CHAPTER 5 MEDICAL USE OF CANNABIS
AND CANNABINOIDS: REVIEW OF THE EVIDENCE
5.1 The main reason
for our inquiry is that there are now calls for the law to be
changed to permit wider medical use of cannabinoids, and to permit
the medical use of cannabis itself. This Chapter reviews the evidence
which we have received about current and proposed medical uses
for cannabis and the cannabinoids. It is important to distinguish
the different substances and preparations; for instance, cannabis
leaf must be distinguished from cannabis extract, and whole cannabis
from THC. It is also important, though not always easy, to distinguish
the various possible routes of administration, e.g. by smoking
and by mouth.
Current
medical use of cannabis
5.2 Today in the United
Kingdom, medical use of cannabis itself is illegal (see Box 3)
but quite widespread. According to the BMA report, "many
normally law-abiding citizens—probably many thousands in
the developed world" use cannabis illegally for therapy.
Most such users smoke their cannabis, but some take it by mouth.
The UK Alliance for Cannabis Therapeutics (ACT) know of 200 people
in the United Kingdom who have used cannabis for MS (p 29);
53 took part in a recent study of perceived effects of smoked
cannabis[18]
(Q 262). Clare Hodges writes, "It is impossible to know
how many people with MS use cannabis...My impression is that most
people with MS do not". A Multiple Sclerosis Society survey
produced a figure of one per cent; but the Society believe the
true figure to be higher (Q 341).
| BOX 3: CURRENT LEGAL CONTROLS
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| The regulation of cannabis in the United Kingdom under the Misuse of Drugs Act 1971 is complicated. Schedule 2 to the Act classifies cannabis itself, and cannabis resin, as Class B controlled drugs, and the cannabinoid cannabinol and its derivatives (defined as THC and 3-alkyl homologues thereof) as Class A controlled drugs. Offences involving Class A drugs attract stiffer penalties. Under the Act it is an offence to import, export, produce, supply or possess controlled drugs (though it is not an offence to use them); it is also an offence to cultivate cannabis plants, or to permit premises to be used for smoking cannabis.
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| Reference is often made in this context to "Schedule 1 and Schedule 2". These are Schedules not to the Act itself, but to the Misuse of Drugs Regulations 1985 (No. 2066) made under the Act. Schedules 2-5 list drugs to which various exemptions from the Act apply; in particular, drugs in Schedule 2 may be administered by, or on the instructions of, a doctor or dentist (Regulation 7), may be produced by a practitioner or pharmacist (Reg. 8), may be supplied (Reg. 8) and possessed (Reg. 10) by various classes of person, including practitioners, pharmacists and heads of laboratories, and may be possessed by patients (Reg. 10). Schedule 1 lists drugs to which the exemptions do not apply; cannabis, cannabis resin, and cannabinol and its derivatives (other than dronabinol—see Box 5) appear in Schedule 1.
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| The 1985 Regulations also empower the Secretary of State to license anyone to produce, possess or supply any controlled drug, including a Schedule 1 drug (Reg. 5); to license cultivation of cannabis plants (Reg. 12); and to approve premises for smoking cannabis for research purposes (Reg. 13).
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| The position in practice is therefore that cannabis and most of its derivatives may not be used in medicine, and may be possessed for research only under Home Office licence. There are two psychoactive cannabinoids, nabilone and dronabinol, which may be used for medicine: see Boxes 4 and 5. Two non-psychoactive cannabinoids, cannabidiol and cannabichromene, are not controlled drugs, and could in theory be prescribed as unlicensed medicines, but no-one is currently doing so.
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| This UK regime is one of the most restrictive in the world. Places with a more liberal regime include the Netherlands, Italy, Spain, Canada, and some states of Germany, Australia and the USA.
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5.3 The ACT also know
of 50 users with spinal injury, and 20 with other conditions.
A survey conducted by the newspaper Disability Now in 1997
among its disabled readers revealed, among 200 respondents, 40
people taking cannabis for MS, 40 for spinal injury, 35 for back
pain, 27 for arthritis and 64 for other conditions. IDMU's surveys
of 2,794 regular cannabis users have revealed 78 whose main reason
for using it is medical (p 244).
5.4 We have received
written evidence (not included in the volume of printed evidence)
from four patients suffering from MS (besides Miss Hodges) who
report that cannabis has a beneficial effect on their symptoms
and call for a change in the law to permit the prescription of
cannabis. Dr Fred Schon, a consultant neurologist, described
the apparently dramatic improvement obtained by selfmedication
with smoked cannabis resin by an MS patient who had developed
a severe and disabling abnormality of eye movements (p 303).
We have also heard from people who have used cannabis against
epilepsy, ME and pain, and as an anti-emetic after chemotherapy.
Further anecdotal evidence was provided by the Alliance for Cannabis
Therapeutics and the London Medical Marijuana Support Group.
5.5 According to Neil
Montgomery, some users of cannabis for medical purposes are also,
or have been, recreational users, and their medical use is to
some extent conditioned by their recreational experience (p 132).
Three of the nine such users who have given us evidence are in
this category. An increasing number are growing their own cannabis,
"primarily to avoid problems of impurity", or buying
in bulk to ensure consistency of dose; either course exposes them
to stiffer sentences, if caught, than the frequent purchase of
small quantities (cp IDMU p 261). Medical users typically take
cannabis as frequently as, but in smaller quantities than, recreational
users (Q 567).
5.6 Use of cannabis
for medical purposes is sometimes connived at by the medical professions.
Clare Hodges took medical advice before trying cannabis for her
MS, and was not dissuaded (p 27). "Over 50 patients
have told the ACT that their doctors have recommended that they
try cannabis for symptomatic relief" (p 29); and 50
of the 200 respondents to the Disability Now survey said
their doctor knew and approved. 100 doctors are associated with
the ACT (Q 96). Most medical users tell the Multiple Sclerosis
Society that their doctors are "mildly supportive" (Q 341).
One user's doctor knows that she uses cannabis for pain relief
and is unconcerned. Another took to cannabis for his epilepsy
on a doctor's recommendation. On the other hand, a third user's
consultant would not support his letter to us, "due to the
advances in anti-emetic drugs". According to Dr William Notcutt,
a consultant anaesthetist[19],
self-medication with cannabis for pain is now common, and "Advising
on its use can be part of the pharmacological management of pain
nowadays" (p 101, Q 434). Finally, the BMA report
on medical use was itself prompted by a resolution in favour of
medical use of "certain additional cannabinoids", passed
by the BMA's Annual Representative Meeting in 1997.
5.7 The Government
consider that the burden of proof rests on the proponents of medical
use of herbal cannabis. As recently as 1 March 1994, the then
Home Office Minister referred in a Commons answer to "long-standing
advice that cannabis has no recognised medical use" (HC WA 632).
Since then, the Government line appears to have softened a little:
on 2 July 1997, Tessa Jowell MP, the Minister of State for Health,
said that officials were keeping available research under review.
"At present the evidence is inconclusive. The key point is
that a cannabis-based medicine has not been scientifically demonstrated
to be safe, efficacious and of suitable quality" (HC WA 174).
On 27 October 1997, Paul Flynn MP put it to George Howarth
MP, Under-Secretary of State at the Home Office, that cannabis
was already widely used, illegally, by sufferers from MS, cerebral
palsy and glaucoma; the Minister replied, "All drugs used
for medical purposes have to be scientifically tested. If cannabis
succeeds in those tests...the Secretary of State for Health...would
be willing to consider allowing medicinal use of it. Unfortunately,
as of now, there is no such evidence" (col. 580; see
also HL 20 April 1998, WA 192, and HC 5 May 1998, WA
351).
5.8 The Department
of Health say the same in written evidence: "There is insufficient
evidence to demonstrate the effectiveness of cannabis as a therapeutic
agent at this stage" (p 48). In oral evidence they went
a little further: "We very much recognise the importance
of research in this area and its potential value, particularly
when addressed to the needs of patients for whom we have relatively
little else to offer" (Q 167). But MS is not the only
condition where conventional treatments are relatively limited
in their effects, and the Department warned against allowing the
"added frisson" of cannabis to distort the perspective
(Q 225).
Advice
to medical users
5.9 Given that use
of cannabis for medical purposes is clearly going on in spite
of the law, we asked some of our witnesses what advice they would
give to people conducting or contemplating medical use, and to
their doctors. The Department of Health suggest that doctors should
advise users as to the legal position, and as to the "limited
evidence" of efficacy. However, "one has also to recognise
that people may choose to do things that their doctors advise
against, and there would be a necessity for the doctor subsequently
to continue to work to support that individual" (Q 172).
One official went so far as to say, off the cuff but not off the
record, "Other people's decisions have to be other people's
decisions" (Q 224).
5.10 The BMA advise
users of cannabis for medical purposes to be aware of the risks,
to enrol for clinical trials, and to talk to their doctors about
new alternative treatments; but they do not advise them to stop
(Q 55). The Multiple Sclerosis Society "does not actually
condone or encourage individuals in breaking the law" (Q 341).
Current
medical uses of cannabinoids
5.11 Although cannabis
itself is illegal, certain cannabinoids are in current use in
UK medicine, within the law. Cannabinoids have antinausea
effects, and have been used clinically to suppress the nausea
and vomiting associated with chemotherapy in cancer patients.
This is the only medical indication for which adequate data from
controlled clinical trials exist, mostly from studies in the 1970s
with pure THC and the synthetic cannabinoid nabilone, an analogue
of THC, which were found to be as effective as prochlorperazine
and other antinausea agents available at the time. On the
basis of this evidence nabilone was licensed and is available
as a prescription medicine in the United Kingdom for this indication
(see Box 4). However, according to Professor Malcolm Lader of
the Institute of Psychiatry, University of London[20]
(Q 7), it has been little used. He believes that this is largely
due to the fact that more powerful antinausea medicines
were introduced in the 1980s—the serotonin antagonists ondansetron
(Zofran), granisetron (Kytril) and tropisetron (Navoban), which
are now widely used in conjunction with cancer chemotherapy (cp
Hall p 221 and Appendix 3 paragraph 13). They have
the advantage over the waterinsoluble cannabinoids that
they can be delivered intravenously as well as by mouth, and they
are effective in up to 90 per cent of patients. There have
been no clinical trials to compare the effectiveness of cannabinoids
with the serotonin antagonists (RPharmSoc p 287).
| Box 4: NABILONE
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| Nabilone is an analogue of D9-THC. It was licensed in 1982 for prescription-only hospital-only use against nausea arising from chemotherapy and unresponsive to other treatment. It is manufactured synthetically by Eli Lilly & Co. Ltd and sold in the United Kingdom by Cambridge Selfcare Diagnostics Ltd; a pack of 20 1 mg capsules (to be taken by mouth) costs £102. 5,400 packs were sold in 1997-98. It is not a controlled drug.
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| According to Dr Kendall of the University of Nottingham, nabilone is not widely used to treat nausea (p 268). Nabilone is used "very infrequently" in MS—probably less than cannabis itself (MSSoc Q 353). However Dr Notcutt is using it for pain control at James Paget Hospital in Great Yarmouth—see paragraph 5.14.
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5.12 This means that
cannabis and cannabinoids are likely to be of benefit as anti-emetics
only to the small proportion of patients who do not respond to
existing treatments, or possibly in the treatment of the delayed
stages of emesis which can occur for some days following cancer
chemotherapy, and which do not respond well to the serotonin antagonists.
Nevertheless, cannabinoids are undoubtedly effective as antiemetics
and more research in this field might explore their use in combination
with the serotonin antagonists, help to determine for which patients
they are most appropriate, and examine the potential of the allegedly
less psychoactive cannabinoid D8THC,
for which there have been encouraging preliminary clinical results
(Q 74).
5.13 THC itself (dronabinol—see
Box 5) is licensed as an anti-emetic in the USA, but not in this
country. The BMA report recommends that it should be licensed
here. This would depend on the manufacturer applying for a licence;
in the mean time, doctors may prescribe it on an unlicensed basis
at their own risk.
| BOX 5: DRONABINOL
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| Dronabinol is THC. It is marketed as Marinol, synthetic D9-THC in sesame oil, supplied in soft gelatine capsules (to be taken by mouth) containing 2.5, 5 or 10 mg of THC. It is licensed in the USA as an anti-emetic, and also to stimulate the appetite of AIDS patients. Marinol is manufactured by Unimed Pharmaceuticals Inc. in the USA; it is significantly more expensive than nabilone (Notcutt Q 427). It is not licensed as an anti-emetic here; but in 1995, on WHO advice, it was moved from Schedule 1 to Schedule 2 of the 1985 Regulations (by the Misuse of Drugs (Amendment) Regulations 1995, No. 2048), and may therefore be prescribed on the named-patient basis defined in the 1985 Regulations (see Box 6).
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| In a 1997 survey in the USA, only 6 per cent of 1,500 oncologists said they had prescribed dronabinol in the previous year (Brett p 204, cp Hall p 222). According to the BMA, take-up in the United Kingdom is low, because of the administrative obstacles and the availability of good alternatives (Q 83). According to Dr Notcutt of James Paget Hospital, Great Yarmouth (Q 422), it is not in practice available in the United Kingdom at present.
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5.14 Dr Notcutt is
currently treating patients suffering from intractable pain with
nabilone, on an unlicensed basis. He has treated a total of 60
patients with a variety of chronic pain conditions, including
MS, cancer, peripheral nerve damage and spinal lesions. As many
as 50 per cent have derived some pain relief from nabilone,
but a significant number of patients are unable to tolerate the
side effects of the drug (unpleasant psychoactive effects and
drowsiness) (Q 400) and the overall success rate is about
30 per cent (p 104).
5.15 Cannabis has been
advocated to treat anorexia, but the scientific basis of this
remains unclear. In normal subjects cannabis intake is followed
about three hours later by an increased appetite ("the munchies"),
particularly for sweet foods (Pertwee Q 256). Regular users
of cannabis, however, become tolerant to this effect and appetite
may even be depressed. According to the BMA report clinical trials
have failed to establish any beneficial effect of THC on appetite
in patients with anorexia nervosa. However, in controlled clinical
trials in patients with advanced AIDSrelated illnesses,
dronabinol significantly reduced nausea, prevented further weight
loss and improved patients' mood. On the basis of such data the
US Food and Drug Administration have licensed dronabinol for the
treatment of anorexia associated with AIDS; Dr Robson sees this
as "the most compelling indication" for cannabis-based
medicines (Q 458).
5.16 There is a concern
with regard to the use of cannabinoids in AIDS because of the
possible immunosuppressive effects of these drugs (BMA QQ 79,
80, Hall Q 742). Such effects could be damaging in patients
whose immune system is already compromised, although there is
no evidence of any relationship between cannabis use and the rate
of progression to AIDS in HIVpositive men (Robson Q 460).
5.17 The BMA report
recommends that the licensed indications for nabilone be extended
to preventing weight loss and treating anorexia in patients with
cancer or AIDS, and that dronabinol should be licensed in this
country for this indication. As noted already, this would depend
on application by the manufacturers; in the mean time, doctors
may prescribe "off-label" at their own risk. Dronabinol
is a controlled drug, listed in Schedule 2 to the Misuse of Drugs
Regulations (see Box 2); so prescription would have to be on the
"named-patient" basis defined in the Regulations (see
Box 6).
| BOX 6: PRESCRIPTION ON THE NAMED-PATIENT BASIS |
| Under Regulation 15 of the Misuse of Drugs Regulations 1985, any prescription for a drug listed in Schedule 2 (or Schedule 3) to the Regulations shall:
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| "(a) be in ink or otherwise so as to be indelible and be signed by the person issuing it with his usual signature and dated by him;
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| (b) insofar as it specifies the information required by sub-paragraphs (e) and (f) below to be specified, be written by the person issuing it in his own handwriting;
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| (c) except in the case of a health prescription, specify the address of the person issuing it;
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| (d) have written thereon, if issued by a dentist, the words "for dental treatment only" and, if issued by a veterinary surgeon or a veterinary practitioner, a declaration that the controlled drug is prescribed for an animal or herd under his care;
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| (e) specify the name and address of the person for whose treatment it is issued or, if it is issued by a veterinary surgeon or veterinary practitioner, of the person to whom the controlled drug prescribed is to be delivered;
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| (f) specify the dose to be taken and—
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| (i) in the case of a prescription containing a controlled drug which is a preparation, the form and, where appropriate, the strength of the preparation, and either the total quantity (in both words and figures) of the preparation or the number (in both words and figures) of dosage units, as appropriate, to be supplied;
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| (ii) in any other case, the total quantity (in both words and figures) of the controlled drug to be supplied;
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| (g) in the case of a prescription for a total quantity intended to be supplied by instalments, contain a direction specifying the amount of the instalments of the total amount which may be supplied and the intervals to be observed when supplying."
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Proposed
new indications for cannabis-based medicines
5.18 Besides those
conditions noted above for which cannabinoids are already used
within the law, the conditions most often cited are MS and pain.
Claims are also made in connection with epilepsy, glaucoma and
asthma. We review the evidence on each of these conditions below.
Multiple
sclerosis
5.19 The Multiple Sclerosis
Society has in its membership 35,000 of the total of 85,000 patients
suffering from this disease in the United Kingdom. The Society
estimate that more than 1 per cent of these patients, and
possibly as many as 3-4 per cent, are illegally using cannabis
for relief of symptoms (Q 341). Representatives of the Society
described for us the commonest symptoms of the disease. Fatigue
is the most frequent in 95 per cent of patients, followed
by balance problems (84 per cent), muscle weakness (81 per
cent), incontinence (76 per cent), muscle spasms (66 per
cent), pain (61 per cent) and tremor (35 per cent) (Q 334).
Although the interferons (alpha and beta) are proving to be of
some value in relapsing-remitting and progressive cases of the
disease, these symptoms are still poorly controlled by existing
treatments, and no cure has been found.
5.20 Dr Lorna Layward
of the Multiple Sclerosis Society, and Dr Pertwee, reviewed
for us the six published clinical trials of cannabis or cannabinoids
in MS. These have involved small numbers of patients (a total
of 41 subjects worldwide), but some positive results have
been reported, especially for spasticity, pain associated with
spasticity, tremor and urinary bladder control (QQ 262, 372).
Dr Pertwee took part in the study of perceived effects of cannabis
on MS noted above: in a postal survey of 112 MS patients selfmedicating
with cannabis in the United Kingdom and the USA, more than 90 per
cent reported a beneficial effect on spasticity, and many also
reported pain relief and improved urinary control (Q 262).
5.21 Dr Layward and
Dr Pertwee referred to experimental results in animals which
offer a scientific basis for the use of cannabis and cannabinoids
in the treatment of MS. In an MSlike disease in mice (experimental
autoimmune encephalomyelitis), low doses of cannabinoids alleviate
the muscle tremor seen in such animals. Cannabinoids also suppress
spinal cord reflexes in animals (QQ 262, 356).
5.22 It is natural
to wonder whether the beneficial effects of cannabis reported
by MS patients might simply be related to the feeling of well-being
caused by the intoxicant properties of the drug. Clare Hodges
said that cannabis greatly helped her physical symptoms, specifically
the relief of discomfort in bladder and spine, and relief from
nausea and tremors (Q 98). "Cannabis helps my body relax.
I function and move much easier. The physical effects are very
clear. It is not just a vague feeling of well-being". She
positively prefers to avoid intoxication, and feels able to control
the dose of cannabis to obtain physical relief without getting
high (p 27, Q 98; cp LMMSG p 270). Professor
Wall likened this to the experience of patients using selfadministered
morphine or related narcotics for pain control, who control the
dose to achieve a bearable level of pain without muddled thinking
(Q 98).
5.23 The BMA report
concluded, "It is somewhat paradoxical that cannabinoids
are reported to be of therapeutic value in neurological disorders...since
very similar symptoms can be caused by cannabis itself...it is
not clear how much of the reputed effects of cannabis in motor
disorders are due to psychoactive or analgesic effects".
Nevertheless, it recommended that "A high priority should
be given to carefully controlled trials of cannabinoids in patients
with chronic spastic disorders which have not responded to other
drugs". This view is shared by many of our witnesses.
5.24 The BMA report
calls for the extension of the licensed indications for nabilone,
and for the licensing of dronabinol, for use in MS and other chronic
spastic disorders unresponsive to standard drugs. The wording
of the report is ambiguous: on p 9 it says, "Depending
on the results of...trials there may be a case for considering
extension of the indications..."; on p 80 it says, "There
is a case for the extension of the indications" for such
use pending trials. The latter is repeated in the BMA's
written evidence to us (p 10). According to Professor Ashton
the ambiguity is inadvertent; and a letter from Professor Nathanson
of the BMA (p 206) confirms that the BMA does indeed support
licensing pending further research.
5.25 The National Drug
Prevention Alliance suggest that this ambiguity reflects disagreement
between Professor Ashton, the main author, and editors at the
BMA. They would regard licensing in advance of trials as "an
extraordinary aberration" (p 279). The Christian Institute
say it would set "a very bad precedent" (p 208).
In any case, the MCA are not prepared to allow anecdotal evidence
as a substitute for clinical trials (QQ 168, 178, 189); and
no application to extend the licence for nabilone has in fact
been made (Q 191).
18 Consroe P, Musty R, Rein J, Tillery W and Pertwee
R, The perceived effects of smoked cannabis on patients with
MS, Eur. Neurol. 1997, 38, 44. Back
19
Dr Notcutt is a consultant in anaesthesia and pain management
at James Paget Hospital, Great Yarmouth, and a senior lecturer
at the University of East Anglia. He has extensive experience
of the clinical use of nabilone (see Box 4) for the unlicensed
indication of pain control. Back
20
Chairman of the Technical Sub-Committee of the ACMD. Back
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