The health and psychological consequences of cannabis use chapter 8
8. The therapeutic effects of cannabinoids 8.1 Historical background Cannabis has had a long history of medical and therapeutic use in India and the Middle East (Grinspoon and Bakalar, 1993; Mechoulam, 1986; Nahas, 1984) where it has been variously used as an analgesic, anti-convulsant, anti-spasmodic, anti-emetic, and hypnotic. Cannabis was introduced to British medicine in the mid-nineteenth century by O'Shaugnessy (1842) who had gained clinical experience with the drug while an Army surgeon in India (Mechoulam, 1986; Nahas, 1984). He recommended its use for the relief of pain, muscle spasms, and convulsions occurring in tetanus, rabies, rheumatism and epilepsy (Nahas, 1984). Partly as the result of his advocacy, cannabis came to be widely used as an analgesic, anti-convulsant and anti-spasmodic throughout the middle part of the 19th century in Britain and the USA. The medical use of cannabis declined around the turn of the present century. Because the active constituents of cannabis were not isolated until the second half of the twentieth century, cannabis continued to be used in the form of natural preparations which varied in purity and, hence in effectiveness. The use of cannabis was largely supplanted by other pharmaceutically purer drugs, which could be given in standardised doses to produce more dependable effects. These included the opiates, aspirin, chloral hydrate, and the barbiturates (Mechoulam, 1986; Nahas, 1984). In the early part of the century, the medical use of such crude cannabis preparations was further discouraged by laws which treated cannabis as a "narcotic" drug and severely restricted its availability. It finally disappeared from the American pharmacopoeia in the early 1940s after the passage of the Marijuana Tax Act (Grinspoon and Bakalar, 1993), although it continued to be used in Australia into the 1960s (Casswell, 1992). THC, the major psychoactive ingredient of cannabis, was not isolated until 1964 (Goani and Mechoulam, 1964), shortly before cannabis achieved widespread popularity as a recreational drug among American youth. Its widespread recreational use, and its symbolic association with a rejection of traditional social values, undoubtedly hindered pharmaceutical research into its therapeutic uses. Consequently, the rediscovery of some of its traditional therapeutic uses was largely serendipitous, as was the discovery of some newer uses. For example, its value as an anti-emetic agent in the treatment of nausea caused by cancer chemotherapy seems to have been rediscovered by young adults who had used cannabis recreationally prior to undergoing chemotherapy for leukemia (Grinspoon, 1990). From the mid-1970s some clinical research on the therapeutic value of cannabis and cannabinoids was undertaken. On the whole, however, this research has been very thin and uneven, and, consequently, many of the claims for the therapeutic efficacy of cannabinoids rely heavily, and, in the case of rare medical conditions, solely upon anecdotal evidence, that is, the testimonies of individuals who claim to have derived medical benefit from its use (e.g. Grinspoon and Bakalar, 1993; Randall, 1990), and small numbers of cases reported by physicians (e.g. Consroe et al, 1975; Meinck et al, 1989). Evidence will be reviewed for the best-supported therapeutic uses of cannabinoids. The review begins with the evidence on the effectiveness of cannabinoids as anti-emetic drugs for nausea caused by cancer chemotherapy, and as agents to control intra-ocular pressure in glaucoma. Briefer reviews are provided of the evidence in favour of other putative therapeutic uses of cannabinoids which are less well supported by clinical evidence, chief among which are its uses as an anti-convulsant, an anti-spasmodic, and an analgesic agent. The value and limitations of the largely anecdotal evidence of efficacy in these latter conditions will also be briefly considered. The review will include a discussion of the controversy in the United States about "marijuana rescheduling" which has coloured much recent discussion of the issue. This controversy concerns the vexatious issue of whether smoked cannabis should be available for medical use in addition to synthetic cannabinoids such as THC. 8.2 Cannabinoids as anti-emetic agents Profound nausea and vomiting can be such serious complications of chemotherapy and radiotherapy for cancer that patients may discontinue potentially life-saving treatment (Institute of Medicine, 1982). Although various types of drugs (e.g. the phenothiazines) have been shown to be effective in controlling nausea and vomiting in cancer patients, substantial minorities of patients do not benefit from these drugs. The seriousness of the problem of chemotherapy-induced nausea, and the incomplete success of existing treatments, prompted oncologists in the late 1970s and early 1980s to take a particular interest in the anti-emetic properties of cannabinoids (Institute of Medicine, 1982). 8.2.1 Clinical trials One of the earliest trials of the effectiveness of THC as an anti-emetic was prompted by patient reports that smoking marijuana relieved nausea and vomiting (Sallan et al, 1975). In this study, 22 patients (10 males and 12 females, average age 30 years) with a variety of neoplasms were studied. In 20 patients, the nausea and vomiting had proven resistant to existing anti-emetic drugs. A randomised placebo-controlled trial with crossover was used, in which patients were randomly assigned to receive oral THC (10mg per m2) and placebo in one of four different orders (THC-placebo-THC; THC- placebo-placebo; placebo-THC-placebo; placebo-THC-THC). Outcome was assessed by grading patients' self-reports of nausea and vomiting after THC and placebo into three categories: complete response if there was vomiting after placebo but not after THC; partial response if there was a greater than 50 per cent reduction in nausea and vomiting after THC compared to placebo; and no response if there was a less than 50 per cent reduction in nausea and vomiting. Ten patients completed all three courses of THC and placebo and vomited on at least one trial. After excluding one trial because of a variation in the chemotherapy dose, there were 29 trails available for analysis, 14 of placebo and 15 of THC. All 14 placebo trials resulted in no response, while in the 15 THC trials there were five complete responses, seven partial responses, and three no responses. This difference was statistically significant when full and partial responses were combined. Most patients (13/16) reported a "high" after receiving THC, an experience which was correlated with the anti-emetic effect. The most common side-effect was somnolence which curtailed activities for two to six hours in a third of patients. Only two patients experienced any symptoms of toxicity, (both after receiving 20mg doses of THC), namely, visual distortions and hallucinations and depression lasting several hours. Sallan et al reported "preliminary" observations from several patients that smoking marijuana produced an equivalent anti-emetic effect to oral THC. A trial by Chang et al (1979) largely supported the findings of Sallan et al. In this study 15 patients with osteogenic sarcoma (10 males and five females, average age 24 years) served as their own controls in the course of monthly high dose methotrexate therapy. They were assigned to receive three THC and three placebo trials in randomised order during six treatment sessions. THC (10mg per m2 of body area) and placebo were administered orally five times at three hourly intervals, beginning two hours before chemotherapy. If the patients vomited, the remaining doses of either THC or placebo were administered by smoking a cigarette using a standardised smoking technique. The effect of THC and placebo were assessed by nursing staff who rated various endpoints (e.g. number of vomiting and retching episodes, volume of emesis, degree and duration of nausea) without being aware of which treatment patients had received. Patient response was graded into three categories: excellent (greater then 80 per cent reduction after THC by comparison with placebo in each of these endpoints); fair (greater than 30 per cent and less than 80 per cent reduction), and no response (less than 30 per cent reduction). The results showed that eight patients had an excellent response, six a fair response, and one had no response. On all endpoints THC produced a statistically significant reduction in nausea and vomiting by comparison with placebo. There was also a dose-response relationship between blood levels of THC and the incidence of nausea and patient reports of feeling "high". Generally, higher THC blood levels were achieved when marijuana was smoked than when THC was taken orally. There were few side effects reported, with sedation being the most common (12/15 patients). Four patients experienced five dysphoric reactions in the course of 281 THC drug doses (2 per cent), none of which lasted more than 30 minutes, and all of which were successfully managed with simple reassurance. In a second phase of the study, four patients who had an excellent response to THC in the first phase were retested under double-blind conditions using two placebo trials in the next 10 treatments. A small number of patients who had a fair response were also studied using an increased dose of THC. All patients showed a reduction in the average anti-emetic benefit of THC, decreasing from excellent to fair in the case of previous excellent responders, and from fair to no response in the case of the fair responders. Chang et al hypothesised that the decline in effect reflected either the development of tolerance to the effects of THC, or the development of conditioned nausea and vomiting that was resistant to the anti-emetic effects of THC. Since these early studies, a large number of controlled clinical studies have been conducted which compared the effectiveness of THC with either a placebo or with other anti-emetic drugs (see Carey et al, 1983; Poster et al, 1981; Levitt, 1986 for reviews). The results of this literature have sometimes been unfairly described as "confused" (e.g. Carey et al, 1983; Nahas, 1984). This description betrays an unreasonably high expectation of the consistency of results from studies which have generally used small samples of heterogenous patients who have received various forms of chemotherapy. It also ignores the fact that the cross-over studies comparing the anti-emetic effects of THC with placebo have generally reported greater anti-emetic effects for THC than placebo (Poster et al, 1981); the single exception to this finding was a study which had a sample size of only eight patients. Comparisons of the effectiveness of oral THC with that of existing anti-emetic agents have been less consistent than the results of comparisons with placebo. Nonetheless, the results have generally indicated that THC is at least equivalent in effectiveness to the widely used anti-emetic drug prochlorperazine (Carey et al, 1983; Levitt, 1986). The inconsistencies in this case arise because some studies have shown THC to be superior, probably because of the practice in some trials of enlisting patients whose nausea had previously proven resistant to prochlorperazine (Carey et al, 1983). The equivalence of THC and prochlorperazine has been supported by the results of one of the largest and best conducted studies (Ungerleider et al, 1982). In this study 214 patients with a variety of forms of cancer (carcinomas, sarcomas, lymphomas and leukemias) were recruited if they had already undergone chemotherapy and experienced nausea and vomiting, or they were to receive a form of chemotherapy which had a high emetic potential. Patients were randomly assigned to receive a paired trial of either oral THC followed by prochlorperazine or vice versa. The dose of THC was dependent on body surface area (7.5mg if less than 1.4m2, 10mg for 1.4 to 1.8m2, and 12.5mg for greater than 1.8m2). Separate analyses were conducted on three groups of patients: patients who received their cancer chemotherapy on a single day some weeks apart (N=98); patients who received their chemotherapy on a daily basis over several successive days (N=41); and patients who discontinued the trial after a single episode of either THC or prochlorperazine. Outcomes were patient self-ratings of nausea and vomiting, and a variety of mood states and behaviours. The results showed that there "were no statistically significant differences in the anti-nausea/anti-emetic effect of THC and prochlorperazine" (p640) in any of the three patient groups, even though there were differences between patients in the single- and multiple-day chemotherapy regimens in the time course of the nausea. There were differences in mood and behaviour between the THC and prochlorperazine trials, with patients reporting greater impairment of concentration and less social interaction after receiving THC. There were also more side effects from THC than prochlorperazine, with sedation, sleepiness and mental clouding being the most common. There was no difference in the frequency of panic attacks between the two drugs. Despite these differences in side effects there was a small patient preference in favour of THC as an anti-emetic, with 41 per cent experiencing less nausea on THC, 31 per cent experiencing less nausea on prochlorperazine, and 29 per cent reporting no difference in effectiveness. The effectiveness of THC was not related to age or prior experience with marijuana, but it was related to the experience of side effects, with patients experiencing them reporting less nausea. Given the wide variety of patients who have been studied in terms of age and type of cancer, the wide variety of chemotherapeutic agents that have been used to treat their cancers, and the variety of different anti-emetics with which THC has been compared, the fact that findings of these studies are generally positive for THC is more impressive than the apparent differences in outcome. The positive results from the controlled trials also seem to be borne out by clinical experience with cannabinoids in managing cancer patients. A recent survey of a large sample of American oncologists, for example, found that 44 per cent of oncologists had recommended marijuana to at least one cancer patient, and 64 per cent of these physicians reported that it was successful controlling nausea in at least half of their patients. Overall, just under half of the oncologists in the sample (44 per cent) believed that cannabinoids could be safely used in the treatment of nausea caused by chemotherapy and radiotherapy (Dobin and Kleiman, 1991). A similar proportion (48 per cent) reported that they would prescribe marijuana for their patients if it was legal. The general conclusion on the available literature is that THC is superior to placebo, and equivalent in effectiveness to other widely-used anti-emetic drugs, in its capacity to reduce the nausea and vomiting caused by some chemotherapy regimens in some cancer patients. There are a number of issues that remain to be resolved in deciding upon the clinical role of cannabinoids as anti-emetic agents in cancer chemotherapy. These issues include: the types of nausea against which it may be most effective, and hence the types of patients for which they are most appropriately prescribed; the degree of patient tolerance of the psychotropic side effects of THC and other cannabinoids; the potential seriousness of possible THC induced immunosuppression in patients who are already immunologically compromised; the most effective dosing schedules for THC as an anti-emetic; the potential use of THC in combination with other anti-emetic drugs; and the extent to which the motivation for the use of THC may have been reduced by the availability of newer anti-emetic drugs that are more effective than prochlorperazine (the main anti-emetic drug in the 1980s). 8.2.2 Which patients? Which patients with what types of nausea are the most suitable for treatment with cannabinoids as anti-emetics? Patients with various forms of cancer have been the most extensively investigated patient group, but the numbers of different types of cancer have been too small to allow convincing analyses of differences in patient response. The same point can be made about types of chemotherapy regimens; they have varied widely in these studies, and have often not been reported, but there has been no systematic analysis of the effectiveness of cannabinoids in controlling emesis produced by different agents. It is uncertain to what extent the cannabinoids may be effective against nausea from other causes. The mechanisms that produce nausea are not well understood but there are believed to be one or more protective mechanisms located in the brain stem that can be triggered by a variety of emetic agents. This raises the possibility that cannabinoids may be therapeutically useful against nausea from a variety of causes. 8.2.3 Side effects The psychoactive effects of cannabis which are prized by recreational users - euphoria, relaxation, drowsiness - are not always welcomed by older patients, most of whom are cannabis-naive. In some studies a substantial minority of such patients have discontinued the use of THC because of the unwelcome dysphoria and somnolence (Levitt et al, 1986). This has not been a universal experience, so further research is required to discover to what extent this has been the result of unnecessarily large doses, or poor patient preparation for these effects, and failure to adequately manage them by reassurance. What does seem to be the case is that the experience of some psychological effects of THC, including the "high", is necessary for the occurrence of a clinically significant anti-emetic effect. This fact has led to the search, so far unsuccessful, for cannabinoid derivatives of THC which possess its anti-emetic properties but not its psychoactive ones. The recent discovery of the cannabinoid ligand and receptor, and receptor subtypes (see pp7-8) has encouraged researchers to believe that this may be an achievable goal (Iversen, 1993). A potentially more serious side effect of therapeutic THC is its possible immunosuppressive effect. Any such effect would limit its use as an anti-emetic in the treatment of cancer, since cancer patients experience immune suppression as a side effect of their treatment. There are several reasons why this may be less serious an issue that it seems at first glance. First, there are doubts about the existence of any immunosuppressive effect of cannabinoids (see Section 6.2 on the immune system, pp62-68), and the effect is small in those studies which report one. Second, the clinical significance of any such effects is doubtful in the use of THC in cancer chemotherapy. Such use would be intermittent, and relatively short-term, and the possible gain in increased life expectancy from being able to complete a course of cancer chemotherapy is such that most patients would be prepared to take the risk, in the same way that they chose to undergo the highly toxic chemotherapy in the first place. 8.2.4 Unresolved clinical issues If THC has a place in the management of nausea from cancer treatment (Poster et al, 1981), and perhaps other causes, a number of clinical issues remain to be resolved (Levitt, 1986). Foremost among these is the best way in which to administer the drug. Should it be given well in advance of treatment at low doses to ensure a stable blood level, or should it be given in larger doses shortly before chemotherapy or radiotherapy? This issue has not been systematically studied (Levitt, 1986). An additional question is whether there is any clinical benefit to be derived from combining THC with existing anti-emetic agents. There is suggestive evidence that there might be, since the mechanisms of action, while not well understood, appear to be different, raising the possibility that there may be positive synergistic effects from the combination of THC and other anti-emetics. One single-blind study of the combination of dronabinol and prochlorperazine, for example, suggested that the combination of these drugs may have a superior anti-nausea effect to either drug used alone (Plasse et al, 1991). Clearly, more research is warranted on this issue, especially as it may enable cannabinoids to be used as anti-emetics at lower doses with fewer unwanted psychotropic effects. It seems surprising that the desirability of undertaking research on dosing and combined use of cannabinoids was highlighted by Poster et al in 1981 and by the Institute of Medicine in 1982. Yet very little research has been done, and THC has not been routinely incorporated into the management of nausea caused by cancer chemotherapy. One of the likely reasons has been the American controversy about the rescheduling of marijuana under the Controlled Substances Act, which some argue has discouraged clinical research on cannabinoids (see below). Another reason has been that the motivation for further research on the anti-emetic properties of THC has been removed by the recent development of newer anti-emetic drugs which are superior to prochlorperazine (Iversen, 1993), the "gold standard" drug when the major controlled trials were conducted on cannabis in the 1970s and 1980s. In the absence of trials comparing THC with these newer drugs, its comparative efficacy is unknown, although given its approximate equivalence to prochlorperazine it is likely to be inferior to the newer drugs. 8.3 Cannabinoids as anti-glaucoma agents Glaucoma is the leading cause of blindness in the United States, affecting two million people and producing 300,000 new cases each year (Adler and Geller, 1986). It is a condition "which is generally characterised by an increase in intraocular pressure ... that progressively impairs vision and may lead to absolute blindness" (Adler and Geller, 1986, p54). Although its causes are not understood, it is believed to involve an obstruction to the outflow of the aqueous humour in the eye leading to a gradual increase in intraocular pressure (IOP) which, if untreated, may damage the optic nerve, resulting in blindness. Its incidence increases over the age of 35, especially among individuals who are myopic (i.e. short-sighted). Although various drugs are available which reduce IOP, all possess unwanted side-effects and patients may become tolerant to their therapeutic effects. The effects of cannabis in reducing IOP were discovered serendipitously by researchers and patients in the early and middle 1970s. Hepler and his colleagues (1971, 1976) observed a substantial decrease in IOP while researching the effects of cannabis intoxication on pupil dilation. They demonstrated that both cannabis and oral THC produced substantial reductions in IOP in both normal volunteers and patients with glaucoma (Hepler and Petrus, 1976; Hepler et al, 1976). Subsequent research identified THC as the agent responsible for producing this effect (Adler and Geller, 1986). Around the same time, patients with glaucoma who had used cannabis recreationally also discovered its therapeutic effects. One such patient, Robert Randall, used cannabis daily to control his glaucoma. When arrested for possession and cultivation of cannabis, he successfully used the defence of "medical necessity" arguing, with the support of his physicians, that he would go blind if he stopped his cannabis use. He subsequently was given legal access to cannabis for medical purposes (Randall Affidavit, in Randall, 1988). Although there have been a number of case reports of the successful use of cannabis in the management of glaucoma (e.g. Grinspoon and Bakalar, 1993; Randall, 1990), there have not been any controlled clinical studies of its effectiveness and safety in the long-term management of glaucoma. Informed clinical opinion has been that THC is an effective anti-glaucoma agent when used acutely, but there are doubts about its effectiveness with chronic use because of the development of tolerance to its effects on IOP (Jones et al, 1981). Ophthalmologists who are opposed to the clinical use of THC point to a number of major disadvantages. First, because THC is not water-soluble, it cannot, unlike other anti-glaucoma agents, be applied topically to the eye to ensure that enough is absorbed to produce a clinically significant reduction in IOP. Second, as a consequence, THC must be absorbed systemically in order to produce a therapeutic effect on IOP, which means that patients must experience the psychoactive effects of THC in order to derive its therapeutic benefits against glaucoma. Third, because glaucoma is a chronic condition, THC or cannabis would need to be taken in substantial doses on a daily basis over long periods of time, if not for the remainder of adult life. There has been an understandable concern about the health risks of chronic daily cannabis use (e.g. Hepler, 1990; American Academy of Ophthalmology, 1990). The position adopted by the American Academy of Ophthalmology has been to insist that cannabis has no accepted medical use in the management of glaucoma, and cannot have such medical use until a large controlled trial has been conducted into its safety and effectiveness in daily chronic use. There has been no evidence that the Academy has any interest in, or has given any encouragement to, the conduct of such a trial. Consequently, its position is that THC and other cannabinoids should not be used be in the management of glaucoma. A contrary position has been taken by Randall, who has argued that patients should be allowed to make the choice between the uncertain health risks of chronic cannabis use and the more certain risks to sight of poorly controlled glaucoma: "People with life- and sense-threatening diseases are routinely confronted by stark choices ... [between] the devastating consequences of a debilitating, progressive disease ... [and] often highly damaging biological and mental consequences of the toxic chemicals required to check the progression of disease. .. Viewed in this medical context, marihuana is more benign and far less damaging that the synthetic toxins routinely prescribed by physicians" (cited in Grinspoon and Bakalar, 1993, p153) 8.4 Cannabinoids and neurological disorders 8.4.1 Anti-convulsant Historically one of the commonest medical uses of cannabis preparations has been as an anti-convulsant. O'Shaughnessy (1842), for example, recommended the use of cannabis to control seizures in epilepsy, tetanus and rabies (Nahas, 1984). Animal studies have provided some support for this use in showing that THC has dual effects on convulsions, i.e. they can produce convulsions in susceptible animals, and suppress the maximum severity of convulsions from a variety of causes, while cannabidiol (CBD) appears to be a potent anti-convulsant (Chesher and Jackson, 1974; Consroe and Snider, 1986; Institute of Medicine, 1982). Despite this animal evidence, there is very limited evidence on the therapeutic effects of cannabinoids in humans with epilepsy. There are a small number of case studies of individuals with epilepsy in which the recreational use of cannabis appeared to enhance the anti-convulsant effects of more traditional anti-convulsant medication (e.g. Consroe et al, 1975; Grinspoon and Bakalar, 1993). There is a single randomised placebo controlled study of the administration of CBD in 15 patients with epilepsy that was not well controlled by conventional anti-convulsants. Four of the eight patients who received CBD in addition to their usual anti-convulsant drugs were free of seizures throughout the study period, and three were improved. By contrast, only one out of seven patients in the placebo condition showed any clinical improvement (Cunha et al, 1980). Despite this suggestive evidence of efficacy in epilepsy, CBD has not been widely used in clinical management. Perhaps this is not surprising given the absence of evidence of its efficacy, the existence of other effective anti-convulsant drugs, and concerns about the safety of chronic use in the management of a chronic disease. It is perhaps more surprising that there has been no further research on the anti-convulsant properties of CBD, especially as it has no psychoactive side effects (Nahas, 1984). 8.4.2 Anti-spasmodic Cannabinoids have been used in an empirical way in the management of some patients with movement disorders, a variety of syndromes that have in common a deficit in non-pyramidal motor control function, which is expressed in usually one or more of the non-epileptic, abnormal involuntary movements, such as those found in Parkinson's disease, Huntington's disease, multiple sclerosis, and spasticity. Although a number of drugs may be of benefit in the management of these conditions, they are not always effective, and may produce troublesome side-effects (Consroe and Snider, 1986). There has been some animal evidence which indicates that THC and its analogues produce a broad spectrum of neurological effects, which include alterations in motor function, and changes in muscle tone and reflexes. The acute motor effects in normal humans - ataxia, tremulousness and subjective weakness - also suggest a potential for therapeutic effects in some movement disorders (Consroe and Snider, 1986). The evidence that cannabinoids have therapeutic effects in patients with movement disorders is largely anecdotal. Grinspoon and Bakalar (1993), for example, present four case histories of individuals with multiple sclerosis whose condition improved while they smoked marijuana, and deteriorated after they stopped smoking. Meinck et al (1989) report a case history of a young man with multiple sclerosis with severe limb and gait ataxia who complained of erectile impotence. After smoking marijuana his gait improved sufficiently to be able to walk unaided, and he was able to achieve and sustain an erection. When cannabis was withdrawn under medical supervision, the patient's motor function deteriorated to the point where he was unable to walk without assistance. There has been one controlled study by Clifford (1983) who examined the effects of THC on tremor in eight patients (four male and four female) with advanced multiple sclerosis who had ataxia and tremor. Five patients reported subjective benefit from THC and there was objective evidence of benefit in two of these cases. Single-blind placebo challenge in these cases produced evidence that their clinical condition deteriorated when given placebo and improved with the reinstatement of THC. Grinspoon and Bakalar (1993) described several case histories of individuals with paraplegia and quadriplegia who reported that cannabis use helped to reduce muscle spasm. The experiences of these individuals were supported by similar reports obtained from a survey of 43 individuals with spinal cord injuries, 22 of whom reported that they used cannabis to control their muscle spasm. The only controlled trial of a cannabinoid in a movement disorder has been an evaluation of the effects of CBD on severity of chorea in patients with advanced Huntington's disease (Consroe et al, 1991). This study was prompted by the authors' observation that CBD had improved the condition of an individual with Huntington's disease (Sandyck et al, 1988). In this study 19 Huntington's patients were enrolled in a double-blind controlled trial in which they received six weeks administration of CBD or placebo in a cross-over design. The outcome was the severity of chorea, as assessed by blind clinical ratings, patient self-report, and a variety of measures of motor function. Although the study had sufficient statistical power to detect a relatively small clinical benefit, there was no evidence of improvement in chorea on any of the clinical, self-report or motor measures. In the light of Consroe et al's failure to replicate the earlier favourable single case, further controlled trials are warranted before any of the cannabinoids can be routinely used in treating movement disorders. 8.5 Cannabinoids as anti-asthmatic agents Smoked cannabis, and to a lesser extent oral THC, have an acute bronchodilatory effect in both normal persons and persons with asthma (Tashkin et al, 1975; Tashkin et al, 1976). Tashkin et al (1975), for example, compared the bronchodilator effect of smoked cannabis with that of a standard clinical dose of the bronchodilator isoproterenol in relieving experimentally induced asthma in asthmatic patients. They found that smoking a 2 per cent-THC cannabis cigarette produced a bronchodilator nearly equivalent to that of a clinical dose of isoproterenol. Despite this early suggestion of a therapeutic effect in asthma, cannabinoids have not been used therapeutically, nor have they been extensively investigated as anti-asthmatic agents other than by Tashkin and his colleagues (Tashkin, 1993). A major obstacle to therapeutic use has been the route of administration. Oral THC produces a smaller bronchodilator effect after a substantial delay, and when used as an inhalant produces irritation and reflex bronchoconstriction. Hence, smoking marijuana has been the most dependable way of delivering a clinically effective dose of THC. There is an understandable concern among clinical researchers that smoking is an unsuitable mode of administering any drug, and an especially inappropriate way to administer a drug to patients with asthma, because it would inevitably involve the delivery of other noxious chemicals that would nullify its therapeutic value in the short term, and carry an increased risk of other respiratory disease and possibly cancer in the long term (Tashkin, 1993). The unwanted psychotropic effects from marijuana smoking have also been a barrier to its use as an anti-asthmatic drug. Some investigators (e.g. Graham, 1986) have nonetheless argued that the suitability of THC as a spray should be further investigated because of the possible hazards of the chronic use of the more widely-used beta-blocker antagonists. The recent discovery of the cannabinoid receptor and ligand may prompt a re-examination of this question. 8.6 Cannabinoids as analgesics There is some animal evidence that THC has an analgesic effect which operates via a different mechanism from that of the opioid drugs (Segal, 1986). There is a small amount of human experimental studies which have reported mixed evidence of an analgesic effect (Nahas, 1984). There has been little clinical evidence beyond historical use for various forms of chronic pain, including migraine, dysmenorrhoea, and neuralgia, and the small number of case histories of its use in chronic pain, dysmenorrhoea, labour pain, and migraine reported by Grinspoon and Bakalar (1993). Only one double-blind controlled cross-over study has been reported. This study compared the analgesic effect of THC and codeine in patients with cancer pain (Noyes et al, 1975). The findings suggested that 20mg of THC was of equivalent analgesic effect to 120mg of codeine. However, neither drug produced substantial analgesia in these patients, and the majority of patients found the psychotropic effects of 20mg of THC sufficiently aversive that they discontinued its use. Clearly, much more basic pharmacological and animal investigation is required before cannabinoids or their derivatives have any clinical use as analgesics. Nevertheless, such investigations may be worth pursuing because of the dependence potential of the more potent opioid analgesics, and the likelihood that any cannabinoid mediated analgesic effect operates by a different mechanism to that of the opioids. 8.7 Other possible therapeutic uses A variety of other therapeutic uses have been suggested, although few have been investigated in any depth. In the late 1940s, for example, there were some investigations of the therapeutic uses of the euphoriant properties of cannabis, as a possible anti-depressant agent in the form of synhexil, a synthetic cannabis analogue. The results in one uncontrolled study were positive, but these were not replicated in later studies using lower doses (Nahas, 1984; Grinspoon and Bakalar, 1993). None of these suggestions have been further investigated, probably because of the potential for THC to produce dysphoric and other unwanted psychotropic side effects. 8.8 Cannabis and AIDS One of the areas of greatest contemporary interest in the therapeutic uses of cannabinoids and cannabis has been their possible roles as an anti-nausea agent, an appetite stimulant and an analgesic in patients with AIDS (Randall, 1989). The development of this interest seems to have replicated the earlier discovery of the anti-emetic effects of cannabis in young cancer patients in the 1970s. AIDS patients often experience nausea and weight loss, either while receiving cytotoxic drugs to suppress HIV, or as a direct effect of the AIDS spectrum diseases. Many patients have been recreational cannabis users, and so have reported that the smoking of marijuana produces a diminution in their nausea, an increased appetite, reduced pain, and general improvements in well being. AIDS advocacy groups have accordingly argued that marijuana should be made legally available to AIDS patients (e.g. Randall, 1991). So far the bulk of evidence for these therapeutic claims has been provided by case reports (see Randall, 1989). There has been one small uncontrolled study of 10 symptomatic AIDS patients which suggested that dronabinol (synthetic THC) may be effective in reducing nausea and stimulating appetite (Plasse et al, 1991). The evidence of its anti-emetic properties in cancer patients seems to support its potential application in AIDS treatment, and is deserving of further investigation. A potential concern with the use of cannabinoids in HIV positive individuals and AIDS patients is the possible immunosuppressive effects of cannabinoids. Although, as argued above, this effect is likely to be small and of limited concern when used intermittently in cancer patients, it is of potentially greater significance in AIDS patients, since cannabis would be used regularly by patients with a major immune system disorder. Even a small impairment in immunity may have major consequences for HIV and AIDS affected individuals. Recent epidemiological evidence does something to allay this concern. A large prospective cohort study of HIV/AIDS in homosexual and bisexual men recently failed to find any relationship between cannabis use, or any other psychoactive drug use, and the rate at which HIV positive men developed clinical AIDS (Kaslow et al, 1989). Nonetheless, the issue of immunosuppression needs to be explicitly investigated in any research which is undertaken into the therapeutic uses of cannabinoids in the treatment of AIDS. 8.9 The limitations of anecdotal evidence Much of the case for the therapeutic uses of cannabinoids as other than anti-emetic agents depends upon anecdotal evidence from case histories. Such evidence has justifiably come to be distrusted as evidence of therapeutic effectiveness in clinical medicine, especially in the case of chronic conditions which have a fluctuating course of remission and exacerbation. In such diseases, it is difficult to exclude alternative explanations of any apparent relationship between the use of a drug (e.g. THC) and an improvement in a patient's condition. Among the alternative explanations that are most difficult to exclude in a single case or even a succession of single cases is simple coincidence: that is, there may be no relationship between the use of the drug and improvement; the apparent relationship between the two may have arisen because the use of the drug preceded an improvement in the patient's condition that would have occurred in its absence. This is especially likely to occur in a chronic condition with a fluctuating course. In addition, the well-known placebo effect which is observed in many conditions may explain the apparent benefits of a drug or other treatment. It is for these reasons that this review has relied upon evidence from controlled clinical trials in appraising the therapeutic uses of cannabinoids. Grinspoon and Bakalar (1993) have attempted to defend anecdotal evidence of therapeutic efficacy of cannabinoids. They argue that a double standard has been used in the appraisal of the safety and efficacy of cannabinoids: anecdotal evidence of harm has been readily accepted while anecdotal evidence of benefit has been discounted. Although at first glance "double standards" may seem to describe the behaviour of the regulatory authorities, it is defensible to use different standards of proof when evaluating the benefits and the costs of therapeutic drugs. It is reasonable to err on the side of caution by requiring stronger evidence of benefit from putatively therapeutic drugs in order to ensure that the possible risks incurred by their therapeutic use do not outweigh their benefits. Moreover, this behaviour is not peculiar to the therapeutic appraisal of cannabinoids; it is standard practice in the therapeutic appraisal of all drugs. Medical practitioners are encouraged to report cases histories of possible adverse effects of prescribed drugs. Such reports are treated as a noisy but necessary way of detecting rare but serious side effects of drugs that have not been detected in clinical trials or animal studies. 8.10 The politics of therapeutic cannabinoid use A puzzle in the field of cannabinoid therapeutics is that despite the positive appraisal of the therapeutic potential of cannabinoids as anti-emetics and anti-glaucoma agents, they have not been widely used. Nor has the detailed type of clinical pharmacological research been undertaken on optimal methods of clinical use in those areas where the cannabinoids do have therapeutic potential (e.g. as anti-emetics). Part of the reason for this is that research on the therapeutic use of these compounds has become a casualty of the debate in the United States about the legal status of cannabis. This emerges from an inspection of the arguments recently advanced for and against an application to the United States Drug Enforcement Agency to change the status of marijuana under the Controlled Substances Act, 1970 from a schedule I drug which has no accepted medical use to a schedule II drug which has an accepted medical use (see Randall, 1988, 1989, 1990). The proponents of rescheduling (National Organisation for the Reform of Marijuana Laws, Alliance for Cannabis Therapeutics, and Cannabis Corporation of America) have argued that marijuana should be available for medical use, as smoking is the most effective mode of delivering THC for some therapeutic purposes. The opponents of rescheduling (Drug Enforcement Agency, International Chiefs of Police, The National Federation of Parents for a Drug Free Youth) have countered that marijuana has no therapeutic use, since its few uses are better met, either by other more effective drugs which do not have the psychoactive effects of THC, or by the oral delivery of synthetic cannabinoids. They have been supported by medical researchers and practitioners who argue for the therapeutic superiority of pharmaceutically pure drugs which can be given in defined doses (e.g. Levitt, 1986; Mechoulam, 1988; Nahas, 1984). Medical researchers who have supported the rescheduling of marijuana (e.g. Grinspoon and Bakalar, 1993; Merritt, 1988; Mikuriya, 1990; Morgan, 1990; Weil, 1988) have argued that smoked cannabis is superior to oral synthetic cannabinoids in effectiveness and has a lower risk of producing unwanted psychoactive side-effects. Apart from the unsuitability of oral medication for patients who are vomiting, their main arguments in favour of smoking as a route of THC administration are similar to the reasons recreational users often give for preferring smoking to the oral use of cannabis. The greater bioavailability of THC via smoking produces a more dependable therapeutic effect, which is more easily controlled because users have a greater ability to titrate their dose, and hence, to maximise the desired effects while minimising the unpleasant effects. An additional argument sometimes used is that there may be other cannabinoids present in the crude plant product which modulate the undesired side effects, including the unpleasant dysphoric effects of THC (Grinspoon and Bakalar, 1993). There is also suggestive evidence that smoked cannabis is as effective as oral THC, and may be preferred by patients because of the greater control they have over dose (Chang et al, 1979). Opponents of marijuana rescheduling argue that the undesirable psychoactive side effects of THC disqualify it from widespread medical use, whatever the route of administration. Most also believe that smoking is a medically unacceptable route of administration of THC because it is unsuitable for very young and very old patients, there is a risk of infection with micro-organisms which may contaminate the plant material, and there is the danger that chronic smoke inhalation may produce or exacerbate bronchitis, and expose the user to carcinogens (e.g. Levitt, 1986; Mechoulam, 1988; Nahas, 1984). The proponents of rescheduling respond that none of these are compelling reasons for rejecting smoked marijuana for therapeutic purposes until more potent and specific therapeutic cannabinoids have been identified and synthesised. Smoking, they point out, would not be a compulsory method of administration; only an option for those patients who preferred it, as would the use of cannabinoids if patients did not like their psychoactive effects. The contamination of micro-organisms reported with blackmarket cannabis can be overcome, they argue, by standardising dose and using an anti-microbial treatment, as has been done by National Institute on Drug Abuse (NIDA) in preparing cannabis cigarettes for research (Randall, 1988). The risks of bronchitis and respiratory tract cancers, it is argued, are small with the intermittent and time-limited smoking of cannabis that would occur in the course of cancer chemotherapy. In any case, proponents of rescheduling argue, it is probably a risk that many patients with a life-threatening illness may be prepared to run, as shown by their preparedness to take highly toxic and carcinogenic anti-cancer agents. Weil (1988) has argued that some opponents have used double standards in appraising the risks of marijuana smoking. According to Weil, the most common psychoactive effects of marijuana (euphoria, somnolence and dysphoria) are minor, non-life-threatening and self-limiting effects that can be easily managed, and are of much less severity than the side effects of many other widely-used therapeutic drugs. Medical witnesses for the government, he claims, "do not contrast marijuana's supposed adverse effects with the known adverse effects of drugs routinely prescribed for the treatment of conditions like cancer, glaucoma and multiple sclerosis. Instead, ... [they] compare marijuana to some abstract, unobtainable standard of perfection" (p437). Merritt (1988) has made a similar point in criticising the arguments raised against the therapeutic use of marijuana to manage glaucoma: " ... each drug family used in glaucoma therapy is capable of producing a lethal response, even when properly prescribed and used .. [p470] [but] these drugs are all deemed "safe" for use in glaucoma therapy .. because their adverse consequences are considered less threatening to the patient than blindness" (p472). Yet marijuana is excluded from therapeutic use because of a possible risk of cancer from long-term daily smoking. "I cannot see", observes Merritt, "how an alleged case of marijuana-induced lung cancer which results in death is significantly different in result from an acute adverse reaction to a myotic drug which results in respiratory failure, except, of course, that the patient with cancer is likely to outlive the patient who is unable to draw in a breath of air" (p474). Although the debate about the rescheduling of marijuana has been ostensibly about the safety and efficacy of marijuana use, it has been driven by the debate about the legal status of recreational marijuana use. For example, some of the groups advocating the therapeutic use of cannabis have also been proponents of cannabis legalisation (e.g. NORML), thereby fuelling the fears of opponents of cannabis use that success in the campaign for marihuana rescheduling will be the thin edge of a wedge to legalise cannabis. Other proponents of legalisation (e.g. Grinspoon and Bakalar, 1993) have turned this reasoning around, by arguing for the legalisation of cannabis as a way of making cannabis available for therapeutic purposes. On the other side of the argument are those opponents of marijuana use who fear that the admission that marijuana, or any of its constituents, may have a therapeutic use will send the "wrong message" to youth. This has led to the denial that cannabinoids have any therapeutic effects, and to attempts to stifle all scientific inquiry into any such effects. For example, Mr Bernstein representing the National Federation of Parents for a Drug Free Youth had the following to say in his summing up against Rescheduling marijuana before Judge Young (1989): "If marijuana were to be rescheduled to Schedule II, what kind of message are we sending to a nation that is engaged in a battle for it's very survival because of epidemic drug abuse? ... will not the message be that marijuana is good for cancer, good for glaucoma, good for spasticity and a host of other illnesses? Now to all of this who are the most vulnerable? The answer is, of course, our young people. Their reaction will be that if it is good for all of these things, it can't be bad for me. We then have another youngster trying marijuana, the gateway drug and probably starting down the road that leads to nowhere but destruction" (in Randall, 1989, p395). It is unfortunate that a connection has been forged between the debates about the legal status of cannabis as a recreational drug and the use of cannabinoids for therapeutic use. Any such connection is spurious, since there is a world of difference between the use of controlled doses of a purified drug under medical supervision and the recreational use of crude preparations of a drug. In a rational world, clinical decisions about whether to use pure cannabinoid drugs should not be abrogated because crude forms of the drug may be abused by those who use it recreationally. As a community we do not allow this type of thinking to deny us the use of opiates for analgesia. Nor should it be used to deny access to any therapeutic uses of cannabinoids derivatives that may be revealed by pharmacological research. 8.11 Conclusions The following provisional conclusions can be drawn on the available evidence. First, there is good evidence for the therapeutic potential of THC as an anti-emetic agent. Although uncertainty exists about the most optimal method of dosing and the advantages and disadvantages of different routes of administration, there is sufficient evidence to justify it being made available in pure synthetic form to cancer patients. In the light of the recent development of more effective anti-emetic agents, it remains to be seen how widely used the cannabinoids will be. Second, there is reasonable evidence for the potential efficacy of THC in the treatment of glaucoma, especially in cases which have proved resistant to existing anti-glaucoma agents. Further research is clearly required, but this should not prevent its use under medical supervision in poorly controlled cases, provided patients make informed decisions about its use in the light of information about the possible health risks of long-term use. Third, there is sufficient suggestive evidence of the potential usefulness of various cannabinoids as analgesic, anti-asthmatic, anti-spasmodic, and anti-convulsant agents to warrant further basic pharmacological and experimental investigation, and perhaps clinical research into their effectiveness. Despite the basic and clinical research work which was undertaken in late 1970s and early 1980s, the cannabinoids have not been widely used therapeutically, nor have further investigations been conducted along the lines suggested in the positive evaluations made by the Institute of Medicine (1982). This seems largely attributable to the fact that clinical research on the therapeutic use of cannabinoids has been discouraged by regulation and a lack of funding in the United States, where most cannabis research has been conducted. The discouragement of therapeutic research, in turn, derives from the fact that THC, the most therapeutically effective cannabinoid, has the psychoactive effects sought by recreational users. In opposing the therapeutic uses of cannabinoids, some researchers have used double standards in appraising efficacy and safety, setting unreasonably high standards in assessing the evidence on the comparative therapeutic safety and efficacy of cannabinoids and existing agents. The application of the same demanding standards to existing agents for the candidate diseases, and more generally, to existing psychoactive drugs that are widely used in medical practice, would denude the pharmacopoeia. 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