Marijuana and Medicine - Chapter 4 part b

Marijuana and Medicine

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

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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

GABA_B receptor agonists baclofen

a-receptor agonists tizanidine

non-competitive GABA_A 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.

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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.

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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.

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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.

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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.

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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.

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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

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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}

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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.

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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

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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.

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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

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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-F_2a 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.

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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.

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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

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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.

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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.

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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}

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