Clinical Studies of Cannabinoids

There have been three kinds of studies of the effects of cannabinoids on pain in human volunteers: studies of experimentally induced acute pain, studies of postsurgical acute pain, and studies of chronic pain. Overall, there have been very few studies—only one since 1981—and they have been inconclusive.

Migraine Headaches

There is clearly a need for improved migraine medications. Sumatriptan (Imitrex) is the best available medication for migraine headaches, but it fails to abolish migraine symptoms in about 30% of migraine patients.^118,147 Marijuana has been proposed numerous times as a treatment for migraine headaches, but there are almost no clinical data on the use of marijuana or cannabinoids for migraine. Our search of the literature since 1975 yielded only one scientific publication on the subject. It presents three cases of cessation of daily marijuana smoking followed by migraine attacks—not convincing evidence that marijuana relieves migraine headaches.⁴³ The same result could have been found if migraine headaches were a consequence of marijuana withdrawal. While there is no evidence that marijuana withdrawal is followed by migraines, when analyzing the strength of reports such as these it is important to consider all logical possibilities. Various people have claimed that marijuana relieves their migraine headaches, but at this stage there are no conclusive clinical data or published surveys about the effect of cannabinoids on migraine.

However, a possible link between cannabinoids and migraine is suggested by the abundance of cannabinoid receptors in the periaqueductal gray (PAG) region of the brain. The PAG region is part of the neural system that suppresses pain and is thought to be involved in the generation of migraine headaches.⁵² The link or lack thereof between cannabinoids and migraine might be elucidated by examining the effects of cannabinoids on the PAG region.¹¹⁰ Recent results indicating that both cannabinoid receptor subtypes are involved in controlling peripheral pain¹⁵ suggest that the link is possible. Further research is warranted.

Conclusions: Analgesia

A key question to address is whether there is any receptor selectivity for the analgesic efficacy of cannabinoids. Are the unwanted side effects (amnesia and sedation) caused by the same receptors in the same brain regions as those producing the analgesia? If the answer is yes, enhancing efficacy will not solve the problem of sedation. Similarly, are the pleasant side effects due to an action at the same receptor? Can the feelings of well-being and appetite stimulation be separated by molecular design? Recent results indicating that both cannabinoid receptor subtypes are independently involved in controlling peripheral pain¹⁵ (discussed in chapter 2) strongly suggest that this is possible and that further research is warranted.

Further research into the basic circuitry underlying cannabinoid analgesia should be valuable. The variety of neural pathways that underlie the control of pain suggests that a synergistic analgesia “cocktail” would be effective. For example, Lichtman and Martin have shown the involvement of an α2 adrenoreceptor in cannabinoid analgesia.¹¹¹ Perhaps a combination of a CB₁ agonist and an α2 agonist (such as clonidine) would provide enhanced analgesia with less severe side effects.

Clinical studies should be directed at pain patients for whom there is a demonstrated need for improved management and where the particular side effect profile of cannabinoids promises a clear benefit over current approaches. The following patient groups should be targeted for clinical studies of cannabinoids in the treatment of pain:

• Chemotherapy patients, especially those being treated for the mucositis, nausea, and anorexia.
• Postoperative pain patients (using cannabinoids as an opioid adjunct to determine whether nausea and vomiting from opioids are reduced).
• Patients with spinal cord injury, peripheral neuropathic pain, or central poststroke pain.
• Patients with chronic pain and insomnia.
• AIDS patients with cachexia, AIDS neuropathy, or any significant pain problem.

In any patient group an essential question to be addressed is whether the analgesic efficacy of opioids can be augmented. The strategy would be to find the ceiling analgesic effect with an opioid (as determined by pain intensity and tolerability of side effects) and then add a cannabinoid to determine whether additional pain relief can be obtained. That would begin the investigation of potential drug combinations. As with any clinical study on analgesic drugs, it will be important to investigate the development of tolerance and physical dependence; these are not themselves reasons to exclude the use of cannabinoids as analgesics, but such information is essential to the management of many drugs that are associated with tolerance or physical dependence.

A secondary question would be whether THC is the only or the best component of marijuana for analgesia. How does the analgesic effect of the plant extract compare with that of THC alone? If there is a difference, it will be important to identify the combinations of cannabinoids that are the most effective analgesics.

In conclusion, the available evidence from animal and human studies indicates that cannabinoids can have a substantial analgesic effect. One exception is the lack of analgesic effect in studies on experimentally induced acute pain, but because of limitations in the design of those studies they were inconclusive. Further clinical work is warranted to establish the magnitude of the effect in different clinical conditions and to determine whether the effect is sustained. Although the usefulness of cannabinoids appears to be limited by side effects, notably sedation, other effects such as anxiolysis, appetite stimulation, and perhaps antinausea and antispasticity effects should be studied in randomized, controlled clinical trials. These very “special” effects might warrant development of cannabinoid drugs for particular clinical populations.

Chemotherapy-Induced Nausea and Vomiting

The use of effective chemotherapeutic drugs has produced cures in some malignancies and retarded the growth of others, but nausea and vomiting are frequent side effects of these drugs. Nausea ranks behind only hair loss as a concern of patients on chemotherapy, and many patients experience it as the worst side effect of chemotherapy. The side effects can be so devastating that patients abandon therapy or suffer diminished quality of life. As a result, the development of effective strategies to control the emesis induced by many chemotherapeutic agents is a major goal in the supportive care of patients with malignancies.

The mechanism by which chemotherapy induces vomiting is not completely understood. Studies suggest that emesis is caused by stimulation of receptors in the central nervous system or the gastrointestinal tract. This stimulation appears to be caused by the drug itself, a metabolite of the drug, or a neurotransmitter.^6,12,35 In contrast with an emetic like apomorphine, there is a delay between the administration of chemotherapy and the onset of emesis. This delay depends on the chemotherapeutic agent; emesis can begin anywhere from a few minutes after the administration of an agent like mustine to an hour for cisplatin.¹²

The most desirable effect of an antiemetic is to control emesis completely, which is currently the primary standard in testing new antiemetic agents (R. Gralla, IOM workshop). Patients recall the number of emetic episodes accurately, even if their antiemetics are sedating or affect memory;¹⁰¹ thus, the desired end point of complete control is also a highly reliable method of evaluation. The degree of nausea can be estimated through the use of established visual analogue scales.^*21,55,101

Another consideration in using antiemetic drugs is that the frequency of emesis varies from one chemotherapeutic agent to another. For example, cisplatin causes vomiting in more than 99% of patients who are not taking an antiemetic (with about 10 vomiting episodes per dose), whereas methotrexate causes emesis in less than 10% of patients.^55,82,83 Among chemotherapeutic agents, cisplatin is the most consistent emetic known and has become the benchmark for judging antiemetic efficacy. Antiemetics that are effective with cisplatin are at least as effective with other chemotherapeutic agents. Controlling for the influence of prior chemotherapy and balancing predisposing factors such as, sex, age, and prior heavy alcohol use among study groups are vital for reliability. Reliable randomization of patients and blinding techniques (easier when there are no psychoactive effects) are also necessary to evaluate the control of vomiting and nausea.

THC and Marijuana Therapy for Chemotherapy-Induced Nausea and Vomiting

Cannabinoids are mildly effective in preventing emesis in some patients who are receiving cancer chemotherapy. Several cannabinoids have been tested as antiemetics, including THC (both Δ⁹-THC and Δ⁸-THC) and the synthetic cannabinoids nabilone and levonantradol. Smoked marijuana has also been examined.

Therapy for Chemotherapy-Induced Nausea and Vomiting

Conclusions: Chemotherapy-Induced Nausea

Most chemotherapy patients are unlikely to want to use marijuana or THC as an antiemetic. In 1999, there are more effective antiemetic agents available than were available earlier. By comparison, cannabinoids are only modest antiemetics. However, because modern antiemetics probably act through different mechanisms, cannabinoids might be effective in people who respond poorly to currently used antiemetic drugs, or cannabinoids might be more effective in combination with a new drug than is either alone. For both reasons, studies of the effects of adjunctive cannabinoids on chemotherapy-induced emesis are worth pursuing for patients whose emesis is not optimally controlled with other agents.

While some people who spoke to the IOM study team described the mood-enhancing and anxiety-reducing effects of marijuana as a positive contribution to the antiemetic effects of marijuana, one-fourth of the patients in the New York state study described earlier were unable to tolerate smoked marijuana. Overall, the effects of oral THC and smoked marijuana are similar, but there are differences. For example, in the residential studies of experienced marijuana users by Haney and co-workers, subjects reported that marijuana made them feel “mellow,”⁷¹ whereas comparable doses of oral THC did not.⁷⁰ Such differences might be due to the different routes of delivery of THC, as well as the different mixture of cannabinoids found in the marijuana plant. As of this writing, no studies had been published that weighed the relative contributions of those different factors.

The goal of antiemetic medications is to prevent nausea and vomiting. Hence, antiemetics are typically given before chemotherapy, in which case a pill is an effective from of drug delivery. However, in patients already experiencing severe nausea or vomiting, pills are generally ineffective because of the difficulty in swallowing or keeping a pill down and slow onset of the drug effect. Thus, an inhalation (but preferably not smoking) cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced nausea.

Until the development of rapid-onset antiemetic drug delivery systems, there will likely remain a subpopulation of patients for whom standard antiemetic therapy is ineffective and who suffer from debilitating emesis. It is possible that the harmful effects of smoking marijuana for a limited period of time might be outweighed by the antiemetic benefits of marijuana, at least for patients for whom standard antiemetic therapy is ineffective and who suffer from debilitating emesis. Such patients should be evaluated on a case-by-case basis and treated under close medical supervision.

Malnutrition in HIV-Infected Patients

By 1997 more than 30 million people worldwide were infected with human immunodeficiency virus (HIV), and the number is predicted to increase to almost 40 million by the year 2000.^126,186 Malnutrition is common among AIDS patients and plays an independent and important role in their prognosis.^95,100,158 Because treatment for malnutrition depends on whether it is caused by starvation or cachexia, one needs to know the effects of HIV infection on metabolic processes. The answer depends on the clinical situation and can be either or both.⁹⁴

The development of malnutrition in HIV infection has many facets. Malnutrition in HIV-infected patients results in a disproportionate depletion of body cell mass,^* total body nitrogen, and skeletal muscle mass; all are consistent with cachexia.^97,194 Body composition studies show that the depletion of body cell mass precedes the progression to AIDS (falling CD4 lymphocyte counts); this suggests that malnutrition is a consequence of the inflammatory response to the underlying viral infection, rather than a general complication of AIDS.¹⁴⁴ In contrast, weight loss is often episodic and related to acute complications, such as febrile opportunistic infections.¹¹³ Mechanisms underlying wasting in HIV-infected patients depend on the stage of HIV infection and on specific associated complications.

The many reasons for decreased food intake among AIDS patients include mouth, throat, or esophageal infections or ulcers (oropharyngeal and esophageal pathology); adverse effects of medications;¹⁹⁶ diarrhea; enteric infection; malabsorption; serious systemic infection; focal or diffuse neurological disease; HIV enteropathy; depression; fatigue; and poverty. Nutrient malabsorption is often the result of microorganism overgrowth or infection in the intestine, especially in the later stages of AIDS.^95,157

Marijuana and THC for Malnutrition in HIV-Infected Patients

Despite their frequency of use, little has been published about the effectiveness of marijuana or cannabinoids for the treatment of malnutrition and wasting syndrome in HIV-infected patients. The only cannabinoid evaluated in controlled clinical studies is THC, or dronabinol. Short-term (six-week) and long-term (one-year) therapy with dronabinol was associated with an increase in appetite and stable weight, and in a previous short-term (five-week) clinical trial in five patients, dronabinol was shown to increase body fat by 1%.^8,9,179 In 1992, the FDA approved THC, under the trade name Marinol (dronabinol), as an appetite stimulant for the treatment of AIDS-related weight loss. Megestrol acetate (Megace) is a synthetic derivative of progesterone that can stimulate appetite and cause substantial weight gain when given in high doses (320– 640 mg/day) to AIDS patients. Megestrol acetate is more effective than dronabinol in stimulating weight gain, and dronabinol has no additive effect when used in combination with megestrol acetate.¹⁸³ HIV/AIDS patients are the largest group of patients who use dronabinol. However, some reject it because of the intensity of neuropsychological effects, an inability to titrate the oral dose easily, and the delayed onset and prolonged duration of its action.³ There is evidence that cannabinoids modulate the immune system (see chapter 2, “Cannabinoids and the Immune System”), and this could be a problem in immunologically compromised patients. No published studies have formally evaluated use of any of the other cannabinoids for appetite stimulation in wasting.

Anecdotes abound that smoked marijuana is useful for the treatment of HIV-associated anorexia and weight loss.^23,62 Some people report a preference for smoked marijuana over oral THC because it gives them the ability to titrate the effects, which depend on how much they inhale. In controlled laboratory studies of healthy adults, smoked marijuana was shown to increase body weight, appetite, and food intake.^47,119 Unfortunately, there have been no controlled studies of the effect of smoked marijuana on appetite, weight gain, and body composition in AIDS patients. At the time of this writing, Donald Abrams, of the University of California, San Francisco, was conducting the first clinical trial to test the safety of smoked marijuana in AIDS patients, and the results were not yet available.

A major concern with marijuana smoking in HIV-infected patients is that they might be more vulnerable than other marijuana users to immunosuppressive effects of marijuana or to the exposure of infectious organisms associated marijuana plant material (see chapter 3, “Marijuana Smoke”).

Therapy for Wasting Syndrome in HIV-Infected Patients

Malnutrition in Cancer Patients

Malnutrition compromises the quality of life of many cancer patients and contributes to the progression of their disease. About 30% of Americans will develop cancer in their lifetimes, and two-thirds of those who get cancer will die as a result of it.⁵ Depending on the type of cancer, 50– 80% of patients will develop cachexia and up to 50% of them will die, in part, as a result of cachexia.^11,40 The cachexia appears to result from the tumor itself, and cytokines (proteins secreted by the host during an immune response to tumor) are probably important factors in this development. Cachexia does not occur in all cancer patients, but generally occurs in the late stages of advanced cancer of the pancreas, lung, and prostate.

The only cannabinoid evaluated for treating cachexia in cancer patients is dronabinol, which has been shown to improve appetite and promote weight gain.⁵⁴ Present treatments for cancer cachexia are similar to that for cachexia in AIDS patients. These treatments are usually indicated in late stages of advanced disease and include megestrol acetate and enteral and parenteral nutrition. Megestrol acetate stimulates appetite and promotes weight gain in cancer patients, although the gain is mostly in fat mass (reviewed by Bruera 1998¹⁴). Both megestrol acetate and dronabinol have dose-related side effects that can be troublesome for patients: megestrol acetate can cause hyperglycemia and hypertension, and dronabinol can cause dizziness and lethargy. Cannabinoids have also been shown to modulate the immune system (see chapter 2, “Cannabinoids and the Immune System”), and this could be contraindicated in some cancer patients (both the chemotherapy and the cancer can be immunosuppressive).

Future treatments will probably depend on the development of methods that block cytokine actions and the use of selective β2-adrenergic receptor agonists to increase muscle mass.^14,73 Treatments for cancer cachexia will also most likely need to identify individual patients' needs. Some patients might need only a cytokine inhibitor, whereas others could benefit from combined approaches, such as an appetite stimulant and β2-adrenergic receptor agonists. In this respect, such cannabinoids as THC might prove useful as part of a combination therapy as an appetite stimulant, antiemetic, analgesic, and anxiolytic, especially for patients in late stages of the disease.

Anorexia Nervosa

Anorexia nervosa, a psychiatric disorder characterized by distorted body image and self-starvation, affects an estimated 0.6% of the U.S. population, with a greater prevalence in females than males.⁵ Its mortality is high, and response to standard treatments is poor.

THC appears to be ineffective in treating this disease. In one study it caused severe dysphoric reactions in three of 11 patients.⁶⁵ One possible explanation of the dysphoria is that THC increases appetite and thus intensifies the mental conflict between hunger and food refusal.¹³ Furthermore, such patients might have underlying psychiatric disorders, such as schizophrenia and depression, in which cannabinoids might be hazardous (see chapter 3, “Psychological Harms”).

Current treatments include psychological techniques to overcome emotional or behavioral problems and dietary intervention to reverse the malnutrition.¹⁹⁵ Pharmacological treatments, such as antidepressants, have been used in addition to psychotherapy but tend to lack the desired level of efficacy.³³ Recently, alterations in a gene for one of the serotonin receptors have been identified in some patients with anorexia nervosa.⁴⁵ The possibility of a genetic component suggests a pathway for the development of new drugs to treat this disease.

Conclusions: Wasting Syndrome and Appetite Stimulation

The profile of cannabinoid drug effects suggests that they are promising for treating wasting syndrome in AIDS patients. Nausea, appetite loss, pain, and anxiety are all afflictions of wasting, and all can be mitigated by marijuana. Although some medications are more effective than marijuana for these problems, they are not equally effective in all patients. A rapid-onset (that is, acting within minutes) delivery system should be developed and tested in such patients. Smoking marijuana is not recommended. The long-term harm caused by smoking marijuana makes it a poor drug delivery system, particularly for patients with chronic illnesses.

Terminal cancer patients pose different issues. For those patients the medical harm associated with smoking is of little consequence. For terminal patients suffering debilitating pain or nausea and for whom all indicated medications have failed to provide relief, the medical benefits of smoked marijuana might outweigh the harm.

Muscle Spasticity

Spasticity is the increased resistance to passive stretch of muscles and increased deep tendon reflexes. Muscles may also contract involuntarily (flexor and extensor spasms). In some cases these contractions are debilitating and painful and require therapy to relieve the spasms and associated pain.

There are numerous anecdotal reports that marijuana can relieve the spasticity associated with multiple sclerosis or spinal cord injury, and animal studies have shown that cannabinoids affect motor areas in the brain—areas that might influence spasticity.^{51,78,130,168}

Multiple Sclerosis

Multiple sclerosis (MS) is a condition in which multiple areas of the central nervous system (CNS) are affected. Many nerve fibers become demyelinated, some are destroyed, and scars (sclerosis) form, resulting in plaques scattered throughout the white matter of the CNS. (Myelin is the lipid covering that surrounds nerve cell fibers and facilitates the conduction of signals along nerve cells and ultimately between the brain, the spinal cord, and the rest of the body.) MS exacerbations appear to be caused by abnormal immune activity that causes inflammation and myelin destruction in the brain (primarily in the periventricular area), brain stem, or spinal cord. Demyelination slows or blocks transmission of nerve impulses and results in an array of symptoms such as fatigue, depression, spasticity, ataxia (inability to control voluntary muscular movements), vertigo, blindness, and incontinence. About 90% of MS patients eventually develop spasticity. There are an estimated 2.5 million MS patients worldwide, and spasticity is a major concern of many patients and physicians.¹³⁴ Spasticity is variably experienced as muscle stiffness, muscle spasms, flexor spasms or cramps, muscle pain or ache. The tendency for the legs to spasm at night (flexor spasms) can interfere with sleep.

Marijuana is often reported to reduce the muscle spasticity associated with MS.^62,123 In a mail survey of 112 MS patients who regularly use marijuana, patients reported that spasticity was improved and the associated pain and clonus decreased.²⁸⁷ However, a double-blind placebo-controlled study of postural responses in 10 MS patients and 10 healthy volunteers indicated that marijuana smoking impaired posture and balance in both MS patients and the volunteers.⁶¹ Nevertheless, the 10 MS patients felt that they were clinically improved. The subjective improvement, while intriguing, does not constitute unequivocal evidence that marijuana relieves spasticity. Survey data do not measure the degree of placebo effect, estimated to be as great as 30 percent in pain treatments.^122,131 Furthermore, surveys do not separate the effects of marijuana or cannabinoids on mood and anxiety from the effects on spasticity.

The effects of THC on spasticity were evaluated in a series of three clinical trials testing a total of 30 patients.^24,148,187 They were “open trials,” meaning that the patients were informed before treatment that they would be receiving THC. Based on patient report or clinical exam by the investigator, spasticity was less severe after the THC treatment. However, THC was not effective in all patients and frequently caused unpleasant side effects. Spasticity was also reported to be less severe in a single case study after nabilone treatment (Figure 4.2).¹¹⁷

FIGURE 4.2

Effect of nabilone on multiple sclerosis symptoms. This figure shows the results of a trial in which a 45-year-old man with MS was given four-week treatments alternately with placebo and nabilone. The patient served as both experimental subject and control; (more...)

In general, the abundant anecdotal reports are not well supported by the clinical data summarized in Table 4.1. But this is due more to the limitation of the studies than to negative results. There are no supporting animal data to encourage clinical research in this area, but there also are no good animal models of the spasticity of MS. Without an appropriate model, studies to determine the physiological basis for how marijuana or THC might relieve spasticity cannot be conducted. Nonetheless, the survey results suggest that it would be useful to investigate the potential therapeutic value of cannabinoids in relieving symptoms associated with MS. Such research would require the use of objective measures of spasticity, such as the pendulum test.^* Since THC is mildly sedating, it is also important to distinguish this effect from antispasticity effects in any such investigations. Mild sedatives, such as Benadryl or benzodiazepines, would be useful controls for studies on the ability of cannabinoids to relieve muscle spasticity. The regular use of smoked marijuana, however, would be contraindicated in a chronic condition like MS.

TABLE 4.1

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

Therapy for Muscle Spasticity

Present Therapy. Present therapy for spasticity includes the various medications listed in Table 4.2. Baclofen and tizanidine, the most commonly prescribed antispasticity drugs, relieve spasticity and spasms with various 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.

TABLE 4.2

Classes of Antispasticity Drugs.

Future Therapy. The discovery of agents that work through mechanisms different from those of existing antispasticity drugs will be an important advance in the treatment of spasticity. The aim of new treatments will be to relieve muscle spasticity and pain without substantially increasing muscle weakness in conditions that result in spasticity. The treatment for MS itself will likely be directed at immunomodulation. Various immunomodulating agents, such as beta-interferon and glatiramer acetate, have been shown to reduce the frequency of symptomatic attacks, the progression of disability, and the rate of appearance of demyelinated lesions as detected by magnetic resonance imaging.⁵

Movement Disorders

Movement disorders are a group of neurological conditions caused by abnormalities in the basal ganglia and their subcortical connections through the thalamus with cortical motor areas. The brain dysfunctions ultimately result 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. This is of particular interest because for many people marijuana reduces anxiety.

Therapy for Movement Disorders

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

TABLE 4.3

Drugs Used to Treat Movement Disorders.

Epilepsy

Epilepsy is a chronic seizure disorder that affects about 2 million Americans and 30 million people worldwide.¹⁵⁶ 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 brain cells. These abnormal electrical events have a wide array of possible causes, including injury to the brain and chemical changes derived from metabolic faults of exposure to toxins.¹⁵⁶

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

Cannabinoids in Epilepsy

There are anecdotal and individual case reports that marijuana controls seizures in epileptics (reviewed in a 1997 British Medical Association report¹³), but there is no solid evidence. 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 co-workers¹³⁷ concluded that marijuana is a protective factor for first-time seizures in men but not women. Men who used marijuana reportedly had fewer first-time seizures than men who did not use marijuana. That report 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 surgery for appendicitis, intestinal obstruction, or 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. It did not include measures of health status prior to hospital admissions for the patients' 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 antiepileptic activity of CBD has been investigated but is not promising. Three controlled trials were conducted in which CBD was given orally to patients who had had generalized grand mal seizures or focal seizures (Table 4.4). Two of these studies were never published, but information about one was published in a letter to the South African Medical Journal, and the other was presented at the 1990 Marijuana International Conference on Cannabis and Cannabinoids.¹⁸⁴

TABLE 4.4

Clinical Trials of Cannabidiol (CBD) in Epileptics.

Even if CBD had antiepileptic properties, these studies were likely too small to demonstrate efficacy. Proving efficacy of anticonvulsants generally requires large numbers of patients followed for months because the frequency of seizures is highly variable and the response to therapy varies depending on seizure type.^4,49

Therapy for Epilepsy

Present Therapy. Standard pharmacotherapy for partial and generalized seizures, listed in Table 4.5, involves a variety of anticonvulsant drugs. These drugs suppress seizures completely in approximately 60% of patients who have chronic epilepsy and improve seizures in another 15% of patients. All of the anticonvulsants listed in Table 4.5 have side effects, some of the more common of which are drowsiness, mental slowing, ataxia, tremor, hair loss, increased appetite, headache, insomnia, and rash. Nevertheless, recurrent seizures are physically dangerous and emotionally devastating, and preventing them outweighs many undesirable side effects of anticonvulsant drugs.

TABLE 4.5

Anticonvulsant Drugs for Various Types of Seizures.

Future Therapy. The goal of epilepsy treatment is to halt the seizures with minimal or no side effects and then to eradicate the cause. Most of the anticonvulsant research on cannabinoids was conducted before 1986. Since then, many new anticonvulsants have been introduced and cannabinoid receptors have been discovered. At present, the only biological evidence of antiepileptic properties of cannabinoids is that CB₁ receptors are abundant in the hippocampus and amygdala. Both regions are involved in partial seizures but are better known for their role in functions unrelated to seizures.²⁶ Basic research might reveal stronger links between cannabinoids and seizure activity, but this is not likely to be as fruitful a subject of cannabinoid research as others. Given the present state of knowledge, clinical studies of cannabinoids in epileptics are not indicated.

Alzheimer's Disease

Food refusal is a common problem in patients who suffer from Alzheimer's type dementia. The causes of anorexia in demented people are 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 were treated for 12 weeks on an alternating schedule of dronabinol and placebo (six weeks of each treatment). The dronabinol treatment resulted in substantial weight gains and declines in disturbed behavior.¹⁹⁰ No serious side effects were observed. One patient had a seizure and was removed from the study, but the seizure was not necessarily caused by dronabinol. Recurrent seizures without any precipitating events occur in 20% of patients who have advanced dementia of Alzheimer's type.¹⁸⁹ 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.

Marijuana and Cannabinoids in Glaucoma

Marijuana and THC have been shown to reduce IOP by an average of 24% in people with normal IOP who have visual-field changes. In a number of studies of healthy adults and glaucoma patients, IOP was reduced by an average of 25% after smoking a marijuana cigarette that contained approximately 2% THC—a reduction as good as that observed with most other medications available today.^{1,16,32,76,77,125,193} Similar responses have been observed when marijuana was eaten or THC was given in pill form (10–40 mg) to healthy adults or glaucoma patients.^76,91 But the effect lasts only about three to four hours. Elevated IOP is a chronic condition and must be controlled continuously.

Intravenous administration of Δ⁹-THC, Δ⁸-THC, or 11-OH-THC to healthy adults substantially decreased IOP, whereas cannabinol, CBD, and β-OH-THC had little effect.^31,146 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, Medical College of Georgia, personal communication).

Three synthetic cannabinoids were investigated; BW29Y, BW146Y, and nabilone. They were given orally to patients who had high IOP. BW146Y and nabilone were as effective as ingesting THC or smoking marijuana but again with a very short duration of action; BW29Y was ineffective.^136,182

Topical treatments with cannabinoids have been ineffective in reducing IOP. When Δ⁹-THC was applied topically as eye drops, whether once or four times a day, there was no decrease in IOP.^60,90 Suspensions of lipophilic THC tended to be irritating to the eye.

In summary, cannabinoids and marijuana can reduce IOP when administered orally, intravenously, or by inhalation but not when administered topically. Even though a reduction in IOP by standard medications or surgery clearly slows the rate of glaucoma symptom progression, there is no direct evidence of benefits of cannabinoids or marijuana in the natural progression of glaucoma, visual acuity, or optic nerve atrophy.^92,115

In addition to lowering IOP, marijuana reduces blood pressure and has many psychological effects. Merritt and co-workers reported hypotension, palpitations, and psychotropic effects in glaucoma patients after inhalation of marijuana.¹²⁵ Cooler and Gregg³¹ also reported increased anxiety and tachycardia after intravenous infusion of THC (1.5–3 mg). All those side effects are problematic, particularly for elderly glaucoma patients who have cardiovascular or cerebrovascular disease. The reduction in blood pressure can be substantial and might adversely affect blood flow to the optic nerve.¹²⁴ Many people with systemic hypertension have their blood pressure reduced to manageable and acceptable levels through medication, but this does not seem to affect their IOP. In contrast, there is evidence that reduction in blood pressure to considerably below-normal levels influences IOP and ocular blood flow.^46,74,142 Hence, in the case of an eye with high IOP or an optic nerve in poor condition and susceptibility to high 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 known how they might interact with other drugs used to treat glaucoma. If the mechanism involves a final common pathway, the effects of cannabinoids might not be additive and might even interfere with effective drugs.

Therapy for Glaucoma

Present Therapy

Six classes of drugs are used to treat glaucoma; all reduce IOP (Table 4.6).⁹³ 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. They are not popular today because of their side effects, such as pupil constriction or dilation, brow ache, tachycardia, and diuresis; all of them have been superseded by the other classes of drugs.⁹³ Surgical options are also available today to lower IOP, including laser trabeculoplasty, trabeculectomy/sclerostomy, drainage implantation, and cyclodestruction of fluid-forming tissues.¹⁷³ Thus, there are now many effective options to slow the progression of glaucoma by reducing IOP.

TABLE 4.6

Classes of Drugs Used to Treat Glaucoma.

One important factor in slowing the progression of glaucoma via medications that reduce IOP is patient compliance with dosing regimens. With respect to compliance, the ideal glaucoma drug is one that is applied at most twice a day (P. Kaufman, IOM workshop). If the dose must be repeated every three to four hours, patient compliance becomes a problem; for this reason, marijuana and the cannabinoids studied thus far would not be highly satisfactory treatments for glaucoma. 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.

Conclusion: Glaucoma

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 and short lived and 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.

SUMMARY

Advances in cannabinoid science of the past 16 years have given rise to a wealth of new opportunities for the development of medically useful cannabinoid-based 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 who are undergoing chemotherapy, and who suffer simultaneously from severe pain, nausea, and appetite loss, cannabinoid drugs might 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 diseases are affected. Trials testing the safety and efficacy of marijuana use are an important component to understanding the course of a disease, particularly diseases such as AIDS for which marijuana use is prevalent. 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 10 years from now. In terms of good medicine, marijuana should rarely be recommended unless all reasonable options have been eliminated. But then what? It is conceivable that 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 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 become available only if there is either enough incentive for private enterprise to develop and market such drugs or 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 involve only short-term marijuana use (less than six months), should be conducted in patients with conditions for which there is reasonable expectation of efficacy, should be approved by institutional review boards, and should collect data about efficacy.

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 nonsmoked rapid-onset cannabinoid drug delivery system becomes available, we acknowledge that there is no clear alternative for people suffering from chronic conditions that might be relieved by smoking marijuana, such as pain or AIDS wasting. 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-1 clinical trials using the same oversight mechanism as that proposed in the above recommendations.

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