APPENDIX 1

Members of the Sub-Committee which conducted the enquiry

* Lord Butterfield * Lord Butterworth * Lord Carmichael of Kelvingrove *
Lord Dixon-Smith * Lord Kirkwood * Lord Nathan * Lord Perry of Walton
(Chairman) * Lord Porter of Luddenham * Lord Rea * Lord Soulsby of Swaffham
Prior * Lord Walton of Detchant * Lord Winston

The Sub-Committee appointed as its Specialist Adviser: Professor Leslie
Iversen FRS, Visiting Professor of Pharmacology, University of Oxford

APPENDIX 2

Witnesses

The following witnesses gave evidence.

** Academy of Medical Sciences (with Royal Society)
** Advisory Council on Misuse of Drugs
** Alliance for Cannabis Therapeutics
** Anonymous
** Professor Heather Ashton
** Association of Chief Police Officers
** Dr Anthony Blowers, Surrey's Drug Action Team
** Mary Brett, Dr Challoner's Grammar School (Boys), Amersham
** British Medical Association
** J Brown
** Christian Institute
** S Cooke
** David Copestake
** Dr Angela Coutts, University of Aberdeen
** Department of Complementary Medicine, University of Exeter
** R Creasey
** P Davidson
** M Davies
** S Day
** Department of Health
** Dutch National Institute of Public Health and the Environment
** Evangelical Coalition on Drugs Executive Committee
** C Fell
** Forensic Science Service
** L Gibson
** Professor Keith Green, Medical College of Georgia, USA
** Dr Geoffrey Guy
** Professor Wayne Hall, Executive Director, National Drug and
Alcohol Research
Centre, Australia
** Professor John Henry, Imperial College School of Medicine (on
behalf of Royal
College of Pathologists)
** Dr Anita Holdcroft, Imperial College School of Medicine
** Home Office
** M Humphreys
** Independent Drug Monitoring Unit
** Institute for the Study of Drug Dependence
** International Drug Strategy Institute
** Edward H Jurith
** Dr David Kendall, University of Nottingham Medical School
** Dr David Lambert
** D Lewis
** London Medical Marijuana Support Group
** Medical Research Council
** Medicines Control Agency
** Dr Tod H Mikuriya
** Austin Mitchell MP
** Mr Neil Montgomery
** Multiple Sclerosis Society
** National Addiction Centre
** National Drug Prevention Alliance
** NHS National Teratology Information Service
** Dr William Notcutt
** Professor David Nutt, University of Bristol
** Dr Roger Pertwee
** A Phillipson
** P Rigby
** Dr Philip Robson
** E Rorison
** Royal College of General Practitioners
** Royal College of Pathologists
** Royal College of Psychiatrists
** Royal Pharmaceutical Society of Great Britain
** Royal Society
** J Sayers
** Dr Fred Schon, Mayday Hospital Croydon and St George's Hospital
** Dr P Shaw
** Councillor C Simpson, Aberystwyth
** L Standen
** Dr Colin Stewart, Dundee Limb Fitting Centre
** G Vincent
** Young Christian Democrats

APPENDIX 3

Notes on Conference "Marihuana and Medicine" at New York University Medical
Center, New York, 20-21 March 1998

by Professor Leslie Iversen FRS, Specialist Adviser

1. The conference, organised by Professor G. Nahas and colleagues, gave an
overview of the current position in the USA. A topical issue there is
whether smoked marijuana should be permitted for medical use, since oral
formulations of tetrahydrocannabinol (THC) and nabilone are already
available medically.

2. M. Huestis (National Institute on Drug Abuse) reviewed new information
on the disposition and metabolism of cannabis in human subjects, using
sensitive analytical techniques to measure THC and some of the major
metabolites. Because a substantial proportion of the absorbed THC is
sequestered in fat tissues, the half life of the drug in blood is > 4 days
and the half life of the major urinary metabolite 11­carboxylic acid THC is
> 30 hours. By measuring the ratio of unchanged THC to this metabolite in
samples of blood or urine it may be possible to calculate when the last
dose of THC was taken-information that could be of importance forensically.
An unexpected finding was the large variability between subjects in the
amount of THC absorbed by smoking a standard marijuana cigarette under
laboratory conditions; even though the number and frequency of puffs was
controlled there was a 3­fold range. For the same subject tested on
different occasions there was also a considerable variability in the amount
of THC absorbed (17 per cent on average).

3. M. El Sohly (University of Mississippi) described the development of a
rectal suppository formulation for delivery of THC in the form of a
"pro­drug" (the hemisuccinate ester) dissolved in a lipid base. Absorption
of THC increased in a dose­dependent manner and was prolonged (THC was
measurable in blood for up to 8 hours). Because this route of absorption
avoids first pass metabolism in the liver, the amount of THC absorbed into
circulation was more than twice as great as after oral dosage.
Unfortunately there was a high variability between subjects in the amount
of THC absorbed (about 3­fold). The advantages of this route of
administration seem clear, but it was thought unlikely to be popular in the
United States where suppository formulations have never been widely accepted.

4. B. Thomas (Research Triangle Institute) reviewed the operation of his
laboratory which supplies standard marijuana cigarettes to the 8 individual
glaucoma patients licensed in the US to receive this medication, and to
research groups in the US and elsewhere. By using standard growing
conditions (at the University of Mississippi) and different strains of
cannabis plant they are able to generate marijuana cigarettes of consistent
quality and standard THC content (standard 1.8 per cent THC; strong 4.0
per cent THC) free of microbial or insect contamination. Placebo cigarettes
are prepared using leaf material extracted with alcohol to remove THC.

5. Roger Pertwee (University of Aberdeen) reviewed current knowledge of
the two cannabinoid receptors CB1 (found in the brain and some peripheral
organs) and CB2 (peripheral only). The presence of CB2 receptors on cells
in the immune system has prompted some pharmaceutical companies to become
interested in this as a possible target for the discovery of novel
immune­suppressant or anti­inflammatory drugs. The French company Sanofi
and the Canadian company Merck­Frosst have reported novel synthetic
antagonists/agonists acting selectively at these sites. The availability of
novel synthetic antagonists acting at the CB1 receptors (eg SR141716A
(Sanofi), LY 320135 (Eli Lilly)) has provided valuable new research tools.
New drugs are also being designed based on the structure of the endogenous
cannabinoid anandamide.

6. R. Mechoulam (Hebrew University, Israel) described his identification
of Ä9­THC as the principal psychoactive compound in cannabis extracts, and
his subsequent discovery of anandamide as the naturally occurring
cannabis­like compound in the brain. Other naturally occurring fatty acid
derivatives also interact with cannabis receptors, and one of these,
2­arachidonylglycerol, may act selectively at CB2 receptors.

7. E. Gardner (Albert Einstein College of Medicine, New York) described
studies of the interaction of THC with reward pathways in rat brain. He
confirmed earlier work from an Italian laboratory (Tanda et al, 1997,
Science, 276:2048­2050) that administration of THC (0.5mg/kg) to rats
caused an increase in dopamine release in the nucleus accumbens region of
the brain and, furthermore, that this release could be blocked by
co­administration of the drug naloxone, which blocks opiate receptors in
the brain. He also found that THC sensitised rats to the rewarding effects
of intracranial self­stimulation and that this effect was also blocked by
naloxone. These results are potentially important as they indicate that THC
stimulates dopamine pathways in the brain known to be activated by various
addictive drugs—nicotine, amphetamine, heroin and cocaine. The blocking
effects of naloxone suggest that THC may exert at least part of its
rewarding effects indirectly by promoting a release of opiate­like
chemicals in the brain.

8. D. Tashkin (University of California Los Angeles) surveyed the effects
on the lung of long-term marijuana use. He conducted large scale studies in
the 1980s in heavy marijuana smokers and compared them with subjects who
smoked tobacco. Marijuana smokers showed some bronchial symptoms (cough,
wheeze and bronchitis), but there was no evidence for any significant
reduction in overall respiratory function. When data were collected
annually for a further 8 years, the marijuana smokers did not show the
age­related decline in respiratory function seen in tobacco smokers.
Nevertheless, there was concern about the longer-term effects of marijuana
smoking. Examination of the lining of the airways revealed inflammatory
changes in chronic marijuana smokers, with an increase in the number of
mucus­secreting cells and sometimes what appeared to be pre­cancerous
alterations in cells lining the lungs. Examination of lung biopsy specimens
showed an increased expression of certain genes that are markers of lung
tumours. In addition the immune defence system appears to be depressed in
the lungs of marijuana smokers. The defending white cells (macrophages),
although present in increased numbers, had a decreased ability to kill
bacteria or fungi and produced reduced amounts of nitric oxide and
cytokines, the normal defence chemicals. Suppression of immune system
function may be related to a direct effect of cannabis on receptors on the
macrophages and other immune system cells. Although there was no evidence
for increases in lung cancers in marijuana smokers, there were some reports
of increases in cancers of mouth and throat. The reduction in immune system
function could make marijuana smokers especially vulnerable to lung
infections.

9. K. Coe (formerly at Pfizer Research) and L. Lemberger (formerly at Eli
Lilly Research) gave historical reviews of the development of novel drugs
for the treatment of pain and prevention of nausea based on cannabinoid
chemical structures. A project at Pfizer in the 1970s led to the discovery
of the synthetic compound levonantradol and the related compound CP­55,940.
These compounds had a much greater water solubility than THC and proved to
be up to 100 times more potent than morphine in some animal tests of pain.
Levonantrodol entered pilot scale clinical trials and was effective in
suppressing post­operative pain and in preventing nausea and vomiting
associated with cancer chemotherapy. It was evident, however, that the drug
did not separate the beneficial clinical effects from intoxicant effects,
and the company abandoned the project in 1980. CP­55,940 proved valuable,
however, in radioactively labelled form as a probe which led to the
identification of the cannabis CB1 receptor in the brain.

10. At Eli Lilly during the same period there was also a hope that the
beneficial effects of cannabinoids could be separated from unwanted
psychoactivity, and this led to the discovery and development of nabilone.
Clinical trials established the effectiveness of this drug in the treatment
of the nausea and vomiting associated with cancer chemotherapy. Although
some patients complained of the drug­induced "high", this appeared milder
than that associated with THC. However, although nabilone was approved for
medical use by the Food and Drug Administration, the US Drug Enforcement
Agency insisted that it be given a "Schedule II" classification [i.e. a
compound with some medical use but a high abuse potential, so doctors using
it have to keep detailed records]. This led to the company withdrawing from
the project and also failing to give any substantial marketing support to
the compound. Post­marketing surveillance reports in the UK, where the
compound has some limited use, have not shown any danger of abuse.

11. W. Notcutt (Great Yarmouth), a consultant in a pain clinic, reported
on the positive effects of nabilone in the relief of pain in some of his
patients who were suffering from chronic pain and not responding to other
medications. In a total of 55 patients he observed beneficial effects of
nabilone (improved sleep, reduced pain) in about one third.

12. K. Green (Medical College of Georgia) and M. Forbes (Columbia
University College, NY) discussed the possible use of cannabis in the
treatment of glaucoma. There are more than 2 million glaucoma patients in
the USA alone, and glaucoma is a major cause of blindness. THC or smoked
marijuana does cause a marked fall in intraocular pressure in both normal
subjects and patients with glaucoma (up to 45 per cent reduction), but the
effect is transient and returns to baseline within 3­4 hours. It is
difficult to achieve longer-term control of intraocular pressure as this
would require frequent repeat dosing. THC cannot be delivered topically to
the eye (the preferred route for anti­glaucoma medications) because of its
low water solubility. It is possible that an improved topical delivery
formulation, or topical use of a more water soluble synthetic cannabinoid,
could be developed in the future. In the USA a small group of patients (8)
have individual permission to use smoked marijuana to treat their glaucoma.

13. R. Graller (New Orleans) reviewed the use of cannabis in the treatment
of nausea and vomiting. Although there have been several controlled
clinical trials showing the effectiveness of orally administered THC and
nabilone in patients receiving cancer chemotherapy, there are few data on
smoked marijuana. In recent years a new class of anti­nausea drugs, the
5­HT3 antagonists (e.g. ondansetron, granisetron) have radically improved
the treatment of nausea and vomiting in cancer patients. He found that a
combination of granisetron and the steroid dexamethasone controlled the
symptoms in more than 90 per cent of patients. Unlike THC which cannot be
given intravenously, granisetron can be given by this route as well as by
mouth.

14. G. Francis (McGill University, Montreal) discussed the use of cannabis
in the treatment of multiple sclerosis. There are few effective treatments
for this disease, and more than 250,000 patients in the USA. Some symptoms
are particularly poorly controlled by existing medicines, notably tremor,
pain and spasticity. There are many anecdotal reports that these symptoms
are eased by smoked marijuana, but so far there have been few controlled
clinical trials. A currently ongoing study with 600 subjects aims to
compare smoked marijuana with a placebo (cigarettes with THC removed).
Results available so far suggest that the subjective reports of improvement
by patients are not always accompanied by improvement in objective measures
of performance.

APPENDIX 4

Notes on the International Cannabinoid Research Society 1998 Symposium on
Cannabinoids, La Grande Motte, France, 23-25 July 1998

by Professor Leslie Iversen FRS, Specialist Adviser

1. The annual meeting of this group of research scientists was held for
the first time outside North America and was attended by about 150
scientists, largely from academia. Of the 135 papers presented 73
originated from the United States and 50 from Europe (including 12 from
Britain, 5 of which were from Dr Pertwee's group in Aberdeen).

Endogenous cannabinoids

2. A substantial number of papers focused on the naturally occurring
cannabinoids in the brain and in peripheral tissues. At least two lipid
derivatives are now recognised: anandamide (arichidonyl­ethanolamide) and
an arichidonic acid ester, 2­arachidonyl­glycerol (2­AG). The latter
substance is as potent as anandamide and is present in much larger
quantities than anandamide in the brain. Several papers focused on the
biochemical mechanisms involved in the synthesis and degradation of these
lipids in the brain, and progress has been made in defining the biochemical
mechanisms involved. Attention has also focused on the development of
metabolically more stable chemical analogues of anandamide and 2­AG with
improved activity in whole animal studies: the naturally occurring
compounds are rapidly degraded and are thus not very active in vivo.
Another lipid, palmitoyl­ethanolamide, may represent the natural activator
of CB2 receptors, although there was some disagreement about its
pharmacological activity and selectivity.

Cannabinoid receptors

3. Several groups are studying the detailed molecular architecture of the
CB1 and CB2 receptors and beginning to identify the precise sites at which
the cannabinoids bind to these proteins. Studies of the receptors in in
vitro model systems have revealed some interesting differences between the
effectiveness of various cannabinoids in activating the receptors. In
particular A9­THC appears to act as only a partial agonist at the CB1
receptor (i.e. it cannot elicit a maximum response). Cannabidiol, one of
the most abundant plant alkaloids, on the other hand appears to act as an
antagonist at the CB1 receptor.

4. The CB1­selective antagonist drug SR141716A and the related
CB2­selective antagonist SR144528 from the French pharmaceutical company
Sanofi were the subject of many papers, and these compounds have proved to
be important new research tools for probing cannabinoid functions.
Scientists from Sanofi revealed that they are developing SR141716A for
clinical trials, with schizophrenia as their first target (on the rationale
that high doses of THC can cause a schizophrenia­like psychosis). A novel
CB1 antagonist CP­272871 from Pfizer was described for the first time; it
has properties similar to those of SR141716A.

5. The CB2 receptor, located principally on cells in the immune system,
has attracted attention from a number of major pharmaceutical companies as
a potential target for discovering novel anti­inflammatory or
immuno-suppressant drugs. There has been progress in identifying
CB2­selective drugs (by Merck Frosst, Glaxo­Wellcome, and Smith Kline
Beecham) but so far there is little confidence that this target will prove
useful. Dr Nancy Buckley (US National Institutes of Health) described the
"CB2 knockout mouse" in which as a result of genetic engineering the CB2
receptor is no longer expressed. These mice seem remarkably normal in their
immune cell population and in immune function and have not so far assisted
in understanding the role normally played by the CB2 receptors.

Adverse effects

6. D. Tashkin (UCLA) reported that treatment of mice with THC (5 mg/kg
four times a week) led to more rapid growth of implanted lung cancer cells
and decreased survival. He suggests that THC may suppress immune­mediated
eradication of tumour cells.

7. A session sponsored by the US National Institute on Drug Abuse focused
on the effects of long-term cannabis use on frontal lobe function in man. A
series of studies using imaging, cerebral blood flow and
electroencephalographic measurements indicated depressed frontal lobe
function in long-term cannabis users, and there were accompanying subtle
deficits in sensory and cognitive processing, the so-called "executive
functions" of the brain. There was little evidence that any of these
effects persisted after cessation of drug intake.

8. Billy Martin et al (Virginia, USA) described an animal model of
cannabis dependence. When dogs were treated with high doses of THC for 7­14
days and then challenged with the CB1 antagonist SR141716A clear physical
signs of withdrawal became apparent; these included trembling, shaking,
restlessness, vomiting and diarrhoea. By using the antagonist challenge
model it has become much clearer that physical dependence and withdrawal
can occur with THC, at least in animals. Furthermore, de Fonseca et al
(Madrid) reported that the administration of SR141716A to
morphine­dependent animals elicited a behavioural and endocrine syndrome
similar to that seen in opiate withdrawal, although considerably milder.
Conversely some withdrawal signs could be elicited in cannabinoid-dependent
animals when challenged with the opiate receptor antagonist naloxone,
suggesting an interaction between the opioid and cannabinoid systems in the
brain.

Possible applications of cannabinoids

9. The interaction of opiate and cannabinoid mechanisms was also
highlighted by Sandra Welch (Medical College of Virginia, USA) who reported
that low doses of THC significantly potentiated the pain­relieving effects
of morphine and other opiates in a mouse model of arthritis­like pain.
Higher doses of THC were also by themselves fully effective in causing
analgesia in this model. She is planning a clinical trial (with the
approval of the US Food & Drug Administration) of low doses of THC
(dronabinol) in conjunction with self­administered morphine in patients
suffering from cancer pain, in the hope that the drug combination may make
morphine more effective in such patients.

10. D. Piomelli ( San Diego, USA) described powerful analgesic effects of
anandamide when injected directly into the rat paw in an inflamed paw model
of inflammatory pain. The mechanism appeared to involve both CB1 and CB2
receptors located on sensory nerve fibres in the skin, and when a
combination of CB1­selective and CB2­selective compounds was injected there
was synergy between them. Experiments using radiolabelled anandamide showed
that >90 per cent of the injected dose remained in the paw, and very little
entered the brain or spinal cord. These results are highly original and
suggest the possibility that cannabinoids can exert pain­relieving actions
without having to penetrate into the central nervous system.

11. P. Consroe and R. Musty (University of Arizona, USA) described the
results of an anonymous survey of 106 patients with spinal cord injuries
who were self­medicating with smoked marijuana. Patients smoked an average
of 4 joints a day, 6 days a week and had been doing so for >10 years. More
than 90 per cent reported that cannabis helped improve symptoms of muscle
spasms of arms or legs, and improved urinary control and function. Around
70 per cent reported pain relief. The results of this survey and a similar
one conducted with R. Pertwee in MS patients may help to pinpoint the
relevant symptoms to focus on as outcome measures in future clinical trials
of cannabis or cannabinoids.

12. D. Pate (University of Kuopio, Finland) described promising results in
the reduction of intraocular pressure when a metabolically stable
anandamide analogue was applied topically to normal rabbit eye. This effect
appeared to involve a local CB1 receptor mechanism as it could be blocked
by pretreating the animals with the antagonist SR141716A. In order to
deliver the water­insoluble lipid derivative to the eye it was dispersed in
an aqueous solution containing a beta­cyclodextrin carrier.

Miscellaneous

13. M. El Sohly (University of Mississippi, USA) summarised results
obtained from the analysis of confiscated marijuana samples, a service
which has been running since 1980 and which involves the analysis of
samples from all regions of the United States. Data from 35,312 samples
were available. The potency of marijuana leaf samples (the commonest in US
seizures) rose from around 1.5 per cent THC content in 1980 to around 3 per
cent in the 1980s and most recently to 3.87 per cent in 1996 and 4.15 per
cent in 1997. The THC content of sinsemilla (the female plant flower head)
rose from around 6.5 per cent in 1980 to 9.22 per cent (1996) and 11.53 per
cent (1997). The increases are thought to be due to improved culture
conditions rather than to any genetic improvements. Analysis of samples of
cannabis resin or oil revealed few discernible trends, with figures ranging
from 3 per cent to 19 per cent THC content.

14. J. Khodabaks and O. Engelsma (Maripharm, Netherlands) described their
development of "The standardised medical grade marihuana plant". Until
recently this group has been supplying Dutch pharmacists with medical grade
marijuana, but its legal status has recently been questioned. The
laboratory cultivates standard cannabis plants selected for a high yield of
THC and low content of other cannabinoids; these are cloned by propagating
(by cuttings) from female plants. The plants are grown under standard
conditions and the female flower heads harvested and vacuum-sealed for
storage and then gamma­irradiated to sterilise the preparations. Samples
are routinely checked for THC and other cannabinoids and to ensure that
they are free of pesticides. The THC content in different batches was
highly consistent at 10.7 + or - 0.1 per cent (standard deviation).
Interestingly, in the light of discussions about the relevance of other
cannabinoids in herbal cannabis, cannabidiol and cannabinol were present in
only minor amounts (<0.1 per cent) in these samples.

(end)

Checked-by: Richard Lake