Marijuana and Medicine Assessing the Science Base (1999) / Chapter Skim
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4 The Medical Value of Marijuana and Related Substances
4 The Medical Value of Marijuana and Related Substances
Pages 137-192
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From page 137... ...
and state levels (see chapter 5~. Consequently, the rapid growth in basic research on cannabinoids contrasts with the paucity of substantial clinical studies on medical uses.
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There are eight sections. The first section explains clinical trials, the following five deal with specific symptoms and conditions, and the last two summarize the medical benefits of marijuana and cannabinoids.
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For example, depending on the person, THC can reduce or increase anxiety; it is important to determine to what extent this "side effect" contributes to the therapeutic effect. While double-blind, randomized, controlled clinical trials offer the highest degree of assurance of drug efficacy, such trials are not always feasible.
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· Its efficacy is enhanced in patients who have developed tolerance to opioids. There have not been extensive clinical studies of the analgesic potency of cannabinoids, but the available data from animal studies indicate that cannabinoids could be useful analgesics.
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Modern methods of pain assessment in humans typically use ratings of the intensity of the sensation of pain; those methods are superior to assessing the effects of a drug on the extremes of pain.~92 Second, Raft and coworkers did not include a positive control; that is, they did not demonstrate the adequacy of their method by showing that an established analgesic, such as an opiate or narcotic, was effective under their study conditions. Clark and co-workers22 tested the effect of smoked marijuana on thermal pain in volunteers and failed to observe an analgesic effect.
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Because the authors did not report the number or percentage of people who responded, it is not clear whether the average represents consistent pain relief in all levonantradol-treated patients or whether some people experienced great relief and a few experienced none. Chronic Pain The most encouraging clinical data on the effects of cannabinoids on chronic pain are from three studies of cancer pain.
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A recent survey of over 100 patients with multiple sclerosis reported that a large number obtained relief from spasticity and limb pain (discussed further under the section on multiple sclerosis) .28 Several said that it relieved their phantom pain and headache.4~ Migraine Headaches There is clearly a need for improved migraine medications.
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The PAG region is part of the neural system that suppresses pain and is thought to be involved in the generation of migraine headaches.52 The link or lack thereof between cannabinoids and migraine might be elucidated by examining the effects of cannabinoids on the PAG region.~° Recent results indicating that both cannabinoid receptor subtypes are involved in controlling peripheral paints suggest that the link is possible. Further research is warranted.
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Further clinical work is warranted to establish the magnitude of the effect in different clinical conditions and to determine whether the effect is sustained. Although the usefulness of cannabinoids appears to be limited by side effects, notably sedation, other effects such as anxiolysis, appetite stimulation, and perhaps antinausea and antispasticity effects should be studied in randomized, controlled clinical trials.
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From page 146... ...
Much more is known about the neural mechanisms that produce vomiting than about those that produce nausea, in large part because vomiting is a complex behavior involving coordinated changes in the gastrointestinal tract, respiratory muscles, and posture, whereas nausea is a sensation involving primarily higher brain centers and lacks a discrete observable action.~04~28 Most reports on the antiemetic effects of marijuana or cannabinoids are based on chemotherapy-induced emesis; they are the subject of the following section. Chemotherapy-Induced Nausea and Vomiting The use of effective chemotherapeutic drugs has produced cures in some malignancies and retarded the growth of others, but nausea and Blood-brain barrier PERIPHERY (H., | M)
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The mechanism by which chemotherapy induces vomiting is not completely understood. Studies suggest that emesis is caused by stimulation of receptors in the central nervous system or the gastrointestinal tract.
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Smoked marijuana has also been examined. Antiemetic Properties of THC The quality and usefulness of antiemetic studies depend on adherence to the methodological considerations outlined above.
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Neither is commercially available in the United States. Antiemetic Properties of Marijuana Among the efforts to study marijuana was a preliminary study conducted in New York state on 56 cancer patients who were unresponsive to conventional antiemetic agents.
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Patients with severe vomiting would have been unlikely to be able to swallow or keep the pills down long enough for them to take effect. The onset of drug effect is much faster with inhaled or injected THC than it is for oral delivery.87 ~2 ~4~ Although many marijuana users have claimed that smoked marijuana is a more effective antiemetic than oral THC, no controlled studies have yet been published that analyze this in sufficient detail to estimate the extent to which this is the case.
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Metoclopramide is somewhat less effective than the serotonin antagonists and has more side effects, including acute dystonic reactions, drowsiness, diarrhea, and depression.~3 37 Side effects associated with phenothiazines are severe or acute dystonic reactions, hypotension, blurred vision, drowsiness, dry mouth, urinary retention, allergic reactions, and occasional jaundice.~3 The cost of effective antiemetic regimens can vary markedly, depending on the agent, dose, schedule, and route of administration. Overall, oral regimens cost less than intravenous regimens because of lower pharmacy and administration costs, as well as lower acquisition costs in many countries.
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Like cannabinoids, smoked marijuana, was apparently effective, but the efficacy was no greater than that of available antiemetic agents now considered to be marginally satisfactory. At present, the most effective antiemetic regimens are combinations of oral serotonin receptor antagonists with dexamethasone in single-dose regimens given before chemotherapy.
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At the time of this writing, clinical trials with NK-1 receptor antagonists were under way (phase II or small phase III comparison studies)
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WASTING SYNDROME AND APPETITE STIMULATION Wasting syndrome in acquired immune deficiency syndrome (AIDS) patients is defined by the Centers for Disease Control and Prevention as the involuntary loss of more than 10% of baseline average body weight in the presence of diarrhea or fever of more than 30 days that is not attributable to other disease processes.~7 Anorexia (loss of appetite)
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; this suggests that malnutrition is a consequence of the inflammatory response to the underlying viral infection, rather than a general complication of AIDS.~44 In contrast, weight loss is often episodic and related to acute complications, such as febrile opportunistic infections.~3 Mechanisms underlying wasting in HIV-infected patients depend on the stage of HIV infection and on specific associated complications. The many reasons for decreased food intake among AIDS patients include mouth, throat, or esophageal infections or ulcers (oropharyngeal and esophageal pathology)
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Anecdotes abound that smoked marijuana is useful for the treatment of HIV-associated anorexia and weight loss.23 62 Some people report a preference for smoked marijuana over oral THC because it gives them the ability to titrate the effects, which depend on how much they inhale. In controlled laboratory studies of healthy adults, smoked marijuana was shown to increase body weight, appetite, and food intake.47 ~9 Unfortunately, there have been no controlled studies of the effect of smoked marijuana on appetite, weight gain, and body composition in AIDS patients.
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Although the findings are still preliminary, anabolic compounds, such as testosterone or growth hormone, might be useful in preventing the loss of or in restoring lean body mass in AIDS patients.~0 44 64 ~70 Enteral and parenteral nutrition have also been evaluated and shown to increase weight, but again the increase is due more to body fat than to lean body mass.96 98 Encouraging advances in the antiviral treatment of HIV infection and developments in the prophylaxis of and therapy for opportunistic infections have recently changed the outlook for the long-term health of HIVinfected people. Death rates have been halved, and the frequency of serious complications, including malnutrition, has fallen markedly.94 ~33 Future Therapy The primary focus of future therapies for wasting in HIV-infected patients is to increase lean body mass as well as appetite.
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Cachexia does not occur in all cancer patients, but generally occurs in the late stages of advanced cancer of the pancreas, lung, and prostate. The only cannabinoid evaluated for treating cachexia in cancer patients is dronabinol, which has been shown to improve appetite and promote weight gain.54 Present treatments for cancer cachexia are similar to that for cachexia in AIDS patients.
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Current treatments include psychological techniques to overcome emotional or behavioral problems and dietary intervention to reverse the malnutrition.~95 Pharmacological treatments, such as antidepressants, have been used in addition to psychotherapy but tend to lack the desired level of efficacy.33 Recently, alterations in a gene for one of the serotonin receptors have been identified in some patients with anorexia nervosa.45 The possibility of a genetic component suggests a pathway for the development of new drugs to treat this disease. Conclusions: Wasting Syndrome and Appetite Stimulation The profile of cannabinoid drug effects suggests that they are promising for treating wasting syndrome in AIDS patients.
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There are numerous anecdotal reports that marijuana can relieve the spasticity associated with multiple sclerosis or spinal cord injury, and animal studies have shown that cannabinoids affect motor areas in the brain areas that might influence spasticity 78 ~30 ~68 Multiple Sclerosis Multiple sclerosis (MS) is a condition in which multiple areas of the central nervous system (CNS)
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The regular use of smoked marijuana, however, would be contraindicated in a chronic condition like MS. Spinal Cord Injury In 1990, there were about 15 million patients worldwide with spinal cord injury, and an estimated 10,000 new cases are reported each year in *
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~ . r ~ ~ .~ -- ~ 2- \ ~ ~ ~ ~ /_~\ V , B A Type of treatment B None FIGURE 4.2 Effect of nabilone on multiple sclerosis symptoms.
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Most will need long-term care and some lifelong care. Many spinal cord injury patients report that marijuana reduces their muscle spasms.~4 Twenty-two of 43 respondents to a 1982 survey of
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The treatment for MS itself will likely be directed at immunomodulation. Various immunomodulating agents, such as beta-interferon and glatiramer acetate, have been shown to reduce the frequency of symptomatic attacks, the progression of disability, and the rate of appearance of demyelinated lesions as detected by magnetic resonance imaging.5 Conclusion: Muscle Spasticity Basic animal studies described in chapter 2 have shown that cannabinoid receptors are particularly abundant in areas of the brain that control TABLE 4.2 Classes of Antispasticity Drugs Drug Class Drug GABAB-receplor agonists oc-Receptor agonists Noncompetitive GABAA-receptor agonists Calcium blockers in skeletal muscle Baclofen Tizanidine Benzodiazepines, including diazepam Dantrolene
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The available clinical data are too meager to either accept or dismiss the suggestion that marijuana or cannabinoids relieve muscle spasticity. But the few positive reports of the ability of THC and related compounds to reduce spasticity, together with the prevalence of anecdotal reports of the relief provided by marijuana, suggest that carefully designed clinical trials testing the effects of cannabinoids on muscle spasticity should be considered (see chapter 1~.25 62 Such trials should be designed to assess the degree to which the anxiolytic effects of cannabinoids contribute to any observed antispastic effects.
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. Animal studies suggest that cannabinoids have antichoreic activity, presumably because of stimulation of CB~ receptors in the basal ganglia.~29 ~68 On the basis of positive results in one of four Huntington's disease patients, CBD and a placebo were tested in a double-blind crossover study of 15 Huntington's disease patients who were not taking any antipsychotic drugs.
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Hyperactivity of the subthalamic neurons, observed in both Parkinson's patients and animal models of Parkinson's disease, is hypothesized to be a major factor in the debilitating bradykinesia associated with the disease.36 Furthermore, although cannabinoids oppose the actions of dopamine in intact rats, they augment dopamine activation of movement in an animal model of Parkinson's disease. This suggests the potential for adjunctive therapy with cannabinoid agonists.~65-~67 ~69 At the time of this writing, we could find only one published clinical trial of marijuana involving five cases of idiopathic Parkinson's disease.48 That trial was prompted by a patient's report that smoking marijuana reduced tremor, but the investigators found no improvement in tremor after the five patients smoked marijuana whereas all subjects benefited from the administration of standard medications for Parkinson's disease (levodopa and apomorphine)
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In addition to medications, surgical interventions, such as pallidotomy and neurosurgical transplantation of embryonic substantia nigra tissue into the patient's striatum, have been tried in Parkinson's disease patients. Surgery is generally palliative and is still considered to be in the developmental phase.
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For example, the anxiolytic effects of cannabinoids might make patients feel that their condition is improved, despite the absence of measurable change in their condition. Compared to the abundance of anecdotal reports concerning the beneficial effects of marijuana on muscle spasticity, there are relatively few claims that marijuana is useful for treating movement disorders.
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Thus, double-blind, placebo-controlled clinical trials of isolated cannabinoids that include controls for relevant side effects should be conducted. Such effects include anxiolytic and sedative effects, which might either mask or contribute to the potential therapeutic effects of cannabinoids.
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Three controlled trials were conducted in which CBD was given orally to patients who had had generalized grand mat seizures or focal seizures (Table 4.4~. Two of these studies were never published, but information about one was published in a letter to the South African Medical Journal, and the other was presented at the 1990 Marijuana International Conference on Cannabis and Cannabinoids.~84 TABLE 4.4 Clinical Trials of Cannabidiol (CBD)
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Most of the anticonvulsant research on cannabinoids was conducted before 1986. Since then, many new anticonvulsants have been introduced and cannabinoid receptors have been discovered.
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The most common form of glaucoma, primary open-angle glaucoma (POAG) , is a slowly progressive disorder that results in loss of retinal ganglion cells and degeneration of the optic nerve, causing deterioration of the visual fields and ultimately blindness.
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Because of impaired outflow of aqueous humor from the anterior chamber of the eye, a high IOP is a risk factor for glaucoma, but the mechanism by which it damages the optic nerve and retinal ganglion cells remains unclear.~74 The two leading possibilities are that high IOP interferes with nutrient blood flow to the region of the optic nerve or that it interferes with transport of nutrients, growth factors, and other compounds within the optic nerve axon (P. Kaufman, IOM workshop)
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In summary, cannabinoids and marijuana can reduce IOP when administered orally, intravenously, or by inhalation but not when administered topically. Even though a reduction in IOP by standard medications or surgery clearly slows the rate of glaucoma symptom progression, there is no direct evidence of benefits of cannabinoids or marijuana in the natural progression of glaucoma, visual acuity, or optic nerve atrophy.92 ~5 In addition to lowering IOP, marijuana reduces blood pressure and has many psychological effects.
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Present therapies, especially combinations of approved topical drugs, can control IOP when administered once or twice a day, at a cost of about $60 per month. Future Therapy In all likelihood the next generation of glaucoma therapies will deal with neural protection, neural rescue, neural regeneration, or blood flow, and the optic nerve and neural retina will be treated directly rather than just by lowering IOP (P.
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The potential harmful effects of chronic marijuana smoking outweigh its modest benefits in the treatment of glaucoma. Clinical studies on the effects of smoked marijuana are unlikely to result in improved treatment for glaucoma.
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For example, the personal medical use of smoked marijuana regardless of whether or not it is approved to treat certain symptoms is reason enough to advocate clinical trials to assess the degree to which the symptoms or course of diseases are affected. Trials testing the safety and efficacy of marijuana use are an important component to understanding the course of a disease, particularly diseases such as AIDS for which marijuana use is prevalent.
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must meet the following conditions: failure of all approved medications to provide relief has been documented, the symptoms can reasonably be expected to be relieved by rapid-onset cannabinoid drugs, such treatment is administered under medical supervision in a manner that allows for assessment of treatment effectiveness, and involves an oversight strategy comparable to an institutional review board process that could provide guidance within 24 hours of a submission by a physician to provide marijuana to a patient for a specified use. 179 Until a nonsmoked rapid-onset cannabinoid drug delivery system becomes available, we acknowledge that there is no clear alternative for people suffering from chronic conditions that might be relieved by smoking marijuana, such as pain or AIDS wasting.
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because it makes them feel better...." In contrast, the American Medical Association House of Delegates, National Institutes of Health (NIH) , and the British Medical Association recommend clinical trials of smoked marijuana for a variety of symptoms.
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1997. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia.
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Kleiman MA.1995. The medical use of marijuana: The case for clinical trials [editorial; comment]
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1988. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory.
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1999. Abstinence symptoms following smoked marijuana in humans.
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1990. Effect of home total parental nutrition on body composition in patients with acquired immunodeficiency syndrome.
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1993. Randomized clinical trials in single patients during a 2-year period.
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1997. Cross-sectional and longitudinal evaluation of body composition in men with HIV infection.
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1997. Spinal cord injury: Emerging concepts: An NIH workshop.
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1975. Antiemetic effect of delta-9-THC in patients receiving cancer chemotherapy.
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1997. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome: The DATRI 004 study group.
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1996. HU-211, a nonpsychotropic cannabinoid, produces short- and long-term neuroprotection after optic nerve axotomy.
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From page 192... ...
Common side effects of many of these c rugs include sedation, lethargy, school and work avoidance, social phobia, and increased risk of parkinsonism and tardive dyskinesia.' With some of these medications, like those used for dystonia, efficacy is lacking in as much as 50 percent of the patients. [n addition to medications, surgical interventions such as pallidotomy and neuro surgical transplantation of embryonic substantia nigra tissue into the patient's striatum have been tried in Parkinson's patients.
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