By Jill U. Adams
August 18, 2008
As the political debates over medical marijuana drag on, a small cadre of researchers continues to test inhaled marijuana for the treatment of pain, nausea and muscle spasms.
All drugs have risks, they point out -- including ones in most Americans' medicine cabinets, such as aspirin and other pain-relievers or antihistamines such as Benadryl. Doctors try to balance those risks against the potential for medical good -- why not for marijuana as well, they ask.
The truth, these researchers say, is that marijuana has medical benefits -- for chronic-pain syndromes, pain, multiple sclerosis, AIDS wasting syndrome and the nausea that accompanies chemotherapy -- and attempts to understand and harness these are being hampered. Also, they add, science reveals that the risks of marijuana use, which have been thoroughly researched, are real but generally small.
Dr. Donald Abrams, chief of hematology and oncology at San Francisco General Hospital and professor of clinical medicine at UC San Francisco, says he sees cancer patients in pain, not eating or sleeping well, experiencing nausea and vomiting from treatment, and being depressed about their situation. He says he is glad that he lives in California, where use of medical marijuana is allowed by state law, although federal officials continue to raid cannabis dispensaries in the state and scrutinize practices of physicians who specialize in writing cannabis recommendations for patients.
"I can talk to patients about medicinal cannabis [and] I'm often recommending it to them for these indications," Abrams says.
Pro marijuana: A balm for pain
Medical marijuana use has a history stretching back thousands of years. In prebiblical times, the plant was used as medicinal tea in China, a stress antidote in India and a pain- reliever for earaches, childbirth and more throughout Asia, the Middle East and Africa.
In recent decades, medical researchers have investigated marijuana's effects on various kinds of pain -- from damaged nerves in people with HIV, diabetes and spinal cord injury; from cancer; and from multiple sclerosis. Marijuana has also been hypothesized to help with nausea induced by chemotherapy and antiretroviral therapy, and with severe loss of appetite as seen in people with the AIDS wasting syndrome.
The weed's actions are due to the active ingredients tetrahydrocannabinol (THC) and some 60 other cannabinoids, which mimic the action of chemicals -- known as endogenous cannabinoids -- that exist naturally in the brain. Those cannabinoids activate receptors in our nerves, triggering physiological responses.
A legal prescription form of THC (Marinol) exists, yet researchers say it's far from a perfect drug. Taken orally, its absorption is highly variable and unpredictable and often delayed, says Dr. Igor Grant, a UC San Diego psychiatrist who directs the university's Center for Medicinal Cannabis Research. "Smoking is a very efficient way to deliver THC," he says.
As a result of its federally illegal status, medicinal use of marijuana is restricted to carefully vetted clinical research studies or to patients in states such as California that have passed laws to allow for personal medical use. Research on the medicinal use of marijuana relies on government-issued marijuana cigarettes, which come in different strengths and are supplied by the National Institute on Drug Abuse.
The UC Center for Medicinal Cannabis Research in San Diego helps coordinate clinical studies to investigate the safety and effectiveness of marijuana. Here's what they've found.
Recent research suggests that marijuana can assuage this chronic-pain syndrome in which burning sensations occur and simple touch can feel like hurt. It is unaffected by aspirin-like drugs and fairly resistant to stronger analgesics such as opiates.
In a 2007 study on neuropathic pain related to HIV infection, 50 patients smoked marijuana cigarettes three times a day or marijuana cigarettes from which active ingredients had been extracted. Subjects then rated their pain on a scale ranging from "no pain" to "worst pain imaginable." The results, published in the journal Neurology, showed a 34% reduction in ratings of pain in the marijuana group compared with 17% in the placebo group over five days of treatment.
Another study in 44 patients reported in June in the Journal of Pain found that marijuana alleviated neuropathic pain arising from a variety of conditions, including spinal-cord injury and diabetes. Participants smoked marijuana on a set schedule -- first two puffs, then three puffs an hour later, then four puffs an hour after that -- from a single cigarette containing either 0%, 3.5%, or 7% THC. Average pain ratings before smoking were 55 on a 100-point scale and decreased by 46% in both treatment groups and by 27% in the placebo group one hour after the last puff.
Analgesic drugs are often tested against experimentally induced pain. Such studies have been conducted for marijuana too. In one 2007 report in the journal Anesthesiology, 15 healthy volunteers received skin injections with capsaicin -- the chemical behind that fiery spice in chile peppers -- and then smoked different-strength marijuana cigarettes. The medium dose, with a 4% THC concentration, lessened the burning pain.
These three pain studies all concluded that smoked marijuana can bring relief to sufferers of neuropathic pain comparable to other analgesic drugs. It is not a cure, Grant says: "It's like other pain medicines, you have to keep taking it."
Study subjects did feel high, an effect that varied among individuals. Marijuana also affected thinking, shown as problems with tasks of memory and complicated reasoning after the strongest marijuana cigarettes were used. Potentially problematic, these effects were tolerated by subjects -- no one opted out of the study because they couldn't think straight.
Grant says it's important to have a choice of treatments because not everyone responds to or can tolerate the available drugs. Antidepressants are used for neuropathic pain but cause dry mouth, constipation and urinary problems, and must be avoided by people with conditions such as glaucoma. Others can't take aspirin-like drugs. "Having an alternative compound is always good," Grant says.
Patients with multiple sclerosis suffer muscle spasms, pain and tremor. Anecdotal reports suggest that marijuana may be helpful, but controlled studies are few. One, presented at an April meeting, had 51 multiple sclerosis patients smoke 0% or 4% THC marijuana cigarettes daily for three days. Intensity of spasms was reduced by 32% and pain ratings by 50% after smoking marijuana, compared with 2% and 22% reductions after placebo cigarettes. Five subjects withdrew, citing side effects: feeling too high, dizzy or fatigued.
Other studies in patients with multiple sclerosis used a cannabis extract that can be taken orally. In a 2007 European Journal of Neurology study, nearly half of 184 patients experienced at least 30% improvement in muscle spasms.
But a 2004 Neurology paper showed no reduction in objective measures of arm tremor with cannabis extract, although five subjects out of 13 reported feeling improvement. This might have resulted from mood-altering effects of the drug or from some aspect of tremor not measured.
A 2008 review published in the European Journal of Cancer Care analyzed 30 clinical studies using cannabinoid drugs synthesized in the lab and concluded that they were better than standard antinausea drugs in alleviating the nausea and vomiting that accompanies chemotherapy. One such drug is Marinol, a THC preparation approved by the Food and Drug Administration for precisely this purpose.
Survey studies suggest that some people with HIV smoke marijuana to counteract nausea caused by antiretroviral therapy. Researchers at the UC Center for Medicinal Cannabis Research have tried to study the effect of smoked marijuana on nausea and vomiting in patients undergoing chemotherapy but have struggled to enroll enough subjects, Grant says.
Bruce Mirken, director of communications for the Marijuana Policy Project -- a group that lobbies for the decriminalization of marijuana -- says he is all for research on the chemical components in marijuana with the goal of making more-purified and perhaps more-targeted drugs that do not deliver a "high," but does not see "criminalizing use of that plant by people who are ill when you are making its main psychoactive ingredient legal in the form of a very expensive pill."
Tom Riley, a spokesman for the White House Office of National Drug Control Policy, says marijuana advocates are seeking a free pass. "They want to be exempted from the regular [drug] approval process," he says.
Con marijuana: Damaging habit?
Marijuana is the most widely used illicit drug in the country -- an estimated 25 million Americans smoked it within the last year and close to 100 million have smoked it at least once in their life, according to the most recent National Survey on Drug Use and Health by the federal Substance Abuse and Mental Health Services Administration.
Rates and severity of marijuana addiction pale in comparison to that of legal addictive drugs, alcohol and nicotine, according to the Advisory Council on the Misuse of Drugs, a panel of independent experts advising the British government, in a rare head-to-head, scientific comparison.
Yet, the fact is, recreational use can lead to addiction, and inhaling marijuana smoke is unhealthful for the lungs. Some researchers argue that marijuana may predispose heavy users to mental illnesses such as psychosis and depression.
How big are these risks and how should they be measured against health benefits? "The FDA has ruled that marijuana has no medical benefits, but its harms are well known and proven," says Tom Riley, a spokesman for the White House Office of National Drug Control Policy, referring to an April 2006 statement released by the FDA and several other federal agencies concluding that smoking marijuana was not of medicinal use.
For comparison's sake, Riley cites the prescription drug Vioxx. The FDA, he notes, pulled Vioxx off the market in spite of its proven efficacy, because it created problems in a small number of people.
Then, too, the number of people adversely affected by marijuana use is large, Riley says. "There are more teens in drug treatment for marijuana dependence than for alcohol or any other drug," he says.
Marijuana is a Schedule 1 drug by the Drug Enforcement Administration's Controlled Substances Act, a classification reserved for drugs carrying the highest risk for addiction and no medical benefit.
Scientists have reviewed the weed's risks and find them to be real, but small. Ten years ago, the Institute of Medicine reviewed the scientific evidence about marijuana at the request of the Office of National Drug Control Policy. The 1999 report states that, "except for the harms associated with smoking, the adverse effects of marijuana use are within the range of effects tolerated for other medications."
In February, the American College of Physicians, the nation's second-largest physicians group, released a position paper in support of medical-marijuana research, protecting doctors from criminal prosecution and rescheduling marijuana as a less harmful drug.
A British advisory group this year found no evidence to reclassify cannabis as a more harmful drug in that country. In contrast to the U.S., the U.K. puts cannabis in the lowest category (Class C) in terms of criminal penalties for possession or sale, although government officials are campaigning to move it to Class B.
To investigate the risks of marijuana, researchers typically use heavy marijuana smokers as subjects. Though such a study design may be convenient, it makes interpretation tricky because heavy users may have traits in common besides smoking pot. Thus, says psychologist and marijuana researcher Stanley Zammit of Cardiff University in Wales, it is not easy in these kinds of studies to separate out the contribution of marijuana to any measurable effect in the group.
Claims of a link between marijuana use and psychotic episodes came under scrutiny after the U.K. downgraded cannabis from Class B to Class C in 2004. In 2007, Zammit was asked by England's Department of Health to survey the existing evidence to determine the long-term risks for mental illness from using cannabis. After researching the literature and including only those studies that satisfied certain criteria, he combined the results in a 2007 Lancet paper.
He concluded that marijuana use was associated with an increased risk of psychosis -- ranging from self-reported symptoms such as delusions or hallucinations to clinically diagnosed schizophrenia.
The risk is small, he adds. Cannabis use was associated with a 40% increase in risk overall and up to a twofold increase in heavy users. Because the risk of any person developing psychosis in their lifetime is about 2% to 3%, cannabis use at worst increases that to 5%. "So 95% of the people are not going to get psychotic, even if they smoke on a daily basis," Zammit says.
Zammit adds that "the main limitations of these studies is that you can never be sure that it's the cannabis itself that's causing this risk." Heavy users of marijuana may differ from nonusers in other traits -- including those that lead independently to increased drug use and risk of psychosis. The studies he reviewed tried to take into account this possibility but could not rule it out entirely.
The bottom line? "The evidence is probably strong enough that people should be aware of this risk," he says.
Even if it's real, the risk of developing psychosis because of marijuana use is smaller than with use of some other drugs -- including legal ones such as cigarettes, says Mitch Earleywine, a psychologist at the State University of New York University at Albany.
Grant says that numbers of schizophrenia cases have not increased since before the 1960s, when widespread marijuana use began. "The data are variable to be sure, but most studies have found that over the years the rate of schizophrenia has been stable or even declining," he says.
In an American Journal of Psychiatry study, 1,920 adults were assessed for marijuana use and depression and followed for 15 years. In those subjects who had no depressive symptoms at the study's start, marijuana abusers were four times more likely to develop depressive symptoms down the road. But Zammit, who reviewed this paper and 23 others in his 2007 Lancet paper, says the data overall are even murkier than for psychosis. Most of the studies he reviewed did not assess symptoms of depression before marijuana use, and so didn't rule out the idea that depression makes someone more likely to smoke marijuana -- and not the other way around.
A review of the scientific literature published in the Journal of the International Neuropsychological Society in 2003 looked at whether marijuana smoking had lasting effects on cognition after THC has left the body. Marijuana use was found to have small effects on memory in long-term users -- measured by asking subjects to recall words, for instance -- but no differences were seen on attention, verbal skills and reaction time. "We were actually surprised," says Grant, an author on the study. Even if the marijuana itself wasn't causing such things, he expected marijuana users might have other less-than-healthful behaviors -- they may drink a bit more, or use some other drugs, and "you might expect them to do a little worse."
A 2002 study published in the Journal of the American Medical Assn. found that a group of 51 heavy marijuana users (two joints per day) recalled two to three fewer words on average than nonusers in a memory test with a list of 15 words.
A second study, published in the Archives of General Psychiatry in 2001, found a similar deficit in 63 daily marijuana smokers who hadn't smoked for up to a week. After 28 days of not smoking marijuana the effect disappeared.
Studies on brain function and mental illness cited above were conducted in adult marijuana users. How the drug affects adolescents is not completely resolved, but the data are more troubling.
A 2000 paper in the Journal of Addictive Diseases recruited 58 marijuana users and found structural changes in the brains of those who had starting smoking marijuana before age 17 but not in those who didn't start smoking until they were older.
"There's also a modest decrease in IQ if teens use heavily, though weekly users and folks who quit don't seem to show it," Earleywine says. Adolescence, he says, is a time when brain neurons are making oodles of new connections, and it's possible that a psychoactive drug such as marijuana may adversely influence that process.
Before it has any effect on the brain, marijuana smoke enters the body through the lungs. Dr. Donald Tashkin, professor of medicine at the UCLA David Geffen School of Medicine, has studied the pulmonary consequences of marijuana use for 25 years, recruiting a group of 280 heavy habitual pot smokers in the early 1980s, including some who also smoked cigarettes. (Subjects averaged three joints per day for an average of 15 years.) For comparison, he also recruited cigarette smokers who didn't use marijuana and people who didn't smoke anything.
Tashkin has done a number of studies over the decades comparing these groups. "I began with the hypothesis that regular smoking of marijuana would have an impact on the lungs qualitatively similar to the impact of regular tobacco smoking," he says. That's because the smoke of both plants are more similar than different.
Tashkin and his colleagues did find symptoms of chronic bronchitis in his marijuana-smoking group. In a 1987 study in the American Review of Respiratory Diseases, they reported that incidence of chronic cough, sputum production and wheezing was similar to that in cigarette smokers.
In a second study in the same subjects published in the American Journal of Respiratory and Critical Care Medicine in 1998, examination of the airways and the cells lining the airways found swelling, redness and increased secretions in marijuana users. Biopsies showed "extensive, widespread damage to the mucosa," Tashkin says, similar to what was seen in tobacco users. "This is amazing, because the marijuana smokers average three joints a day, but the tobacco controls smoked 22 cigarettes, suggesting that on a cigarette-to-cigarette basis, marijuana may be more damaging."
But marijuana smokers differ from tobacco smokers in other, potentially more important ways, Tashkin adds. They do not seem to develop more serious consequences of cigarette smoking, namely chronic obstructive pulmonary disease (COPD) -- the fourth leading cause of death in the U.S., killing 130,000 people each year -- or lung cancer, the most common cancer in Americans and responsible for an additional 160,000 annual deaths, according to 2005 statistics from the Centers for Disease Control and Prevention.
To study lung cancer, Tashkin looked at more than 600 lung cancer patients and more than 1,000 control patients matched for age, socioeconomic class, family history and other alcohol and drug use (along with many other potential influences).
The results, published in a 2006 paper in Cancer Epidemiology Biomarkers and Prevention, found a large number of regular marijuana smokers were present in both groups, but statistically there were no more in the cancer group than control group, suggesting no association between marijuana use and lung cancer. Tobacco smokers, on the other hand, showed a dose-dependent increase in risk: with a 30%, 800% and 2,100% increased risk of lung cancer in those who smoked less than a pack, one to two packs or more than two packs per day, respectively.
Other studies have found increased cancer risk. A study of 79 lung cancer patients and 300 controls published in the European Respiratory Journal this year found a fivefold increased risk in the heaviest marijuana users (daily use for 10 years) and no effect in less heavy users.
But Tashkin says this conflicting report was much smaller in scale, having fewer than 20 subjects in the group of heaviest marijuana users. "My critique would be: It's a small study. I think that their small sample size is responsible for vastly inflated estimates," he says.
Vapor versus smoke
Smoking anything is perceived as bad these days, says Dr. Donald Abrams, chief of hematology and oncology at San Francisco General Hospital and professor of clinical medicine at UC San Francisco. And so he devised a pilot study to evaluate a novel inhalation method conducted in 18 otherwise-healthy subjects. "We used a device that heated cannabis below the point of combustion -- basically, a heating element and a fan. The fan filled up a balloon from which the patients could inhale," Abrams says.
The findings, published in Clinical Pharmacology and Therapeutics in 2007, showed that levels of THC were "virtually identical," as were patients' reports of subjective "high." No increase in exhaled carbon monoxide was observed with vaporized marijuana, as was the case with smoked marijuana, and patients preferred vaporization to smoking.
"The fact is that whole marijuana, particularly when vaporized and not smoked, is a safe and effective delivery system," says psychiatrist Dr. Igor Grant, director of the UC Center for Medicinal Cannabis Research in San Diego.
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