SECTION 6 MEDICINAL USES OF CANNABIS - LITERATURE REVIEWS

6.1.2 Much of the debate about therapeutic use of cannabis has centred on the reduction of the raw matter to its specific chemical compounds. Studies then try to determine the exact physiological and psychological effects of each constituent on its own. This is, of course, quite in keeping with accepted modern pharmaceutical and medical practice, but often results in scientists and medical experts rejecting the possible inclusion of cannabis derivatives in the pharmacopoeia, on the grounds that existing drugs are available with more precise or efficacious properties.

6.1.3 Such conclusions conflict with modern anecdotal reports citing cannabis in natural form as the most effective treatment in a variety of cases, as well as with long traditions of medical uses. It may be that each of the conditions treated is affected by a number of different compounds present in cannabis, both as agonises and antagonists. Many current pharmaceutical treatments rely on a cocktail of drugs to treat a single condition.

6.1.4 For example, the cannabimimetic effects of *9THC are well documented and frequently cited as arguments against the use of cannabis in therapy. Yet as long ago as 1981 reports appeared citing the presence in raw cannabis of a water soluble inhibitor of the action of THC. Similarly, CBD has been shown to reduce the anxiety caused by high-dosage *1THC. It has been suggested that the use of such natural inhibitors in conjunction with the active derivatives might allow the unwanted cannabimimetic effects to be negated while preserving the desired therapeutic properties..

6.1.5 The case against cannabis on the grounds of non-specific action is only valid within the context of a broader argument against alternative therapy in general. The modern NHS and those in private medicine are already moving towards acceptance and even support of alternative and complementary medicine. Many of the treatments in this sphere include the use of similar non-specific natural remedies.

6.1.6 In 1988, US Supreme Court Judge Francis L Young in a ruling on a petition for the rescheduling of marijuana to allow medicinal use, held that such rescheduling should occur, finding that cannabis was "one of the safest therapeutically active substances known to man". He approved cannabis for the treatment of glaucoma, multiple sclerosis and treatment of the side effects associated with cancer chemotherapy.

6.1.7 In a 1991 report, the World Health Organisation Expert Committee on Drug Dependence recommended that THC and related compounds be rescheduled from schedule 1 to schedule 2 of the Convention on Psychotropic Substances 1971. This effectively recognised the therapeutic value of cannabis compounds, would permit wider use in the treatment of organic diseases, and may lead to a dramatic increase in research devoted to therapeutic applications. Discovery of the "cannabis receptor" in the central nervous system and other areas has led to an increase in recent research into the therapeutic applications of cannabinoids.

6.2.2 Analgesic - This effect is now well-established and the BMA have recommended that some cannabinoids be available for prescription. (literature review below).

6.2.3 Anti-emetic - The use of cannabinoids (e.g. Nabilone) in treating the side-effects of cancer chemotherapy is well established, there is increasing evidence at to efficacy as an appetite stimulant in AIDS patients.

6.2.4 Anticonvulsant - first reported by O"Shaughnessy in 1838, there is substantial evidence for the efficacy of some cannabinoids (e.g. CBD) in treatment of epileptic disorders. As CBD has few psychotropic effects, there would appear to be no logical reason for preventing or discouraging research and/or clinical trials of this cannabinoid. (literature review below).

6.2.5 Anxiolytic - Relief of stress and relaxation is the most commonly-reported "therapeutic" benefit by most users. However, stress levels can increase dramatically in na"ve users exposed to the drug. (literature review below).

6.2.6 Bronchodilator - The BMA report covers potential use of cannabinoids in the treatment of asthmatic disorders. (literature review below)

6.2.7 Opiate/Alcohol dependence - There is limited evidence suggesting that high doses of cannabis may ameliorate the opiate withdrawal syndrome, and the anticonvulsant action of cannabinoids may assist during detoxification of individuals following withdrawal of opiates or alcohol. While there is anecdotal evidence of individuals successfully using cannabis as a long-term substitute for opiates or alcohol, the scientific evidence does not lead to great optimism for this aspect of potential treatment (literature reviews below).

6.3.2 Rubin reviewed evidence of traditional medicinal usage of the plant from a variety of native cultures. The Pan Ts"oo Ching, a Chinese pharmacopoeia dating from the second century AD, stated that an infusion of cannabis "undoes rheumatism". Rabelais, the classical French author, physician and botanist suggested that the "root, boiled in water, softens hardened sinews, contracted joints ...(and) gouty swellings.

6.3.3 O"Shaughnessy, in the first modern (1837) treatise on the medicinal use of cannabis, described the widespread medicinal use of the drug in India, including cases where he had successfully used the drug for the relief of convulsions.

6.3.4 Mattison reported of cannabis that "its analgesic virtue is shown in allaying the intense itching of eczema, so as to permit sleep." He cites clinical study of 1000 patients treated with cannabis as a hypnotic (sleep inducing agent) found complete success in 53% and partial success in 22% of cases. Reynolds , personal physician to Queen Victoria, recommended cannabis for use in "senile insomnia".

6.3.5 Mikuriya reviewing 19th Century and early 20th Century medical reports, quotes 1968 correspondence from Parke Davis, who produced medicinal cannabis products until the 1930s, suggesting that an effective dose of an alcoholic tincture was 1ml per kilo body weight, and of the solid extract (i.e. the purified cannabinoids) 4mg per kilo was required as an oral dose.

6.4.2 The dosages required to produce detectable pain relief in animal models were substantially in excess of dosages encountered in normal social use (typically 0.1-1.0 mg/kg). The effective dose of THC in the early mouse studies (approx. 5mg/kg) would be the equivalent of an average 70kg man consuming 350mg THC, or smoking 10 grams of cannabis with a potency of 3.5%.

6.4.3 Mechoulam found inconclusive results on pain relief from human subjects, although the dosages in most studies were lower than those found effective in animal models. He concluded that there was "significant analgesic activity" from THC, remarking that the lack of any physical dependence was "a plus", although he was concerned about the "psychotomimetic" effects (i.e. the high) particularly for individuals unused to the drug. In an earlier review Mechoulam had considered the traditional use of cannabis preparations as analgesic and anti-rheumatic agents to have "some modern substantiation".

6.4.4 Noyes et al found a clear dose-related analgesic effect from oral administration of THC. In a second study the analgesic effect was found to be six times as powerful as that of codeine, with 20mg THC producing significant pain relief for over 5 hours. He considered the side effects (sedation and light-headedness) to mitigate against wider clinical use. However, his subjects were inexperienced with marijuana use and as such may have found the psychological effects of the high more disturbing, and thus less tolerable, than experienced users. Milstein et al found that experienced marijuana users exposed to approximately 7.5mg THC by inhalation, achieved a greater analgesic effect than naive subjects, and were less likely to report adverse side effects. Whether this increased response is due to more efficient inhalation techniques in the experienced group, or through a "reverse tolerance" whereby THC has a greater effect in habitués, is not clear.

6.4.5 In Judge Young"s report numerous cases histories were described outlining the use of cannabis to reduce muscle tension (spasticity) in individuals with multiple sclerosis or spinal injury. The potential efficacy of cannabis in treatment of MS is increasingly accepted by patients and medical practitioners alike. Ungerleider et al demonstrated clear dose-related reduction of spasticity with doses of 7.5 to 15mg THC.

6.4.6 Pertwee reports a number of patients suffering spinal injury or multiple sclerosis claiming cannabis relieves spasticity and pain associated with muscle spasms more effectively than conventional muscle relaxants and with more tolerable side effects. Several clinical trials have supported these claims , indicating that oral THC or inhalation of cannabis smoke can relieve muscle pain and spasticity.

6.4.7 Cannabis was the treatment of choice for migraine in the last century, and a modern report has supported the efficacy of the drug in this respect.

6.4.8 The BMA report made the following recommendations concerning cannabinoids and pain:

6.4.9 Our own recent study of cannabis users asked respondents to report any physical or mental health problems and/or benefits which they attributed to cannabis use. Thirty two individuals cited "pain relief" as the main benefit they received, the fourth most common benefit reported (after relaxation (n=89), stress relief (n=67) and improvements in personal development and outlook (n=36)). Two individuals specifically mentioned use of cannabis as a muscle relaxant.

6.5.2 In 1949, Davis & Ramsey tested two homologues of THC in a clinical trial on 5 institutionalised epileptic children, three responded as well as to previous therapy, with two virtually symptom free. The authors considered that the cannabinols deserved further trial in non-institutionalised epileptics.

6.5.3 In a 1950 paper, Loewe considered a number of cannabinoids to show antiepileptic activity, and considered that these showed much greater potency (up to 150 times) and an incomparably greater margin of safety than diphenylhydantoin.

6.5.4 Consroe et al reviewed numerous animal experiments showing anticonvulsant or antiepileptic activity in rat, mouse, frog, cat, baboon and gerbil, some studies showing the development of tolerance to the anticonvulsive effects, and also experiments showing convulsant activity in rat, dog, monkey, cat and rabbit, several of which involved extremely high THC doses of 60-3600mg/kg. Their own experiments confirmed both anticonvulsant and convulsant activity, and recommended further research in this area. In a previous study the same author found that a single epileptic patient receiving conventional anticonvulsant medication (phenobarbitone and diphenylhydantoin) was only able to control seizures when illicit marijuana was used (2-5g per day) in conjunction with the conventional drugs. In 1981, Consroe & Fish considered Nabilone (a synthetic cannabinoid) to be 7.5 times as effective as THC in provoking convulsions in a hypersensitive rabbit model. CBD provoked no seizures.

6.5.6 In a double-blind clinical trial of CBD, Cunha et al found it to be effective in abolishing or reducing seizures in 7 out of 8 subjects receiving 100mg daily, whereas only 1 out of 7 placebo controls reported any improvement. Concluded that CBD had a beneficial effect in patients suffering from secondary generalised epilepsy, who did not benefit from known antiepileptic drugs.

6.5.7 Karler & Turkanis considered both D9-THC and 11-hydroxy THC (metabolite) to have anticonvulsant activity, and noted that CBD prolonged the effects of common antiepileptic drugs such as phenobarbitone and diphenylhydantoin, suggesting that the effectiveness of these drugs could be increased in combination with CBD, and considered CBD to have the most promising antiepileptic potential of the cannabinoids. In a later study, the same authors suggested the widespread and specific anticonvulsant effects of stereoisomeric cannabinoids was evidence of a specific receptor, and considered CBD to be the most effective non-psychoactive agent, causing a depression of seizure spread. They considered the effect of THC to be attributable to the three major metabolites, with CBD showing a clear dose (brain concentration) response curve, whereas THC showed delayed responsiveness, consistent with the increase in metabolites following THC breakdown. There were considerable species differences in response between rat, mouse and frog. They concluded that CBD met all the requirements as a potentially useful drug in the treatment of epilepsy, being devoid of psychotoxicity, showing anticonvulsant selectivity, and appeared to be free of CNS excitatory effects characteristic of most anticonvulsants.

6.5.8 In a large-scale epidemiological study, Ng et al found marijuana use to be protective against the development of first onset seizures, however there was no indication of the dosages used, differentiating only between 'ever' used and used within the previous 90 days.

6.5.9 A critical review of the accepted anticonvulsant activity of cannabinoids by Feeney et al, considered previous studies to be inconclusive, with most showing some reduction in seizure activity, although in some individual subjects the frequency or duration of seizures could be exacerbated. Further experiments on dogs, using daily doses of 0.5 to 5.0mg/kg THC, claimed to show a dose-related increase in duration of EEG seizure activity, with 20mg/kg showing the greatest increase (equivalent to 1.4g pure THC for a 70kg human, or 14g-28g of cannabis at 10% and 5% purity respectively). They considered their data to show an increased risk of seizures in persons with pre-existing pathology. However these studies involved small numbers of animals, and CBD dosages failed to increase seizure activity significantly over controls, and the authors considered Cannabidiol (CBD) to be worthy of further study.

6.5.10 In a 1976 survey of epileptic patients, Feeney found a number of marijuana users, most reporting no effect, one that symptoms decreased, one that marijuana 'caused' his seizures. In a later report, Feeney considered THC to have both convulsant and anticonvulsant action, provoking symptoms including grand mal seizures in epileptic beagles, but blocking electroshock seizures in rats at comparable doses. Considered CBD to exert anticonvulsant effects with no convulsant or psychotropic action, and recommended clinical trials of CBD to test anticonvulsant action in epileptic humans.

6.5.11 Keeler & Riefler reported a single case history of seizure-free epileptic finding symptoms recurring following a period of marijuana use, called attention to the risk of using marijuana for seizure-prone individuals. Perez Reyes et al found an increase of EEG spikes following i.v. administration of 40mg cannabinol to a single 24 year old epileptic patient. Earlier case studies included one epileptic whose seizures were considered to have been precipitated by an experimental exposure to cannabis extract.

6.5.12 Grinspoon, after reviewing other studies reported above, noted two case histories of individuals who had successfully used marijuana for treating epileptic symptoms, the first found marijuana abolished frequent petit-mal seizures which had been unresponsive to other medication, the other found that cannabis abolished grand-mal seizures, and substantially reduced petit mal seizures, enabling him to reduce his conventional medication by over 50%. The seizures returned during the patient's imprisonment on a marijuana cultivation charge.

6.5.12 Summary on anticonvulsant effects. The studies show that cannabis may have beneficial effects for some epileptic patients, primarily attributable to CBD and metabolites of THC. In particular, CBD appears to show the most consistent anticonvulsant action, and has been shown to increase the effectiveness of prescribed anticonvulsant medication. Most studies have reported the therapeutic effectiveness to differ between individuals or between different types of epilepsy, with some individuals receiving no benefit or adverse effects, while others can show a complete cessation of symptoms. If an individual has experienced a positive effect on the frequency and/or severity of symptoms following cannabis use, it is probable that the drug would have contributed to this effect. However, I would consider cannabis resin, with a relatively high CBD content, possibly to provide a greater benefit than indoor herbal cannabis, which typically has relatively low CBD.

6.6.2 Recent advances in fundamental cannabinoid research have been interpreted as indicating a common modality of action of cannabis and opiate drugs, in that naloxone (an opiate antagonist) blocks cannabinoid-induced dopamine release in the limbic system (a primitive brain structure associated with control of emotion and mood),. A cannabinoid antagonist administered to rats, pre-treated with a powerful synthetic cannabinoid agonist, can precipitate corticotrophin releasing factor (CRF), which is held to be the mechanism responsible for mediating the psychological aspects of drug withdrawal symptoms, and leading to anxiety-type behaviours. This was interpreted as demonstrating a cannabis withdrawal syndrome. However the potency of the synthetic cannabinoid used was many times that of THC, and the administration of an antagonist (blocker) would not effectively mimic the gradual decrease in plasma THC which occurs with cessation of normal use. The fact that a potent cannabis blocker caused anxiety symptoms in rats would be consistent with a general diminution of anxiety levels arising from cannabis use.

6.6.3 Laurie reported that in a few cases 'anxiety, which may approach panic, often associated with a fear of death or an oppressive foreboding, is infrequently seen, usually giving way to an increasing sense of calmness... to euphoria'. Grinspoon refers to the initial state as a 'happy anxiety' where the experience is internally redefined as pleasurable. Rosenthal et al report that panic reactions and anxiety are rare, and most commonly found with overdose (particularly from oral preparations), in na"ve users, or in those who do not like the effects of marijuana, and attributed the incidence of anxiety reports with Marinol (dronabinol - pure THC) to the lack of CBD within the preparation. Mikuriya considered that 'the power of cannabis to fight depression is perhaps its most important property'. Patients were reported to self-medicate with cannabis rather than use benzodiazepines as the former produced less dulling of mental activity. The authors cited one study where marijuana was found to increase anxiety in na"ve users, but to decrease anxiety in experienced users, and another of 79 psychotics who used marijuana recreationally and reported less anxiety, depression, insomnia or physical discomfort. They concluded that natural marijuana - containing CBD and THC - appeared more effective than THC alone in treating depression, and that patients suffering stress as a result of pain or muscle spasms would be most likely to be helped by the drug. They differentiated the use of cannabis to cope with everyday life stresses from the use of benzodiazepines in treating 'severe anxiety disorders' with an organic aetiology.

6.6.4 Bello in a passionate treatise on the benefits of cannabis for physical and mental health, likened the anxiolytic effect of marijuana to a state of relaxed alertness brought on by 'balancing' the autonomic nervous system.

6.6.5 Explanations of the panic and anxiety experienced by some na"ve users exposed to cannabis would include a low tolerance to the drug, and 'set and setting' i.e. a drug taken in the course of a laboratory experiment would provide different expectations of an experience to an informal party or gathering of friends. Secondly, the increase in heart rate can be interpreted by some older na"ve users as a heart attack and cause panic attacks, this 'tachycardia' is normally associated with a reduction in blood pressure. Some individuals may be more susceptible to the effects of cannabis than others, and those whose initial experience is unpleasant may be more likely to discontinue use of the drug. By contrast, many first-time users fail to notice the influence of the drug.

6.6.6 Thompson & Proctor, treating withdrawal conditions, noted the synthetic cannabinoid pyrahexyl to produce significant increases in alpha brain waves, indicating increased relaxation, and Adams reported similar results. However Williams et al found no significant increase in alpha activity either with pyrahexyl or smoked marijuana.

6.6.7 Davies et al, in a study of cancer patients, considered the management of stressful patients to have been improved by oral THC. However a study of intravenous THC used as a premedication for oral-facial surgery found that patients showed pronounced elevation of anxiety, and considered noxious stimuli to be more painful. Mechoulam considered a number of synthetic cannabinoids to be worthy of investigation as potential sedative-relaxants.

6.6.8 Musty compared the effects of THC, CBD (cannabidiol) and diazepam (valium) on anxiety-related behaviours in mice. THC produced similar reductions in anxiety behaviours to diazepam, however the effect of CBD was more pronounced than either in measures of shock-avoidance, grooming and reduction of delirium tremens in alcohol-withdrawn mice. Both THC and CBD produced dose-related reductions in ulcer formation in stressed mice. However in all tests the CBD dosages used were higher than THC dosages.

6.6.9 Mechoulam reviewed studies of Nabilone (synthetic cannabinoid) on anxiety, finding two studies which suggested a superior effect on anxiety, mood and concomitant depression, whereas two other studies found little or no effect. Benowitz & Jones reported initial tachycardia and hypertension in volunteer subjects administered up to 210mg THC per day, but found development of tolerance to tachycardia and CNS effects over the 20 day experiment, with blood pressure reduced and stabilised at around 95/65. Fabre & McLendon reported a dramatic improvement in anxiety in the nabilone-treated group compared to placebo. Nakano et al reported antianxiety effects of nabilone and diazepam in a controlled trial of experimentally-induced stress, but was unable to conclude which was more effective due to differences in dosage and metabolism. Hollister reported these and other nabilone studies indicating significant anti-anxiety effects of low doses, and commented on the scarcity of studies of potential anti-anxiety effects of cannabinoids.

6.7.2 Cannabis products have long been considered to be effective in the treatment of depressive disorders, in 1845 it was recommended for melancholia (with obsessive rumination) and mental disorder in general. In 1947 Stockings found improvements in 36 out of 50 depressed mental patients treated with a synthetic cannabinoid.

6.7.3 Bolls reported a case of post-natal depression successfully treated by a large oral dose (4g of alcoholic cannabis tincture) and counselling. The subject reported anxiety at the peak of the drugs effect, however the study involved a single case, was not controlled under current scientific methodology, and it could not now be concluded whether any recovery was due to the drug, the psychotherapy, or would have occurred in any event.

6.7.4 Kotin et al, in a double-blind experiment, found no effect on moderate to severe depression from relatively high doses (0.3mg/kg) of THC. Grinspoon considered cannabinoids to be of promise where depression is secondary to some life event (reactive depression) rather than a primary diagnosis, but did not consider general optimism about such treatment to be justified by the state of knowledge in 1977.

6.7.5 Regelson et alia reported a number of significant effects in a controlled study of THC in terminal cancer patients, including a reduction in depression, greater emotional stability, more self-reliant/less dependent, less suspiciousness, increased forthrightness, less apprehension, more normal level of control and more tranquil/relaxed, however two patients who discontinued the study reported fear and anxiety, confused thinking and dissociation. The authors commented that such effects would appear to be confined to a susceptible population.

6.7.6 Grinspoon considered some patients who fail to respond to traditional antidepressant drugs, or who find the side-effects of these unbearable, to have been helped by illicit marijuana use, quoting 3 case studies all involving long histories of severe clinical depression, all treated unsuccessfully with all types of antidepressive medication, and all now living normally through use of cannabis, twice daily in one case, on re-appearance of symptoms in the others, each attributing the improvement to greater self-insight, a reduction of a negative self-image, and/or a general euphoria arising from cannabis intoxication.

6.7.7 Conclusions re Anxiety & Depression: There is a great deal of anecdotal evidence to suggest that cannabis may have a beneficial effect on mood disorders such as mild anxiety or depression. However, the results of scientific studies are inconclusive, and the anecdotal reports cannot be reliably confirmed at the present time. In particular the human studies which have been cited in support of such psychological benefits either used synthetic cannabinoid homologues, or failed to use the double-blind experimental methodologies now required to eliminate possible bias in the experimenters or subjects.

6.7.8 Whereas experienced cannabis users quote 'relaxation' as the most commonly perceived health benefit derived from the drug, many novice users experience a severe bout of anxiety which can approach a panic attack. These are very rare among experienced users of the drug, and can often be attributed to a hostile environment and/or negative expectations of the drugs effects.

6.7.9 The effect of cannabis and cannabinoids is not adequately predictable for dosage regimes to be developed for the general population. Cannabis affects different people in different ways - one person may feel relaxed when the next might feel anxious and paranoid - and could not be used in the treatment of mental disorders without close monitoring of the effects on individual patients. However, where conventional medications have failed to control the symptoms adequately, there may be a case for trial use of cannabis to determine whether the drug could aid existing treatment or replace drugs with unwanted side effects.

6.7.10 The most recent research into cannabinoid neurochemistry provide qualified support for the view that cannabis drugs can promote relaxation and a less stressful mental state. However whether this is a learned effect, or an effect of tolerance to the drug's effects and the avoidance of withdrawal (mediated by CRF release in the amygdala), cannot yet be determined.

6.7.11 I would not consider the case yet to be made for the widespread prescription of cannabis as an antidepressant or antianxiety medication. There is clearly a need for much additional research into the efficacy of cannabis on these conditions. Where many cannabis users report a general improvement in mood, others find the experience highly disturbing, and the risks of prescribing the drug to unsuitable individuals may well outweigh the potential benefits.

6.8.2 Modern research has tended to confirm traditional therapeutic use as an anti-inflammatory and bronchodilator agent. Vachon et al, using volunteer asthma patients, found that smoke from low-potency material (1.9% & 0.9% THC) showed highly significant bronchodilator effects, which did not appear to be dose related, lasting for up to 90 minutes after administration.

6.8.3 Tashkin et al in double-blind experiments using smoked cannabis with 2% or 0% THC (0% - placebo - all cannabinoids extracted before administration), as well as 15mg synthetic THC administered orally, found increases in specific airway conductance (bronchodilation) with smoked and oral drug conditions, and concluded that the 0% THC placebo may contain some as yet unidentified bronchodilator, as there was no broncho-constriction, which might have been expected in asthmatics following inhalation of particulate matter. They concluded that THC was effective in relieving exercise-induced bronchospasm, with the duration of the bronchodilatory action lasting from 2hr to 4hr after administration. Oral THC produced significant, but less pronounced, effects. In 1977 the same team used aerosolised THC in 5mg and 20mg doses, producing similar and significant bronchodilation after all doses, with the lower dose producing fewer physical (tachycardia) or psychological (high) side effects than the higher dose or smoked marijuana. The effect was slower in onset but longer in duration than isoproterenol, a conventional bronchodilator agent. Williams et al also concluded that THC and salbutamol (ventolin) were equally effective in improving ventilatory function 1 hour after administration by aerosol, with THC having the longer duration of action.

6.8.4 Abboud & Sanders found that bronchodilator effects were unreliable when 10mg oral THC was used, some slight increase in airway conductance was noted although one patient developed severe bronchoconstriction.

6.8.5 Reviewing the evidence in 1986, Graham concluded that THC is an active bronchodilator with a different mode of action from the common preparations such as salbutamol and terbutaline, and active when ingested orally or by inhalation. Oral use (2mg to 20mg in a sesame oil capsule) was slower in onset than inhalation, which although not ideal, due to the particulate matter in smoke, could produce swift relief from symptoms. Higher amounts - i.e. 50-75mg of THC - showed a dose-related effect. Tests of CBN (600mg) and CBD (1200mg) showed these cannabinoids not to have bronchodilator activity. Prolonged administration produced no evidence of clinical tolerance to any of the actions of THC. Speculated that the action of THC may involve suppression of the release of endogenous substances causing asthma (e.g. SRS-A), rather than inhibiting their activity.

6.9.2 The effect of cannabis in reducing the severity of opiate withdrawal symptoms was widely-described in the 19th century. In the very first volume of the Lancet, Birch reported using 300mg cannabis extract daily to treat withdrawal symptoms in a young opium (laudanum) user, noting "improved appetite and sound sleep", strengthened pulse and a complete physical recovery within 6 weeks. Mattison recounted 10 years experience in treating opium and morphine addicts, and considered it to be 'an efficient substitute for the poppy. Its power in this regard has sometimes surprised me.' One long term morphine injector, with a habit broadly equivalent to over 2g per day of 'street' heroin was stated to have recovered with 10 doses of fluid extract of 'Indian hemp'. The author William Burroughs wrote in 1953

6.9.3 Mikuriya reports successful use of 120mg synthetic THC (dronabinol) per day (oral in sesame oil) to withdraw an patient from a 70mg/day methadone addiction. There have been a small number of reports of self-medication of cannabis by withdrawing addicts, and 'de-escalation', i.e. reducing opiate use in favour of cannabis use over the long term. I have spoken with heroin addicts who had smoked very large quantities of cannabis during the acute withdrawal phase, reporting the symptoms to be more tolerable, thus enabling them to complete the detoxification period successfully.

6.9.4 Chesher et al found that D9 THC reduced the severity of a number of symptoms associated with the quasi-morphine withdrawal syndrome in rats, concluding that the effects were not due to sedation, that absence of naloxone activity indicated the effect to be independent both of the opiate receptor, and of dopaminergic neurotransmitter systems. A later study found that cannabinol (CBN) was also effective in reducing such symptoms, but not cannabidiol (CBD). THC was also found to decrease naloxone-induced withdrawal symptoms in rats, and other studies have found similar effects in rats, mice, guinea-pigs and dogs. Radouco-Thomas, studying hypersensitive mice, found morphine to show opposite effects between THC-pretreated and control mice, with substantial increase in locomotion following the morphine administration in THC animals, and sedation in controls.

6.9.5 Pertwee reviewed the interactions between opiate antagonists and cannabinoids, finding some attenuation of naloxone activity, and enhancement of morphine activity in a variety of laboratory animals. Recent research suggests that the activity of cannabis is caused by binding to a specific cannabinoid receptor, which would normally bind to an endogenous 'cannabinoid' inhibiting the metabolism of cyclic adenosine monophosphate (c-AMP). Cyclic AMP influences the degree to which the binding of neurotransmitters on opiate (and other) receptors causes the firing of the target neurones. Put simply, it affects the sensitivity of neurones to chemical stimuli. Cohen considered the attenuation of opiate withdrawal symptoms by clonidine to be due to opening of potassium channels mediated by c-AMP in the locus ceruleus - a group of cells extending from the brainstem to the midbrain, close to the cerebellar peduncles and the vagal nucleus (which controls stomach activity), and which are closely exposed to substances within cerebrospinal fluid. Gold and Miller note that both morphine and THC caused similar changes in dopamine activity, and postulate that the reinforcing potential of both drugs had a common neurochemical basis.

6.9.6 In 1990 Navaratam, in a study of adjunctive drug use of 249 heroin users, discovered that two thirds of these were using cannabis as an adjunctive drug with the primary aim of increasing the euphoric effects of the heroin, only a minority used cannabis as a way of helping with withdrawal symptoms. Unlike heroin and benzodiazepines, alcohol and cannabis were usually only taken in the company of friends. The combined use of opiates and benzodiazepines in the last twelve months and last thirty days was higher than the combined use of opiates with alcohol or opiates with cannabis. Alcohol and cannabis, if used, were usually taken after opiate use, while benzodiazepines were used concomitantly with opiates.

6.9.7 In a recent UK study by Jackson forty male clients from both non-statutory and statutory agencies in North Yorkshire were asked to complete a questionnaire concerning their cannabis use. The study included both current and ex-users of opiates and covered users of heroin as well as those using methadone. The clients were specifically invited to provide information about their adjunctive use of opiates and cannabis and its uses in dealing with opiate withdrawal, the availability of cannabis to heroin users and on the motivation to start using heroin during a perceived lack of cannabis.

6.9.8 The study indicated that opiate users combined cannabis with their use of heroin or methadone for specific reasons. Most frequently quoted was as an aid to sleeping, or as a replacement for benzodiazepines. There was little support for the idea that cannabis relieved the physical symptoms of opiate withdrawal (indeed, it was commonly seen as making things worse).

6.9.9 Cannabis was regarded favourably as treatment for the psychological aspects of the process, especially as an adjunct to methadone during withdrawal of heroin. In such cases it was seen as being able to help prevent the purchase of black market heroin by fulfilling some of the addict's mental needs.

6.9.10 Similarly, a study by Saxon found methadone patients who were consistently THC positive had a smaller percentage of urines positive for other drugs.

6.9.11 With regard to the social aspect of cannabis/heroin interaction, the Jackson study suggested, perhaps surprisingly, that heroin users felt that the cannabis using society had cut them off in many ways. The respondents are reported as "feeling quite isolated from the cannabis using scene, all seeing it as a completely separate culture, with its own set of dealers and a closed door attitude to heroin users. The general view was that cannabis users did not associate themselves with harder (heroin, cocaine) drug users and would not welcome them into their circle, certainly not to the extent where heroin could be used in these circles."

6.9.12 The third major area of the study touches on the 'gateway' theory. When asked if they knew people who had started using heroin as a result of the lack of cannabis, 63% said they knew of at least one person who had started this way (59% of these saying they knew some people and 33% knew lots of people). This was also confirmed by 16 of the 40 clients questioned having bought heroin themselves at times because there was no cannabis around. However, this does not necessarily support the contention that cannabis use per se predicates toward heroin use.

6.9.13 Di Chiara's recent paper (among others) has excited much media attention with the revelation that *9-THC and heroin both affect the same area of the brain, boosting the levels of dopamine in the nucleus accumbens.

6.9.14 The popular press, broadsheet and tabloid alike, ran stories implying that the paper had somehow proven a physiological basis for 'escalation'. However, as the less populist journals such as the New Scientist pointed out, Di Chiara's paper itself stated that

6.9.15 The New Scientist pointed out that the group's own previous research has also shown the same Dopamine surge with alcohol. As the editorial explained:

6.9.16 This view is upheld by such reports as Nace where studies of 101 multi-drug using soldiers showed that prior to the onset of heroin addiction, relatively few differences in drug using patterns existed between those addicted to heroin and those not, the differences emerged after the initiation of heroin.

6.9.17 The theory of social escalation (that cannabis users turn to heroin because the drug scenes cross over, and that such progression disappears when the markets are separated) does not seem validated by the Jackson study. 75% of respondents claimed that it was harder to find cannabis to buy than heroin and nearly 95% of those expressing a view felt that cannabis and heroin were not sold by the same dealers.

6.9.18 These figures prompted the report to conclude that a significant section of the drug using population were finding it easier to buy hard drugs than cannabis. Considering the fact that many hard drug users finance their habit through the sale of their drug of addiction, it was suggested that this could potentially lead to an increase in the incidence of hard drug abuse.

6.9.19 Certainly this contrasts starkly with figures from Holland where the public at large view cannabis in a tolerant way and hence users of it are not subject to the problem of a criminal record or the stigma of treatment in a psychiatric hospital. This has resulted in fewer and fewer young people swapping from soft to hard drugs, the percentage of addicts younger than age 22 dropping from 14.4% in 1981 to 2.5% in 1991 . One conclusion must be that for a separation of drug markets to work and any escalation to end then a controlled and monitored distribution of the drugs provides a better framework for success.

6.9.20 Summary: The potential value of cannabis and cannabinoids as a substitute drug in the treatment of opiate and alcohol addiction has been reported since the 19th Century, and is briefly noted in the recent BMA report. There appears to be a growing body of scientific evidence suggesting a potential role for cannabinoids in alleviating opiate withdrawal symptoms, and there have been a number of anecdotal reports of effective substitution of alcohol with cannabis, but few controlled clinical studies have been performed.

6.9.21 There is increasing but conflicting anecdotal evidence of efficacy as an adjunctive drug or as a substitute for opiates. The evidence cannot be regarded as conclusive, but the common modality suggested by Di Chiara et al offers a theoretical basis both for common analgesic activity of THC and morphine, and for attenuation of opiate withdrawal symptoms by cannabis. There would appear to be sufficient evidence to justify further research in this area.

(d) It is possible to compare the alcohol consumption of IDMU respondents with that of a comparable age cohort from the 1996-97 General Household Survey data. For each age group the consumption of respondents was higher than the GHS "control" sample. This difference was increasingly marked in the older age groups, although overall use in each sample declined with age. There was a notable sex difference, with female IDMU respondents drinking twice as much as the national average, whereas male respondents drank one third more. This difference was more marked at younger and older age groups (see fig 2 below).