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Commentary

The IOM Report:
What It Says, What It Doesn't Say

National Families in Action's Analysis of Marijuana and Medicine: Assessing the Science Base, Institute of Medicine, National Academy of Sciences.

We wish to express our appreciation to NFIA's Science Advisor, David Friedman, Ph.D., of the Wake Forest University School of Medicine, for his assistance in reviewing and commenting on this analysis.)

National Families in Action presents this summary of the IOM report to provide the reader with information about the report's findings and recommendations. The full report may be read online at www.nap.edu/catalog/6376.html, where information about how to order a hard copy is also available.

Main Finding: Little Future in Smoked Marijuana

Marijuana, Like Opium, Has Compounds that May Become Useful Medicines

A Word About Scientific Studies

A Word About NFIA's Analysis of This Report

A. Pain Relief

B. Relieving Nausea and Vomiting

C. Wasting Syndrome and Appetite Stimulation

D. Muscle Spasticity and Multiple Sclerosis

E. Spinal Cord Injury

F. Movement Disorders

G. Epilepsy

H. Alzheimer's Disease

I. Glaucoma

J. The Medical Value of Marijuana and Related Substances

Main Finding: Little Future in Smoked Marijuana as Medicine
While there are some notable exceptions, the press has generally failed to present the findings of this report accurately. The reader may therefore be surprised to learn of the principal finding of the Institute of Medicine's analysis of marijuana's potential use in medicine:

"While we see a future in the development of chemically defined cannabinoid drugs, we see little future in smoked marijuana as a medicine." (John A. Benson, Jr., Co-Principal Investigator, in a press statement announcing the release of the report.)

This may seem like a paradoxical conclusion. However, despite the scientific complexity surrounding the issue itself, despite poor, sometimes unclear, press coverage, and politically motivated efforts to obscure the issue, this conclusion should not be surprising. Examples abound of useful medicines being developed from compounds found in harmful or addictive plant extracts.

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Marijuana, Like Opium, Has Compounds That May Become Useful Medicines
The opioid drugs purified from opium represent classic examples. Both codeine and morphine are purified opioids extracted from opium. Using the basic opioid chemical structure as a starting point, many other opioids have been isolated and purified or synthesized in laboratories and chemically manipulated to make safer and more effective drugs to relieve pain and other symptoms. The fact that opium contains compounds that have become medicines, however, does not make raw opium itself a medicine (although it used to be) -- because we now have so many pure, effective opiod drugs to choose from, we wouldn't dream of asking patients smoke opium to obtain relief from pain.

It is the same with marijuana. Like opioids in opium, marijuana contains many molecules, called cannabinoids, which may one day be developed into useful medicines. A synthetic version of the main psychoactive cannabinoid in marijuana, THC (tetra-hydrocannabinol), is already available in pill form to be taken by mouth (dronabinol, trade name Marinol®). The fact that useful medicines may originate in the marijuana plant does not make smoked marijuana a medicine.

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A Word About Scientific Studies
Various kinds of studies are referred to throughout the IOM report, and it is helpful to know how they differ. Preclinical studies are those conducted with animals, tissues, cells, or molecules. Clinical studies are conducted with humans. Once a new chemical compound that may become a medicine has been identified or discovered, the goal of research is to establish whether it is safe and effective for treating specific diseases or symptoms. Safety studies are carried out in animals (preclinical studies) and later in healthy human volunteers (clinical studies). Efficacy is then determined in clinical studies by comparing the new compound, called an experimental drug, with standard medications, or, if no treatment currently exists, with a placebo. Patients enrolled in a study of safety or efficacy are randomly assigned to an experimental group (which receives the experimental drug) or a control group (which receives the standard medication or placebo).

Only with such comparisons can scientists determine what is causing improvements (or no improvements) seen in patients.

An open label study is one in which both the doctor and the patient know that the patient is receiving an experimental drug. Such studies are only useful for the initial identification of drugs that might be useful in treating certain conditions.

A blind study, or trial, is one in which the patient does not know which substance -- experimental drug, standard drug, or placebo--he is actually receiving. A double-blind trial is one in which neither patient nor researcher knows. These safeguards are taken to eliminate any unconscious bias that patients or researchers may have about the effectiveness of an experimental drug. Because of their rigorous design, clinical researchers place most faith in findings derived from double- blind trials.

For some kinds of chronic disease, a double-blind cross-over study is the gold standard in research. In this kind of clinical trial, all patients, whether they start off in the experimental group or the control group, ultimately receive both the experimental drug and the standard medication or placebo. At some point in the study, the medications are switched, again without the knowledge of patient or researcher. Prior to the study, a technician not involved with the study codes the experimental and standard (or placebo) drugs so that no one can tell which is which. At the end of the study, the code is broken and patients' responses, recorded during the study, are matched with the drugs they were taking to determine if the experimental drug had any effect.

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A Word About NFIA's Analysis of This Report
In this summary of the IOM report, page numbers containing material we have summarized and text we have quoted are indicated in brackets [ ]. Within quotations, brackets also enclose clarifications we have added to the quotations. We begin with summaries and excerpts of the specific findings and recommendations concerning pain relief, nausea and vomiting, wasting syndrome and appetite stimulation, muscle spasticity, multiple sclerosis, spinal cord injury, movement disorders, epilepsy, Alzheimer's disease, and glaucoma. We conclude with the full-text summary and recommendations of Chapter 4, "The Medical Value of Marijuana and Related Substances."

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A. Pain Relief
1. There is not yet enough evidence from human studies.

2. There is solid evidence from preclinical research that cannabinoids reduce pain in animals.

3. There is no evidence that marijuana or cannabinoids relieve migraine headaches.

4. Research should be done to learn:

a) if cannabinoids can enhance the pain-relieving effects of opiate drugs

b) which cannabinoids might be useful pain medications.

Excerpts and Summaries from the IOM Report:
"There have not been extensive clinical studies on the analgesic potency of cannabinoids, but data from animal studies indicate that cannabinoids . . . .seem to be mild to moderate analgesics. Opiates, such as morphine and codeine, are the most widely used drugs for the treatment of acute pain. But they are not consistently effective in chronic pain, they often induce nausea, and sedation and tolerance might occur in some patients." [4.4]

"In light of the solid evidence that cannabinoids can reduce pain in animals. . , it is important to carefully re-evaluate the evidence concerning analgesic efficacy in humans, and to ask, what clinical evidence is needed to help us decide whether cannabinoids have any use in the treatment of pain." [4.5]

"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." [4.7]

Conclusions:
The report calls for more research to answer two questions: 1) Can cannabinoids augment the pain-relieving efficacy of opioids? 2) Is THC the only or best component of marijuana for pain-relief or are other cannabinoids better analgesics? [4.8, 4.9]

"The available evidence from both animal and human studies indicates that cannabinoids can produce a significant analgesic effect." [4.9]

"Although the usefulness of cannabinoids appears to be limited by side effects, notably sedation, there are other effects, such as anxiolysis [anxiety reduction], appetite stimulation, and perhaps antinausea and antispasticity effects that should be studied in randomized, controlled clinical trials. It is this particular combination of effects that might warrant development of cannabinoid drugs for certain clinical populations." [4.9]

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B. Relieving Nausea and Vomiting
1. Neither smoked marijuana nor cannabinoids are as effective as current medicines that stop nausea and vomiting in cancer chemotherapy patients.

2. Cannabinoids, however, might be effective in:

a) those few patients who respond poorly to current antiemetic (anti-nausea) drugs

b) or more effective in combination with current antiemetics.

3. Research should be pursued for patients who do not respond completely to current antiemetics.

4. A safe (non-smoking) delivery system for cannabinoids should be developed.

5. Until then, the harmful effects of smoking marijuana for a limited period of time may be outweighed by marijuana's antiemetic benefits for those few cancer patients for whom current antiemetics do not work.

6. Doctors should evaluate such patients on a case by case basis and provide marijuana to them under close medical supervision for a limited period.

Excerpts and Summaries from the IOM Report:
The goal for drugs that treat nausea and vomiting produced by cancer chemotherapy is complete control [stop vomiting completely] or major control [two or fewer episodes of vomiting]. [4.11]

THC
A controlled double-blind study compared THC with a standard antiemetic drug, metoclopramide, in cancer patients who received cisplatin, the chemotherapeutic drug that causes vomiting in more than 99 percent of patients. [4.11-4.12]

Conclusion
". . .results suggest that THC reduces chemotherapy-induced emesis [vomiting]. These studies also indicate that the degree of efficacy is not high." [4.12]

THC Analogues
"As with the THC trials, nabilone and levonantradol [two synthetic analogues of THC] reduced emesis, but not as well as other available agents. . . ." [4.13]

Smoked Marijuana
A double-blind, cross-over, placebo controlled study compared THC pills to smoked marijuana in 20 cancer patients receiving a variety of chemotherapeutic drugs. Only 25 percent of patients achieved complete control of vomiting. [4.13]

Conclusions
"Although many marijuana users have claimed that smoked marijuana is a more effective antiemetic than oral THC, no controlled studies have yet been published that analyze this in sufficient detail to estimate the extent to which that is the case." [4.14]

"Major progress, generally not well-known to the public, in controlling chemotherapy-induced acute nausea and vomiting has been made since the 1970s. Patients receiving the most difficult to control emetic agents now have no more than a 20-30 percent likelihood of experiencing acute emesis, whereas in the 1970s the likelihood was nearly 100 percent despite antiemetic." [4.15]

"Cannabinoids are not as effective as several other classes of agents. . ." [4.16]

"As with cannabinoids, efficacy was apparent with smoked marijuana, but the degree of efficacy was no better than that seen with available antiemetic agents now considered to be marginally satisfactory." [4.16]

"It is theoretically possible. . .that added to more effective regimens, THC might enhance control of emesis. . . .The critical issue is not whether marijuana or cannabinoid drugs might be superior to the new drugs, but rather whether there is a group of patients who might obtain added or better relief from marijuana or cannabinoid drugs." [4.16]

Recommendations
"Most chemotherapy patients are unlikely to want to use marijuana or THC as an antiemetic. In 1998, there are more effective antiemetic agents available than were available earlier. By comparison, cannabinoids are only modest antiemetics." [4.17]

"However. . .cannabinoids might be effective in people who respond poorly to currently used antiemetic drugs, or cannabinoids might be more effective in combination with the new drugs than either are alone." [4.17]

Therefore research should be pursued for patients whose nausea and vomiting is not completely controlled by standard antiemetic. [4.17]

Antiemetic pills are given to cancer patients before chemotherapy begins and then afterwards. In those patients who nonetheless experience nausea and vomiting after chemotherapy, "an inhalation (but preferably not smoking) cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced nausea." [4.17]

Until the development of such a system, "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." [4.17]

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C. Wasting Syndrome and Appetite Stimulation
1. No published research shows marijuana or cannabinoids are effective in treating malnutrition or wasting in AIDS patients.

2. A standard drug is more effective than THC in stimulating appetite in AIDS patients.

3. Cannabinoids modulate the immune system, which could be a problem in patients whose immune system is already compromised.

4. A major concern is that HIV-infected patients who smoke marijuana may be more vulnerable to the immunosuppressive effects of marijuana or to infectious organisms found in the plant material.

5. Cannabinoids, in combination with other drugs, might help increase appetite, help reduce nausea and vomiting caused by protease inhibitors, and help reduce the pain and anxiety associated with AIDS and cancer in late stages of these diseases.

6. There are medications that are more effective than marijuana for treating the nausea, appetite loss, pain, and anxiety associated with wasting, but these drugs are not equally effective for all patients.

7. A rapid onset form of THC should be developed and tested for these patients.

8. Smoking marijuana is not recommended. The long-term harms from smoking make it a poor delivery system for patients with chronic diseases.

9. For terminally ill patients who get relief from no other drugs, the medical benefits of smoking marijuana may outweigh the harms.

10. THC is ineffective in treating anorexia.

Excerpts and Summaries from the IOM Report:
"Despite their frequency of use, there is little published information about the effectiveness of marijuana or cannabinoids for the treatment of malnutrition and wasting syndrome in HIV-infected patients." [4.19]

"In 1992, the FDA approved THC, [dronabinol] under the trade name Marinol , as an appetite stimulant for the treatment of AIDS related weight loss. Megestrol acetatee (Megace ), an appetite stimulant, is more effective that dronabinol in stimulating weight gain, and there is no additive effect of dronabinol when used in combination with megestrol acetate." [4.19]

"There is evidence to suggest that cannabinoids modulate the immune system. . . , which might be a problem in immunologically-compromised patients." [4.19]

"Anecdotes abound that smoked marijuana is useful for the treatment of HIV-associated anorexia and weight loss." [4.19]

"In controlled laboratory studies on normal, healthy adults, smoked marijuana was shown to increase body weight, appetite, and food intake. Unfortunately, there have been no controlled studies of the effect of smoked marijuana on appetite, weight gain and body composition in AIDS patients." [4.19]

The first such study to test the safety of smoked marijuana in AIDS patients is underway but no results are available. [4.19]

"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 with marijuana plant material." [4.19]

Current Therapy
"Few therapies have proven successful in the treatment of AIDS wasting syndrome." Megestrol acetate increases food intake by about 30 percent but the weight gain that results is in fat tissue, not lean body mass. Preliminary findings suggest that "anabolic compounds, such as testosterone or growth hormone, might be useful in preventing the loss of, or help in restoring, lean body mass in AIDS patients." [4.20]

Future Therapy
"The primary focus of future therapies for wasting in HIV-infected patients is to increase lean body mass as well as appetite." [4.20]

"Even though cannabinoids do not appear to restore lean body mass, they might be useful as adjunctive therapy." [4.20]

"Additionally, cannabinoids could be beneficial for a variety of effects, such as increased appetite while reducing the nausea and vomiting caused by protease inhibitors, as well as the pain and anxiety associated with AIDS." [4.20]

"Considering current knowledge about malnutrition in HIV infection, cannabinoids, by themselves, will not likely be a primary therapy for this condition, but might be useful in combination with other therapies." [4.20]

Malnutrition in Cancer Patients
"The only cannabinoid evaluated for treating cachexia in cancer patients is dronabinol, which has been shown to improve appetite and promote weight gain." [4.21]

"Both megestrol acetate and dronabinol result in dose-related side effects that can be troublesome for patients. . . ." [4.21]

"Cannabinoids have also been shown to modulate the immune system. . .which could be contraindicated for certain cancer patients (both the chemotherapy and the cancer can be immunosuppressive)." [4.21]

"Cannabinoids such 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." [4.21]

Anorexia Nervosa
"THC appears to be ineffective in treating this disease." [4.21]

Recommendations
"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 there are medications that are more effective than marijuana for these problems, they are not equally effective for all patients. Thus we recommend the development and clinical testing of a rapid onset (that is, within minutes) form of THC for such patients. We do not recommend smoking. The long-term harms from smoking make it a poor drug delivery system, particularly for patients with chronic illnesses." [4.22]

"Terminal patients raise different issues. For those patients, the medical harms of smoking are 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 harms." [4.22]

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D. Muscle Spasticity and Multiple Sclerosis
1. There is little research evidence to support claims that marijuana reduces muscle spasticity in Multiple Sclerosis.

2. Research should be conducted to determine whether cannabinoids might relieve symptoms associated with MS.

3. Marijuana should not be smoked by patients with MS, a chronic disease.

Excerpts and Summaries from the IOM Report:
"Animal studies have shown that cannabinoids affect motor areas in the brain--areas that might influence spasticity." [4.23]

"Marijuana is frequently reported to reduce the muscle spasticity associated with this disease [multiple sclerosis]. In a mail survey of 112 MS patients that regularly use marijuana, patients reported that spasticity was improved and the associated pain and clonus [rapid contractions and relaxations of muscles] decreased. However, a double- blind placebo-controlled study on postural responses in 10 MS patients and 10 normal volunteers indicated that marijuana smoking impairs posture and balance in MS patients as well as normal volunteers. Nevertheless, the 10 MS patients felt that they were clinically improved." [4.23]

"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. Furthermore, surveys do not separate the effects of marijuana or cannabinoids on mood and anxiety from spasticity." [4.23]

"The effects of THC on spasticity were evaluated in a series of three clinical trials testing a total of 30 patients. They were 'open trials,' which means 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." [4.23]

Conclusions
"In general, the abundant anecdotal reports are not well-supported by clinical data." [4.26]

"Nonetheless, the survey results suggest that it would be useful to investigate the potential therapeutic value of cannabinoids in relieving symptoms associated with MS." [4.26]

"The regular use of smoked marijuana, however, would be contraindicated in a chronic condition such as MS." [4.26]

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E. Spinal Cord Injury
1. Animals research indicates that areas of the brain that control movement contain abundant cannabinoid receptors.

2. Clinical trials testing the effects of cannabinoids on muscle spasticity in spinal cord injury should be considered.

3. If THC is proven to relieve spasticity, then a pill might be the preferred delivery route for nighttime use.

4. An inhaled form of THC, if found to be effective, might be appropriate to relief acute episodes of spasticity.

Excerpts and Summaries from the IOM Report:
"Twenty-two of 43 respondents to a 1982 survey of people with spinal cord injuries reported that marijauna reduced their spasticity. 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." [4.28]

"The caveats described for surveys of spasticity relief in MS also apply here." [4.28]

Conclusions
"Basic animal studies. . .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." [4.29]

"The available clinical data are too meager to either accept or dismiss the suggestion that marijuana or cannabinoids relieve muscle spasticity. But. . .carefully designed clinical trials testing the effects of cannabinoids on muscle spasticity should be considered. Such trials should be designed to assess the degree to which the anxiolitic effects of cannabinoids contribute to any observed anti-spastic effects." [4.29]

"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." [4.29]

"The intensity of the symptoms resulting from spasticity, particularly in MS, can rapidly increase in an unpredictable fashion such that the patient develops an 'attack' of intense muscle spasms lasting minutes to hours. An inhaled form of THC (if it were shown to be efficacious) might be appropriate for those patients." [4.29]

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F. Movement Disorders
1. There is no research evidence that marijuana or cannabinoids are helpful in reducing symptoms that occur in movement disorders.

2. The anxiety-reducing aspects of marijuana and cannabinoids might be beneficial to some patients with movement disorders.

3. However, chronic marijuana smoking is a health risk for chronic conditions such as movement disorders.

4. Animal studies should be undertaken to determine if cannabinoids might play a role in movement disorders.

5. Clinical trials of isolated cannabinoids should be undertaken.

Excerpts and Summaries from the IOM Report:
"The movement disorders most often considered for marijuana or cannabinoid therapy are dystonia, Huntington's disease, Parkinson's disease, and Tourette's syndrome." [4.30]

Dystonia
"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 studies." [4.30]

Huntington's Disease
"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-over study on 15 Huntington's disease patients who were not taking any neuroleptic drugs. The symptoms neither improved nor worsened with CBD treatment." [4.31]

"Thus far there is little evidence to encourage clinical studies of cannabinoids in Huntington's disease." [4.31]

Parkinson's Disease
"At the time of this writing, we could find only one published clinical trial evaluating marijuana in five cases of idiopathic Parkinson's disease. . .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)." [4.31]

"Current data do not recommend clinical trials of cannabinoids in patients with Parkinson's disease." [4.31]

Tourette's Syndrome
"The clinical reports consist of four case histories indicating that marijuana use can reduce tics in Tourette's patients. 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." [4.32]

Summary and Recommendations
The abundance of cannabinoid receptors in parts of the brain that control movement "suggest that cannabinoids might be useful in treating movement disorders in humans. . .However, clinical evidence is largely anecdotal with no well-controlled studies of adequate numbers of patients." [4.33]

"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." [4.33]

"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." [4.33]

"Since stress often transiently exacerbates movement disorders, it is reasonable to hypothesize that the anxiolytic [anxiety-reducing] 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." [4.34]

Knowledge developed about the actions of cannabinoids in one part of the brain suggests that "there is clear a reason to recommend pre-clinical studies; that is, animal studies to test the hypothesis that cannabinoids play an important role in movement disorders." [4.34]

"With the possible exception of multiple sclerosis, the evidence to recommend clinical trials of cannabinoids in movement disorders is relatively weak." [4.34]

Because there are no good animal models for these disorders, however, "we recommend double-blind, placebo-controlled clinical trials of isolated cannabinoids that include controls for relevant 'side effects.'" [4.34]

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G. Epilepsy
1. Neither marijuana nor cannabinoids are effective in treating epilepsy.

Excerpts and Summaries from the IOM Report:
"There are anecdotal and individual case reports that marijuana controls seizures in epileptics. . .but there is no solid evidence to support this belief." [4.35]

"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 indicaed." [4.37]

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H. Alzheimer's Disease
1. Further clinical research should be conducted to determine if cannabinoids have a role in stimulating appetite in Alzheimer's patients with severe dementia.

2. Because short-term memory loss is a common side-effect of THC, the effect of cannabinoids on memory in Alzheimer's patients who are less severely disturbed must be considered.

Excerpts and Summaries from the IOM Report:
"Eleven Alzheimer's patients with dementia were treated for 12 weeks on an alternating schedule of dronabinol and placebo (six weeks of each treatment). The dronabinol treatment resulted in significant weight gains and declines in disturbed behavior. . . .These results are encouraging enough to recommend further clinical research with cannabinoids." [4.37-4.38]

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I. Glaucoma
1. Both cannabinoids and marijuana lower intraocular pressure (IOP).

2. However, both also lower blood pressure, which might reduce the flow of blood through the optic nerve and actually increase the progression of glaucoma.

3. Many effective medications are available to treat glaucoma at a cost of about $60 per month.

Excerpts and Summaries from the IOM Report:
"Cannabinoids or marijuana can reduce IOP [intraocular pressure] 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 to support the benefits of cannabinoids or marijuana on the natural progression of glaucoma, visual acuity, or optic atrophy." [4.39]

"In addition to lowering IOP, marijuana reduces blood pressure and has many psychological effects. . . .The reduction of blood pressure can be substantial, and might adversely affect blood flow to the optic nerve. . . .Hence, [for] 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." [4.39-4.40]

"There are many effective options to choose from today to slow the progression of glaucoma by reducing IOP." [4.40]

"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. [4.41]

Conclusions
"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." [4.41]

"Future research might reveal a therapeutic effect of isolated cannabinoids. For example, it might be possible to design a cannabinoid drug with longer-lasting effects on IOP and with less psychoactivity than THC." [4.41]

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J. The Medical Value of Marijuana and Related Substances Chapter 4, Summary (Full Text) [4.42-4.44]
"Advances in cannabinoid science of the last 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 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 have 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 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 systems 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 for 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.

"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-1' clinical trials using the same oversight mechanism as that proposed in the above recommendations." [4.42-4.44]

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