. Institute of medicine

Index

THE MEDICAL VALUE
OF MARIJUANA AND RELATED SUBSTANCES

Chapter 4 - Continued

Table 4.1. Studies on the Effects of Marijuana and Cannabinoids in Multiple Sclerosis

Drug and Dose

Study Design

Results

Reference
Marijuana Mail survey 112/233 MS patients Survey was mailed to 233 MS patients, of whom 112 (48 %) responded. 97% of respondents reported improved spasticity and reduced pain. Consroe and coworkers, 1997
Marijuana Clinical trial 1 MS patient Reduction in spasticity and improved ataxia Meinck, 1989
Marijuana Double-blind, placebo-controlled 10 MS patients; 10 normal individuals MS patients felt they were improved, but posture and balance were impaired. Greenberg, 1994
Oral THC 5-15 mg 6 hourly, up to 18 hours Open trial
8 MS patients		 5 patients experienced subjective, but not objective improvement in motor coordination; objective improvement in tremor demonstrated in 2 of the 8 patients. Clifford, 1983
Oral THC
5 and 10 mg,
single doses		 Double-blind, placebo controlled 9 MS patients Spasticity was improved based on examiner ratings Petro and Ellenberger, 1981
Oral THC
2.5 - 15 mg, once or twice daily for 5 days		 Double-blind, placebo controlled, crossover
13 MS patients		 Patients reported subjective
decreases in spasticity at doses of 7.5 mg or greater, but no changes in objective measures of spasticity or weakness were observed.		 Ungerleider, 1987
Nabilone (THC analogue) Placebo controlled
1 MS patient		 The patient reported increased well-being; less frequent nocturia, and reduced severity of muscle spasticity during nabilone treatment (Figure 4.2). Martyn, 1995

4.27

Spinal Cord Injury

In 1990 there were approximately 15 million patients worldwide with spinal cord injury, and an estimated 10,000 new cases are reported each year in the United States alone.136 140 Approximately 60 percent of these injuries are to those younger than 35 years. Most of these patients will need long-term, and some life-long care.118

Many spinal cord injury patients report that marijuana reduces their muscle spasms (IOM public workshop 42 ). 116 Twenty-two of 43 respondents to a 1982 survey of people with spinal cord injuries reported that marijuana reduced their spasticity. 116 One single case double-blind study of a paraplegic patient with painful spasm in both legs suggested that oral THC was superior to codeine in reducing muscle spasms. 76, 122 Victims of spinal cord injury reporting at IOM workshops noted that smoking marijuana reduces their muscle spasms, while also reducing nausea and sleepless nights. The caveats described for surveys of spasticity relief in MS patients also apply here.

Therapy for Muscle Spasticity

Present Therapy

Present therapy for spasticity includes the various medications listed in table 4.2 below.

TABLE 4.2 Classes of Anti-spasticity Drugs

Drug Class Drug
GABAB receptor agonists baclofen
a-receptor agonists tizanidine
non-competitive GABAA receptor agonists benzodiazepines, including diazepam
calcium blockers in skeletal muscle dantrolene

Baclofen and tizanidine, the most commonly prescribed anti-spasticity drugs, relieve spasticity and spasms with varying degrees of success. The benefit of these agents is generally only partial. Their use is complicated by the side effects of drowsiness, dry mouth, and increased weakness.

4.28

Future Therapy

The discovery of agents that work through different mechanisms than existing anti-spasticity drugs will be an important advance in the treatment of spasticity. The aim of these new treatments will be to relieve the muscle spasticity and pain without significantly increasing muscle weakness in conditions that result in spasticity. The treatment for MS itself will likely be directed toward immunomodulation. Various immunomodulating agents, such as beta-interferon and glatirarner 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 MRI.5

Conclusion

Basic animal studies described in chapter 2 have shown that cannabinoid receptors are particularly abundant in areas of the brain that control movement, and cannabinoids affect movement and posture in animals, as well as humans. The observations are consistent with the possibility that cannabinoids have anti-spastic effects, but they do not offer any direct evidence that cannabinoids affect spasticity, even in animals. 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 suggests that carefully designed clinical trials testing the effects cannabinoids on muscle spasticity should be considered (see chapter 1).26, 66 Such trials should be designed to assess the degree to which the anxiolytic effects of cannabinoids contribute to any observed anti-spastic effects.

Spasticity occurring at night can be very disruptive to sleep. Thus a long-lasting medication would be especially useful for MS patients at bedtime when drowsiness would be a beneficial rather than an unwanted side effect, and mood altering effects would be less of a problem. One caution is the effects of THC on the stages of sleep architecture, which should be evaluated in MS patients who have sleep disturbances. If THC is proven to relieve spasticity, then a pill might be the preferred route of delivery for nighttime use because of its long duration of action. Compared to the currently available therapies, the long half-life of THC might allow for a smoother drug effect throughout the day. The intensity of the symptoms resulting from spasticity, particularly in MS, can rapidly increase in an unpredictable fashion such that the patient develops an 'attack' of intense muscle spasms lasting minutes to hours. An inhaled form of THC (if it were shown to be efficacious) might be appropriate for those patients.

4.29

Movement Disorders

Movement disorders are a group of neurological conditions caused by abnormalities in the basal ganglia and its subcortical connections through the thalamus with cortical motor areas. This dysfunction within the brain ultimately results in abnormal skeletal muscle movements in the face, limbs, and trunk. The movement disorders most often considered for marijuana or cannabinoid therapy are dystonia, Huntington's disease, Parkinson's disease, and Tourette's syndrome. Movement disorders are often transiently exacerbated by stress and activity and improved by factors that reduce stress, which is of particular interest since for many people marijuana is an anxiolytic (anxiety reducer).

Dystonia

Dystonia can be a sign of other basal ganglia disorders, such as Huntington's disease or tardive dyskinesia, or can be a primary basal ganglia disorder. Primary dystonias are a heterogeneous group of chronic, slowly progressive, neurological disorders characterized by dystonic movements - slow, sustained involuntary muscle contractions often resulting in abnormal postures of limbs, trunks, and neck. Dystonias can be confined to one part of the body, such as spasmodic torticollis (neck), h, 45 or Meige's syndrome (facial muscles), or may affect many parts of the body, such as dystonia musculorum deformans. Dystonia can cause mild to severe disability and sometimes pain secondary to muscle aching or arthritis. Some dystonias are genetic; others are caused by drugs. The specific neuropathological changes in these diseases have not been determined.

No controlled study of marijuana in patients with dystonia has been published, and the only study on cannabinoids was a preliminary open trial using cannabidiol which suggested modest dose-related improvements in the five dystonic patients studied.31 In mutant dystonic hamsters, however, the cannabinoid receptor agonist, WIN 55,212-2, can produce antidystonic effects.155

Huntington's Disease

Huntington's disease is an inherited degenerative disease usually appearing in middle age, and results in atrophy or loss of neurons in the caudate nucleus, putamen and cerebral cortex. This disease is characterized by arrhythmic, rapid muscular contractions (chorea), emotional disturbance, and dementia (impairment in intellectual and social ability). Animal studies suggest that cannabinoids might have anti-choreic activity, presumably due to stimulation of CB1 receptors in the basal ganglia.131 171

Based on positive results in one of four Huntington's disease patients, cannabidiol (CBD) and placebo (sesame oil) were tested in a double-blind, cross

h Spasmodic torticollis is defined by contractions of the neck and shoulder muscles, producing recurrent head turning, head extensions and, in some cases, shoulder elevations.

4.30

over study on 15 Huntington's disease patients who were not taking any neuroleptic drugs. The symptoms neither improved nor worsened with CBD treatment.28 167

The effects of other cannabinoids on patients with Huntington's disease are largely unknown. THC or other CB1 agonists are more likely candidates than CBD2 which does not even bind to the CB1 receptor, that is densely distributed on the very neurons that perish in Huntington's disease 154. Thus far there is little evidence to encourage clinical studies of cannabinoids in Huntington's disease.

Parkinson's Disease

This late-in-life degenerative disease affects about one million Americans over the age of 50 years.57 Parkinson's disease is characterized by bradykinesia (slowness in movement), akinesia (abrupt stoppage of movement), resting tremor, muscular rigidity, and postural instability.

Theoretically, cannabinoids could be useful for treating Parkinson's patients because cannabinoid agonists specifically inhibit the subthalamo-nigral pathway, and probably also the subthalmopallidal pathway.168 172 The latter effect was not directly tested, but is consistent with what is known about these neural pathways. Hyperactivity of the subthalamic neurons, observed both in Parkinson's patients and in animal models of Parkinson's disease, is hypothesized to be a major factor in the debilitating bradykinesia associated with the disease.37 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, suggesting the potential for adjunctive therapy with cannabinoid agonists.168 169,170, 172

At the time of this writing, we could find only one published clinical trial evaluating marijuana in five cases of idiopathic Parkinson's disease.51 The trial was prompted by a patient's report that smoking marijuana reduced tremor, but the investigators found no improvement in tremor after the patients smoked marijuana- although all five subjects benefited from the administration of standard medications for Parkinson's disease (levodopa and apomorphine). 51 Although new animal data might someday indicate a use for cannabinoids in treating Parkinsons's disease, current data do not recommend clinical trials of cannabinoids in patients with Parkinson's disease.

Tourette's Syndrome

Tourette's syndrome usually begins in childhood, and is characterized by motor and vocal tics (involuntary, rapid repetitive movements or vocalizations). It has been suggested that these symptoms might be mediated by a reduction in the activity of limbic-basal ganglia-thalamocortical circuits (shown in figure 2.4).43 These circuits, while not well-understood, appear to be responsible for translating a person's intentions to move into actual movements. Damage to these structures leads to either involuntary increases in movement (as in Huntington's) or the inability to make voluntary movements (as in Parkinson's). The nature of the deficit in Tourette's is unknown.

4.31

No clear link has been established between symptoms of Tourette's and cannabinoid sites or mechanism of action. Pimozide and haloperidol, two widely used treatments for Tourette's, inhibit effects mediated by the neurotransmitter, dopamine, whereas cannabinoids can increase dopamine release. 156 184 The physiological relevance, if any, of these two observations has not been established.166

The clinical reports consist of four case histories indicating that marijuana use can reduce tics in Tourette's patients. 79 166 In three of the four cases, the investigators suggest that beneficial effects of marijuana might have been due to anxiety-reducing properties of marijuana rather than to a specific anti-tic effect. 166

Therapy for Movement Disorders

There are a variety of drugs available, listed in table 4.3, to treat the different movement disorders. Common side effects of many of these drugs include sedation, lethargy, school and work avoidance, social phobia, and increased risk of parkinsonism and tardive dyskinesia. i With some of these medications, like those used for dystonia, efficacy is lacking in as much as 50 percent of the patients. In addition to medications, surgical interventions such as pallidotomy and neurosurgical transplantation of embryonic substantia nigra tissue into the patient's striaturn have been tried in Parkinson's patients. Surgery is generally palliative, and is still considered to be in the developmental phase.

i Dyskinesia is the development of irreversible, involuntary dyskinetic movements.

4.32

TABLE 4.3 Drugs Used to Treat Movement Disorders

___________________________________________

Huntington's 
chorea  Parkinson's disease reserpine levodopa/carbidopacombinatior 
j 
 tetrabenazine amantadine 
 haloperidol bromocriptine 
 pergolide  
pramipexole  ropinirole 
 selegiline Dystonia 
trihexyphenidyl  
benzodiazepines benztropine  
tetrabenazine  intramuscular 
botulinum toxin anticholinergics 
 Tourette 's Syndrome Tics baclofen pimozide  
clonidine  haloperidol

___________________________________________

Summary

The abundance of CB1 receptors in basal ganglia and animal studies showing the involvement of cannabinoids in the control of movement suggest that cannabinoids might be useful in treating movement disorders in humans. Marijuana or CB,1 receptor agonists might provide symptomatic relief from chorea, dystonia, some aspects of parkinsonism, and tics. However, clinical evidence is largely anecdotal with no well-controlled studies of adequate numbers of patients. Further, non-specific effects may confound interpretation of studies. For example, the anxiolytic effects of cannabinoids might make patients feel that their condition is improved, despite the lack of any measurable change in the 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. This might reflect a lack of effect or a lack of individuals with movement disorders who have tried marijuana. In any case, while there are a few isolated reports of individuals with movement disorders who report a benefit from marijuana, there are, as yet, no published surveys indicating that a substantial percent of patients with movement disorders find relief from marijuana. Existing studies involve too few patients from which to draw conclusions. The most promising reports involve symptomatic treatment of spasticity. If the reported neuroprotective effects of cannabinoids discussed in chapter 2 prove to be therapeutically useful, this could benefit patients with

j Tablet contains both drugs = combination therapy.

4.33

movement disorders - although, at this point, such is highly speculative. Since stress often transiently exacerbates movement disorders, it is reasonable to hypothesize that the anxiolytic effects of marijuana or cannabinoids might be beneficial to some patients with movement disorders. However, chronic marijuana smoking is a health risk that could increase the burden of chronic conditions such as movement disorders.

Cannabinoids inhibit both major excitatory as well as inhibitory inputs to the basal ganglia. This suggests that a cannabinoid agonist could produce opposite effects on movement, depending on the type of transmission (excitatory or inhibitory) that is most active at the time of drug administration. This property could be used to design treatments in basal ganglia movement disorders such as Parkinson's disease where either the excitatory subthalamic input becomes hyperactive or the inhibitory striatal input becomes hypoactive. The dose employed would be a major factor in designing therapeutic uses for cannabinoids in movement disorders; low doses should be desirable while higher doses could be expected to further aggravate pathological conditions Thus, there is a clear reason to recommend pre-clinical studies, that is, animal studies to test the hypothesis that cannabinoids play an important role in movement disorders.

With the possible exception of multiple sclerosis, the evidence to recommend clinical trials of cannabinoids in movement disorders is relatively weak. Ideally, clinical studies would follow animal research that provided stronger evidence than is currently available indicating a potential therapeutic value of cannabinoids in the treatment of movement disorders Unfortunately, there are no good animal models for these disorders. Thus we recommend double-blind, placebo controlled clinical trials of isolated cannabinoids that include controls for relevant 'side effects.' Such effects include anxiolytic and sedative effects, which might either mask or contribute to the potential therapeutic effects of cannabinoids.

Epilepsy

Epilepsy is a chronic seizure disorder that affects about two million Americans and 30 million people world wide.158 It is characterized by recurrent, sudden attacks of altered consciousness, convulsions, or other motor activity. A seizure is the synchronized excitation of large groups of cells. These abnormal electrical events have a wide array of possible causes, including trauma or injury to the brain and chemical changes derived from metabolic faults of exposure to toxins.158

Seizures are classified as partial (focal) or generalized. Partial seizures are associated with specific sensory, motor or psychic aberrations that reflect the function of part of the cerebral cortex from which the seizures arise. Generalized seizures are usually the result of pathology at brain sites that project to widespread regions of the brain. Such pathology can produce petit mal seizures or major grand mal convulsions

4.34

Cannabinoids in Epilepsy

There are anecdotal and individual case reports that marijuana controls seizures in epileptics (reviewed in BMA 1997 report14), but there is no solid evidence to support this belief. While there are no studies indicating that either marijuana or THC worsen seizures, there is no scientific basis to justify such studies.

In the only known case-controlled study that was designed to evaluate illicit drug use and the risk of first seizure, Ng and coworkers139 concluded that marijuana is a protective factor for first-time seizures in men but not for women; that is, men who used marijuana reportedly had fewer first-time seizures than men who did not use marijuana. This was based on a comparison of 308 patients who had been admitted to a hospital after their first seizure with a control group of 294 patients. The control group was made up of patients who had not had seizures and were admitted for emergency surgery (such as appendicitis, intestinal obstruction, acute cholecystitis). Compared to men who did not use marijuana, the odds ratio of first seizure for men who had used marijuana within 90 days of hospital admission was 0.36 (95% confidence interval=0.18-0.74). An odds ratio of less than one is consistent with the suggestion that marijuana users are less likely to have seizures. The results for women were not statistically significant. However, this was a weak study. The study did not include measures of health status prior to hospital admissions for their serious conditions, and differences in their health status might have influenced their drug use rather than - as suggested by the authors that differences in their drug use influenced their health.

The potential anti-epileptic activity of cannabidiol (CBD) has been investigated, but is not promising. Three controlled trials were conducted in which cannabidiol was given orally to patients with generalized grand mal seizures or focal seizures (table 4.4). Two of these studies were never published, but information about one study was published in a letter to the South African Medical Journal, the other was presented at the Marijuana 1990 International Conference on Cannabis and Cannabinoids.188

Even if CBD had anti-epileptic properties, these studies were likely too small to demonstrate efficacy.. Proving efficacy of anticonvulstants generally requires large numbers of patients followed for months because the frequency of seizures are highly variable and the response to therapy varies depending on seizure type.4, 53

4.35

Table 4.4 Clinical Trials of Cannabidiol in Epileptics

Study Design Results Reference
Double-blind placebo-controlled trial - 8 epileptic patients were given 200-300 mg CBD/day in conjunction with standard antiepileptic therapies. Four out of 8 remained almost free of convulsions. Three of the 4 were partially improved for up to 4.5 months. Cunha et al35
Double-blind placebo-controlled study - 12 epileptic patients were given 200-300 mg CBD/day along with standard antiepileptic drugs CBD had no effect on seizure frequency. Ames4

Double-blind placebo-controlled, add-on cross-over trial - 10 epileptic patients were given 300mg. CBD/day for 6 months.

Open trial
- 1 patient was given 900-1200 mg. CBD/day for 10 months.

CBD had no effect on seizures.

Seizure frequency was reduced in the patient.

 Trembly et al.188 (reviewed in Consroe, 199230)

Therapy for Epilepsy

Present Therapy

Standard pharmacotherapy for partial and generalized seizures, listed in table 4.5, involve a variety of anticonvulsant drugs.

4.36

TABLE 4.5 Anticonvulsant Drugs for Various Types of Seizures5

____________________________________________________

Generalized 
grand mal  Partial (focal) carbamazepine carbamazepine 
 valproate phenytoin 
 phenytoin valproate 
 phenobarbital phenobarbital 
 clonazepam Generalized 
petit mal gabapentin  
ethosuximide lamotrigine  
clonazepam tiagabine (as adjunct   
valproate therapy)  
____________________________________________________

These drugs suppress seizures completely in approximately 60 percent of patients with chronic epilepsy and improve seizures in another 15 percent of patients All of the above mentioned anticonvulsants present side effects, some of the more common ones being drowsiness, mental slowing, ataxia, tremor, hair loss, increased appetite, headache, insomnia, and rash. Nevertheless, recurrent seizures create a physically dangerous and emotionally devastating environment, and preventing them outweighs the undesirable side effects seen with anticonvulsant drugs.

Future Therapy

The goal in epilepsy treatment is to halt the seizure attacks completely with minimal or no side effects, followed by efforts to eradicate the cause whenever possible. Most of the anticonvulsant research with cannabinoids was conducted before 1986. Since then, many new anticonvulsants have been introduced and cannabinoid receptors have been discovered. At present the only biological evidence that cannabinoids might have antiepileptic properties is that CB1 receptors are abundant in the hippocampus and amygdala. Both regions are involved in partial seizures, but are better known for their rule in functions unrelated to seizures. 7 While basic research might reveal stronger links between cannabinoids and seizure activity, this is not likely to be as fruitful an area of cannabinoid research as others. At this stage of knowledge, clinical studies of cannabinoids in epileptics are not indicated.

Alzheimer's Disease

Food refusal is a common problem in patients suffering from Alzheimer's type dementia. The causes of anorexia in demented individuals is not known, but may be a symptom of depression. Antidepressants improve eating in some, but not all, patients with severe dementia. Eleven Alzheimer's patients with dementia were treated for 12 weeks on an alternating schedule of dronabinol and placebo (six weeks

4.37

of each treatment). The dronabinol treatment resulted in significant weight gains and declines in disturbed behavior.194 No serious side effects were observed. One patient had a seizure and was removed from the study, but it is not clear that this was due to the dronabinol. Recurrent seizures develop without any precipitating events in 20 percent of patients with advanced dementia of the Alzheimer's type.193 Nevertheless, these results are encouraging enough to recommend further clinical research with cannabinoids.

The patients in the study discussed above were in long-term institutional care, and most were severely demented with impaired memory. Although short-term memory loss is a common side effect of THC in healthy patients, it was not a concern in this study However, the effect of dronabinol on memory in Alzheimer's patients who are not as severely disturbed as those in the above study would be an important consideration.

Glaucoma

After cataracts, glaucoma is the second leading cause of blindness in the world and almost 67 million people are expected to be affected worldwide by the year 2000151 (for an excellent review, see Alward 19982). 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. The mechanisms behind this disease are not understood, but three major risk factors are known: age, race and elevated intraocular pressure (IOP). POAG is most prevalent among the elderly, with 1 percent affected in those older than 60 years of age and more than 9 percent affected in those older than 80 years.7 For African-Americans older than 80 years there is more than a 10 percent chance of having the disease. 186 Older African-Caribbeans (who are less racially mixed than African -Americans) have a 20 - 25 percent chance of having the disease. 110

The eye s rigid shape is normally maintained, in part, by IOP which is regulated by the circulation of a clear fluid, called the aqueous humor,k between the front of the lens and the back of the cornea Because of impaired outflow of aqueous humor from this anterior chamber of the eye, an elevated IOP is a risk factor for glaucoma, but the mechanism by which it damages the optic nerve and retinal ganglion cells remains unclear.177 The two leading possibilities suggest that elevated IOP interferes with 1) the nutrient blood flow to the region of the optic nerve, and 2) the transport of nutrients, growth factors and other compounds within the optic nerve axon (P. Kaufman, IOM workshop). If this interference continues, both the retinal ganglion cells and optic nerve will permanently atrophy with

k The cornea and lens of an eye must be optically clear, which means there cannot be blood circulation in these tissues. The aqueous humor is a clear fluid that functions as alternative circulation across the rear of the cornea and to the lens to provide nutrients and remove waste from these tissues.

4.38

consequent blindness.72 Because elevated IOP is the only known major risk factor that can be controlled, most treatments have been designed to reduce IOP. Unfortunately, reducing IOP does not always arrest or slow the progression of visual loss.21, 113

Marijuana and Cannabinoids in Glaucoma

Both marijuana and THC have been shown to reduce IOP by 24 percent on average in people with normal IOP that have visual field changes.80 81 a number of studies on normal adults and glaucoma patients, IOP was reduced by an average of 25 percent after smoking a marijuana cigarettes that contained approximately 2 percent THC, a reduction as good as that observed with most other medications available today.1, 17, 33, 80, 81, 127, 197 Similar responses have been observed when marijuana is eaten or THC was given in pill form (10 - 40 ma) to normal, healthy adults or glaucoma patients.80 95 But the effect lasts only about 3 to 4 hours. Elevated IOP is a chronic condition and must be controlled continuously.

Intravenous administration of 9-THC, 8-THC, or 11-OH-THC to normal adults significantly decreased IOP, whereas cannabinol (CBN), CBD and b-OH-THC had little effect. 32, 148 The cause for the reduction in IOP remains unknown, but the effect appears to be independent of the frequently observed drop in arterial systolic blood pressure (Keith Green, personal communication).

Three synthetic cannabinoids were investigated, BW29Y, BW146Y and nabilone. These were given orally to patients with elevated IOP. BW146Y and nabilone turned out to be as effective as ingesting THC or smoking marijuana, but again with a very short duration of action, while BW29Y was ineffective. 138, 185

Topical treatments of cannabinoids have been ineffective in reducing IOP. When 9-THC was applied topically as an eye drop, whether as a single dose or multiple doses, whether once or four times a day, there was no decrease in IOP. 64 94 Suspensions of lipophilic THC tended to be irritating to the eye.

In summary, cannabinoids or marijuana can reduce IOP when administered orally, intravenously, or by inhalation, but not when administered topically. Even though a reduction in IOP by standard mediations or surgery clearly slows the rate of glaucoma symptom progression, there is no direct evidence to support the benefits of cannabinoids or marijuana on the natural progression of glaucoma, visual acuity, or optic atrophy. 96 117

In addition to lowering IOP, marijuana reduces blood pressure and has many psychological effects. Merritt and coworkers reported hypotension, palpitations and psychotropic effects in glaucoma patients after inhaling marijuana. 127 Cooler and coworkers 32 also reported increased anxiety and tachycardia with an intravenous infusion of THC (1.5 - 3 mg). All of these side effects are problematic, particularly for elderly glaucoma patients with cardiovascular or cerebrovascular disease. The reduction of blood pressure can be substantial, and might adversely affect blood flow to the optic nerve. 126 Many people with systemic hypertension have their blood

4.39

pressure reduced to manageable and acceptable levels through medication, but this does not seem to affect IOP. In contrast, there is evidence that reduction in blood pressure below normal levels (considerably below) will influence IOP, and particularly ocular blood flow.48 78, 144 Hence' an eye with elevated IOP, or an optic nerve in poor condition with susceptibility to increased IOP, reduced blood flow to the optic nerve could compromise a functional retina and be a factor in the progression of glaucoma.

Because it is not known how these compounds work, it is also not know how they might interact with the other drugs used to treat glaucoma. If the mechanism involves a final common pathway, the effects of cannabinoids may not be additive and might even interfere with effective drugs.

Therapy for Glaucoma

Present Therapy

There are currently six classes of drugs used to treat glaucoma, all of which reduce IOP (table 4.6). 97

TABLE 4.6 Classes of Glaucoma Drugs

_______________________________________________________

Cholinergic 
Agonists Carbonic Anhydrase Inhibitors pilocarpine acetazolamide dorzolamide 
(Trusopt®) B2- 
Adrenergic Agonists 
epinephrine Prostaglandin-F2a 
Analogs dipivefrin 
latanoprost unoprostone B2-Adrenergic 
Antagonists timolol 
betaxolol (Betoptic(R) a2-Adrenergic Agonists aproclonidine brimonidine

_____________________________________________________

In the late 1970s when early reports of the effects of marijuana on IOP surfaced' only cholinomimetics, epinephrine, and oral carbonic anhydrase inhibitors were available. None are popular today because of their side effects such as pupil constriction or dilation, brow ache, tachycardia and diuresis, and all been superseded by the other classes of drugs. 97 Additionally, there are surgical options available today to lower IOP, including laser trabeculoplasty, trabeculectomy/sclerostomy, drainage implants, and cyclodestruction of fluid-forming tissues. 176 Thus, there are many effective options to chose from today to slow the progression of glaucoma by reducing IOP.

4.40

One important factor in slowing the progression of glaucoma via medications that reduce IOP is patient compliance with dosing regimens. For compliance purposes, the ideal glaucoma drug is one that is applied at most twice a day (P. Kauffman, IOM workshop). If the dose must be repeated every 3 - 4 hours, patient compliance becomes a serious issue and for this reason marijuana and the cannabinoids studied thus far would not be highly satisfactory treatments for glaucoma. Additionally, 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 The next generation of glaucoma therapies will in all likelihood deal with neural protection, neural rescue, neural regeneration, or blood flow where the optic nerve and neural retina are treated directly, rather than just lowering IOP (P. Kauffman, IOM workshop). There is some evidence that a synthetic cannabinoid, HU-211, might have neuroprotective effects in vitro, which presents a potential approach having nothing to do with IOP. 201 HU-211 is commonly referred to as a cannabinoid, because its chemical structure is similar to THC; however, it does not bind to cannabinoid receptor.

It is known that cannabinoids lower IOP fairly substantially, but not how. No one has tested whether the effect is receptor-mediated (B. Martin, IOM workshop). To do so, one could test whether a receptor antagonist blocked the effects of THC or other cannabinoids. If the decrease were shown to be receptor-mediated, then it would be important to know whether it was through CB1 which mediates central nervous system effects, or CB2 receptors, which are not involved in CNS effects. If the latter were true, then it might be possible to reduce IOP without the CNS side effects. Finally, it is not known if the endogenous cannabinoid system is a natural regulator of IOP.

Summary

Although glaucoma is one of the most frequently cited medical indications for marijuana, the data do not support this indication. High intraocular pressure (IOP) is a known risk factor for glaucoma and can, indeed, be reduced by cannabinoids and marijuana. However, the effect is too short-lived, requires too high doses, and there are too many side effects to recommend lifelong use in the treatment of glaucoma. 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.

Future research might reveal a therapeutic effect of isolated cannabinoids. For example, it might be possible to design a cannabinoid drug with longer-lasting effects on IOP and with less psychoactivity than THC.

4.41

Summary

Advances in cannabinoid science of the last 16 years have given rise to a wealth of new opportunities for the development of medically useful cannabinoidbased drugs. The accumulated data suggest a variety of indications, particularly for pain relief, antiemesis, and appetite stimulation. For patients, such as those with AIDS or undergoing chemotherapy who suffer simultaneously from severe pain, nausea, and appetite loss, cannabinoid drugs might thus offer broad spectrum relief not found in any other single medication. The data are weaker for muscle spasticity, but moderately promising. The least promising categories are movement disorders, epilepsy, and glaucoma. Animal data are moderately supportive of a potential for cannabinoids in the treatment of movement disorders and might eventually yield stronger encouragement. The therapeutic effects of cannabinoids are most well established for THC, which is the primary psychoactive ingredient of marijuana. But it does not follow from this that smoking marijuana is good medicine.

Although marijuana smoke delivers THC and other cannabinoids to the body, it also delivers harmful substances, including most of those found in tobacco smoke. In addition, plants contain a variable mixture of biologically-active compounds and cannot be expected to provide a precisely defined drug effect. For those reasons, there is little future in smoked marijuana as a medically-approved medication. If there is any future in cannabinoid drugs, it lies with agents of more certain, not less certain composition. While clinical trials are the route to developing approved medications, they are also valuable for other reasons. 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 their diseases are affected. Trials testing the safety and efficacy of marijuana use are an important component to understanding the course of disease, particularly for diseases such as AIDS where marijuana use is prevalent. The argument against the future of smoked marijuana for treating any condition is not that there is no reason to predict efficacy, but that there is risk. That risk could be overcome by the development of a nonsmoked, rapid onset delivery system for cannabinoid drugs.

There are two caveats to following the traditional path of drug development for cannabinoids. The first is timing. Patients who are currently suffering from debilitating conditions unrelieved by legally available drugs, and who might find relief with smoked marijuana, will find little comfort in a promise of a better drug ten years from now. In terms of good medicine, marijuana should rarely be recommended unless all reasonable options had been eliminated. But then what? It is conceivable the medical and scientific opinion might find itself in conflict with drug regulations. This presents a policy issue that must weigh - at least temporarily - the needs of individual patients against broader social issues. Our

4.42

assessment of the scientific data on the medical value of marijuana and its constituent cannabinoids is but one component of attaining that balance.

The second caveat is a practical one. Although most scientists who study cannabinoids would agree that the scientific pathways to cannabinoid drug development are clearly marked, there is no guarantee that the fruits of scientific research will be made available to the public. Cannabinoid-based drugs will only become available if either there is enough incentive for private enterprise to develop and market such drugs, or if there is sustained public investment in cannabinoid drug research and development. The perils along this pathway are discussed in chapter 5. Although marijuana is an abused drug, the logical focus of research on the therapeutic value of cannabinoid-based drugs is the treatment of specific symptoms or diseases, not substance abuse. Thus, the most logical research sponsors would be the several institutes within the National Institutes of Health or organizations whose primary expertise lies in the relevant symptoms or diseases.

CONCLUSION: Scientific data indicate the potential therapeutic value of cannabinoid drugs, primarily THC, for pain relief, control of nausea and vomiting, and appetite stimulation; smoked marijuana, however, is a crude THC delivery system that also delivers harmful substances.

RECOMMENDATION: Clinical trials of cannabinoid drugs for symptom management should be conducted with the goal of developing rapid onset reliable, and safe delivery systems.

RECOMMENDATION: Clinical trials of marijuana use for medical purposes should be conducted under the following limited circumstances: trials should be approved by institutional review boards; involve only short-term marijuana use (less than 6 months); be conducted in patients with conditions for which there is reasonable expectation of efficacy; and collect data about efficacy.

4.43

RECOMMENDATION: Short-term use of smoked marijuana (less than six months) for patients with debilitating symptoms (such as intractable pain or vomiting) 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.

Until a non-smoked, 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. One possible approach is to treat patients as n-of-1 clinical trials, in which patients are fully informed of their status as experimental subjects using a harmful drug delivery system, and in which their condition is closely monitored and documented under medical supervision, thereby increasing the knowledge base of the risks and benefits of marijuana use under such conditions. We recommend these "n-of-l" clinical trials using the same oversight mechanism as that proposed in the above recommendations.

Other Reports on Marijuana as Medicine

Since 1996, five important reports pertaining to the medical uses of marijuana have been published, each prepared by deliberative groups of medical and scientific experts (appendix D). They were written to address different facets of the medical marijuana debate, and each offers a somewhat different perspective. With the exception of the report by the Health Council of the Netherlands, each concluded that marijuana can be moderately effective in treating a variety of symptoms. They also agree that current scientific understanding is rudimentary; indeed, the sentiment most often stated is "more research is needed." And these reports record the same problem with herbal medications as noted here: the uncertain composition of plant material makes for an uncertain, and hence often undesirable, medicine. The 1996 report by the Health Council of the Netherlands concluded that there is insufficient evidence to justify the medical use of marijuana or THC, despite the fact that the latter it is an approved medication in the United States and Britain.

4.44

However, that committee addressed only whether there was sufficient evidence to warrant the prescription of marijuana or cannabinoids, not whether the data are sufficient to justify clinical trials. Conclusions of the Health Council of the Netherlands contrast with that country's tolerance of marijuana use. The Health council's report noted that marijuana use by patients in the terminal stages of illness is tolerated in hospitals. It also said that they did "not wish to judge patients who consume marihuana (in whatever form) 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. The NIH report, however, was alone in recommending clinical studies of marijuana for the treatment of glaucoma- and even then there was disagreement among the panel members (William T. Beaver, chair, NIH Ad Hoc Expert Panel on the Medical Use of Marijuana, personal communication).

Recent reviews that have received extensive attention from those who follow the medical marijuana debate have been written by strong advocates for (Grinspoon and Bakalar 1993 66; Zimmer and Morgan 1997 202) or against (Voth and Schwartz 1997 195) the medical use of marijuana. Those reports represent the individual views of their authors, and they are not reviewed here but have been reviewed in major scientific journals. 8, 73, 181 183

4.45

References

1. Alm A, Camras CB1 Watson PG. 1997. Phase III latanoprost studies in Scandinavia, the United Kingdom and the United States. Survey of Ophthalmology 41 Suppl 2:S105-S110.

2. Alward WL. 1998. Medical management of glaucoma. The New England Journal Of Medicine 339:1298-1307.

3. AMA (American Medical Association Council on Scientific Affairs). 1997. Report to the AMA House Of Delegates. AMA.

4. Ames FR. 1986. Anticonvulsant effect of cannabidiol. South African Medical Journal 69:14.

5. Andreoli TE, Carpenter CC, Bennet CJ, Plum F. Editors. 1997. Cecil Essentials of Medicine. Fourth Edition. Philadelphia: W.B. Saunders Co.

6. Andrews PL, Davis CJ. 1995. The physiology of emesis induced by anti-cancer therapy. In: Reynolds DJ, Andrews PL, Davis CJ, Editors Serotonin and the scientific basis of anti-emetic therapy. Oxford; Oxford Clinical Communications. Pp. 2549.

7. Bankes JL, Perkins ES, Tsolakis S. Wright JE. 1968. Bedford glaucoma survey. British Medical Journal 1(595):791-796.

8. Bayer R O'Connell TJ, Lapey JD. 1997. Medicinal Uses of Marijuana (To the Editor). Annals of Internal Medicine 127: 1134-1135.

9. Beal JE, Olson RLL, Morales JO, Bellman P. Yangco B. Lefkowitz L, Plasse TF, Shepard KV. 1995. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. Journal of Pain and Symptom Management 10:89-97.

10. Beal JE, Olson R. Lefkowitz L, Laubenstein L, Bellman P. Yangco B. Morales JO, Murphy R. Powderly W. Plasse TF, Mosdell KW, Shepard KV. 1997. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. Journal of Pain and Symptom Management 14:7-14.

11. Bhasin S. Storer T W. Asbel-Sethi N. Kilbourne A, Hays R. Sinha-Hikim I, Shen R. Arver S. Beall G. 1998. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. Journal Clinical of Endocrinology and Metabolism 83:3155-62.

12. Billingsley KG, Alexander HR. 1996. The pathophysiology of cachexia in advanced cancer and AIDS. In: Bruera E, Higginson I, Editors Cachexia-Anorexia in Cancer Patients. New York: Oxford University Press In. Pp. 1-22.

13. Borison HL, McCarthy LE. 1983. Neuropharmacology of chemotherapy-induced emesis. Drugs 25:8-17.

14. British Medical Association. 1997. Therapeutic uses of cannabis. Amsterdam, The Netherlands: Harwood Academic Publishers.

4.46

15. Bruera E. 1998. Pharmacological treatment of cachexia: any progress? Supportive Care of Cancer 6-109-1 13.

16. Calignano A, La Rana C, Giuffrida A. Piomelli D. 1998. Control of pain initiation by endogenous cannabinoids. Nature 394:277-281.

17. Camras CB, Alm A, Watson P. Stjernschantz J. 1996. Latanoprost, a prostaglandin analog, for glaucoma therapy: Efficacy and safety after I year of treatment in 198 patients. Latanoprost Study Groups. Ophthalmology 103:1916-1924.

18. (CDC) Centers for Disease Control. 1992. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR (Morbidity Mortality Weekly Report) 41 :(RR- 17): 1 - 19 .

19. Chang AK, Shiling DJ, Stillman RC, et al. 1979. Delta-9-tetrahydrocannabinol as an Antiemetic in patients receiving high-dose methotrexate: A prospective, randomized evaluation. Annals of Internal Medicine 91:819-824.

20. Chang AK, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I, Rosenberg SA. 1981. A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy. Cancer 47:1746-51.

21. Chanhan BC, Drance SM. 1992. The relationship between intraocular pressure and visual field progression in glaucoma. Graefes Archives of Clinical and Experimental Ophthalmology 230:521-526.

22. Clark RA, Tyson LB, Frisone M. 1985. A correlation of objective and subjective parameters in assessing antiemetic regimens. Proceedings of the Tenth Anniversary Congress of the Oncology Nursing Society 2:96.

23. Clark WC, Janal MN, Zeidenberg P. Nahas GG. 1981. Effects of moderate and high doses of marihuana on thermal pain: a sensory decision theory analysis. Journal of Clinical Pharmacology 21:299S-310S.

24. Clarke RC. 1995. Marijuana Botany An Advanced Study: The Propagation and Breeding of Distinctive Cannabis. Berkeley, CA: Ronin Publishing.

25. Clifford DB. 1983. Tetrahydrocannabinol for tremor in multiple sclerosis. Annals of Neurology 13:669-671.

26. Consroe P. l 998a. Clinical and Experimental Reports of Marijuana and Cannabinoids in Spastic Disorders.

27. Consroe P. 1998b. Brain cannabinoid systems as target for the treatment of neurological disorders. Neurobiology of Disease 5

28. 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.

29. Consroe P. Musty R. Rein J. Tillery W. Pertwee RG. 1997. The perceived effects of smoked cannabis on patients with multiple sclerosis. European Neurology 38:44-48.

4.47

30. Consroe P. Sandyk R. 1992. Potential role of cannabinoids for therapy of neurological disorders. In: Bartke A, Murphy LL, Editors Marijuana/Cannabinoids: Neurobiology and Neurophysiology. Boca Raton: CRC Press Inc. Pp. 459-524.

31. Consroe P. Sandyk R. Snider SR. 1986. Open label evaluation of cannabidiol in dystonic movement disorders. International Journal of Neuroscience 30:277-282.

32. Cooler P. Gregg JM. 1977. Effect of delta-9-tetrahydrocannabinol on intraocular pressure in humans. Southern Medical Journal 70:951 -954.

33. Crawford WJ, Merritt JC. 1979. Effects of Tetrahydrocannabinol on arterial and intraocular hypertension. International Journal of Clinical Pharmacology and Biopharmacy 17:191-196.

34. Crow S. 1997. Investigational drugs for eating disorders. Expert Opinion on Investigational Drugs 6:427-436.

35. Cunha JM, Carlini EA, Pereira AK, Ramos OL, Pimentel C, Gagliardi R. Sanvito WL, Lander N. Mechoulam R. 1980. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21: 175- 185.

36. Davis CJ. 1995. Emesis research: A concise history of the critical concepts and experiments. In: Reynolds DJ' Andrews PL, Davis CJ, Editors. Serotonin and the scientific basis of anti-emetic therapy. Oxford: Oxford Clinical Communications. Pp. 9-24.

37. DeLong M R. Georgopoulos A P. Crutcher M D, Mitchell S J. Richardson R T. Alexander G E. 1984. Functional organization of the basal ganglia: contributions of single-cell recording studies. CIBA Foundation Symposium 107:64-82.

38. DeMulder PH, Seynaeve C, Vermorker JB, et al. 1990. Ondansetron compared with highdose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: A multicenter, randomized, double-blind, crossover study. Annals of Internal Medicine 113:834-840.

39. Doblin R. Kleiman MA. 1995. The medical use of marijuana: the case for clinical trials [editorial; comment]. Journal of Addictive Diseases 14:5-14. Comment on J Addict Dis 1994;13(1):53-65.

40. Doblin R. Kleiman M. 1991. Marijuana as Antiemetic Medicine: A Survey of Oncologists' Experiences and Attitudes. Journal of Clinical Oncology 9:1314-1319.

41. Dunlop R. 1996. Clinical epidemiology of cancer cachexia. In: Bruera E, Higginson I, Editors Cachexia-anorexia in cancer patients. 5. Oxford: Oxford University Press. Pp. 76-82.

42. Dunn M, Davis R. 1974. The perceived effects of marijuana on spinal cord injured males. Paraplegia 12:175.

43. Eidelberg D., Moeller JR, Antonini A., Kazumata K, Dhawan V, Budman C, Feigin A. 1997. The metabolic anatomy of Tourette's syndrome. Neurology 48:927-934.

44. El-Mallakh RS. 1987. Marijuana and migraine. Headache 27:442-443.

4.48

45. Endicott JN, Skipper P. Hernandez L. 1993. Marijuana and head and neck cancer. In: Friedman et al, Editors Drugs of Abuse, Immunity and AIDS. New York: Plenum Press. Pp. 107- 113.

46. Engelson E S. Rabkin J G. Rabkin R. Kotler D P. I 996. Effects of testosterone upon body composition.. Journal of Acquired immune Deficiency Syndrome and Human Retrovirology 11:510-511.

47. Enoch M, Kaye WH, Rotondo A, Greenberg BD, Murphy DL, Goldman D. 1998. 5-HT2A promoter polymorphism-1438G/A, anorexia nervosa, and obsessive-compulsive disorder. The Lancet 351: 1785-1786.

48. Follmann P. Paltotas C, Suveges 1, Petrovits A. 1996-1997. Nocturnal blood pressure and intraocular pressure measurement in glaucoma patients and healthy controls International Ophthalmology 20:83-87.

49. Foltin R W. Fischman M W. Byrne M F. 1988. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 11 :1-14.

50. Fozard JR. 1984. Neuronal 5-HT receptors in the periphery. Neuropharmacology 23: 14731486.

51. Frankel JP, Hughes A, Lees AT, Stern GM. 1990. Marijuana for Parkinsonian Tremor. Journal of Neurology, Neurosurgery and Psychiatry 53:436.

52. French ED. 1997. Delta-9-tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors. Neuroscience Letters 226: 159-162.

53. French J. 1998. The art of antiepileptic trial design. Advances in Neurology 76:113- 123.

54. Frytak S. Moertel CG, O'Fallon J. et al. 1979. Delta-9-tetrahydrocannabinol as an antiemetic in patients treated with cancer chemotherapy: a double comparison with prochloperazine and a placebo. Annals of Internal Medicine 91 :825-830.

55. Glass M, Dragunow M, Faull RLM. 1997. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299-318.

56. Goadsby PJ, Gundlach AL. 1991. Localization of [3H]-dihydroergotamine binding sites in the cat central nervous system: Relevance to migraine. Annals of Neurology 29:91-, 94.

57 Gonzalez EC, Brownlee HJ. 1998. Movement disorders. In: Taylor RB, Editor Family Medicine: Principles and Practice. 5th Edition. New York: Springer-Verlag. Pp. 565-573.

58. Gorter R. 1991. Management of anorexia-cachexia associated with cancer and HIV infection. Oncology (Supplement) 5: 13-17.

59. Gralla RJ, Itri LM, Pisko SE, et al. 1981. Antiemetic efficacy of high dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy induced nausea vomiting. New England Journal of Medicine 305:905-909.

4.49

60. Gralla RJ, Navari RM, Hesketh PJ, et al. 1998. Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin based chemotherapy. Journal of Clinical Oncology 16:1-7.

61. Gralla RJ, Rittenberg CN, Lettow LA, et al. 1995. A unique all-oral, single-dose, combination antiemetic regimen with high efficacy and marked cost saving potential. Proceedings of the American Society for Clinical Oncology 14:526.

62 Gralla RJ, Tyson LB, Borden LB, et al. 1984. Antiemetic therapy a review of recent studies and a report of a random assignment trial comparing metoclopramide with delta-9-tetrahydrocannabinol. Cancer Treatment Reports 68:163-172.

63. Grandara DR, Roila F. Warr D, Edelman MJ, Perez EA, Gralla RJ. 1998 Consensus proposal for 5HT3 antagonists in the prevention of acute emesis related to highly emetogenic chemotherapy. Dose, schedule, and route of administration. Supportive Care in Cancer 6:237-243.

64. Green K, Roth M. 1982. Ocular effects of topical administration of delta-9- Tetrahydrocannabinol in man. Archives of Ophthalmology 100:265-267.

65. Greenberg HS, Werness SA, Pugh JE, Andrus RO, Anderson DJ, Domino EF. 1994. Short term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clinical Pharmacology and Therapeutics 55:324-328.

66. Grinspoon L, Bakalar JB. 1993. Marijuana, the forbidden medicine. New Haven: Yale University Press.

67. Grinspoon L, Bakalar JB, Zimmer L, Morgan JP. 1997. Marijuana addiction [letter]. Science 277:749; discussion 750-2.

68. Grinspoon S. Corcoran C, Askari H. Schoenfeld D, Wolf L, Burrows B. Walsh M, Hayden D, Parlman K, Anderson E, Basgoz N. Klibanski A. 1998. Effects of androgen administration in men with the AIDS wasting syndrome. Annals of Internal Medicine 129:18-26.

69. Gross H. Egbert MH, Faden VB, Godberg SC, Kaye WH, Caine ED, Hawks R. Zinberg NE. 1983. A double-blind trial of delta-9-THC in primary anorexia nervosa. Journal of Clinical Psychopharmacology 3:165-171.

70. Guyatt GH, Keller JL, Jaeschke R. Rosenbloom D, Adachi ID, Newhouse MT. 1990. The N-of--1 randomized controlled trial - clinical usefulness: our three-year experience. Annals of internal Medicine 112:293-299.

71. Guyatt GH, Sackett D, Taylor DW, Chong J. Roberts R. Pugsley S. 1986. Determining optimal therapy: randomized trials in individual patients. New England Journal of Medicine 314:889-892.

72. Guyton AC. 1986. Textbook of Medical Physiology. Seventh Edition. Philadelphia: WB Saunders Company.

73. Hall W. 1997. An Ongoing Debate. Science 278:75.

74. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. 1999. Abstinence symptoms following oral THC administration to humans. Psychopharmacology 141:385-394.

4.50

75. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. 1999. Abstinence symptoms following smoked marijuana in humans. Psychopharmacology 141 :395-404.

76. Hanigan WC, Destree R. Truong XT. 1986. The effect of delta-9-THC on human spasticity. Clinical Pharmacology and Therapeutics 39:198.

77. Hardin TC. 1993. Cytokine mediators of malnutrition: Clinical implications. Nutrition in Clinical Practice 8:55-59.

78. Hayreh SS, Zimmerman MB, Podhajsky P. Alward W. 1994. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. American Journal of Ophthalmology 117:603-624.

79. Hemming M, Yellowlees PM. 1993. Effective treatment of Tourette's syndrome with marijuana. Journal of Psychopharmacology 7:389-391.

80. Hepler RS, Frank IM, Petrus R. 1976 Ocular effects of marijuana smoking. In: Braude MC, Szara S. Editors The Pharmacology of Marijuana. New York: Raven Press. Pp. 815-824.

81 Hepler RS, Frank in 1971. Marihuana smoking and intraocular pressure. Journal of the American Medical Association 217(10):1392.

82. Herkenham M, Lynn AB, de Costa BR, Richfield EK. 1991a. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Research 547:267-274.

83. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. l991b. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. Journal of Neuroscience 11 :563-583.

84. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC. 1990. Cannabinoid receptor localization in the brain. Proceedings of the National Academy of Sciences of the United States of America 87:1932- 1936.

85. Herrstedt J. Aapro MS, Smyth JF, Del Favero A. 1998. Corticosteroids, dopamine antagonists and other drugs. Support Care in Cancer 6:204-214.

86. Hesketh PJ, Gralla RJ, duBois A, Tonato M. 1998. Methodology of antiemetic trials: response assessment, evaluation of new agents and definition of chemotherapy emetogenicity. Supportive Care in Cancer 6:221-227.

87. Hesketh PJ, Kris MG, Grunberg SM, Beck T. Hainsworth ID, Harker G. Aapro MS, Gandara D, Lindley CM. 1997. Proposal for classifying the acute emetogenicity of cancer chemotherapy. Journal of Clinical Oncology 15:103-109.

88. Hill SY. Schwin R. Goodwin DW, Powell BJ. 1974. Marihuana and pain. Journal of Pharmacology and Experimental Therapeutics 188:415-418.

89. Holdcroft A, Smith M, Jacklin A, Hodgson H. Smith B. Newton M, Evans F. 1997. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 5:483486.

4.51

90. Homesley HD. Gainey JM, Jobson VN, et al. 1982. Double-blind placebo-controlled study of metoclopramide in cisplatin-induced emesis New England Journal of Medicine 307:250-251.

91. Huestis MA, Henningfield JE, Cone EJ. 1992. Blood Cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. Journal of Analytical Toxicology 16:276-282.

92. Italian Group for Antiemetic Trials. 1995. Dexamethasone, granisetron, or both for the prevention of nausea and vomiting during chemotherapy for cancer. New England Journal of Medicine 332:332-337.

93. Jain AK, Ryan JR, McMahon FG, Smith G. 1981. Evaluation of intramuscular levonantradol
and placebo in acute postoperative pain. Journal of Clinical Pharmacology 21 :320S-326S.

94. Jay WM, Green K. 1983. Multiple-drop study of topically applied I % D9 Tetrahydrocannabinol in human eyes. Archives of Ophthalmology 101 :591-593.

95. Jones RT, Benowitz NL, Herning RI. 1981. Clinical relevance of cannabis tolerance and dependence. Journal of Clinical Pharmacology 21:143S-152S.

96. Kass MA, Gordon MO, Hoff MR, Pardinson JM, Kolker AK, Hart WM, Becker B. 1989. Topical timolol administration reduces the incidence of glaucomatous damage in ocular hypertensive individuals. A randomized, double-masked, long-term clinical trial. Archives of Ophthalmology 107:1590-1598.

97. Kaufman P. Mittag TW. 1994. Medical therapy of glaucoma. In: Kaufman P. Mittag TW, Editors Textbook of Ophthalmology. Volume 7. London: Mosby-Year.

98. Kotler DP. 1997. Wasting Syndrome Pathogenesis and Clinical Markers. Institute of Medicine Workshop. Irvine, CA, December 15, 1997, Pp.56-66. Washington, DC: Institute of Medicine.

99. Kotler DP, Gaetz HP, Klein EB, Lange M, Holt PR. 1984. Enteropathy associated with the acquired immunodeficiency syndrome. Annals of Internal Medicine 101 :421-428.

100. Kotler DP, Tierney AR, Culpepper-Morgan JA, Wang J. Peirson RN. 1990. Effect of home total parental nutrition on body composition in patients with acquired immunodeficiency syndrome. Journal of Parenteral Nutrition 14:454-458.

101. Kotler DP, Tierney AR, Dilmanian FA, Kamen Y. Wang J. Pierson Jr RN, Weber D. 1991. Correlation between total body potassium and total body nitrogen in patients with acquired immunodeficiency syndrome. Clinical Research 39:649A.

102. Kotler DP, Tierney AR, Ferraro R. et al. 1991. Enteral alimentation and repletion of body cell mass in malnourished patients with acquired immunodeficiency syndrome. American Journal of Clinical Nutrition 53:149-154.

103. Kotler DP, Tierney AR, Wang J. Pierson RN. 1989. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. American Journal of Clinical Nutrition 50:444-447.

4.52

104. Kotler DP, Wang J. Pierson RN. 1985. Studies of body composition in patients with the acquired immunodeficiency syndrome. American Journal of Clinical Nutrition 42: 1255-1265.

105. Kris MG, Gralla RJ, Clark RA, et al. 1987. Antiemetic control and prevention of side effects of anticancer therapy with lorazepam or diphenhydramine when used in combination with metoclopramide plus dexamethasone: a double-blind randomized trial. Cancer 60:2816-2822.

106. Kris MG, Radford JE, Pizzo BA, et al. 1997. Use of an NK-1 receptor antagonist to prevent delayed emesis following cisplatin. Journal of the National Cancer Institute 89:817-818.

107. Kris MG, Roila F. De Mulder PH, Marty M. 1998. Delayed emesis following anticancer chemotherapy. Supportive Care in Cancer 6:228-232.

108. Lang IM, Sarna SK. 1989. Motor and myoelectric activity associated with vomiting, regurgitation, and nausea. In: Wood JD, Editor Handbook of Physiology, the Gastrointestinal System. 1, Motility and Circulation. Bethesda. American Physiological Society. Pp. 1179-1198.

109. Larson EB, Ellsworth AJ, Oas J. 1993. Randomized clinical trials in single patients during a 2-year period. Journal of American Medical Association 270:2708-2712.

110 Leske MC, Connell AM, Schachat AP, Hyman L 1994 The Barbados Eye Study: Prevalence of open angle glaucoma. Archives of Ophthalmology 112:821-829.

111. Levitt M, Faiman C, Hawks R. et al. 1984. Randomized double-blind comparison of delta-9- THC and marijuana as chemotherapy antiemetics. Proceedings of the American Society for Clinical Oncology 3:91.

112. Libman E, Stern MH. 1985. The effects of delta-9-tetrahydrocannabinol on cutaneous sensitivity and its relation to personality. Personality, Individuality and Difference 6: 169-174.

113. Lichter PR. 1988. A wolf in sheep's clothing. Ophthalmology 95:149-150.

114. Lindgren JE, Ohlsson A, Agurell S. Hollister LE, Gillespie H. 1981. Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis. Psychopharmacology (Berl) 74:208-12.

115. Macallan DC, Noble C, Baldwin C, Foskett M, McManus T. Griffin GE. 1993. Prospective analysis of patterns of weight change in stage IV human immunodeficiency virus infection. American Journal of Clinical Nutrition 58:417-424.

116. Malec J. Harvey RF, Cayner JJ. 1982. Cannabis effect on spasticity in spinal cord injury. Archives of Physical Medicine and Rehabilitation 63: 116- 118.

117. Mao LK, Stewart WC, Shields M. 1991. Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma. American Journal of Ophthalamology 111:51-55.

118. Marotta JT. 1995. Spinal injury. In: Rowland LP, Editor Merrit's Textbook of Neurology. 9th Edition. Philadelphia: Lea and Febiger. Pp. 440-447.

4.53

119. Martyn CN, Illis LS, Thom J. 1995. Nabilone in the treatment of multiple sclerosis [letter]. Lancet 345:579.

120. Mathew NT. 1997. Serotonin 1D (5-MT 1D) agonists and other agents in acute migraine. Neurologic Clinics 15:61-83.

121 Mattes Rn, Engelman K, Shaw LM, Elsohly MA. 1994. Cannabinoids and appetite stimulation. Pharmacology, Biochemistry and Behavior 49:187-195.

122. Maurer M, Henn V, Dittrich A, Hoffman A. 1990. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. European Archives of Psychiatry and Clinical Neuroscience 240: 1-4.

123. McCarthy LE, Flora KP, Vishnuvajjala BR. 1984. Antiemetic properties and plasma concentrations of delta-9-tetrahydrocannabinol against cisplatin vomiting in cats. In: Agurell S. Dewey WL, Willette RE, Editors The Cannabinoids: Chemical, Pharmacologic and Therapeutic Aspects. Orlando, FL: Academic Press. Pp. 859- 870.

124. McQuay H. Carroll D Moore A. 1996 Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems. Pain 64:331-335.

125. Meinck HM, Schonle PW, Conrad B. 1989. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. Journal of Neurology 236:120-122.

126 Merritt JC, Cook CE, Davis KH. l982. Orthostatic hypotension after delta 9-tetrahydrocannabinol marihuana inhalation. Ophthalmic Research 14:124-128.

127. Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. 1980. Effect of marihuana on intrasocular and blood pressure in glaucoma. Ophthalmology 87:222-228.

128. Mertens TE' Low-Beer D 1996. HIV and AIDS: where is the epidemic going? Bulletin of the World Health Organization 74: 121 - 129.

129. Miller AD. 1998. Nausea and vomiting: Underlying mechanisms and upcoming treatments Journal of the Japan Broncho-Esophagological Society 49:57-64.

130. Miller AD, Nonaka S. Siniaia MS, Jakus J. 1995. Multifunctional ventral respiratory group: Bulospinal expiratory neurons play a role in pudendal discharge during vomiting. Journal of the Autonomic Nervous System 54:253-260.

131. Miller AS, Walker JM. 1995. Effects of a cannabinoid on spontaneous and evoked neuronal activity in the substantia nigra pars reticulate. European Journal of Pharmacology 279: 179-185.

132. Miller AS, Walker JM. 1996. Electrophysiological effects of a cannabinoid on neural activity in the globus pallidus. European Journal of Pharmacology 304:29-35.

133. Moertel CG, Taylor WF, Roth A, Tyce FA. 1976. Who responds to sugar pills? Mayo Clinic Proceedings 51 :96-100.

134. Moldawer LL, Andersson C, Gelin J. Lundholm KG. 1988. Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. American Journal of Physiology 254:G450-G456.

4.54

135. Mulligan K, Tai VW, Schambelan M. 1997. Cross-sectional and longitudinal evaluation of body composition in men with HIV infection. Journal of Acquired Immunodeficiency Syndromes 15 :43-48.

136. Murray C J L, Lopez A D. 1996. Global Health Statistics. A compendium of incidence, prevalence, and mortality estimates for over 200 conditions. Global Burden of Disease and Injury Series, Volume II. Boston, MA: The Harvard School of Public Health.

137. Navari RM, Reinhardt RR, Gralla RJ, Kris MG, Hesketh PJ, et al. 1999. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. The New England Journal of Medicine 340: 190-195.

138. Newell FW, Stark P. Jay WM, Schanzlin DJ. 1979. Nabilone: a pressure-reducing synthetic benzopyran in open-angle glaucoma. Ophthalmology 86:156-160.

139. 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.

140. NIH. 1997. Spinal cord injury: Emerging concepts: An NIH workshop. Proceedings of an NIH Workshop on Spinal Cord Injury. Bethesda, MD, September 30-October 1, 1996. Bethesda, MD: National Institute of Neurological Disorders and Stroke.

141. Noyes R. Jr, Brunk SF, Avery DH, Canter A. 1975b. The analgesic properties of delta-9- Tetrahydrocannabinol and codeine. Clinical Pharmacology and Therapeutics 18:84- 89.

142. Noyes R Jr. Brunk SF, Baram DA, Canter A. 1975a. Analgesic effect of delta-9-tetrahydrocannabinol. Journal of Clinical Pharmacology 15:139-143.

143. Ohlsson A, Lindgren J-E, Wahlen A, Agurell S. Hollister L E, Gillespie HK. 1980. Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clinical Pharmacology and Therapeutics 28:409-416.

144. Orgul S. Kaiser HJ, Flammer J. Gasser P. 1995. Systemic blood pressure and capillary blood-cell velocity in glaucoma patients: a preliminary study. European Journal of Ophthalmology 5:88-91.

145. Orr LE, McKernan JF, Bloome B. 1980. Antiemetic effect of Tetrahydrocannabinol. Compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis. Archives of Internal Medicine 140:1431 -3.

146. Ott M, Lambke B. Fischer H. Jagre R. Polat H. Geier H. Rech M, Staszeswki S. Helm EB, Caspary WF 1993. Early changes of body composition in human immunodeficiency virus-infected patients: tetrapolar body impedance analysis indicates significant malnutrition. American Journal of Clinical Nutrition 57:15-19.

147. Perez EA, Chawla SP, Kaywin PK, et al. 1997. Efficacy and safety of oral granisetron versus IV ondansetron in prevention of moderately emetogenic chemotherapy-induced nausea and vomiting. Proceedings of the American Society for Clinical Oncology 16:43.

4.55

148. Perez-Reyes M, Wagner D, Wall ME, Davis KH. 1976. Intravenous administration of cannabinoids and intraocular pressure. In: The Pharmacology of Marihuana, New York: Raven Press. Pp. 829-832.

149. Peroutka SJ. 1996. Drugs effective in the therapy of migraine. In: Hardman JG, Limbird LE, Editors Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th Edition. New York: McGraw-Hill. Pp. 487-502.

150. Petro D, Ellenberger Jr C. 1981. Treatment of human spasticity with delta 9- tetrahydrocannabinol. Journal of Clinical Pharmacology 21:413S-416S.

151. Quigley HA. 1996. Number of people with glaucoma worldwide. British Journal of Ophthalmology 80:389-393.

152. Raft D, Gregg J. Ghia J. Harris L. 1977. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain: Psychological correlates of the analgesic response. Clinical Pharmacology and Therapeutics 21 :26-33.

153. Razdan RK. 1986. Structure-activity relationships in cannabinoids. Pharmacology Review 38:75-149.

154. Richfield E K, Herkenham M. 1994. Selective vulnerability in Huntington's disease: preferential loss of cannabinoid receptors in lateral globus pallidus . Annals of Neurology: 577-584.

155. Richter A, 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.

156. Rodriguez de Fonseca F. Carrera MRA, Navarro M, Koob G. Weiss F. 1997. Activation of corticotrophin-releasing factor in the limbic system during cannabinoid withdrawal [see comments Science 1997. 276: 1967- 1968]. Science 276:2050-2054.

157. Roila F. Tonato M, Cognetti F. et al. 1991. Prevention of cisplatin-induced emesis: a double- blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. Journal of Clinical Oncology 9:674-678.

158. Rosenzweig MR, Leiman AL, Breedlove SM. 1996. Biological Psychology. Sunderland, MA: Sinauer Associates, Inc.

159. Roth R I, Owen R L, Keren D F. Volberding P A. 1985. Intestinal infection with Mycobacterium avium in acquired immune deficiency syndrome (AIDS). Histological and clinical comparison with Whipple's disease. Digestive Disease science 30:497-504

160. Russo E. 1998. Cannabis for Migraine Treatment: The Once and Future Prescription?: An Historical and Scientific Review. Pain 76

161. Suttmann U. Ockenga J. Selberg O. Hoogestraat L, Deicher H. Muller MJ. 1995. Incidence and prognostic value of malnutrition and wasting in human irnmunodeficiency virus - infected outpatients. Journal of Acquired immune Deficiency Syndromes and Human Retrovirology 8:239-246.

4.56

162. Sackett D, Rosenberg W. Haynes B. Richardson S. 1997. Evidence-based medicine: How to practice and teach EBM. New York: Churchhill Livingston.

163. Sallan SE, Cronin CM, Zelen M, et al. 1980. Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. New England Journal of Medicine 302: 135 - 138.

164. Sallan SE, Zinberg NE, Frei E. 1975. Antiemetic effect of delta-9-THC in patients receiving cancer chemotherapy. New England Journal of Medicine 293 :795-797.

165. SAMHSA (Substance Abuse and Mental Health Services Administration). 1998. National Household Survey on Drug Abuse: Population Estimates 1997. DHHS Pub No. (SMA) 98-3250. Rockville, MD: SAMHSA, Office of Applied Studies.

166. Sandyk R. Awerbuch G. 198X. Marijuana and Tourette's syndrome. Journal of Clinical Psychopharmacology 8:444-445.

167. Sandyk R. Consroe P. Stern P. Biklen D. 1988. Preliminary trial of cannabidiol in Huntington's disease. Marijuana: An International Research Report Editors Chesher G. Consroe P. Musty R. Canberra: Australian Government Publishing Service.

168. Sanudo-Pena MC, Patrick SL, Patrick RL, Walker JM l 996 Effects of intranigral cannabinoids on rotational behavior in rats: Interactions with the dopaminergic system. Neuroscience Letters 206:21 -24.

169. Sanudo-Pena MC, Tsou K, and Walker JM. Cannabinoid dopamine interactions in the basal ganglia in an animal model of Parkinson disease. (in preparation).

170. Sanudo-Pena MC, Tsou K, and Walker JM. Superior colliculus and turning: dopamine and cannabinoids. (in preparation).

171. Sanudo-Pena MC, Walker JM. 1997. Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat. Journal of Neurophysiology 77: 1635-1638.

172. Sanudo-Pena MC, Walker JM. 1998. Effects of intrastriatal cannabinoids on rotational behavior in rats: interactions with the dopaminergic system . Synapse 30:221 -226.

173. Schambelan M, Mulligan K, Grunfeld C, Daar ES, LaMarca A, Kotler DP. 1996. Recombinant human growth hormone in patients with HIV-associated wasting: a randomized, placebo-controlled trial: Serostim Study Group. Annals of Internal Medicine 125:873-882.

174. Schwartz RH, Beveridge RA. 1994. Marijuana as an antiemetic drug: how useful is it today? Opinions from clinical oncologists [see comments]. Journal of Addictive Diseases 13:53-65.

175 Schwartz RH, Voth EA. 1995. Marijuana as Medicine: Making a Silk Purse Out of a Sow's Ear. Journal of Addictive Diseases 14: 15-21.

176. Shields MB. 1998. Textbook of glaucoma. 4th. Baltimore, MD: Williams & Wilkins.

177. Sommer A, Tielsch JM, Katz J. Quigley HA, Gottsch JD, Javitt J. Singh K. 1991. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: The Baltimore Eye Survey. Archives of Ophthalmology 109: 1090-1095.

4.57

178. Staquet M, Gantt C, Machin D. 1978. Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clinical Pharmacology and Therapeutics 23:397401.

179. Steele N. Gralla RJ, Braun DW, Jr. 1980. Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis. Cancer Treatments Report 64:219-224.

180. Stimmel B. 1995. Medical marijuana: to prescribe or not to prescribe, that is the question [editorial]. Journal of Addictive Diseases 14: 1-3.

181. Strassman RJ. 1998. Marijuana: The forbidden medicine (book review). Journal of the American Medical Association 279:963-964.

182. Struwe M, Kaempfer SH, Geiger CJ, Pavia AT, Plasse TF, Shepard KV, Ries K, Evans TG. 1993. Effect of dronabinol on nutritional status in HIV infection. Annals of Pharmacotherapy 27;827-31.

183. Swift RM, 1994. Marijuana: The forbidden medicine (book review). The New England Journal of Medicine 331 :749-750.

184. Tanda G. Pontieri FE, Di Chiara G. 1997. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common u1 opioid receptor mechanism. Science 276:2048-2049.

185. Tiedeman JS, Shields MB, Weber PA, Crow JW, Cocchetto DM, Harris WA, Howes JF. 1981. Effect of synthetic cannabinoids on elevated intraocular pressure. Ophthalmology 88:270-277.

186. Tielsch JM, Sommer A, Katz J. Royall RM, Quigley HA, Javitt J. 1991. Racial variations in the prevalence of primary open-angle glaucoma: The Baltimore Eye Survey. Journal of the American Medical Association 266:369-374.

187. Timpone JG, Wright DJ, Li N. Egorin MJ, Enama ME, Mayers J. Galetto G. DATRI 004 Study Group. 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. AIDS Research and Human Retroviruses 13:305-15.

188. Trembly B. Sherman M. 1990. Double-blind clinical study of cannabidiol as a secondary anticonvulsant. Marijuana '90 International Conference on Cannabis and Cannabinoids. Kolympari, Crete, July 8-11, 1990. Unpublished manuscript presented at the conference.

189. Tyson LB, Gralla RJ, Clark RA, et al. 1985. Phase I trial of levonantradol in chemotherapy- induced emesis. American Journal of Clinical Oncology 8:528-532.

190. UNAIDS, WHO. 1998. Report on the Global HIV/AIDS Epidemic, June 1998.

191. Ungerleider JT, Andrysiak TA, Fairbanks L, Ellison GW, Myers LW. 1987. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse 7:39-50.

4.58

192. Vinciguerra V, Moore T. Brennan E. 1988. Inhalation marijuana as an antiemetic for cancer chemotherapy. New York State Journal of Medicine 88:525-527.

193. Volicer L, Smith S. Volicer BJ. 1995. Effect of seizures on progression of dementia of the Alzheimer type. Dementia 6:258-263.

194. 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.

195. Voth E A, Schwartz R. H. 1997. Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Annals of Internal Medicine 126:791-798.

196. Wall PD, Melzack R. 1994. Textbook of Pain. Edinburgh: Churchill Livingstone.

197. Walters TR. 1996. Development and use of brimonidine in treating acute and chronic elevations of intraocular pressure: a review of safety, Efficacy dose response, and dosing studies. Survey of Ophthalmology 41 Suppl 1 :S19-S26.

198. Wang ZM, Visser M, Ma R. Baumgartner RN, Kotler DP, Gallagher D, Heymsfield SB. 1996. Skeletal muscle mass: Validation of neutron activation and dual energy X-ray absorptiometry methods by computerized tomography. Journal of Applied Physiology 80:824-831.

199. Whitney EN. 1994. Nutrition and Wasting Disorders: Cancer and AIDS. In: Whitney EN, Cataldo CB1 Rolfes SR, Editors Understanding Normal and Clinical Nutrition. Minneapolis: West Publishing Co. Pp. 948-977.

200. Wood. 1998. HIV-protease inhibitors. Drug Therapy 338:1281-1292.

201. Yoles E, Belkin M, Schwartz M. 1996. HU-211, a nonpsychotropic cannabinoid, produces short- and long-term neuroprotection after optic nerve axotomy. Journal of Neurotrauma 13:49-57.

202. Zimmer L, Morgan JP. 1997. Marijuana myths marijuana facts. New York, NY: The Lindesmith Center.

4.59

Chapter 5 --->>>
UKCIA does not encourage anyone to grow or use cannabis. The aim of the site is as an information resource which will help people fight the injustice of prohibition with the strongest of weapons: Knowledge.

Please note this site uses Cookies - small downloads to your computer. These make certain aspects of the site work properly. We assume you're happy with this if you continue using the site. If you're not, you can turn cookies off in your browser and delete any which have been downloaded, but if you do, some parts of the site may not work.