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

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.

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.

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).

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.

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.

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

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 1mg capsules (to be taken
by mouth) costs £102. 5,400 packs were sold in 1997-98. It is not a
controlled drug.

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.

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

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 10mg 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).

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.

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:

(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;

(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;

(c) except in the case of a health prescription, specify the address of the
person issuing it;

(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;

(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;

(f) specify the dose to be taken and --- (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; (ii) in any
other case, the total quantity (in both words and figures) of the
controlled drug to be supplied;

(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."

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.

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.

20 Chairman of the Technical Sub-Committee of the ACMD.

(continued in Part 2)

Checked-by: Richard Lake