Abstract
Background: A significant minority of patients with multiple sclerosis (MS) use cannabis, yet no study has examined the possible effects on mentation. Here, we report the emotional and cognitive correlates of street cannabis use in patients with MS.
Methods: A sample of 140 consecutive patients with MS were interviewed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Axis I disorders (SCID-IV) from which details of cannabis use were recorded. Cognition was assessed using the Neuropsychological Battery for MS supplemented with the Symbol Digit Modalities Test (SDMT), an index of information processing speed, working memory, and sustained attention.
Results: Ten subjects (7.7%) were defined as current cannabis users based on use within the last month. Compared to non-cannabis users (n = 130), they were younger (p = 0.001). Each of the 10 current cannabis users was matched on demographic and disease variables to four subjects with MS who did not use cannabis (total control sample n = 40). Group comparisons revealed that the proportion of patients meeting DSM-IV criteria for a psychiatric diagnosis was higher in cannabis users (p = 0.04). In addition, on the SDMT, cannabis users had a slower mean performance time (p = 0.006) and a different pattern of response compared to matched controls (group × time interaction; p = 0.001).
Conclusions: Inhaled cannabis is associated with impaired mentation in patients with multiple sclerosis, particularly with respect to cognition. Future studies are required to clarify the direction of this relationship.
GLOSSARY: 7/24 = 7/24 Spatial Learning Test; BSS = Beck Suicide Scale; COWAT = Controlled Oral Word Association Test; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders; EDSS = Expanded Disability Status Scale; HADS = Hospital Anxiety and Depression Scale; MS = multiple sclerosis; NPBMS = Neuropsychological Battery for MS; PASAT = Paced Auditory Serial Addition Task; SCID-IV = Structured Clinical Interview for DSM-IV Axis I disorders; SDMT = Symbol Digit Modalities Test; SRT = Selective Reminding Test; SSSI = Social Stress and Support Inventory.
The use of cannabis as a therapeutic agent in multiple sclerosis (MS) is controversial.1 Unequivocal, objective evidence of efficacy in MS symptom control is lacking, as exemplified by a large scale clinical trial of cannabinoids that failed to find improvement in spasticity as noted on the primary outcome measure, the modified Ashworth score of spasticity.2 Nonetheless, other data suggest benefits for lower urinary tract symptoms3 and pain.4 Furthermore, a significant minority of patients with MS in Europe5 and North America6,7 endorse smoking cannabis as an alternative treatment for symptom control, notwithstanding the availability of conventional medications including cannabinoid-based therapeutic agents.
Although cannabis is a well-recognized psychoactive substance known to induce delirium, psychosis, and anxiety in healthy individuals,8 no study has specifically examined the potentially deleterious effects of cannabis (be it prescribed or smoked illicitly) on mentation in patients with MS. This is an important clinical question, for patients with MS have significantly higher rates of depression9 and suicide10,11 compared to the general population and cognitive dysfunction affects 40% of community-based patients.12 Faced with this dearth of behavioral data, we undertook a study looking at the emotional and cognitive correlates of street cannabis use in patients with MS.
METHODS
A total of 140 of 148 consecutive, community-dwelling patients with MS13 attending an outpatient MS clinic in Toronto, Ontario, Canada, were enrolled in the study. Seven of the eight refusals were for difficulties with transportation. The following data were collected.
Demographic, social, and illness variables.
Each patient was examined by a neurologist and neuropsychiatrist, and demographic, social, and neurologic variables were collected from the case notes. Neurologic variables included disease course and duration; presence of exacerbation; use of medications; and physical disability rated with the Expanded Disability Status Scale (EDSS).14
Psychiatric assessment.
All subjects were interviewed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Axis I disorders (SCID-IV).15 This in-depth interview is used to generate current and lifetime DSM-IV diagnoses of mental illness. Details of current and lifetime substance use (class of substance, route of administration, amount, frequency, duration, reasons for use) were collected using the substance use section of the SCID-IV. Current cannabis users were defined as those who smoke cannabis on a regular basis with a frequency of at least once a month. This is in accordance with the definition of “current cannabis use” employed by Chong et al. in their study of cannabis use by patients with MS.5 The interviews were supplemented with three self-report questionnaires: The Beck Suicide Scale (BSS),16 the Hospital Anxiety and Depression Scale (HADS),17 and the Social Stress and Support Inventory (SSSI).18 The BSS assesses lifetime suicidal intent and attempts. The HADS consists of seven questions pertaining to depression and seven to anxiety; it was developed specifically for use with medically ill patients and minimizes somatic symptoms. Scores of 10 or greater for each subscale are indicative of pathologic levels of symptomatology. The SSSI is a six-item scale examining stress (scored as −1) and support (scored +1) in the following areas: work, finances, housing, marriage/relationships, friendships, and family supports. A score of zero is given if neither stress nor support is present in a particular domain.
Cognitive assessment.
Subjects were assessed using the Neuropsychological Battery for MS (NPBMS).19 Developed specifically for patients with MS, it consists of four tests: the Selective Reminding Test (SRT), the 7/24 Spatial Learning Test (7/24), the Paced Auditory Serial Addition Task (PASAT), and the Controlled Oral Word Association Test (COWAT). Performance below the fifth percentile on two or more tests is indicative of cognitive impairment.19 The NPBMS was supplemented with a computerized version of the Symbol Digit Modalities Test (SDMT). In the SDMT, nine different symbols, each associated with a number, were presented visually to the subject. Nine symbols at a time were shown to the subject in various orders and the subject had to respond by naming the number that corresponded to each symbol according to the original code. This approach minimizes a sensorimotor component to the procedure. Eight consecutive trials were administered at a constant time interval and presentation times for symbols and trials were the same for each subject. Mean times per individual trial were obtained. The computerized version of the SDMT has been used previously in MS–neuropsychological studies20,21 where it proved to be a sensitive indicator of cognitive problems, even in the early stages of demyelination. Data on the performance of the SDMT in healthy controls have also been published.20-22
Statistical analysis.
t Tests were for used for continuous, normally distributed data, and χ2 analyses for ordinal data. Where appropriate, median (range) rather than mean (SD) data were given with associated Mann–Whitney U test. Significance levels were set at p < 0.05.
Ethical approval.
This study received approval from the Ethics Committees at Sunnybrook Health Sciences Centre and St Michael’s Hospital, which are affiliated with the University of Toronto, Ontario, Canada. Informed, written consent was obtained after subjects had been given a complete description of the study.
RESULTS
Entire sample.
The sample comprised 140 patients with MS with a mean ± SD age of 43.9 ± 10.7 years, of whom 104 subjects (74.3%) were women. MS disease course was relapsing-remitting in 82 subjects (58.6%), secondary progressive in 49 subjects (35.0%), and primary progressive in 9 subjects (6.4%). The mean ± SD duration of MS diagnosis was 8.8 ± 6.8 years. The median EDSS was 3.5 (range: 0.0 to 8.5).
Cannabis users.
Ninety-five subjects (67.9%) denied having ever used illicit drugs. Thirty-two subjects (22.9%) had used cannabis at least once in their lives. Ten subjects (7.7%) were defined as current cannabis users based on use within the last month.5 Table 1 shows their individual disease characteristics and patterns of cannabis use. In all cases, route of administration was by inhalation (i.e., smoking). A single use ranged in amount from one-quarter to one marijuana cigarette. Time of last use of cannabis ranged from 1 to 30 days before testing. None of the current cannabis users used other illicit drugs in the previous year.
Table 1 Characteristics of current cannabis users
Comparisons between patients with MS who currently use (n = 10) and do not use (n = 130) cannabis.
Compared to the rest of the sample (n = 130), current cannabis users (n = 10) were younger (mean ± SD = 35.8 ± 6.0 vs 44.5 ± 10.8 years, t = 4.1, p = 0.001). There were no significant differences between these groups with respect to gender, education, MS disease course, MS duration, or EDSS.
Comparison between patients with MS who currently use cannabis (n = 10) and a matched sample (n = 40) who do not.
Since age is a factor that could potentially affect cognition independent of cannabis use,23 the 10 current cannabis users were each age matched to four subjects who did not use cannabis (total control sample n = 40).24 An attempt was also made to match cannabis and control subjects for other demographic and disease-related variables. Individual matching was possible with respect to years of education, gender, EDSS, and duration of MS symptoms, but not disease course, where a small, non-significant difference was present. Table 2 summarizes the sociodemographic and illness variables of the two groups.
Table 2 Sociodemographic and illness variables of current cannabis users vs matched controls
The SCID-IV data showed no difference between current cannabis users and matched controls on any individual DSM-IV diagnostic category (table 3). However, the proportion of patients meeting DSM-IV criteria for any psychiatric diagnosis was higher in cannabis users (χ2 = 4.2, p = 0.04). There were no significant differences between the groups on the BSS, HADS, or SSSI (table 3).
Table 3 Psychiatric and cognitive variables of current cannabis users vs matched controls
There were no between-group differences on the four cognitive variables on the NPBMS (table 3). However, on the SDMT, cannabis users had a slower mean performance time (t = −2.9, p = 0.006, table 3). As shown in the figure, the group × time interaction revealed a difference (repeated measures ANOVA, F = 3.7, p = 0.001).
Figure Results of the Symbol Digit Modality Test
Results of the Symbol Digit Modality Test for patients with multiple sclerosis currently using cannabis vs matched controls. p = 0.001 (group × time interaction).
DISCUSSION
The main findings of this study were that patients with MS who regularly smoke cannabis have more extensive cognitive abnormalities and greater lifetime psychopathology than those who do not use cannabis. In the absence of previously published research, our data provide the first evidence of the injurious effect of inhaled cannabis on the mentation of patients with MS.
We studied a consecutive sample of 140 community-dwelling patients with MS of whom 8% admitted using cannabis within the last month. This is lower than prevalence estimates for current cannabis use by patients with MS surveyed with self-report questionnaires in Nova Scotia (14%),6 Alberta (16%),25 and the United Kingdom (18%).5 Variations in general population rates of cannabis use in different geographic locations may partly explain this discrepancy. This is supported by figures from the Canadian Addiction Survey26 which showed lower lifetime and 1-year prevalences of cannabis use in Ontario compared to Nova Scotia or Alberta.
The importance of eliciting potential cognitive consequences of cannabis use is underscored by the fact that MS is by itself a cause of neuropsychological impairment in 40 to 65% of patients.27 Moreover, cognitive dysfunction is an important predictor of patients’ and caregivers’ quality of life.28,29 The hallmarks of MS-related cognitive decline are impaired attention and slowness of information processing, with the disease also affecting episodic memory, executive functioning, and real world decision-making.30 Our data suggest that cognitive difficulties may be elevated further by inhaled cannabis. Here, the findings from the SDMT are informative. This test, an index of information processing speed and working memory, has emerged as one of the most sensitive markers of cognitive impairment in MS, exceeding that of the widely used PASAT.31-34 It was also the one cognitive test that most closely correlates with brain atrophy in this population.35,36 Indirect support for our finding of cannabis-related cognitive dysfunction comes from a study examining the efficacy of a cannabis-based oromucosal spray vs placebo for central neuropathic pain in MS.4 Cognitive variables appeared as secondary outcome measures and showed that cannabis users had more deficits with respect to long-term verbal memory as measured by the Selective Reminding Test.
Regarding the relationship between current cannabis use and poorer SDMT performance in patients with MS, three additional points warrant consideration. First, the cannabis users were carefully matched to MS control subjects on age, gender, education, disease course, disease duration, and disability. However, there were subtle, nonsignificant differences between the groups on disease course. Given that previous research has either failed to find an association between disease course and cognitive status21 or at best reported a modest link,27 this minor mismatch is unlikely to have affected our cognitive data. A second point concerns medication differences between our study groups. A higher proportion of control subjects were on disease-modifying treatments while more cannabis users were taking antidepressants. Neither of these differences achieved significance. As the relationship between disease-modifying treatments and cognition remains equivocal,37 and data suggest that patients with MS taking antidepressants are not more impaired on tests such as the SDMT,38 these medication differences are unlikely to account for the greater cognitive problems found in our cannabis group. A final point relates to a recent study showing that mild visual acuity disturbances in patients with MS (elicited by Snellen chart examination on the day of testing) could adversely affect performances on the SDMT.39 Such data are lacking in our study where subjects were only screened for the presence of coarse visual problems. As such, it is possible that some of the cognitive problems experienced by cannabis users in our study were attributable to impaired visual acuity, although it is worth noting that the previously published Snellen chart data could account for only 13% of the SDMT performance variance.
The etiologic inferences that apply to cannabis use and more impaired cognition are not as clear when it comes to the relationship between cannabis and psychopathology. Here, association does not necessarily equate with causality.40 Our finding of higher lifetime rates of psychiatric diagnoses in the cannabis users is therefore not necessarily a consequence of illicit drug use. An alternative explanation may be that some patients with psychological problems to begin with smoke cannabis as a means of self-medication. Our data do not allow us to accurately determine the direction of this association. Of note, however, is that current levels of psychological distress in our sample as measured by the HADS and BSS did not differ between cannabis users and controls, suggesting cannabis was not precipitating current psychopathology. Future research, ideally with a longitudinal design, will be needed to tease out this complex interplay of factors.
Our study is not without limitations, namely a small sample size of current cannabis users and a reliance on patient self-reports concerning the details of their cannabis use in the absence of confirmatory urine toxicology data. Nevertheless, despite these drawbacks, we present data showing that inhaled cannabis has a deleterious effect on mentation in MS, particularly within the cognitive domain. Future studies are required to replicate these findings and determine whether they hold true for cannabinoid-based therapeutic agents as well.
ACKNOWLEDGMENT
The authors thank Nancy Blair for assistance with data collection and Paul O’Connor for access to his MS clinic.
Footnotes
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ant.feinstein{at}utoronto.ca
Editorial, page 160
e-Pub ahead of print on February 13, 2008, at www.neurology.org.
The study was funded by grant 15001 from the Canadian Institutes for Health Research (CIHR). O.G. is supported by a CIHR Fellowship.
Disclosure: O.G. has received honoraria from Cerebrio, a continuing medical education company. A.F. has received lecture honoraria from Berlex Canada, Serono Canada, Serono USA, Teva Neuroscience, and Avanir Pharmaceuticals.
Received July 30, 2007. Accepted in final form October 30, 2007.
REFERENCES
Letters: Rapid online correspondence
- Multiple sclerosis and cannabis. A cognitive and psychiatric study
- Reply from the authors
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