8

MARIJUANA AND NEUROLOGICAL DISORDERS

While frequently touted as a folk remedy for spasticity, marijuana is only occasionally mentioned with regard to other neurological disorders. Perhaps people with movement disorders, epilepsy, or Alzheimer 's disease derive little benefit from marijuana, but it may also be the case that relatively few patients with these conditions have tried it.

Only a handful of clinical trials have explored the effects of marijuana or cannabinoids on the symptoms of neurological disorders other than multiple sclerosis. For the most part these studies are too small to be considered conclusive, and their results are far from promising. Nevertheless, they are worth considering in light of the abundance of cannabinoid receptors in the brain, especially in areas associated with Parkinson's and Huntington's diseases. And since conventional treatments for movement disorders, epilepsy, and Alzheimer's disease leave much to be desired, no source of potential remedies should be overlooked.

MOVEMENT DISORDERS

This group of neurological diseases is caused by defects in the basal ganglia, clusters of nerve cells in the brain that control muscular activity. Injury to these regions ultimately affects the



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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy 8 MARIJUANA AND NEUROLOGICAL DISORDERS While frequently touted as a folk remedy for spasticity, marijuana is only occasionally mentioned with regard to other neurological disorders. Perhaps people with movement disorders, epilepsy, or Alzheimer 's disease derive little benefit from marijuana, but it may also be the case that relatively few patients with these conditions have tried it. Only a handful of clinical trials have explored the effects of marijuana or cannabinoids on the symptoms of neurological disorders other than multiple sclerosis. For the most part these studies are too small to be considered conclusive, and their results are far from promising. Nevertheless, they are worth considering in light of the abundance of cannabinoid receptors in the brain, especially in areas associated with Parkinson's and Huntington's diseases. And since conventional treatments for movement disorders, epilepsy, and Alzheimer's disease leave much to be desired, no source of potential remedies should be overlooked. MOVEMENT DISORDERS This group of neurological diseases is caused by defects in the basal ganglia, clusters of nerve cells in the brain that control muscular activity. Injury to these regions ultimately affects the

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy motion of muscles in the face, limbs, and trunk. The movement disorders most often discussed as candidates for marijuanabased therapies are dystonias, Huntington's disease, Parkinson's disease and Tourette's syndrome. As a general consideration, it is important to note that stress and anxiety tend to worsen the symptoms of movement disorders. Thus, marijuana's calming effect could be a primary reason why some patients claim that it brings them relief. Dystonias are a subgroup of movement disorders that share similar symptoms: slow, sustained, involuntary muscle contractions that often cause sufferers to hold their limbs, trunks, or necks in odd positions. They may be confined to one part of the body; for example, spasmodic torticollis affects only the neck, while Meige's syndrome distorts the face. These chronic, slowly progressive disorders are often painful and can cause mild to severe disability. Some dystonias are inherited, while others occur as side effects of certain drugs. Scientists have yet to discover the specific neurological malfunctions that cause dystonias. Several different drugs are used to treat various forms of dystonia. The most commonly prescribed drugs—benzodiazepines, baclofen, Botulinum toxin, anticholinergic agents, and tetrabenazine—merely relieve the symptoms of dystonia rather than resolving the condition itself. In many cases the relief they provide is incomplete. Baclofen (Lioresal) and benzodiazepines, including diazepam (Valium) and clonazepam (Klonopin, Rivotril), act by reducing the nervous system's ability to stimulate muscle contractions. Both drugs usually make patients drowsy and may also cause a range of additional side effects, including muscle weakness and behavioral problems. Botulinum toxin—a bacterial compound that also causes food poisoning—also blocks muscle stimulation; it produces few side effects but must be injected directly into the affected muscles. Anticholinergic drugs such as trihexyphenidyl (Artane) and diphenhydramine (Benadryl) deactivate muscle contractions; they, too, cause drowsiness and other side effects that can become severe at high doses. Tetrabenazine, although not available in the United States, is a dopaminedepleting compound available in Canada and Europe that is often prescribed for the relief certain types of dystonia. No controlled study of marijuana in patients with dystonia

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy has yet been published. Cannabidiol, a chemical component of marijuana (see Chapter 2), was tested in a preliminary open trial in which patients knew they were receiving the experimental drug. The five participants showed only modest improvements, which increased with the amount of drug they received.1 Better results occurred in a study of an animal model for dystonia —a mutant strain of hamsters—in which researchers tested a synthetic cannabinoid that activates the same cellular receptors as THC. The hamsters exhibited a type of dystonia that produces either sudden spasms of rapid, jerky motions or slow, repetitive writhing movements, both of which decreased under the influence of the cannabinoid.2 Besides being a diagnosis in its own right, dystonia is also a symptom of other major movement disorders, including Huntington's disease. This inherited disorder usually manifests itself in middle age, continues to worsen, and ultimately leads to death within 15 years of its appearance. Symptoms include rapid, uncontrolled muscle movements (called “chorea, ” from the Greek word for dance), emotional disturbance and eventually dementia. Patients may take drugs, including reserpine or haloperidol, mainly to control their psychological symptoms. All of these medicines produce adverse side effects, so physicians often wait to prescribe them until a patient's symptoms become severe. Since anxiety and stress appear to worsen involuntary movements in many patients with Huntington's disease and since marijuana reduces those feelings in most users, some have proposed it as an alternative to existing medications. Animal studies suggest that cannabinoids might suppress choreic movements, presumably by stimulating receptors in the basal ganglia (see Chapter 2). In a preliminary study of four people with Huntington's disease, one patient showed improvement under the influence of cannabidiol.3 Based on this limited success, researchers attempted a double-blind crossover study (see Introduction to Part II for a discussion of clinical study design) on 15 patients who were not taking medications to inhibit chorea but found that participants ' symptoms neither improved nor worsened after treatment with cannabidiol. 4 These results are perhaps to be expected, though, since cannabidiol does not bind to the predominant type of cannabinoid receptor (CB1) on neurons affected by Huntington's dis-

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy ease. THC or other cannabinoids that readily bind CB1 receptors seem likelier candidates as medications for Huntington 's disease, but their effects on patients with the disorder remain unknown. One of the most devastating movement disorders, Parkinson's disease, affects approximately 1 million Americans age 50 and older. Symptoms include tremor, muscular rigidity, instability, and impeded motion (both slowed movement and abrupt stopping in midmovement). The single most effective drug to treat Parkinson's disease, levodopa (L-Dopa, Larodopa, Dopar), has many drawbacks, so physicians tend to reserve it for functionally impaired patients. After several years of use, levodopa tends to wear off quickly after each dose, so patients constantly cycle through phases of mobility and disability. Additional side effects include nausea, hallucination, and confusion. Researchers also suspect that, while levodopa dramatically improves all of the signs and symptoms of Parkinson's disease, its use may accelerate the disease's progress; no clinical evidence confirms this concern. Because they act on the same neurological pathways that Parkinson 's disease disrupts, cannabinoids could in theory be useful in treating the disorder (see Chapter 2). The IOM team found only one published account of a clinical trial of marijuana for Parkinson's disease. The study was prompted by a patient's report that smoking marijuana reduced tremor, but when researchers tested the drug on five additional patients with tremor, they found no evidence of improvement. On the other hand, conventional medications, including levodopa, successfully reduced tremor in all five patients.5 Unlike Huntington's and Parkinson's diseases, Tourette's syndrome typically appears during childhood. Patients exhibit a variety of rapid, involuntary, repetitive movements and vocalizations, collectively called tics. The causes of Tourette's syndrome are largely unknown but are thought to impair brain areas that convert a person's intent to move into actual movements. Damage to these same areas produces involuntary movement in Huntington's disease and restricts voluntary movement in Parkinson's disease. Two widely used medications for Tourette's syndrome, pimozide (Orap) and haloperidol (Haldol) inhibit the effects of

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy the neurotransmitter dopamine. Cannabinoids, by contrast, increase dopamine release, so one might predict that cannabinoids would actually exacerbate the symptoms of Tourette's syndrome. Yet four clinical case histories indicate that marijuana use can reduce tics in Tourette 's patients. In three of the four cases, however, the investigators suggest that marijuana's anxiety-reducing properties—rather than any specific effect on the neural pathway that produces tics—caused the patients' symptoms to improve.6 In summary, while persuasive basic evidence exists for the role of cannabinoids in movement, clinical evidence for their usefulness in relieving the symptoms of movement disorders is lacking. The few existing studies were performed on small numbers of patients and without consideration that marijuana's antianxiety effects might reduce the symptoms in question. Moreover, while there are a few isolated anecdotal reports that marijuana helps patients with these disorders, there are no surveys to suggest that these patients' experiences are at all representative. Thus, with the possible exception of spasticity in multiple sclerosis, there is little reason to recommend additional clinical trials of marijuana or cannabinoids for movement disorders, the IOM study team concluded. That is not to say that more extensive animal studies will never provide stronger evidence in favor of human trials. But until reliable animal models exist for most movement disorders, such evidence is unlikely to be forthcoming. In the meantime the IOM team recommends conducting double-blind, placebo-controlled clinical trials of individual cannabinoids such as THC—but not smoked marijuana—for the treatment of movement disorders. The IOM team further specified that these trials should test the effects of cannabinoids on movement alone—that is, the experiments should distinguish cannabinoids' effects on movement from their effects on anxiety or mood. For if cannabinoids merely provide a psychological boost to people with multiple sclerosis, their use would probably not warrant the risk of short-term memory loss, cognitive impairment, and other known side effects. But if cannabinoids directly improve spasticity and other movement-related symptoms, as well as mood, they would offer a uniquely useful treatment. Cannabinoids therefore represent an

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy interesting possibility for treating movement disorders but one that has yet to be proven. EPILEPSY A chronic seizure disorder, epilepsy affects about 2 million Americans and an estimated 30 million people worldwide. Symptoms include recurrent sudden attacks of altered consciousness, convulsions, and other uncontrolled movement, apparently brought on by the simultaneous stimulation of numerous nerve cells. People may become vulnerable to epileptic seizures through a wide variety of possible causes, including physical injury and exposure to chemical toxins. Some people with epilepsy have partial seizures, which are also known as focal seizures. These disturbances arise in the cerebral cortex, a part of the brain that governs consciousness, movement, and sensation —functions that become temporarily disordered when partial seizures occur. Other people with epilepsy, who develop the condition after sustaining damage to centrally important regions in the brain, experience seizures that affect many aspects of behavior. These generalized seizures may occur as either relatively mild petit mal or violent grand mal events. A variety of conventional anticonvulsant medications may be used in attempts to control epileptic seizures. Because different drugs work better for different types of seizures, patients must often try several medications before finding the most effective treatment. In general, antiepilepsy drugs suppress seizures completely in about 60 percent of patients and reduce their severity in another 15 percent or so. Many of the remaining 25 percent suffer from a serious underlying brain disease that cannot be relieved through anticonvulsant therapy; others continue to have seizures because they refuse prescribed medication, they use it incorrectly, or their bodies do not reliably absorb the drugs. Anticonvulsants commonly make people feel drowsy and mentally slow; the drugs may also cause tremor, hair loss, headache, dermatitis, and several other side effects. Nevertheless, most people with epilepsy endure these drawbacks in order to prevent seizures, which can be both physically dangerous and emotionally devastating.

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy Although some anecdotal accounts—as well as a few reports from small clinical and individual case studies—suggest that marijuana helps control epileptic seizures, no solid evidence supports this assertion.7 The only relevant controlled study that has been published to date was designed to evaluate whether illicit drug use affected the age at which people with epilepsy had their first seizures. In this study of 600 patients, researchers found that men, but not women, who used marijuana were less prone to develop seizures than men who did not use the drug, suggesting that marijuana provided some sort of protection for men.8 However, it is also possible that the marijuana-using men in this study tended to be healthier than those who had not used the drug; in other words, their health status influenced their drug use rather than the other way around. Researchers have also investigated the antiepileptic properties of cannabidiol, which shows little promise. In three controlled trials conducted with patients with both focal and generalized epilepsy, oral doses of cannabidiol failed to lessen the frequency of either type of seizure.9 Even if cannabidiol had appeared to suppress seizures, however, these trials would have been far too small to prove its effectiveness. Studies of drugs for epilepsy generally require large numbers of patients who must be followed for months, since symptoms are highly variable and tend to occur unpredictably. Currently, the only biological reason to believe that cannabinoids could suppress epileptic seizures is the abundance of CB1 receptors in some of the regions of the brain (the hippocampus and amygdala) where partial seizures originate. While basic research could reveal stronger links between cannabinoids and seizure initiation, this does not seem as promising as other potential uses for marijuana-based medicines. ALZHEIMER'S DISEASE An estimated 4 million Americans currently have Alzheimer's dementia, a number that is likely to grow as the country's population ages. Alzheimer's is an incurable progressive disease of the nervous system that typically begins with memory loss and behavioral changes. At present, therapies for

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy Alzheimer's are limited to relieving its various symptoms. Even the two drugs, donepezil (Aricept) and tacrine (Cognex), that improve mental functions in some patients do not stop the progression of the disease. There are two possible applications for cannabinoid treatments in Alzheimer's disease: to stimulate patients' appetites and to improve their behavior. Food refusal, which may be symptomatic of depression, is a common problem among people with Alzheimer's dementia; sometimes, but not always, antidepressant medications improve patients' appetites. Treatments would also be welcome that reduced agitation or antisocial behavior in Alzheimer 's patients—behaviors that are not only unsafe but that also reduce caregivers ' ability to help patients. In one study, 11 Alzheimer's patients were treated with oral THC (dronabinol, Marinol) for six weeks, followed by six weeks of a placebo. Researchers found that the drug produced significant weight gain and reduced disturbed behavior without causing serious side effects.10 Most of the patients were severely demented, and their memories were also seriously impaired. Although short-term memory loss is a common side effect of THC in healthy people, it was not measured in this study. In the future it would be useful to study how THC and other cannabinoids affect people with Alzheimer's whose memories remain largely intact. Such patients would be ill served by a medication that accelerated memory loss. At the time of writing, additional clinical trials of Marinol in Alzheimer's patients and others with dementia appear likely to begin soon. In late 1998, Unimed Pharmaceuticals, which makes Marinol, received a U.S. patent for use of the drug in improving disturbed behavior in people with dementia, including the dementia of Alzheimer 's and Parkinson's diseases. NOTES 1. Consroe P, Sandyk R, Snider SR. 1986. “Open label evaluation of cannabidiol in dystonic movement disorders. ” International Journal of Neuroscience 30:277-282. 2. Richter A and Loscher W. 1994. “(+)-WIN55,212-2 a novel cannabinoid receptor agonist, exerts antidystonic effects in mutant dystonic hamsters.” European Journal of Pharmacology 264:371-377.

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MARIJUANA AS MEDICINE?: The Science Beyond the Controversy 3. Sandyk R, Consroe P, Stern P, Biklen D. 1988. “Preliminary trial of cannabidiol in Huntington's disease,” in Marijuana: An International Research Report. Chesher G, Consroe P, Musty R, eds. Canberra, Australia: Australian Government Publishing Service. 4. Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, Kennedy K, Schram K. 1991. “Controlled clinical trial of cannabidiol in Huntington's disease.” Pharmacology, Biochemistry, and Behavior (New York) 40:701-708. 5. Frankel JP, Hughes A, Lees AJ, Stern GM. 1990. “Marijuana for Parkinsonian tremor.” Journal of Neurology, Neurosurgery, and Psychiatry 53:436. 6. Hemming M and Yellowlees PM. 1993. “Effective treatment of Tourette's syndrome with marijuana.” Journal of Psychopharmacology 7:389-391; Sandyk R, Awerbuch G. 1988. “Marijuana and Tourette's syndrome.” Journal of Clinical Psychopharmacology 8:444-445. 7. British Medical Association. 1997. Therapeutic Uses of Cannabis. Amsterdam, The Netherlands: Harwood Academic Press. 8. Ng SKC, Brust JCM, Hauser WA, Susser M. 1990. “Illicit drug use and the risk of new-onset seizures.” American Journal of Epidemiology 132:47-57. 9. Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press, pp. 170-172. 10. Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. 1997. “Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease.” International Journal of Geriatric Psychiatry 12:913-919.