CHAPTER 5 MEDICAL USE OF CANNABIS AND CANNABINOIDS: REVIEW OF THE EVIDENCE
(continued)

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

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.

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 + or - 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.

22 Mrs Brett has written widely on cannabis, and advises the NDPA.

Checked-by: Richard Lake