ARTICLE IN BRIEF
✓ An advocacy group that supports legalizing medical marijuana filed a legal challenge to the FDA position that marijuana has no proven medicinal value following a study in Neurology showing it was effective for relieving pain caused by HIV-associated sensory neuropathy.
San Francisco was the epicenter of a late-winter rumble of scientific and legal developments regarding medical marijuana, the aftershocks of which could lead to a seismic shift in how the herb is used and regulated across the country.
On Feb. 13, a San Francisco researcher published one of the first randomized trials of smoked marijuana (as opposed to orally delivered extracts) showing that it significantly relieved the symptoms of HIV-associated sensory neuropathy (Neurology 2007;68:515–521).
Eight days later, a San Francisco advocacy group filed suit against the federal government over its insistence that the drug has no medical value.
Then, on Mar. 14, federal appellate judges in San Francisco ruled that a woman using marijuana on a doctor's recommendation for a variety of ailments was not exempt from prosecution under federal law, but noted that “the use of marijuana for medical purposes is gaining traction.”
While there was no direct link between the new study and either of the legal cases, the attorney who crafted the legal challenge to federal statements on medical marijuana conceded that the timing was no coincidence.
“From a legal perspective, the study is not part of our case, but we consciously chose to file it a week after the study came out to help draw attention to the issue,” said Joe Elford, staff attorney for Americans for Safe Access, a national group advocating the legalization of marijuana for medical purposes.
HIV-ASSOCIATED NEUROPATHY TRIAL
Among the 50 patients who completed the trial, cannabis cigarettes smoked three times daily for five days reduced daily HIV-associated sensory neuropathy by 34 percent, vs. 17 percent with placebo cigarettes with the cannabinoids extracted (p = 0.03), according to the study in Neurology. The findings were greeted with a mixture of caution and enthusiasm by neurologists in Canada, England, and the United States.
“I think it was a very well-designed study,” said Donald W. Gross, MD, assistant professor of neurology in the department of medicine at the University of Alberta and director of the university's Comprehensive Adult Epilepsy Program. “From my perspective, the results are not a big surprise. There is a fair amount of information about analgesic properties of cannabinoids.”
Joseph I. Sirven, MD, associate professor of neurology at the Mayo Clinic College of Medicine in Arizona, agreed that the study was well designed. “Rigorous scientific standards have been applied,” he said. But, he added, “It is unclear whether this represents the beginning of a flood of evidence to support cannabis.”
Perhaps the most rigorous element of the trial was its inclusion of an experimental pain model, used on 30 of the 50 patients, which sought to overcome the potential for unblinding among patients due to the mood-altering effects of cannabinoids.
“The experimental pain model is difficult to influence with bias, because none of the patients knew what we were doing or measuring,” said the study's principal investigator, Donald I. Abrams, MD, professor of clinical medicine at the University of California-San Francisco (UCSF), and assistant director of the UCSF Positive Health Program at San Francisco General Hospital.
THE EXPERIMENTAL PAIN MODEL
The first part of the study's pain model involved the long thermal stimulation procedure, in which subjects rate the amount of pain they feel in response to having a thermode heat their non-dominant shoulder to 45 degrees C for one minute.
The second part involved the heat/capsaicin sensitization model, in which hyperalgesia is induced by heating a small patch of a subject's forearm with a thermode for five minutes, then treating it with topical capsaicin cream for 30 minutes, and periodically reheating it throughout the test period. The site and surrounding area is then mapped for secondary hyperalgesia in response to a one-inch foam brush and a 26-g von Frey hair, which produces a mildly noxious pin-like sensation. Both tests were performed once prior to smoking marijuana, and three times after.
Among the 30 patients who completed the experimental pain model, there was no significant difference in pain perception between active and placebo on the long thermal stimulation procedure, but significant differences in the heat/capsaicin sensitization model did emerge.
After the first smoked cannabis cigarette on the first day of the study, the area of secondary hyperalgesia to brush stimuli dropped a median of 34 percent, compared to a drop of 11 percent among those who smoked the placebo cigarettes (p = 0.05). On von Frey hair stimuli, the area of secondary hyperalgesia dropped a median of 52 percent, compared to an increase of 3 percent among the placebo group (p = 0.05).
The data from the experimental pain model, the paper concluded, suggest “that cannabis has analgesic effects on acute central neuronal sensitization produced by the experimental pain model as well as on the neuronal mechanisms associated with painful [HIV-associated sensory neuropathy].”
SIDE EFFECTS FROM CANNIBIS
The study also showed significant, albeit modest, increases in anxiety, sedation, disorientation, paranoia, confusion, dizziness, and nausea among patients receiving active vs. placebo marijuana. Surprisingly, the Profile of Mood States found a reduction in total mood disturbances among both active and placebo groups.
Dr. Sirven said, “Cannabis does produce considerable adverse effects, but then so does morphine. The issue is the risk-benefit analysis.”
Dr. Gross expressed particular concern about the risk of impaired driving ability following marijuana use. “There is clear evidence that cannabinoids impair driving ability,” he said. What's more, he added, “The degree and duration of impairment is not very predictable, which would make it difficult to set limits as we do with alcohol.”
The only previously established therapies for HIV-associated sensory neuropathy are the anticonvulsant drugs lamotrigine and gabapentin, but some patients fail to respond or cannot tolerate them.
Dr. Abrams' study included an analysis of the number of patients needed to treat with cannabis to reduce the painful neuropathy by at least 30 percent, finding that 3.6 patients would be necessary for one to achieve that benefit — a number comparable to previous studies of anticonvulsives.
“Although we didn't do a head-to-head comparison, we concluded that smoked cannabis was in the same ballpark as what's currently the standard of care for HIV-associated neuropathic pain,” Dr. Abrams said.
While a growing body of research has found that oral extracts of cannabis, including dronabinol (Marinol) pills and Sativex spray, can relieve pain and nausea and improve appetite, few well-designed trials have involved smoked cannabis. The new study is the first to use marijuana provided by the National Institute of Drug Abuse.
David Baker, PhD, professor of neuroscience at Barts and the London School of Medicine and Dentistry, Queen Mary University of London, said the study was too short to determine whether the effects are sustainable and safe in the long-term.
However, he added, “The important point should be not whether one legalizes smoked marijuana, but whether we can find a non-smoked alternative, which can achieve similar or greater benefit. If it is possible to show benefit from smoked cannabis in controlled studies, then one has a yardstick with which it should be possible to test non-smoked alternatives.”
Dr. Abrams insisted that smoked cannabis has benefits over non-smoked oral cannabinoids. “Marijuana has 60 cannabinoids and hundreds of other ingredients that may have important benefits,” he said. “I think there's room for a variety of cannabinoid therapeutics.”
APPROVAL FOR SATIVEX
Although not yet legalized in the United States, Sativex spray received approval from the FDA last year to begin a late-stage trial for advanced cancer pain. The maker, GW Pharmaceuticals, has announced plans with its U.S. marketing partner, Otsuka Pharmaceutical Co., to begin a phase 2/3 cancer pain dose-ranging study later this year.
In March, a randomized, six-week trial of Sativex for relief of intractable spasticity in 189 patients with multiple sclerosis found it significant over placebo as subjectively rated by patients (p = 0.048) but not as objectively measured on the Ashworth scale (Eur J Neurol 2007;14:290–296). Similar results were reported in a 2003 trial of 667 MS patients treated with either oral cannabinoids or placebo that found no effect on spasticity as measured by the total Ashworth score, but did see a small but significant improvement in patients' subjective reports of spasticity and pain (Lancet 2003;362:1517–1526).
As a result of such findings, Dr. Gross said he remains unconvinced of cannabinoids' efficacy in treating spasticity, muscle spasms, or tremors in MS patients, and is even more doubtful of any effect of cannabinoids on epileptic seizures, his specialty. As a result, he remains reluctant to participate in the Canadian system that permits patients to obtain legal access to marijuana with a physician's consent.
“I've struggled with the ethics,” Dr. Gross said. “When patients ask me, I say honestly there isn't any good evidence that marijuana is an effective treatment for epilepsy.”
THE CASE FOR THE LAWSUIT
Yet for the advocacy group challenging the FDA's published statements, the evidence was already strong enough as of October 2004 to show that at least some medical benefits had been demonstrated. It was then that Americans for Safe Access initiated the legal process, which, this February, culminated in the filing of the lawsuit.
The challenge rests upon a requirement of a federal law, the Data Quality Act, that government information be accurate and based on sound science. The suit claims that the FDA's published statements, that “marijuana has no accepted medical value,” and that “there have been no studies that have scientifically assessed the efficacy of marijuana for any medical condition,” are factually inaccurate.
In its latest statement on marijuana, the FDA released an inter-agency advisory on April 20, 2006, in response to claims that smoked marijuana is a medicine. “Some have argued that herbal marijuana is a safe and effective medication and that it should be made available to people who suffer from a number of ailments upon a doctor's recommendation,” the statement noted. But, it continued, “Marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision.”
Although he has no involvement with the lawsuit, Dr. Abrams said of this new study, “For people who say there is no evidence that cannabis has any medical benefit, I would say there is now some evidence.”
The Mar. 14 ruling by federal appellate judges involved the case of Angel McClary Raich, who in 2002 filed suit against the government to gain the legal right to take marijuana to increase her appetite and relieve pain due to an inoperable brain tumor and other illnesses. In 2005, the US Supreme Court had rejected most of her claims, and now the Court of Appeals for the Ninth Circuit rejected the remainder. While the court acknowledged that it had seen what it called “uncontroverted evidence” that she needed the marijuana to survive, it ruled that the right to use medicinal marijuana has not yet been shown to be fundamental.
Elford, the attorney representing Americans for Safe Access, said the decision in the Raich case held out hope for advocates of the legalization of marijuana for medical purposes. “The Ninth Circuit was very careful to say that there may well be a fundamental liberty interest in using medical marijuana in the future, as the science grows,” he said.