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".

  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).

  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.

  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).

  5.38     The BMA report called on the Clinical Cannabinoid Group (an informal network of interested researchers convened by Dr Pertwee), patient groups, pharmaceutical companies and the Department of Health to "work together to encourage" trials. In their written evidence the BMA say, "the accumulation of scientific evidence has been hampered by regulations restricting the use of cannabinoids to one clinical indication" [anti-emesis] (p 11). Following their report, the BMA met the Government's Chief Medical Officer in March 1998 "to discuss likely further actions in moving forward clinical trials of cannabinoids for therapeutic uses". At the meeting, it was agreed that an appropriate body to conduct such trials was required and that it should be an independent or institutional research organisation.

  5.39     Clinical trials are expensive, but the research funding bodies have no objection of principle to funding work in this field. The MRC report a shortage of high-quality research proposals in this area (Q 629); but they would be "supportive" of funding well-conceived clinical trials in this field, and would even be prepared to consider a grant application "out of turn" (QQ 638, 769). In February 1998 the MRC had three grants, one to Dr Pertwee and two to Dr Kendall; Dr Pertwee's has now finished, as has one of Dr Kendall's (Q 621). The Wellcome Trust had made nine grants since 1990: five project grants, including three to Dr Pertwee, and four research career re-entry fellowship grants, all to colleagues of Dr Pertwee. The Multiple Sclerosis Society and the BMA are also willing to help fund a trial (MSSoc p 89; Q 769). The Department of Health do not normally fund trials, but might "facilitate" (Q 194). Besides the Wellcome Trust, Dr Pertwee's research group in Aberdeen is also funded by the USA's National Institute on Drug Abuse (part of the National Institutes of Health) and a pharmaceutical company (Q 252).

  5.40     Professor Edwards (Q 19) questions the justification for carrying out expensive controlled trials with cannabis. He is concerned about the possibility of diversion to misuse of the drug. As a preliminary, he favours a series of smaller-scale clinical investigations in individual patients.

  5.41     Several of our witnesses have commented on the difficulties of conducting clinical trials with cannabis. How can a standardised product be made available? What formulation is to be used? How can the dose be predicted for any particular medical condition? How consistent and predictable would blood levels of THC be (QQ 7, 8, 180, 781)? In addition, individual patients are likely to differ considerably in the dose needed to control their symptoms—as with the use of opiates in the control of severe pain, where Professor Wall points out that a tenfold range of doses is commonly observed (QQ 112-3).

  5.42     Professor David Grahame­Smith, Chairman of the Advisory Council on the Misuse of Drugs (Q 8), raised the question of the difficulty of carrying out a double­blind placebo-controlled trial with a psychoactive agent, as the drug could easily be distinguished from the inert placebo. Professor Lader suggested that one solution to this might be to test cannabis by comparison with some other psychoactive drug, rather than against an inactive placebo. Other possibilities are to use doses of the active drug too small to have psychoactive effect; or to proceed with an inactive placebo, and find out at the end of the trial how far patients could tell whether they were receiving the active drug or the placebo (Q 779).

  5.43     In addition to these practical problems, clinical researchers face extra legal hurdles, and a generally negative climate of opinion, because of the status of cannabis as a Schedule 1 controlled drug. We consider this problem, and what might be done about it, in Chapter 7.

  5.44     Clinical trials are now under active consideration in several fora. First, Dr Geoffrey Guy, a pharmaceutical entrepreneur, has recently set up GW Pharmaceuticals, to conduct licensed research and develop cannabis-based medicines, in collaboration with HortaPharm BV of Holland (see Dr Guy's evidence, and QQ 107, 135, 413-420, 447). The aim is to produce standardised whole-plant extracts, rather than single chemicals, from plants bred for standard cannabinoid content, with a non-smoking mode of administration offering the advantages of smoking without the harm, and to proceed via clinical trials to an application for a product licence. Dr Guy received licences to cultivate cannabis, and to possess and supply it for research, from the Home Office in June 1998. He is now recruiting patients for trials, with help from the ACT.

  5.45     Dr Guy is confident that rigorous trials can be mounted, and that contamination of the plant material can be avoided. He advocates the use of plant-derived products, and cites the examples of gentamicin, papaveretum and digitalis as approved plant­derived products that contain complex mixtures of alkaloids. He believes that, by using controlled growing conditions and cloned cannabis plants, it will be possible to produce a herbal preparation of consistent composition with adequate quality controls. This position is reinforced by data from the Dutch organisation Maripharm (see Appendix 4 paragraph 14), who have been able to produce medical-grade herbal cannabis selected to have a consistent content of THC (10.7 ± 0.1 per cent) and a low content of other cannabinoids.

  5.46     Secondly, following the meeting between the BMA and the CMO (see above, paragraph 5.38), the Royal Pharmaceutical Society have set up a "working party on therapeutic uses of cannabinoids", chaired by Professor Sir William Asscher, a past Chairman of the Committee on Safety of Medicines. The group includes representatives of the NHS R&D Directorate, the MRC and the Multiple Sclerosis Society, and researchers including Dr Pertwee. Its objectives are "to produce guidelines for pilot clinical trials for cannabinoids as proof of principle of their effectiveness, and to assist those who wish to conduct such trials to successfully complete them and publish the results". The group has drawn up protocols for two trials: one for spasticity arising from MS, the other for post-operative pain. In each case the trial will be longitudinal (i.e. not a cross-over trial), involving three groups of patients: one will be given dronabinol, another an extract of cannabis containing the same quantity of THC, and the third a placebo. Smoking has been ruled out; administration will be by oral capsule. The lead clinician for the pain trial is Dr Anita Holdcroft, whose previous single-patient trial of cannabis was noted above; the lead clinician for the MS trial is Dr John Zajicek of Derriford Hospital, Plymouth. The protocols are to be launched shortly, at which point applications will be made for funding (from non-industrial sources) and for Home Office licences. (See the evidence of members of the working party, QQ 768-811.)

  5.47     In addition, Jo Barnes of Exeter University is launching a pilot study of oral THC involving 30 MS patients, funded by the university, intended to "provide data which can be used for a sample size calculation for a full-scale study" (p 217). Dr Robson is planning pilot studies using nabilone and dronabinol for detoxification from opiates and as an anxiolytic/hypnotic in acute drug-related problems (p 118, Q 458). Professor Wall knows of three other United Kingdom trials at an advanced planning stage, by Dr Pertwee, Dr Notcutt (Q 448), and Dr Clare Fowler at the National Hospital for Neurology and Neurosurgery in London.

  5.48     These various initiatives are, or may become, interrelated. The Asscher group trials, and others, may use GW Pharmaceuticals as the source of supply of cannabis material; in that case they might be covered by an extension of Dr Guy's Home Office licence. The Exeter group, and others, may bring their trials within the Asscher group's protocols, so as to become part of a national study. In the end, it is possible that all or most of these initiatives will come together into two national trials, using the Asscher group's protocols and Dr Guy's licence and materials.

  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.

  5.54     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).