probably not suitable as anticonvulsants".
Glaucoma
5.32 Cannabinoids cause
a lowering of pressure in the eye both in animals and in man,
although the site of action and the mechanism involved remain
unknown. It has been suggested that cannabis or cannabinoids might
be useful in the treatment of elevated intraocular pressure (IOP)
in glaucoma, one of the commonest causes of blindness (see the
BMA and WHO reports). Keith Green, Professor of Ophthalmology
at the Medical College of Georgia, USA, told us the results of
his own studies in more than 300 human subjects with both normal
and raised IOP. Cannabis caused an average 25 per cent decrease
in IOP which lasted for 3-4 hours. However, in order to maintain
IOP at baseline levels, patients would have to smoke as many as
10 cannabis cigarettes a day, which is not practicable in view
of the psychoactive effects of the drug and its ability to impair
cognitive function. Professor Green calls for further research
to determine the mechanisms involved, in order to see whether
the desired ocular effects could be dissociated from the intoxicant
effects (p 219; cp Appendix 3, paragraph 12). A similar
view is expressed in the BMA and AMA reports, and by Professor
Hall (Q 753).
Bronchial
asthma
5.33 Cannabis and THC
dilate the small airways of the lung, and this has suggested a
possible application in the treatment of bronchial asthma. However,
according to the BMA report, there have been few clinical trials
and these were mostly in the 1970s before the advent of the more
powerful drugs now available for the treatment of this illness.
Smoked cannabis is clearly unsuitable for the treatment of asthma
because of the irritant effects of the smoke, and THC delivered
by aerosol also appears to have irritating effects. The Royal
Society, however, conclude, "Cannabinoids...seem to be no
less effective than conventional drug treatments. Further studies
are required to improve cannabinoid formulation for administration
as an aerosol" (p 294, cp Hall Q 753).
5.34 It is interesting
to note that, if cannabis were effective in both glaucoma and
bronchial asthma, it would be especially useful for patients suffering
from both conditions, since many treatments for one of these conditions
are contra-indicated for the other.
Need
for clinical trials of cannabis and cannabinoids
5.35 As noted above,
the Government consider that the burden rests on the proponents
of wider medical use to satisfy the Medicines Control Agency that
the proposed medicine fulfils the normal criteria of quality,
safety and efficacy. Dr Brian Davis of the MCA (QQ 167-171)
emphasised that efficacy can be established only by undertaking
controlled scientific trials; anecdotal evidence is not acceptable.
The BMA report and the Multiple Sclerosis Society (Q 389)
accept this position.
5.36 The requirements
for approval of a new medicine are summarised as follows by the
Royal Pharmaceutical Society (p 290):
" — The
active compound must be characterised chemically and physically;
— The active
compound must be presented in a standardised dosage formulation;
— Adequate
tests must have been conducted on its safety;
— Adequate
controlled clinical studies must have been conducted in well-defined
disease entities and efficacy demonstrated objectively;
— The evidence
must have been published and subjected to peer review."
No-one claims that cannabis, or any
cannabis-based medicine other than nabilone and dronabinol, has
yet passed any of these tests.
5.37 There have been
few adequately controlled clinical trials to date on cannabis
and the cannabinoids, except as anti-emetics (see above); those
which have been published are listed in Appendix III to the BMA
report. (For details of what constitutes a clinical trial, see
Box 7.) In MS, there have been only six trials, with a total of
only 41 patients. There is broad agreement that more and better
clinical trials would be a good thing (eg DH Q 180, ACT p 28).
As Dr Pertwee pointed out, there is an element of urgency: "Cannabis
is already being used...We are not in a situation where we can
wait and see" (Q 317). The situation is particularly
urgent with respect to symptom control in MS, as the BMA report
acknowledges, because of a current lack of treatments. Similarly,
in analgesia (pain control), there has been no new drug for 20
years (Notcutt Q 411).
| BOX 7: CONTROLLED CLINICAL TRIALS
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| The approval of new medicines for human use requires that they be tested rigorously in controlled clinical trials. "Controlled" means comparing the test drug with an inactive dummy or "placebo". Placebo tablets or capsules are prepared in such a manner that they cannot be distinguished from the active test drug. In a "double-blind" placebo-controlled trial neither the patient nor the doctor or nurse knows whether active drug or placebo is given to any particular patient; this information is held in coded form by a person not actively involved in the conduct of the trial and is not made available until the trial has ended. Patients are randomly allocated to placebo and test drug groups to avoid any possible bias in the selection of those who are to receive the active drug. The outcome of the trial should involve objective measurements wherever possible, using predetermined outcome measures or "endpoints". The success or failure of the trial is measured by criteria established in a written trial protocol before the start of the trial. The trial should include a sufficiently large number of subjects to provide statistically significant differences in outcome measures between the placebo and drugtreated groups.
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| A variant on the use of separate groups of patients to receive placebo or test drug is the socalled "crossover" design, in which the same patients receive placebo and test drug at different stages during the trial and are crossed over from one to the other after a "wash-out" period in a random order, so that the trial remains double-blind.
|
| The conduct of any clinical trial involving patients must be approved by the Medicines Control Agency, who issue a Clinical Trial Certificate (CTX) if the detailed written protocol for the trial meets with their approval. In addition the conduct of a clinical trial requires the prior approval of the local Ethics Committee at the site where the study is to be conducted.
|
5.38 The BMA report
called on the Clinical Cannabinoid Group (an informal network
of interested researchers convened by Dr Pertwee), patient groups,
pharmaceutical companies and the Department of Health to "work
together to encourage" trials. In their written evidence
the BMA say, "the accumulation of scientific evidence has
been hampered by regulations restricting the use of cannabinoids
to one clinical indication" [anti-emesis] (p 11). Following
their report, the BMA met the Government's Chief Medical Officer
in March 1998 "to discuss likely further actions in moving
forward clinical trials of cannabinoids for therapeutic uses".
At the meeting, it was agreed that an appropriate body to conduct
such trials was required and that it should be an independent
or institutional research organisation.
5.39 Clinical trials
are expensive, but the research funding bodies have no objection
of principle to funding work in this field. The MRC report a shortage
of high-quality research proposals in this area (Q 629);
but they would be "supportive" of funding well-conceived
clinical trials in this field, and would even be prepared to consider
a grant application "out of turn" (QQ 638, 769).
In February 1998 the MRC had three grants, one to Dr Pertwee
and two to Dr Kendall; Dr Pertwee's has now finished,
as has one of Dr Kendall's (Q 621). The Wellcome Trust
had made nine grants since 1990: five project grants, including
three to Dr Pertwee, and four research career re-entry fellowship
grants, all to colleagues of Dr Pertwee. The Multiple Sclerosis
Society and the BMA are also willing to help fund a trial (MSSoc
p 89; Q 769). The Department of Health do not normally fund
trials, but might "facilitate" (Q 194). Besides
the Wellcome Trust, Dr Pertwee's research group in Aberdeen
is also funded by the USA's National Institute on Drug Abuse (part
of the National Institutes of Health) and a pharmaceutical company
(Q 252).
5.40 Professor Edwards
(Q 19) questions the justification for carrying out expensive
controlled trials with cannabis. He is concerned about the possibility
of diversion to misuse of the drug. As a preliminary, he favours
a series of smaller-scale clinical investigations in individual
patients.
5.41 Several of our
witnesses have commented on the difficulties of conducting clinical
trials with cannabis. How can a standardised product be made available?
What formulation is to be used? How can the dose be predicted
for any particular medical condition? How consistent and predictable
would blood levels of THC be (QQ 7, 8, 180, 781)? In addition,
individual patients are likely to differ considerably in the dose
needed to control their symptoms—as with the use of opiates
in the control of severe pain, where Professor Wall points out
that a tenfold range of doses is commonly observed (QQ 112-3).
5.42 Professor David
GrahameSmith, Chairman of the Advisory Council on the Misuse
of Drugs (Q 8), raised the question of the difficulty of
carrying out a doubleblind placebo-controlled trial with
a psychoactive agent, as the drug could easily be distinguished
from the inert placebo. Professor Lader suggested that one solution
to this might be to test cannabis by comparison with some other
psychoactive drug, rather than against an inactive placebo. Other
possibilities are to use doses of the active drug too small to
have psychoactive effect; or to proceed with an inactive placebo,
and find out at the end of the trial how far patients could tell
whether they were receiving the active drug or the placebo (Q
779).
5.43 In addition to
these practical problems, clinical researchers face extra legal
hurdles, and a generally negative climate of opinion, because
of the status of cannabis as a Schedule 1 controlled drug.
We consider this problem, and what might be done about it, in
Chapter 7.
5.44 Clinical trials
are now under active consideration in several fora. First, Dr
Geoffrey Guy, a pharmaceutical entrepreneur, has recently set
up GW Pharmaceuticals, to conduct licensed research and develop
cannabis-based medicines, in collaboration with HortaPharm BV
of Holland (see Dr Guy's evidence, and QQ 107, 135, 413-420,
447). The aim is to produce standardised whole-plant extracts,
rather than single chemicals, from plants bred for standard cannabinoid
content, with a non-smoking mode of administration offering the
advantages of smoking without the harm, and to proceed via clinical
trials to an application for a product licence. Dr Guy received
licences to cultivate cannabis, and to possess and supply it for
research, from the Home Office in June 1998. He is now recruiting
patients for trials, with help from the ACT.
5.45 Dr Guy is
confident that rigorous trials can be mounted, and that contamination
of the plant material can be avoided. He advocates the use of
plant-derived products, and cites the examples of gentamicin,
papaveretum and digitalis as approved plantderived products
that contain complex mixtures of alkaloids. He believes that,
by using controlled growing conditions and cloned cannabis plants,
it will be possible to produce a herbal preparation of consistent
composition with adequate quality controls. This position is reinforced
by data from the Dutch organisation Maripharm (see Appendix 4
paragraph 14), who have been able to produce medical-grade herbal
cannabis selected to have a consistent content of THC (10.7 ± 0.1 per
cent) and a low content of other cannabinoids.
5.46 Secondly, following
the meeting between the BMA and the CMO (see above, paragraph
5.38), the Royal Pharmaceutical Society have set up a "working
party on therapeutic uses of cannabinoids", chaired by Professor
Sir William Asscher, a past Chairman of the Committee on
Safety of Medicines. The group includes representatives of the
NHS R&D Directorate, the MRC and the Multiple Sclerosis Society,
and researchers including Dr Pertwee. Its objectives are "to
produce guidelines for pilot clinical trials for cannabinoids
as proof of principle of their effectiveness, and to assist those
who wish to conduct such trials to successfully complete them
and publish the results". The group has drawn up protocols
for two trials: one for spasticity arising from MS, the other
for post-operative pain. In each case the trial will be longitudinal
(i.e. not a cross-over trial), involving three groups of patients:
one will be given dronabinol, another an extract of cannabis containing
the same quantity of THC, and the third a placebo. Smoking has
been ruled out; administration will be by oral capsule. The lead
clinician for the pain trial is Dr Anita Holdcroft, whose previous
single-patient trial of cannabis was noted above; the lead clinician
for the MS trial is Dr John Zajicek of Derriford Hospital, Plymouth.
The protocols are to be launched shortly, at which point applications
will be made for funding (from non-industrial sources) and for
Home Office licences. (See the evidence of members of the working
party, QQ 768-811.)
5.47 In addition, Jo Barnes
of Exeter University is launching a pilot study of oral THC involving
30 MS patients, funded by the university, intended to "provide
data which can be used for a sample size calculation for a full-scale
study" (p 217). Dr Robson is planning pilot studies
using nabilone and dronabinol for detoxification from opiates
and as an anxiolytic/hypnotic in acute drug-related problems (p 118,
Q 458). Professor Wall knows of three other United Kingdom
trials at an advanced planning stage, by Dr Pertwee, Dr Notcutt
(Q 448), and Dr Clare Fowler at the National Hospital
for Neurology and Neurosurgery in London.
5.48 These various
initiatives are, or may become, interrelated. The Asscher group
trials, and others, may use GW Pharmaceuticals as the source of
supply of cannabis material; in that case they might be covered
by an extension of Dr Guy's Home Office licence. The Exeter group,
and others, may bring their trials within the Asscher group's
protocols, so as to become part of a national study. In the end,
it is possible that all or most of these initiatives will come
together into two national trials, using the Asscher group's protocols
and Dr Guy's licence and materials.
Should
clinical trials be limited to cannabinoids?
5.49 Both Dr Guy and
the Asscher group propose to conduct trials involving extracts
of herbal cannabis; but according to several of our witnesses
this may be a mistake. Professor Ashton and Professor Nathanson
of the BMA (Q 55), reflecting the position of the BMA report
itself, argued strongly in favour of trials of synthetic cannabinoids
rather than herbal cannabis, because of the difficulties of obtaining
standardised preparations of the plant material. Both Dr Guy and
the Asscher group believe that they can solve the problem of standardised
preparations.
5.50 The Association
of Chief Police Officers argue that clinical research should be
confined to individual cannabinoids: ACPO believe that cannabis
is a harmful substance, the control of which must be continued
(p 196). The Christian Institute take a similar view, arguing
inter alia that medical use might serve as a front for
legalisation (p 208). (We consider this argument below in
Chapter 7.) Mary Brett, Head of Health Education at Dr Challoner's
Grammar School[22],
writes, "All scientific evidence is unequivocal in favour
of maintaining prohibition of crude marijuana for both medical
and recreational use. However, purified cannabinoids may, after
rigorous testing and clinical trials in comparison with other
and existing treatments, prove to be beneficial in certain disorders
..." (p 206).
5.51 Others, however,
favour research on herbal preparations derived from cannabis.
Professor Wall argues in favour of trials of cannabis rather
than pure cannabinoids. He criticises the BMA report for recommending
that trials be confined to synthetic cannabinoids (p 32);
he considers that it would be premature at this stage of our knowledge
to assume that the only active substance in cannabis is THC (Q 103).
We have received anecdotal evidence that users who have tried
cannabis and nabilone and/or dronabinol prefer cannabis (LMMSG
p 271; ACT pp 28, 30; IDMU p 228).
5.52 The Royal Society
(p 295) also conclude that "Several components of cannabis
might be required to reproduce the effects seen with the whole
drug". Others in favour of including cannabis itself in any
programme of trials include the Royal Pharmaceutical Society (p 284),
Dr Kendall (p 268), Dr Pertwee (QQ 266, 315),
Dr Robson (Q 480), Dr Stewart and Dr Schon.
The Multiple Sclerosis Society (Q 352) point out that cannabis
is available, and is what existing medical users are using; the
ACT observe that including it in trials would permit existing
users to regularise their position (by enrolling for trials) without
changing their medication (Q 149). Professor George
Radda, Chief Executive of the MRC, would not rule out extracts
of herbal cannabis; "but we must know the composition"
(Q 645).
5.53 Some witnesses
point out that the variable chemical composition of herbal cannabis
can be turned to medical advantage. The London Medical Marijuana
Support Group argue that differing strains of cannabis containing
different proportions of THC, cannabinol (CBN) and cannabidiol
(CBD) might have different medical effects: "The more CBN
and CBD, the greater the intensity of body related sensations;
the less CBN and CBD and the more THC, the more mentally active
the stimulation will generally be. High CBN and CBD cannabis is
more effective for the control of symptoms which are generally
felt as being body related, such as chronic pain" (p 270).
Neil Montgomery also maintains that cannabis resins of different
geographic origin elicit distinct patterns of psychoactive effect
(Q 594). There is, however, no scientific evidence available
on these topics.
Should
clinical trials include smoking?
5.54 Both Dr Guy and
the Asscher group have ruled out smoking for the purposes of their
trials; and many of our witnesses would support them (e.g. Notcutt
p 104, Henry p 224, RPharmSoc p 284, Wall Q 103,
Pertwee QQ 266, 315, MSSoc Q 364, ACT Q 154). Smoking
is felt to carry too great a potential health risk: see Chapter 4.
However, as noted above, there are anecdotal reports that those
who use cannabis for medical purposes favour smoked cannabis over
orally administered cannabinoids such as nabilone. The perceived
advantages of smoked cannabis may be due to the rapid absorption
and flexibility of dosecontrol offered by smoking as a route
of administration: see Chapter 3.
5.55 Dr Robson suggested
that there should be a comparison in clinical trials between smoked
cannabis and smoked THC (Q 480). The Asscher group's proposal,
to compare orally administered THC with an orally administered
cannabis product, will achieve the same result, namely a comparison
of like with like.
5.56 There is considerable
discussion of possible improvements in the mode of administration
of cannabis and synthetic cannabinoids (e.g. QQ 60, 266-273).
IDMU (p 235) described recent research in the United States on
the ability of various methods of smoking herbal cannabis to reduce
tar intake relative to THC. Surprisingly, the use of a water pipe,
in which the cannabis smoke is passed through water prior to being
inhaled, and the use of a vaporiser, in which herbal cannabis
is heated but not burned, had relatively little effect in reducing
the amount of tar inhaled. Unfortunately the slow and unreliable
absorption of herbal cannabis and synthetic cannabinoids taken
by mouth can lead to both under and overdosing. Other
possibilities include the development of inhalers (e.g. Guy QQ 713-4),
sprays, rectal suppositories (see Appendix 3, paragraph 3) and
skin patches, and a sub-lingual method (taking a tincture under
the tongue—LMMSG p 270). Research on such alternative
delivery systems is held to be a high priority by many witnesses.
5.57 Although there
is general agreement that smoked cannabis carries a potential
risk for long-term users, the medical application of smoked cannabis
is not ruled out by all. The US National Institutes of Health
report says, " ...there might be some patient populations,
e.g. cancer patients experiencing nausea and vomiting during chemotherapy,
for whom the inhalation route might offer advantages over the
currently available capsule formulation [of THC]". They conclude,
"In summary, the testing of smoked marijuana to evaluate
its therapeutic effects is a difficult, but not impossible, task".
The American Medical Association report recommends "that
adequate and well controlled studies of smoked marijuana be conducted
in patients who have serious conditions for which preclinical,
anecdotal or controlled evidence suggests possible efficacy including
AIDS wasting syndrome, severe acute or delayed emesis induced
by chemotherapy, multiple sclerosis, spinal cord injury, dystonia
[involuntary muscle movements, e.g. a tic], and neuropathic pain...".
Among our witnesses, those who would include smoking in trials
include Dr Schon (p 304), Dr Stewart (p 305)
and Dr Robson (Q 480); and Professor Radda of the
MRC would be prepared to do so, provided that the trial protocols
were satisfactory (QQ 646, 654).
21 Holdcroft A et al. Pain relief with oral
cannabinoids in familial Mediterranean fever. Anaesthesia,
1997, 52, 483. Back
22
Mrs Brett has written widely on cannabis, and advises the NDPA. Back
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