(JAMA. 1997;277:867-868)
IN 1988, Paul Palmberg, MD, PhD, was treating a glaucoma patient who did not respond to any of the conventional treatments. So his patient, Elvy Mussika, obtained marijuana from a federal government compassionate use program in hopes that it would lower her intraocular pressure.
Last month, Palmberg told his fellow members of a panel specially convened by the National Institutes of Health (NIH) in Bethesda, Md, that marijuana was the only agent that helped Mussika, who spoke during an activist-sponsored news conference at the meeting. "There may be a residual group of people for whom marijuana is essential. We ought to find out," Palmberg, professor of ophthalmology at the University of Miami School of Medicine in Miami, Fla, told the panel.
After a day and a half of hearing expert testimony and patients' testimonials, panel members said they believe sufficient rationale exists to conduct additional studies on the therapeutic use of marijuana. "For at least some of the potential indications, we feel that it looks promising," said William Beaver, MD, professor of pharmacology and anesthesia at Georgetown University School of Medicine in Washington, DC, and panel moderator.
Political Issue
Leaders from 10 centers of the NIH organized the 2-day workshop and nonpartisan panel in response to last fall's voter initiatives in California and Arizona that supported medicinal use of marijuana. The initiatives, said National Institute on Drug Abuse Director Alan Leshner, PhD, launched a public debate about which the NIH feels a "strong obligation" to provide information.
Leshner said the NIH is "quite open" to supporting further research on inhaled marijuana. However, activists at the workshop charged that the meeting was little more than a Clinton administration stalling tactic aimed at keeping the 2 new state initiatives in limbo. Steve Michael of ACT UP Washington, an AIDS activist group, called the meeting "a politically motivated dog and pony show."
Activists and patients with various medical conditions that marijuana is reported to benefit -- glaucoma, wasting syndrome from human immunodeficiency virus (HIV) infection, multiple sclerosis, and nausea from cancer chemotherapy -- gave brief comments during a public comment period. They asked the federal government to expedite marijuana research by moving the drug to schedule II of the Controlled Substances Act from schedule I, which indicates no therapeutic benefit. They also asked that the Investigational New Drug compassionate access program that was closed to new applicants in 1992 be reopened.
"Let [treatment] decisions be made in doctors' offices, not by federal bureaucrats," said Chuck Thomas, communications director of the Marijuana Policy Project in Washington, DC.
A formal report from the panel is expected this month. It will attempt to answer several basic questions concerning research that already has been done, questions that still need to be answered, medical conditions for which marijuana may be beneficial, and special issues in designing clinical trials.
Following testimony by experts in several specialty areas, the panelists said the drug warrants further study in the treatment of AIDS wasting syndrome, glaucoma, neuropathic pain, and nausea from cancer chemotherapy.
Appetite Stimulation
Richard Mattes, PhD, MPH, associate professor of foods and nutrition at Purdue University, West Lafayette, Ind, cited several studies showing that marijuana boosts food consumption. In a study of 131 people, 91% said they ate every time they smoked marijuana, 67% reported eating after smoking even if they weren't hungry, and 64% said smoking marijuana enhanced the sensory appeal of food (Br J Addict. 1970;65:347).
Additional studies, Mattes said, show that people using marijuana ate more than those taking a placebo and that marijuana smokers also ate more in social settings with other people than when they were alone. Studies of dronabinol (Marinol, Roxane Laboratories Inc, Columbus, Ohio), the synthesized form of marijuana's active ingredient, Delta9-tetrahydrocannabinol (THC), show that the medication does not cause the same enhanced taste sensations that smoking marijuana does, Mattes said.
Even though many of the studies were conducted more than 2 decades ago, said Mattes, it still is not clear how smoked marijuana affects the appetite and food intake. It could be involved in a collapse of the satiety mechanism, he said, which is different from the process that causes hunger.
"Intoxication and subjective sensations contribute to the therapeutic effect in food intake," Mattes said.
The topic is an important one for future research because, as new drug combinations improve survival for people with HIV infection, the proportion of people who have wasting syndrome as an AIDS-defining event is increasing. The proportion is up to 31% in some studies, said Kathleen Mulligan, PhD, assistant professor of medicine at the University of California, San Francisco, School of Medicine.
Mulligan said currently approved medications and investigational therapies such as anabolic hormones and cytokine suppressors have provided "no satisfactory solution" for patients with wasting syndrome. In placebo-controlled studies of megestrol acetate, Mulligan said, patients gain weight, but it is predominantly fat.
Studies of dronabinol show the drug increases appetite, but findings on weight increase are inconsistent, Mulligan said. Dronabinol also is associated with delayed onset of effectiveness, prolonged duration, and patients' complaints of getting "too stoned." Adding dronabinol to megestrol produces no benefit, Mulligan noted.
Questions that further research might answer, Mulligan said, include whether marijuana helps to increase total energy intake in patients with catabolic illnesses, whether snacking increases but consumption of full meals decreases, and what the composition is of weight gained.
Nausea From Chemotherapy
New therapies developed in the last 15 years have substantially improved nausea and vomiting control for cancer patients receiving chemotherapy, Richard Gralla, MD, director of the Ochsner Cancer Institute in New Orleans, La, told the NIH panel.
Gralla said the list of effective antiemetics includes corticosteroids and serotonin antagonists such as the highly effective ondansetron and granisetron. Standards for efficacy have also improved. Gralla said clinicians today "focus on complete control -- no vomiting whatsoever." Some patients consider 3 or more chemotherapy-related episodes of nausea to be severe, he said, because emesis can be so well controlled with the newer drugs.
Even so, Gralla called smoked marijuana "a strategy that needs to be investigated," mainly because patients ask about it. He said several studies conducted in the 1970s with small numbers of patients showed dronabinol to be more effective than placebo in the control of nausea and vomiting, so "THC clearly has antiemetic effects." However, in a double-blind randomized study he conducted in the 1980s, Gralla said, metoclopramide hydrochloride was "significantly more effective than dronabinol."
Gralla said the medical literature contains just a single study comparing the efficacy of inhaled marijuana with dronabinol and a cannabinoid-containing placebo as an antiemetic (Proc 20th Annu Mtg Amer Soc Clin Oncol. 1984;3:91). The prospective randomized, double-blind comparison -- a crossover design trial -- of 20 patients showed that only 5 (25%) were free of vomiting and 3 (15%) had no nausea. "The overwhelming number had both vomiting and nausea regardless of whether they got THC or inhaled marijuana," Gralla said. The main end point of the study was patient preference, he said, and the result was that 45% of patients stated no preference, 35% preferred dronabinol, and 20% preferred marijuana.
Because of the recent state initiatives, Gralla said, patients are asking about marijuana, but there currently isn't enough evidence to tell them whether it should be used as a frontline therapy or in conjunction with other drugs. Without further study, he said, lingering questions may never be resolved.
What About Glaucoma?
Currently, manipulation of intraocular pressure is the only effective treatment for glaucoma, said Paul Kaufman, MD, professor of ophthalmology and director of glaucoma services at the University of Wisconsin Medical School, Madison.
Currently used treatments include beta2 adrenergic agonists and antagonists, prostaglandin analogues, and laser surgery. But after reviewing the medical literature, Kaufman said, "there is very little question in my mind that marijuana lowers the intraocular pressure." Kaufman said the original study at the University of California at Los Angeles in the 1970s showed that inhaled marijuana could decrease intraocular pressure by 24%. Other studies have shown decreases of 7 mm Hg to 9 mm Hg, he noted.
But marijuana and orally administered THC were not widely used because the therapeutic effect was not long-lasting. "You would have to pretty much use it around the clock to treat this disease," Kaufman said.
He also expressed concern that marijuana constricts the pupils and causes hyperemia of the conjuctiva. Some reports also indicate that marijuana lowers blood pressure, which could affect optic nerve blood flow. However, during a discussion among panel members, Palmberg said his patient has experienced no change in blood pressure during long-term use. "Acute administration might be different," he said. "It should be studied."
Kaufman also pointed out that many of the drugs now used to treat glaucoma didn't exist when the initial studies on marijuana's effects were done. "It's almost like we have to start all over again to see where the place of marijuana is with all of these other drugs."
Movement Disorders and Analgesia
Marijuana use has been associated with decreased spasticity in multiple sclerosis patients, but the data are scant, said Paul Consroe, PhD, professor of pharmacology and toxicology at the University of Arizona College of Pharmacy in Tucson, Ariz.
Clinical studies contain very small numbers of patients, and findings are conflicting, Consroe said. Some patients experience decreased spasticity and ataxia; others find it difficult to maintain their balance. Dronabinol reduces tremors in some patients but causes overwhelming dysphoria in others.
For conditions such as dystonia, Huntington disease, and Tourette syndrome, Consroe said there are few or no clinical data, but animal studies show potential benefit. However, he said clinical studies, anecdotal evidence, and case studies dating back to the 1800s show that marijuana and oral THC can reduce seizures in patients with epilepsy. Overall, Consroe concluded that more studies are needed. "Show me the money," he said, using the quip popularized by the film Jerry Maguire.
Data indicating whether marijuana has analgesic properties also are weak, said Richard Payne, MD, chief of pain and symptoms management at M. D. Anderson Cancer Center in Houston, Tex. "The evidence we have for [producing an analgesic effect] in animal models is confusing," he said.
In some studies using rats, THC was as potent as morphine in delaying the animals' response to a painful stimulus. But in mice THC appeared more effective than morphine in delaying the response. In other studies, however, THC appeared less potent than morphine in both species. In humans, Payne said, the 20-mg dose of THC needed to produce an analgesic effect causes severe adverse effects of delirium and dysphoria.
In rat models of neuropathic pain, cannabinoid analogues decrease hyperalgesia and allodynia and can reverse them, Payne said. In humans, he added, marijuana may have a role in easing neuropathic pain because even though opioids are effective, they are needed at very high doses. Payne said the question of whether smoked marijuana or oral THC has true analgesic properties in doses that don't cause adverse effects remains unanswered.
Additional Hurdles
Questions about how to design clinical trials of smoked marijuana that will produce valid results have dogged researchers for years and continue to do so.
Because of its unique smell when smoked, maintaining blinded studies is difficult at best. Individuals also inhale different amounts during the beginning, middle, and end stages of smoking, and puff volume can differ from one smoking episode to another. Some people simply cannot tolerate smoking, and it presents a risk for pulmonary disease.
For some patients in clinical studies, Beaver suggested that the use of an inhaler or vaporizer would be beneficial. He noted that one of smoked marijuana's most appealing aspects for patients with nausea from cancer chemotherapy is that it doesn't require swallowing a pill.
In addition to the possibility of laying to rest a host of unanswered questions about smoked marijuana's therapeutic properties, members of the NIH panel and experts who testified said further research will be valuable in uncovering basic information about human physiology and disease processes.
Palmberg said additional research into the use of marijuana for glaucoma could reveal whether and to what extent THC receptors are located in the eye. Mulligan pointed out that further study may determine whether continued wasting in patients with AIDS contributes to the disease process independent of opportunistic infections.
To date, Mulligan said, there are no studies to demonstrate that reversal of wasting can improve survival in patients with AIDS.
-- by Rebecca Voelker
(JAMA. 1997;277:867-868)
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