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Neurology Today:
doi: 10.1097/01.NT.0000368754.06325.0a
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As Another State Approves Medical Marijuana, Neurologists Urge Caution About Prescribing

FALLIK, DAWN

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ARTICLE IN BRIEF

Neurologists point out the dearth of evidence-based research to support medical marijuana for neurological conditions, but some offer anecdotal reports that show it helps manage certain symptoms.

Last month, New Jersey became the 14th state to approve the use of medical marijuana for specific diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

But some neurologists practicing in already approved states said that while a chemical in the plant may help some patients, more research is needed on how it affects symptoms and causes. And they cautioned doctors to set boundaries within their own practice to prevent the “free-for-all” storefronts in place in California, which they say has become too lax in its standards.

“How do you separate wishful thinking versus clinical data?” asked Denis Petro, MD, a neurologist in Pennsylvania who has been openly supportive of medical marijuana laws and helped found Patients Out of Time, a patient advocacy group.

Dr. Petro, who testified in support of the law in New Jersey, said that while some patients would benefit from using marijuana, particularly for neuropathic pain, the drug is not appropriate across the board for symptom management and disease modification.

Figure. NEUROLOGISTS...
Figure. NEUROLOGISTS...
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The FDA has not approved botanical marijuana for medical use in the US, but it has approved two drugs in capsule form for therapeutic uses — dronabinol (Marinol) and nabilone (Cesamet). Both contain synthetic delta-9-tetrahydrocannabinol (THC), the active ingredient in botanical marijuana. The FDA approved dronabinol in 1985 and nabilone in 2006 for nausea and vomiting in chemotherapy patients who had failed to respond to conventional antiemetic treatments. In 1992, dronabinol was approved for anorexia associated with weight loss in AIDS patients.

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RESEARCH CHALLENGES

In March 1999, a report by the Institute of Medicine, “Marijuana and Medicine: Assessing the Science Base,” called for evidence-based research into the effects of marijuana and its cannabinoid components, for specific diseases, concluding that “if there is any future of marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives.”

In May 1999, the Department of Health and Human Services (HHS) released guidelines specific to conducting research on marijuana. Among procedures, the HHS established that investigators had to first make an inquiry to the National Institute on Drug Abuse (NIDA) to determine the availability and costs of marijuana, and the NIDA had to determine that marijuana is available to support the study; researchers had to file an Investigational New Drug application through the FDA, and investigators had to register with the federal Drug Enforcement Agency to conduct research using a Schedule I controlled substance. (Under the Controlled Substances Act, Schedule 1 substances are defined as having a very high potential for abuse, having no accepted medical use in the US, and lacking accepted safety data for use under medical supervision.)

“A few years ago, to do research on this was almost like asking for trouble; everyone assumed that if you did research on cannabinoids that meant you agreed with it,” said Joseph I. Sirven, MD, chair and professor of neurology at the Mayo Clinic in Scottsdale, AZ. In a 2004 paper in Neurology, Dr. Sirven reviewed studies regarding the efficacy of marijuana for the management of epilepsy and MS; he found limited scientific evidence regarding its use.

“Now the doors have opened, so we can at least ask the questions without fear of reprisal. But we're just in the infancy stages as far as research,” he said.

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THE UNDERLYING MECHANISM

Cannabinoids affect neurological function through THC, which binds to cannabinoid receptors and triggers a cellular response. There are two kinds of cannabinoid receptors: CB1 receptors are mainly found in the brain, and CB2 receptors are located in the immune system and peripheral nerves throughout the body.

The body produces its own internal “endocannabinoids,” which appear to function primarily in helping the body maintain homeostasis. Via specific receptor binding, cannabinoids inhibit the release of potentially toxic, excitatory neurotransmitters, such as glutamate, thus protecting the nervous system from overstimulation. Cannabinoids are also strong antioxidants and reduce CNS inflammation by removing free radicals, which are damaging, electrically charged oxygen species.

The main advantage of using marijuana over other drugs such as opiates for pain management is its side effect profile, doctors said. There is little chance of an overdose with marijuana and it does not cause constipation, which can cause problems in those with neuromuscular diseases.

Figure. DR. JOSEPH I...
Figure. DR. JOSEPH I...
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PERSPECTIVES ON CLINICAL USE

Doctors in states that have medical marijuana laws varied greatly on how they incorporated the drug in their practice. Some said they would rather use other medications and rarely mentioned cannabis to their patients because they were skeptical of its success. Others said their patients had had success with the drug, and that the public perception of how it was used was skewed.

Gregory T. Carter, MD, a professor of rehabilitation medicine who co-directs the ALS clinic at the University of Washington in Seattle, has been recommending medical marijuana under state law for a decade. His patients, a majority of whom are older and never used marijuana recreationally, either eat the drug or use it in a vaporizer, inhaling the mist three times, two to three times daily.

Dr. Carter is the senior author of a 2004 paper in the American Journal of Hospice and Palliative Medicine that included results of an anonymous survey about marijuana use among ALS patients; 13 of 131 respondents reported using cannabis in the previous 12 months. Although the small number of people with ALS that reported using cannabis limits the interpretation of the survey findings, the study authors suggested that the results indicated that cannabis may be moderately effective for reducing symptoms of appetite loss, depression, pain, spasticity, and drooling. Cannabis was reported to be ineffective for reducing difficulties with speech and swallowing, and sexual dysfunction. The longest relief was reported for depression (approximately two to three hours).

Figure. DR. GREGORY ...
Figure. DR. GREGORY ...
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Dr. Carter pointed to several studies in which cannabanoids provided neuroprotective benefit, including a 2004 study by the Forbes ALS Research Center in San Francisco, published in the journal Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. The investigators reported that treatment with THC was “extremely effective” at reducing oxidative damage in spinal cord cultures and delayed motor impairment in ALS mouse models.

“For patients, it works really well to treat the symptoms of ALS,” he said. “It dries the mouth out, eases pain and spasticity, elevates mood, and improves appetite. It replaces four or five other medications.”

In his June 2009 literature review in the Journal of Opioid Management, Dr. Carter found only 33 American controlled clinical trials on the safety and therapeutic use of cannabinoids since 1998 for a variety of medical conditions.

The dearth and size of published studies, as well as the lack of long-term studies, makes Mark Spitz, MD, hesitant about recommending medical marijuana. The professor of neurology and director of the comprehensive epilepsy program at the University of Colorado-Denver in Aurora said maybe a couple dozen of his 2,000 patients use the legally approved marijuana.

“They don't like getting high,” he said. “Patients wouldn't take it in the morning or during the day because they feel like it impairs their thinking and concentration. They would only take it before bed.”

Those who do use marijuana tell him that it helps the frequency and the duration of their seizures, Dr. Spitz said. When they can't get it for financial reasons, they say they feel worse, he added.

Dr. Spitz said much of the current research was indirect. He cited, for example, a 1990 study in the American Journal of Epidemiology that found that among risk factors for illicit drug use and first onset seizure, marijuana use was shown to be protective factor, while regular alcohol use was a risk factor.

“It's not a substitute for western medicine,” he said. “I have been working with regular seizure medications as the first line of therapy.”

Although Colorado approved the use of medical marijuana in 2000, Dr. Spitz said patients initially had a hard time finding it. The original state law allowed growers and dispensers to each supply only five patients. In 2007, the law was changed, however, and now storefront operations are in many locations across the state, as ubiquitous as Starbucks.

It's a scene that's popular in California, which passed the first medical marijuana use law in 1996. Unlike New Jersey, which strictly limits prescriptions to specific diseases, California's law is broader and more prone to abuse, doctors said. The California law does not restrict medical marijuana for use in specific diseases. Doctors must provide a physician's recommendation for state residents to legally purchase and smoke eight ounces. The business there has expanded to an estimated $14 billion marijuana market, according to an April 2009 story in The Washington Post.

Dr. Sirven, who specializes in epilepsy, said he has not written any prescriptions for medical marijuana, because he isn't sure whether it's effective for his patients. The decision not to prescribe it was made collectively by his practice at Mayo, he said.

But he said that doesn't mean the door is closed, particularly when it comes to pain management and appetite stimulation. “Given the absence of evidence, I feel uncomfortable prescribing it until I have better data,” he said. “My advice to New Jersey would be to advocate for clinical trials because they have the opportunity to help other states decide — is there anything to this or should we just be stopping this?”

Figure. DR. MARK SPI...
Figure. DR. MARK SPI...
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REFERENCES

• Guidance on Procedures for the Provision of Marijuana for Medical Research, Department of Health and Human Services, May 1999: http://bit.ly/dDkoA7
• Medical Marijuana and Medicine: Assessing the Science Base. Institute of Medicine: National Academy of Sciences 1999: http://bit.ly/b5jok
• Sirven JI, Berg AT. Marijuana as a treatment for epilepsy and multiple sclerosis? A “grass roots” movement. Neurology 2004;62(11):1924–1925.

• Amtmann D, Weydt P, Carter GT, et al. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat Care 2004 Mar-Apr;21(2):95–104.
• Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care 2010;33(1):128–130. E-pub 2009 Oct 6.
• Abrams DI, Jay CA, Petersen KL, et al. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial. Neurology 2007;13;68(7):515–521.
• Ellis RJ, Toperoff W, Atkinson JH, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009:34(3):672–680. E-pub 2008 Aug 6.
• Rog DJ, Nurmikko TJ, Young CA, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005;65(6):812–819.

• R Chandrasekaran, McAllister SD, Abood MA, et al. Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. Amyotroph Lateral Scler Other Motor Neuron Disord 2004; 5(1):33–39.

• Wallace M, Schulteis G, Abramson I, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 2007;107(5):785–796.

• Ng SK, Brust JC, Hauser WA, et al. Illicit drug use and the risk of new-onset seizures. Am J Epidemiol 1990;132:47–55.

©2010 American Academy of Neurology

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