ARTICLE IN BRIEF
On a battery of neuropsychological tests, multiple sclerosis patients who were regular users of marijuana performed worse than nonusers and had more diffuse cerebral activation on MRI while performing working memory tasks.
Multiple sclerosis patients who regularly smoke marijuana were found to have functional brain abnormalities associated with significant cognitive impairments, according to a cross-sectional study published ahead of print in the April 30 online edition of Neurology.
The 20 MS patients who said they regularly use cannabis and whose urine tested positive for cannabis metabolites were asked to refrain from using it for 12 hours prior to testing, and a screening test in saliva that detects cannabis use within the last four to six hours was administered. These patients were matched with 19 MS patients who had never used cannabis, and who had negative urine and saliva tests.
After being matched on demographic and neurological variables, all patients in the study underwent fMRI while completing the N-back, a test of working memory. Resting state fMRI and structural MRI data were collected, including lesion and normal appearing brain tissue volumes, as well as diffusion tensor imaging metrics. Neuropsychological tests included verbal (Selective Reminding Test Revised) and visual (10/36 Spatial Recall Test) memory; information processing speed (Paced Auditory Serial Addition Test and Symbol-Digit Modality Test); and attention (Word List Generalization).
After controlling for age, sex, education, premorbid intelligence, score on the Expanded Disability Status Scale, disease course, as well as duration and use of disease-modifying drugs, the study found that regular cannabis users performed significantly worse than nonusers on a variety of cognitive measures, including working memory and information processing speed.
Although MRI exams detected no between-group differences in whole-brain grey, white, or lesion volume, cannabis users had more diffuse cerebral activation than nonusers when performing a working-memory task, and displayed greater activation in parietal and anterior cingulate regions associated with working memory.
Expanding upon two previous studies by the same group of researchers, the new paper is the first to demonstrate functional brain abnormalities in MS patients who use marijuana.
“Both of our previous studies showed that MS patients who smoke marijuana seem to have more cognitive difficulties,” said the study's senior author, Anthony Feinstein, MD, professor of psychiatry at the University of Toronto. “This time, we brought in brain imaging as well. We showed that the cannabis group did the working-memory task fairly well when it wasn't too demanding, but as it became harder, they made more errors, which was associated with a pattern of brain dysfunction on functional MRI.”
By carefully controlling for so many factors, Dr. Feinstein said he believed the study was detecting true effects of marijuana.
“Is there something about individuals who choose to smoke cannabis that sets them apart to begin with?” he mused. “That might be the case. But when you put together all three of my group's studies, we've now looked at 100-plus M.S. patients. We were very careful to match the groups: same duration, same severity, and matched with both premorbid IQ and education. In terms of their intellectual capacity prior to diagnosis, the groups were well matched. People who smoke marijuana might be more prone to risk-taking than those who don't, but that doesn't mean they're cognitively different.”
The study's design and findings drew favorable mention from the senior author of an evidence-based guideline for the use of complementary and alternative medicine in MS. The report by the AAN Guideline Development Subcommittee was published in the March 25 issue of Neurology.
“The [current] study is well-designed with a robust control group,” said Pushpa Narayanaswami, MD, FAAN, an assistant professor of neurology at Harvard Medical School.
She emphasized that even the nuanced evidence cited in the AAN guideline in favor of offering oral cannabis extract or oromucosal cannabinoid spray for spasticity and pain in MS applies only to the two specific, standardized forms of cannabis and cannot be extrapolated to other forms including smoked cannabis.
Cannabis, the new guideline stated, “may cause adverse effects, some of which can be serious. Clinicians should counsel patients about the potential for psychopathologic, cognitive and other side effects associated with cannabis.”
“We specifically stated in the guideline that we did not have data on the safety or efficacy of smoked cannabis,” Dr. Narayanaswami said. “With MS, we're talking about a population that may already be vulnerable because of depression, predisposal to psychosis, and cognitive impairment associated with the disorder itself. We now have even more evidence that smoking cannabis may worsen cognitive function in this group. We need to exercise caution.”
[In an AAN review of the literature on medical marijuana for neurological conditions, the study authors found that there was evidence, albeit limited, to suggest the use of medical marijuana for MS spasticity and pain, but not for other neurological conditions.]
A neurologist who has long specialized in the neurological effects of substance abuse cautioned that the cognitive and brain function changes seen in the study could still have been due to acute rather than chronic effects.
“In daily users, marijuana can stay around in the system for weeks,” said John C. M. Brust, MD, FAAN, a professor of neurology at Columbia University and author of Neurological Aspects of Substance Abuse (Butterworth-Heinemann, 2004). “I'm not at all convinced that this paper is looking solely at chronic effects. They weren't dealing with people who were high as kites, but I think they were probably seeing acute effects, rather than more long-term, structural effects.”
Still, enough risks have been associated with the smoking of marijuana that he said he would urge patients to consider other alternatives. “It's a smoke that contains over 400 compounds, some of which cause cancer,” Dr. Brust said. “It carries a risk for heart attack and stroke. And at least in young people, it does very likely cause permanent cognitive impairment.”
Dr. Brust was also a coauthor of the new systematic review issued by the AAN on April 29 on the safety and efficacy of medical marijuana in selected neurologic disorders.
Fresh evidence of the risks of marijuana in otherwise healthy young adults has also recently come to light. In contrast to the MS study, which measured overall brain volume, a paper in the April 16 edition of the Journal of Neuroscience evaluated several structural features of two brain regions implicated in prior animal and human studies. On the basis of high-resolution MRI scans, the study detected abnormalities in two of three measures (volume, shape, and density of grey matter) in the nucleus accumbens and amygdala of young adult recreational marijuana users, compared with controls who didn't use the drug. The nucleus accumbens showed increased density compared with nonusers, and its alteration in size, shape, and density was directly proportional to how frequently the individual claimed to smoke marijuana.
“This suggests there may be a dose-related effect of smoking marijuana, and if this is the case, people should know about that,” said one of the study authors, Anne J. Blood, PhD, director of the Mood and Motor Control Laboratory in the departments of psychiatry and neurology at Massachusetts General Hospital in Boston.
For all the concerns raised by the new studies, Dr. Feinstein said he remains open-minded about the risk-benefit profile of marijuana.
“I treat a lot of patients with MS,” he said. “In Canada, you can prescribe marijuana for medical reasons. If a patient tells me that cannabis really helps his or her pain or spasticity, I listen carefully to that. From time to time, maybe once a year, I give a prescription for marijuana, most usually for the intractable pain of trigeminal neuralgia. Sometimes I would prefer that the patient has marijuana rather than a strong opiate. I inform the patient about the potential risks on cognition and brain function, but when it comes to severe pain, that trumps just about anything.”
EXPERTS COMMENT ON CANNABIS & MS STUDY
•. Pavisian B, MacIntosh BJ, et al. The effects of cannabis on cognition in MS patients: a psychometric and MRI study. Neurology. 2014: E-pub 2014 Apr 30.
•. Honarmand K, Tierney MC, et al. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology. 2011; 76:(13):1153–1160.
•. Ghaffar O, Feinstein A. Multiple sclerosis and cannabis: a cognitive and psychiatric study. Neurology 2008; 71:(3):164–169.
•. Yadav V, Bever C Jr, et al. Summary of evidence-based guideline: Complementary and alternative medicine in multiple sclerosis: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014; 82(12):1083–1092.
•. Brust, John C.M.. Neurological Aspects of Substance Abuse, second edition. Butterworth-Heinemann. May 21, 2004.
•. Gilman JM, Kuster JK, et al. Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. J Neurosci. 2014; 34(16):5529–5538.
•. Koppel BS, Brust JCM, Fife T, et al. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders. Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014; 82:(17):1556–1563.