J Neuropsychiatry Clin Neurosci 20:36-51, February 2008

doi: 10.1176/appi.neuropsych.20.1.36
2008 American Neuropsychiatric Association

Multiple Sclerosis, Cannabinoids, and Cognition

Panagiotis Papathanasopoulos, M.D., Ph.D., Lambros Messinis, Ph.D., Epameinondas Lyros, M.D.,
Andreas Kastellakis, Ph.D. and George Panagis, Ph.D.
Received May 17, 2007; revised August 13, 2007; accepted August 14, 2007. Drs. Papathanasopoulos,
Messinis, and Lyros are affiliated with the Department of Neurology, Neuropsychology Section, at the
University of Patras Medical School; Drs. Kastellakis and Panagis are affiliated with the Department of
Psychology, Laboratory of Behavioral Neuroscience, at the University of Crete. Address correspondence
to Lambros Messinis, Ph.D., Department of Neurology, Neuropsychology Section, University of Patras
Medical School, Rion, Patras, Greece; lmessinis@upatras.gr (e-mail).
ABSTRACT
There is increasing interest in the therapeutic potential of cannabis-based medicinal extracts in
multiple sclerosis. Cognitive deficits that have been attributed to long-term heavy recreational use of
cannabis are not necessarily extended to controlled pharmaceutical use of cannabis-based medicinal
extracts. Available data indicate that after relatively short-term administration of cannabis-based
medicinal extracts no significant cognitive decline occurs. Due to the absence of large scale long-term
systematic clinical trials of cannabis-based medicinal extracts in multiple sclerosis therapeutics,
however, many issues remain unresolved, including the possible adverse effects of cannabis-based
medicinal extracts on cognition. This article critically reviews the current literature and considers the
potential for cognitive adverse effects of long-term cannabinoid use in multiple sclerosis therapeutics.
INTRODUCTION
Although cannabis has been used for various medical purposes over centuries,1 it is currently not
being officially prescribed due to law restrictions and lack of solid evidence regarding its objective clinical
effects and safety. Nevertheless, there has recently been a growing interest about the potential
therapeutic value of cannabis in several medical conditions.14 Beneficial effects of cannabis in multiple
sclerosis have focused much of the attention of scientists in the past few years.2,4 Illegal self-medication
with cannabis both in smoked and in oral forms has, however, been reported for years.5 Anecdotal
reports suggest that cannabis can relieve not only muscle spasticity and pain but, in some cases, can also
improve bladder control. Many randomized placebo-controlled clinical trials have attempted to
investigate the potential efficacy of various cannabinoid treatments in managing spasticity, pain,
bladder problems, sleep disturbances, and tremor due to multiple sclerosis.4,616 Results of clinical trials
have been mixed, but together with insights from basic research and animal models of multiple
sclerosis, they provide reasonable evidence for the potential therapeutic use of cannabinoids in the
treatment of multiple sclerosis related symptoms.1,17 Findings of biological experiments have also
revealed the possible immunomodulatory and neuroprotective properties of cannabinoids,4,18,19 thus

further supporting their potential utility in multiple sclerosis therapeutics. However, many issues still
remain unresolved.20
Accordingly, synthetic cannabis-based preparations [dronabinol (Marinol), nabilone (Cesamet), 9
tetrahydrocannabinol + cannabidiol (Sativex)] have been used in the U.S., Canada and some other
countries as an authorized treatment for nausea and vomiting in cancer chemotherapy, appetite loss in
AIDS wasting syndromes and symptomatic relief of neuropathic pain in multiple sclerosis.3,21 Recent
research developments regarding the therapeutic use of cannabis analogues in several medical
conditions and the concurrent possibility that cannabis might be fully legalized for patients with severe
and chronic medical conditions such as multiple sclerosis provided the motive for this article. If cannabis
products were to be used legally in the future for therapeutic purposes, this would naturally raise the
concern of possible adverse effects associated with long-term use and especially with respect to the
central nervous system (CNS) and cognition. It has been suggested that these effects may be greater in
vulnerable groups such as patients suffering from diseases of the CNS. Non-acute cognitive dysfunction
resulting from accumulative cannabis exposure has been a matter of investigation mainly with
recreational cannabis users.2224 Psychiatric effects of long-term exposure to cannabis, such as comorbid
depression and predisposal to psychosis, are issues that have also been reported in the literature.2527
Nevertheless, the focus of this article is the potential adverse effects of long-term exposure to cannabisbased medicinal extracts on cognition. The article provides a review of the current literature on this
issue and critically considers the potential that cognitive deficits attributed to long-term heavy
recreational exposure might be extended to controlled pharmaceutical use in multiple sclerosis patients.
We performed a search of the PubMed database for articles dated from 1986 to March 2007 in order to
locate studies of cannabinoid use in multiple sclerosis, cannabis and cognitive dysfunction, long-term
effects of exposure to cannabis on cognition, and neuropsychological/neuropsychiatric aspects of
multiple sclerosis. Key words used in the search strategy were: "multiple sclerosis," "cannabinoids,"
"cognition," combined with the terms cannabis-based medicinal extracts, tetrahydrocannabinol (THC),
marijuana, neuropsychology and neuropsychiatry. These searches were limited to English-language
articles and augmented by bibliographical searches of the obtained references. Further, we hand
searched the following journals dated from 2003 to March 2007: Archives of Clinical Neuropsychology,
Journal of the International Neuropsychological Society, Neurology, and The Clinical Neuropsychologist.
We included only relevant articles published in peer-reviewed journals.
Neurobiology and Pharmacology of Cannabis and the Endocannabinoid System
The main psychoactive component of cannabis is 9tetrahydrocannabinol ( 9THC). The drug is most
commonly delivered by smoking a plant-derived cigarette. Acute effects of cannabis have been well
recognized, including euphoria and relaxation, intoxication, short-term memory impairment, disruption
of psychomotor control, poor executive functions, distorted sense of time, increased appetite, and
analgesia.3 Acute panic, paranoia, and psychosis have been reported in some subjects.26,28 Although
some researchers claim that marijuana is not particularly addictive, there is evidence that heavy and
chronic users are likely to develop tolerance and dependence on the drug.3,2930 On the basis of current
research, cannabis does not appear to induce a clear withdrawal syndrome, as do other drugs of abuse,
such as opiates.31 However, there is no doubt that individuals suffer unpleasant effects when abstaining
from chronic cannabis use.31 Thus, although addictive behaviors such as compulsive drug seeking due to
craving are rarely induced by marijuana use, preparations containing higher 9THC concentrations,
such as hashish, have been shown to induce addictive behaviors, especially in populations at risk.32
Furthermore, some users develop problems related to the drug, and many request professional

assistance in limiting their consumption.33 Indeed, cannabis dependence is a DSM-IV diagnostic

category. However, it has been proposed that dependence on cannabis should deal only with
psychological dependence.34 Whether a certain individual will eventually succumb to the addictive
potential of cannabis will obviously be the outcome of a combination of factors. Thus, it has been
suggested that the dependence syndrome on cannabis via international classification systems (e.g.,
DSM-IV) should be revised.34
Recent investigations have shed light on the mechanisms of the pharmacological actions of 9THC and
other chemically related molecules known as cannabinoids. Exogenous cannabinoids include
phytocannabinoids such as 9THC, cannabinol, cannabidiol, and other cannabinoid compounds
present in extracts of the plant Cannabis sativa, as well as synthetic cannabinoids produced in the
laboratory. Two endogenous cannabinoid receptors (CB1 and CB2) have been identified35,36 although
additional cannabinoid receptors may exist but have not yet been cloned.37 Furthermore, endogenous
ligands for these receptors have been isolated. These endogenous cannabinoids comprise a series of
arachidonic acid derivatives such as anandamide, 2-arachidonoylglycerol (2-AG), 2-arachidonoylglycerol
ether, virodhamine and N-arachidonoyldopamine which are referred to as "endocannabinoids" (for a
review, see Mechoulam et al.).38 9THC and other synthetic analogues exert their effects by acting as
agonists at the cannabinoids (CB1 and CB2) receptors. However, some of the other constituents of
cannabis, such as cannabidiol, which have well-documented biological effects of potential therapeutic
interest, such as antianxiety and anticonvulsive properties, do not significantly interact with CB1 or CB2
receptors. This fact possibly explains the reason why cannabidiol does not possess psychotropic actions.
Its effects have been largely attributed to inhibition of anandamide degradation or its antioxidant
properties.39 CB1 receptors are thoroughly expressed in the CNS, most densely in the frontal cortex,
basal ganglia, cerebellum, hypothalamus, anterior cingulate cortex, and hippocampus, and are localized
to axons and nerve terminals while being absent from the neuronal soma and dendrites.3 In consistency
with their presynaptic localization, the activation of CB1 receptors is thought to modify synaptic function
by inhibiting the release of various neurotransmitters (L-glutamate, GABA, dopamine, 5-HT, and
acetylcholine).40 CB2 receptors, in contrast, are mostly found in peripheral tissues, predominantly in the
immune system.3 Interestingly, very recent evidence suggests that the CB2 receptors are expressed in
the mammalian brain and may influence behavior.41 The endocannabinoid system controls signaling
processes between neurons in a retrograde manner. Endocannabinoids are not stored but are rapidly
generated by postsynaptic neurons in response to Ca2+ influx resulting from depolarization induced
opening of voltage-controlled Ca2+ channels.42 When endocannabinoids are released from the
postsynaptic membrane, they act backward across the synapse, tonically activating presynaptic CB1
receptors to decrease release of either inhibitory or excitatory transmitters.40 Following an assumed
cellular uptake mechanism, endocannabinoids are then degraded by intracellular enzymes. Fatty acid
amide hydrolase (FAAH) and a monoacylglycerol (MAG) lipase are the enzymes proposed to catalyze the
hydrolysis of endocannabinoids.4
Endocannabinoids have been implicated in a variety of physiological functions. These areas of central
activity include pain reduction, motor regulation, learning/memory, and emotion. Interestingly, recent
evidence has emerged that tissue concentration of endocannabinoids and/or cannabinoid receptor
density-activity changes (increasing or decreasing depending on the specific disease or pathological
state) in a range of disorders.43
The Neuroprotective Role of Cannabinoids
Endocannabinoids might serve several functions in the brain. Of great interest is the potential

neuroprotective role in the CNS. Experimental data indicate that endocannabinoids are released and
accumulated in response to many different types of toxic insult, such as excitotoxicity, excitotoxic stress,
traumatic injury and ischemia possibly representing a compensatory repair mechanism.4447 The
excitotoxicity hypothesis is used to explain the common biochemical basis behind many acute and
chronic neurodegenerative disorders, including stroke, brain injury, amyotrophic lateral sclerosis,
multiple sclerosis, Parkinsons disease, and Huntingtons disease.48,49 Thus, the cannabinoid system can
serve to protect the brain against excitotoxicity and neurodegeneration and may play a primary role in
limiting brain damage. Researchers current hypothesis of how cannabinoids provide their protective
effects is perhaps that their general dampening of neural activity reduces excitotoxicity.50 Cannabinergic
activity through CB1 receptors is linked to signaling pathways that are protective against pathogenic
insults and promote cell survival and maintenance. Such pathways include the activation of mitogenactivated protein kinases (MAPKs), such as the extracellular signal-regulated kinase. Activation of CB1
receptors has been shown to block presynaptic release of glutamate.51 Interestingly, endocannabinoid
levels were increased in a mouse model of multiple sclerosis,52 although in a more recent study brain
concentrations of endocannabinoids were not raised despite the cell damage induced by experimental
allergic encephalomyelitis (EAE) in mice.53 The disruption of the neuroprotective effect of
endocannabinoids was more pronounced in purinergic P2x7 receptor knockout mice after induction of
EAE. The authors showed that in this mouse model of multiple sclerosis the limited production of
endocannabinoids could be attributed to an interferon gamma-mediated disruption of the function of
P2x7 receptors, the activation of which leads to increased production of endocannabinoids by microglia.
Collectively, these results strengthen the concept that the endogenous cannabinoid system may serve
to establish a defense system for the brain. This system may be functional in several neurodegenerative
disorders as well as in acute neuronal damage.
Residual Neurocognitive Effects of Cannabis Use
Although the acute effects of cannabis use have been well established, the question of whether chronic
cannabis use causes residual neurocognitive deficits has produced conflicting data. Despite intensive
research efforts in this regard, the literature remains divided and controversial, as no hard findings or
consistent results have emerged. The cognitive deficits observed in chronic cannabis users may be
temporary and reversible after a period of abstinence (attributable to late intoxication or withdrawal
effects) or permanent (due to neurotoxicity). This question apart from its theoretical interest also
harbors practical considerations regarding former drug users functional capacity after cessation of
cannabis use. Even subtle cognitive impairments may prove a serious impediment especially for people
whose occupation calls for intact agility and creative thinking. As far as current users are concerned, it is
important to examine whether and how cognition is afflicted within unintoxicated intervals, in order to
realistically assess functional operations in activities of daily living. Furthermore, it is essential to
determine which variables of cannabis consumption (dosage, frequency, duration, or age at onset)
independently correlate with cognitive deficits in cannabis users. The drug delivery is perhaps a critical
parameter as well, since speculated neurotoxicity of cannabis may be dependent on the
pharmacokinetic profile of the drug entering the organism. The smoked route is subject to wide
variation.54 Orally or sublingually delivered cannabis used in modern clinical trials may not provide
standard dose absorption; however, the concentration curve of the drug is not as sharp as with smoked
cannabis.54 Intravenous administration retains control of dose but requires strict laboratory conditions.54
Evidence of cognitive impairment in chronic cannabis users is available in the literature, mainly
concerning memory, attention, and executive functions, but it is not clear how long such impairments
persist after cannabis use is terminated or whether these deficits are accompanied by drug-induced

neuropathology. Studies of nonacute effects of cannabis on brain function require a period of

abstinence to eliminate the acute pharmacological actions of the drug.55 Another general issue affecting
most studies on the nonacute effects of cannabis exposure is that the premorbid neurocognitive abilities
of these participants are largely unknown; some of the cognitive deficits noted possibly reflect
preexisting cognitive impairments rather than consequences of cannabis exposure.22,24,55 Potential
neurocognitive effects of cannabis withdrawal syndrome might also need to be considered.29
Pope et al. reported cognitive deficits in current heavy cannabis users after at least 7 days of abstinence.
These, however, did not persist after 28 days of drug cessation and were related to recent, not
cumulative, drug use.55 On the contrary, Bolla et al. reported a dose-related effect of cannabis use on
neurocognitive performance even after 28 days of abstinence.56 Moreover, Solowij et al. have
demonstrated cognitive impairments in long- versus short-term cannabis users after a median 17-hour
abstinence period, indicating an important influence of duration of cannabis consumption on cognitive
measures, predominantly verbal learning and memory.57 In line with previous reports demonstrating
cognitive impairment of long-term cannabis users in the unintoxicated state, Messinis et al. recently
reported neuropsychological deficits in long-term heavy cannabis users after at least 24 hours (range=36
to 240) of abstinence, indicating duration, frequency, and possibly dosage of cannabis administration as
determinants of this effect.23 In the Messinis et al. study, verbal learning was the cognitive domain most
substantially affected by chronic heavy cannabis use, followed by psychomotor speed, attention, and
executive functioning.23 Prior to this study, a meta-analysis of a small number of select studies on the
long-term residual neurocognitive effects of cannabis use concluded that among various cognitive
domains, impaired learning and retrieval of information were the only cognitive domains to
demonstrate a significant effect size.22,24 See Table 1 for a summary of recent studies evaluating the
effects of cannabis use on neuropsychological functions. Therefore, deficits in verbal learning and
memory tasks in long-term heavy cannabis users have variously been attributed to duration,23,57
frequency of cannabis use,23,55 or cumulative dosage effects.56 The most pronounced evidence of
impaired learning are effects on recall after interference or delay, flatter learning curves, fewer words
recalled on each learning trial, and poorer recognition performance.24

The age of the cannabis users participating in neuropsychological studies also appears to influence their
verbal learning abilities. More specifically, Fletcher et al. reported that only older ( 45 years) cannabis
users differed from control subjects in list learning abilities, whereas users younger than 28 years
remained unaffected.58 Age at onset of cannabis use also seems to influence the occurrence of cognitive
impairment, possibly attributable to a neurotoxic effect of cannabis on the developing brain.59 Pope et
al. recently reported that early onset of cannabis use (before the age of 17) is associated with poorer
verbal IQ, even after adequate abstinence periods.60 One important caveat in interpreting these results
is that different behavioral trends of adolescents who use cannabis could account for these
observations. In addition, visual search was found to be disturbed in early onset, long-term cannabis
users.61 The latency of auditory-evoked potentials has been reported to be significantly longer in
cannabis users, especially in early onset users compared to healthy control subjects. In further
investigating this issue, brain imaging studies report that adolescents who begin cannabis use before the
age of 17 exhibit brain morphological changes, such as smaller brain volume, less cortical gray matter,
increased cortical white matter, and increased cerebral blood flow, compared with late-onset users.62
Increasing evidence further suggests that cannabis-based medicinal extracts may have toxic effects on
the fetal nervous system.19 Macleod et al.,63 in a systematic review of the psychological and social
sequelae of cannabis and other illicit drug use by young people, reported that available data do not
support a causal relationship between cannabis use by young people and psychosocial harm, but cannot
exclude the possibility of such a relationship existing.
There is laboratory evidence in support of neurotoxicity of THC. Results of both animal studies and in
vitro cell experiments, however, have provided conflicting results.3,44 Chronic heavy cannabis use is not
associated with structural changes within the brain as a whole or the hippocampus in particular,64 so
functional alterations might rather account for the observed neurocognitive effects.
Clinical neurophysiological studies have further contributed toward investigating this issue. Regular use
of cannabis was associated with abnormalities in the P300 wave of event-related potentials during an
auditory discrimination task65 and electroencephalographic abnormalities in another study.66

Neuroimaging studies have also provided results indicative of persistent effects of cannabis on brain
functions. Block et al.67 and Matochik et al.68 observed structural alterations in the brain tissue of
frequent and heavy users, respectively, while Wilson et al.62 reported brain morphological and
functional changes in early onset cannabis users. Using positron emission tomography (PET), Block et
al.69 detected altered memory-related regional blood flow in the brain of frequent marijuana users after
a minimum 26 hours of abstinence. Two other PET studies revealed altered patterns of brain activity in
abstinent heavy cannabis users while performing tasks depending on executive functioning either in
lack70 or in presence71 of performance differences. A functional magnetic resonance imaging (fMRI)
study showed increased and more widespread brain activation in heavy cannabis users compared to
controls while performing a spatial working memory task.72 Two additional fMRI studies have
demonstrated alterations in brain activity in heavy cannabis users during working memory
assessments.73,74 Recently reported preliminary data from an fMRI study of verbal learning and memory
in long-term cannabis users found altered activation of the frontal, medial, parietal, and cerebellar
regions during the encoding and retrieval processes of words learned from the Rey Auditory Verbal
Learning Test.24,75
Cannabis users seem to exhibit compensatory shifts and recruitment of additional brain regions to meet
the demands of various cognitive tasks. These findings could mean that long-term heavy cannabis
consumption causes neurophysiological deficits, even in the case of minimally impaired or even normal
superficial performance on neuropsychological tests. The subtle cannabis-induced changes in brain
function may, therefore, have a huge impact on behavioral and cognitive measures in multiple sclerosis
patients, in whom cognitive reserve is assumedly limited and compensatory mechanisms insufficient, as
will be discussed below.
Cognition in Multiple Sclerosis
Multiple sclerosis is a multifocal demyelinating disease of the CNS, in which neuroinflammatory as well
as degenerative processes are involved.76 It is the most common cause of nontraumatic neurological
disability in young adults and has a major negative impact on quality of life indices.76 Cognitive
impairment is considered one of the clinical markers of the disease.77 Neuropsychological deficits of
varying degree are present in almost 50% of multiple sclerosis patients, interfering with occupational
and social functioning even in the absence of significant physical disability.77,78 Cognitive deficits in
patients show no strong association to disease characteristics, such as disease duration, physical
disability, disease subtype, or disease severity (lesion load in structural magnetic resonance imaging),
with studies providing discrepant results.77 No general consensus exists on the prevalence and special
characteristics of cognitive dysfunction in multiple sclerosis, possibly reflecting disease heterogeneity
and demyelination of different areas of the CNS. A review of the neuropsychological literature of
multiple sclerosis using an effect size analysis, which gathered neuropsychological test results from a
total of 1,845 multiple sclerosis patients and 1,265 healthy controls, confirmed that neurocognitive
impairments are indeed evident in patients with multiple sclerosis on a number of cognitive measures.79
This review also reported that chronic progressive multiple sclerosis patients display maximal deficits on
frontal-executive tasks, whereas patients with relapsing-remitting multiple sclerosis present
impairments predominantly on tasks of memory function.79 Although the pattern of cognitive deficits
identified in multiple sclerosis is not uniform, the domains most essentially affected are information
processing speed and verbal memory.77,80,81 A recent review of cognitive impairment in multiple sclerosis
confirmed that measures of information processing speed appeared to be the most robust and sensitive
markers of this impairment, and that single, predominantly speed-related cognitive measures may be
superior to extensive and time-consuming test batteries in detecting cognitive decline.82 Cognitive

flexibility and executive functions, such as planning, have also been reported to be deficient.77 A recent
meta-analysis indicated that phonemic and semantic fluency, measures of executive functions, were
among the most sensitive neuropsychological tests to detect cognitive impairment in multiple sclerosis
patients.83 In a large series of relapsing-remitting multiple sclerosis patients, information processing
speed was the cognitive domain most frequently impaired, followed by memory.81 On
neuropsychological testing of early phase relapsing-remitting multiple sclerosis patients, information
processing speed and memory task performances were impaired.84 Deficits in the tasks of attention and
information processing occurring early in the disease course have been attributed to working memory
impairment and may, at least in part, account for subsequent decline in memorymainly retrieval of
information and conceptual reasoning.85 Working memory deficits occurring early in multiple sclerosis
were evident in two studies.86,87 Working memory is dependent on a network of functionally
interconnected brain regions, which subtends rehearsal loops handling information load, that exceeds
short-term memory storage capacity.88,89 Cognitive dysfunction in multiple sclerosis may result from an
interruption of these loops, possibly due to white matter lesions. Compensatory mechanisms operate
within the network of regions involved. Reserved brain regions may be recruited as a consequence of an
adaptive response to neuronal dysfunction in one region in order to meet the demands of a cognitive
task. Cognitive measures are not strongly and consistently correlated to structural damage (lesion load
or brain atrophy) in conventional magnetic resonance imaging (MRI).77,90 More advanced MRI methods,
such as magnetization transfer ratio or diffusion tensor imaging, capable of detecting subtle
abnormalities in the normal-appearing white matter have been used, and the findings were shown to
better correlate with cognitive impairment in multiple sclerosis patients.91,92
Explaining cognitive deficits in multiple sclerosis using multiple disconnections has recently focused
interest. A dynamic assessment of brain activity during cognitive tasks has been attempted by three
recently published fMRI studies. Two of these93,94 reported altered cerebral activation in multiple
sclerosis patients performing equally well with controls in a sustained attention task and interpreted this
as being indicative of compensatory and integrative mechanisms. On the other hand, one study95 found
no different pattern of brain activation in multiple sclerosis patients performing poorer than controls in
a planning ability task, possibly reflecting exhaustion of compensatory mechanisms. Combined data of
fMRI and structural equation modelingrepresentative of the change of activity of a target cortical area
in response to a change in activity of a source area in a defined cognitive networkwere used to assess
effective connectivity inside the working memory network in patients at the earliest stage of multiple
sclerosis.96 Decreased effective connectivity between communicating components of this network was
evident in this study and was attributed to regional fiber tract injury, as suggested by the authors. Higher
activation and connectivity enhancement between some of the areas involved was also observed in
patients and might be indicative of reorganization occurring in the CNS to compensate for diffuse white
matter damage and limit its impact on working memory function. The neurochemical bases of such
compensatory shifts in the impaired brain have not yet been established. Neuronal plasticity could
account for this effect and might be triggered by a signal transmitted through the neural circuits of the
implicated brain regions.97
A final issue that needs to be considered in this overview of cognition in multiple sclerosis is the
potential influence of mood disorders, particularly depression, on cognitive dysfunction. Two recent
reviews examining the neuropsychiatry of multiple sclerosis noted that nearly 50% of patients with
multiple sclerosis will experience clinically significant depression in their lifetime.95,96 They further report
that this figure is higher than in other neurologic disorders95 and that it is approximately three times the
prevalence rate of the general population.95,96 Recent reports further suggest that the core symptoms of

depression may affect cognitive capacity by negatively influencing the executive component of working
memory.97,98 Whether treatment of depression in this population may improve cognitive capacity,
however, remains unresolved, as no direct studies examining this issue are available in the literature.
Neuropsychological Assessment in Clinical Trials of Cannabis-Based Medicinal Extracts (CBME)
Evidence from animal studies suggests that cannabinoids may inhibit muscle spasticity and pain in
multiple sclerosis and may also play a role beyond symptom amelioration in this disease. Such evidence
has led to clinical trials for investigating the potential therapeutic efficacy of cannabinoid treatments in
patients with multiple sclerosis. Although the evidence for the therapeutic efficacy of cannabinoids in
the treatment of multiple sclerosis provided by these clinical trials is increasing, it is not as yet
convincing.1315 The available clinical trial data suggest a beneficial effect on spasticity and pain based
mainly on subjective measures.14,19 The data further suggest that the adverse side effects associated
with cannabis-based medicinal extract use are generally mild and patients do not develop toxicity.19
The aim of this article, however, is not to discuss the effect of cannabinoids on various clinical measures
of the disease reported in these trials. We specifically focus on parallel assessments of cognitive status of
patients to discover whether any disruptive effects on cognition have been documented in these trials of
cannabis-based medicinal extracts.
In 2001, 33 clinical centers in the United Kingdom and the United States undertook the study
"Cannabinoids in Multiple Sclerosis (CAMS)." Its aims were to explore the effects of a cannabis extract,
i.e., the combination of THC and cannabidiol (CBD) (Cannador) or synthetic THC alone (dronabinol),
versus placebo on spasticity, pain, tremor, bladder function, and cognitive function.15 A total of 630
patients suffering from multiple sclerosis were treated for 15 weeks; 206 received the oral 9THC in
capsule form, 211 patients consumed an oral cannabis extract in capsules containing 2.5 mg of THC,
1.25 mg of cannabidiol and less than 5% other cannabinoids per capsule, and 213 patients took a
placebo.15 Medication dosage was based on body weight, with a maximum possible dose of 25 mg daily.
The authors reported absence of beneficial effects on spasticity evaluated by the Asworth scale, but
noted the limitations of this scale in measuring the highly complex symptoms of spasticity. An objective
improvement in mobility was further noted with oral THC. The reported adverse effects were generally
mild and well tolerated.1,15 In a 1-year follow up of this trial, in which 502 (80%) of the initial 630 patients
took part, overall objective improvements of spasticity were observed mainly in patients taking
Marinol, although beneficial effects were reported by patients taking Cannador. Overall, there were
no major adverse effects, but minor adverse effects were reported by the majority of patients.16
The neuropsychological effects of cannabinoids were evaluated in a substudy (CAMS-PEC) of the main
CAMS program. Eighty-nine patients completed a battery of neuropsychological tests before, during, and
after the medication period. The battery was comprised of the California Verbal Learning Test, the Paced
Auditory Serial Addition Test, the Digit Span, Digit Symbol, and the self-report Dysexecutive
Questionnaire. The preliminary results of this substudy of the CAMS trial report a significant reduction in
performance on the California Adult Verbal Learning Test (verbal learning and memory) in those
receiving cannabis extracts compared with placebo.102
In 2002, Killestein et al.8 were the first to publish the results of a randomized, double-blind, placebocontrolled clinical trial of the effects of oral 9THC and a Cannabis sativa plant extract on multiple
sclerosis (2.5 mg b.i.d. increased to 5 mg b.i.d.). In addition to various clinical assessments, the authors
assessed the 16 patients who participated for possible changes in cognition with the Paced Auditory

Serial Addition Test (PASAT), but did not comment on any alterations at reevaluation. Rog et al.9
performed a randomized, controlled trial of a THC:CBD 1:1 extract in 66 multiple sclerosis patients
suffering from neuropathic pain. The mean dose achieved of 25.9 mg THC (range=5.4 to 67.5) and 24 mg
CBD is in excess of that used in other cannabinoid trials. The patients also underwent a brief repeatable
battery of neuropsychological testing prior to first dosing and after 5 weeks at study completion or
before in case of withdrawal. No significant changes were observed in four of the five
neuropsychological outcomes measured. However, a significant difference in the long-term memory
storage capacity assessed by the Selective Reminding Test was detected in favor of the placebo group as
opposed to the active treatment one at the final evaluation. A randomized, controlled trial of the effects
of the synthetic cannabinoid CT-3 on chronic neuropathic pain reported that CT-3 was effective in
reducing chronic neuropathic pain compared with placebo, but noted carryover and period effects on
the Trail-Making Test, a measure of psychomotor speed and attention.103 Another randomized, doubleblind, parallel groups, placebo-controlled study of 6 weeks duration examined the specific effects of
Sativex on symptoms in multiple sclerosis.13 These authors detected significant reductions in spasticity
and subjective improvements in sleep quality. In addition, participants were tested on cognition using
the Adult Memory and Information Processing Battery Test of Attention adapted for patients with
multiple sclerosis. No significant adverse effects on cognition were noted. In a recent long-term followup (mean = 434 days; range=21814 days) of the Wade et al.13 study, six multiple sclerosis patients
complained of altered attention capacities. However, no formal neuropsychological data were reported
in the follow-up study.14 Another randomized, double-blind, crossover, placebo-controlled study using
the PASAT and the Digit Span Test found no significant adverse effects on cognition.12 More recently, a
study104 evaluating the safety and efficacy of low dose treatment with the synthetic cannabinoid
nabilone (1 mg/day) on spasticity-related pain in patients with upper motor neuron syndrome (UMNS)
assessed neuropsychological functioning in a subset of these patients105 and reported no cognitive side
effects in the domains of attention, psychomotor speed, and mental flexibility after 9 weeks of
treatment. There are also reports106 from other neurological entities, with low doses of 9THC (max 10
mg/day) that had no short- or long-term effect on neuropsychological performance of 24 patients with
Tourettes syndrome (see Table 2 for a summary of recent cannabis-based medicinal extracts clinical
trial data on neuropsychological functions).

Potential for Cognitive Adverse Effects of Long-term Cannabinoid Treatment in Multiple Sclerosis
Cognitive deficits resulting from chronic heavy cannabis use reported in neuropsychological
studies23,56,57 may become more apparent in populations already demonstrating cognitive impairment
such as multiple sclerosis patients. Interestingly, memory and information processing speed deficits
appear to emerge in both cumulative cannabis consumption and multiple sclerosis. In support of this
hypothesis are the observed alterations in brain activities, which accompany both multiple sclerosis
patients and long-term cannabis users. As mentioned above, endocannabinoids are major regulators of
synaptic transmission in the CNS and might serve the signaling between functionally connected brain
regions. Thus, endocannabinoids could mediate altered cerebral activation under certain circumstances,
such as highly demanding tasks or coexistence of brain pathology.
By interfering with the elements of the endocannabinoid system, exogenous cannabinoids may disrupt
rather than imitate its regulatory functions. Serious concern arises from the evidence that long-term
exposure to both natural and synthetic cannabinoid agonists causes down-regulation and
desensitization of CB1 receptors in the brain and perhaps underlying tolerance mechanisms.107
Tolerance might have an impact on the multiple effects resulting from activation of CB receptors. The
therapeutic efficacy could therefore dissipate over time, while a state of dependence could develop.

Tolerance of many of the behavioral consequences of cannabis or to several of its adverse effects also
develops. Recordings of hippocampal neuronal activity suggest that the hippocampus may become
tolerant to the effects of cannabinoids on memory.108 Interestingly, in a study assessing the effects of
long-term heavy cannabis use on information processing speed, a deficit appears in users when they are
in the subacute state (prior to cannabis consumption) which is normalized in the acute phase. The
authors note that these results may be attributed to a withdrawal effect, but may also be due to
tolerance development after prolonged cannabis use.109 This would mean that due to changes in the
molecular substrates, chronic cannabis users actually have a latent specific cognitive dysfunction which
is masked by their cannabis dosing. The concerns extend to the neuroprotective effects of cannabinoids
as well. As a result of decreased expression of CB receptors, cannabinergic signals may also be downregulated and repair responses could be disrupted. Long-term users would be highly dependent on their
medication to preserve any protective effects and perhaps an increase in the dose would be required to
achieve the same level of neuroprotection or symptom relief. The patients might be vulnerable to the
very insult the treatment was intended for.
The endocannabinoid system has been shown to mediate synaptic plasticity in an increasing number of
brain structures and synapses. 9THC and the cannabinoid receptor agonists have been shown to
impair long term potentiation in the hippocampus, a proposed mechanism for memory and learning.3
Chronic exposure to cannabis might cause permanent neurophysiological deficits that could influence
endocannabinoid-mediated synaptic plasticity in the CNS.110,111 Chronic THC exposure impairs
endocannabinoid-mediated synaptic plasticity in mice; however, compensatory mechanisms may be
employed to rescue plasticity expression.112 Such neurophysiological deficits possibly account for the
residual effects of cannabis on cognition reported by neuropsychological studies.
As was shown in rats, cannabinoids may disrupt hippocampal neural encoding for short-term memory113
and prevent the formation of new synapses between hippocampal neurons independent of the direct
effects on neurotransmitter release.114 Loss of synaptic efficacy induced by chronic cannabis
consumption could result in an early breakdown of adaptive mechanisms in the context of preexisting
brain pathology. Thus, influence of white matter lesions on cognitive functions in multiple sclerosis
otherwise initially restricted by remodeling of neuronal circuitscould be more pronounced in patients
exhibiting blockade of neural plasticity due to long-term cannabis use. In accordance with this
assumption lies the observed localization of CB1 receptors in the brain, which is denser in the
hippocampus, prefrontal cortex, and cerebellum. These brain areas are critically implicated in the
neurocognitive functions most negatively affected by cannabis use. They have also been reported to
participate in alternative brain activation patterns during complex memory and information processing
tasks, even in the absence of disturbed neuropsychological performance. A selective deficit in learning
and memory performance is observed in rat EAE, a popular animal model to mimic human multiple
sclerosis.115 Neuroprotective effects of CB1 receptor agonism have been reported in EAE,2,4 but to our
knowledge, possible deterioration of cognitive status in EAE after prolonged treatment with cannabis
has not yet been investigated.
To test a possible synergistic effect hypothesis between multiple sclerosis and cannabis use in disrupting
cognitive functions, longitudinal, high-population, prospective follow-up studies would be required.
Retrospective studies are easier to conduct, but controlling for confounding factors may not be
satisfactorily achieved. It is critical to control for baseline neuropsychological performance both in
respect to disease onset and to initiation of cannabinoid treatment, as well as the potential for
concurrent situations or factors that may affect cognitive functions, such as use of other drugs,

premorbid intelligence (crystallized intelligence), and presence of other neurological or psychiatric

disease. In any case, it would be difficult to be certain to which degree cognitive decline observed at the
time of reassessment could be attributable to cannabinoid treatment in medicated patients. Disease
characteristics should be distributed as equally as possible between medicated and unmedicated
patients.
HIV-infected individuals, prematurely demonstrating cognitive disturbances,116 have similarly been
shown to exhibit abnormal brain activation on fMRI preceding clinical expression of cognitive deficits.117
A synergistic effect of HIV infection and chronic marijuana use on cognitive function was recently
reported, although limited to advanced HIV cases.118
Symptomatic Treatment and Comparison of Cannabinoid Treatments in Multiple Sclerosis
Despite an advance on the treatment of multiple sclerosis in recent years, no treatment exists which
definitely stops its evolution and numerous ongoing studies are searching for new therapeutic
options.119,120 The traditional treatment for multiple sclerosis has been symptomatic, treating acute
relapses without affecting the underlying disease. For the acute phase of the disease, there is
generalized consensus on the use of corticoids; the most commonly used is intravenous
methylprednisolone.119 The introduction of interferon-beta (IFN-beta) has offered significant clinical
benefits by reducing the frequency of relapses and slowing the disease progression.121 Although
interferon beta is considered the treatment of choice in preventing the evolution of remittent multiple
sclerosis, there are questions as to which cases would benefit most, when it should be used, the type of
interferon beta, the dose, and the route of administration. In this regard, a multicenter, randomized,
double-blind, placebo-controlled trial examining the efficacy, safety, and tolerability of every-other-day
interferon beta-1b 250 g subcutaneous treatment in patients with a first clinical event suggestive of
multiple sclerosis (clinically isolated syndrome) reported that interferon beta-1b delayed conversion to
clinically definite multiple sclerosis, and that it should be considered as a therapeutic option in patients
presenting with a first clinical event suggestive of multiple sclerosis.122 A possible alternative to
interferon beta may be the use of copolimere-1 or azathioprine.119 Besides immunomodulation and
immunosuppression, symptomatic treatment is an essential component of the overall management of
multiple sclerosis.120
Symptomatic treatment in multiple sclerosis is aimed at reducing and eliminating those symptoms
impairing the functional abilities and quality of life of the affected patients. Despite numerous
therapeutic techniques and medications used for the treatment of multiple sclerosis symptoms, only a
few have been investigated in multiple sclerosis patients and are approved by the respective national
health authorities.120 In addition, very few evidence-based studies exist despite the overwhelming
number of publications.119,120 Recently, a consensus statement on the symptomatic treatment of
multiple sclerosis was developed, comprising the existing evidence-based literature and therapeutic
experience of neurologists who had dealt with such issues over a long time period.120 In this consensus,
statement proposals for the treatment of the most common multiple sclerosis symptoms, including
disorders of motor function and coordination, cranial nerve function, autonomic, cognitive, and
psychological functions, multiple sclerosis-related pain syndromes, and epileptic seizures, were
presented.120 Due to the fact that a more detailed description of the symptomatic treatment of multiple
sclerosis is beyond the scope of this article, readers are referred to the Henze et al.120 consensus
statement for a comprehensive up-to-date report on this issue.
As stated previously, evidence from basic science and human trials suggests that cannabis-based

medicinal extracts may have therapeutic potential in multiple sclerosis, particularly in the treatment of
pain, spasm, spasticity and bladder dysfunction. Cannabis extracts contain a variety of chemical
compounds and are likely to exert a multitude of effects, some of them undesirable or counteracting to
the beneficial ones. The plant-derived cannabinoid preparation Sativex, an oromucosal spray which
delivers 9THC and CBD in approximately equal concentrations, has already gained regulatory approval
in Canada for the treatment of spasticity and pain associated with multiple sclerosis.21 It has been
postulated that the synergistic effect of both 9THC and CBD will be more beneficial than a simple CB1
receptor agonistic action. Interestingly, patients with multiple sclerosis treated with Sativex
experienced improvements in the most disturbing symptoms, including spasticity, lower urinary tract
symptoms, and neurogenic symptoms, without experiencing significant adverse effects in either
cognition or mood and only mild intoxication.6,9,12,13,123,124 9THC acts on both CB1 and CB2 receptors
and therefore lacks specificity. Selective CB1 agonists could therefore produce a selective therapeutic
effect not observed with the use of medicinal extracts of cannabis. However, even selective activation of
CB1 receptors can influence the release of more than one neurotransmitter in different brain areas.
Synthetic agonists such as CP 55,940 and WIN 55,2122 act as full agonists and could increase the
potency of the effects produced by the activation of receptor. In this case, the adverse effects are not
disengaged. As already mentioned, endocannabinoids are locally released at the site of neuronal
damage in order to activate signaling pathways in the brain that are important for neuronal repair and
cell maintenance. Such effects have been shown to result from cannabinoid receptor agonism. Thus, by
enhancing the action of endocannabinoids we could promote endogenous repair signaling. Against this
background, it remains to be seen whether novel molecules, optimized for modifying neural excitability
and inflammation, may be useful in multiple sclerosis treatment. This strategy includes the
administration of novel agents that can act as weak agonists at the CB1 receptor or agents that may not
directly activate the CB receptors but might otherwise modify cannabinoid transport or metabolism.
Specifically, weak/partial agonists at the CB receptors could have a therapeutic effect and also widen the
therapeutic window since the current window between symptom relief and adverse effects of THC or
direct cannabinoid agonists is narrow. Alternatively, modulating the availability of endocannabinoids by
blocking the processes of their deactivation could locally target sites of damage where
endocannabinoids are unregulated while sparing cognitive sites and reducing unwanted side effects.2,4
This latter approach includes therapeutic agents that inhibit endocannabinoid transport and
degradation such as FAAH inhibitors, anandamide transport inhibitors and MAG lipase inhibitors.
Boosting on-demand, region-specific brain endocannabinoid tone in treating multiple sclerosis is further
supported in light of the recent report that the neuroprotective increase of endocannabinoids might
actually be inhibited by a disease-associated cytokine. Interestingly, recent studies in a viral model of
multiple sclerosis support this notion. Treatment of encephalomyelitis virus-infected mice with the
anandamide transport inhibitors OMDM1 and OMDM2 enhanced anandamide levels, down-regulated
inflammatory responses and ameliorated the motor symptoms associated with the demylenating
disease.125 Furthermore, recent data indicate that endogenously released cannabinoids and exogenously
administered CB1 receptor agonists can differentially regulate synaptic inputs,126 thus providing support
of their discrete functional properties that may be of pharmacological interest.
DISCUSSION
In view of the prospect of chronically administering direct cannabinoid agonists not only as
symptomatic treatment in advanced multiple sclerosis, but also as a neuroprotective agent in early
multiple sclerosis patients, careful evaluation of neurocognitive effects of cannabis and diseaseassociated brain tissue damage should be undertaken. Hypothetically, a critical threshold has to be

reached before cognitive impairment is clinically evident in multiple sclerosis. Cumulative lifetime
cannabis use could synergistically further disrupt cognitive function in patients than the disease process
alone. The assumed threshold for cognitive impairment to translate into clinically significant decline and
influence functioning abilities or activities of daily living may be more easily reached in those patients
who receive long-term high-dose cannabinoid treatment. This possibility, although not fully discouraging
to the cannabis therapeutic application in multiple sclerosis, should at least pose limitations regarding
dose and duration of therapy beyond individual acute intoxication effects. Dosage instructions may,
however, be overlooked, as patients could develop dependence on the drug during therapy. Although
the pharmacokinetic profiles of the orally or sublingually delivered versus smoked cannabis are
different, the fear of abuse still exists.
Most clinical trials of cannabinoids in multiple sclerosis report generally mild and well-tolerated adverse
side effects such as dry mouth, dizziness, somnolence, and acute intoxication. Nevertheless, more
subjects in the active treatment groups than in the placebo group drop out of the follow-up studies due
to adverse side effects. There is yet no direct evidence that multiple sclerosis patients might suffer a
significant cognitive decline after prolonged administration of cannabis-based medicinal extracts.
Available data indicate that this is not a serious problem at least in the short term. Because of the
relatively short history of large-scale systematic clinical trials for cannabinoids in the treatment of
multiple sclerosis, no definite information is provided on possible long-term cognitive adverse effects of
cannabinoids. Cognitive deficits that have been attributed to long-term heavy recreational use are not
necessarily extended to controlled pharmaceutical use. Such results, however, form the basis on which
to raise this concern. Given the fact that multiple sclerosis patients differ from normal individuals in that
they suffer from cognitive disturbances, this consideration certainly deserves further investigation. A
more thorough and, in due course, repeated neuropsychological evaluation of the participants in the
clinical studies is needed. Enhancing the responses of endogenous cannabinoids by inhibition of their
deactivating processes may be the most preferable therapeutic strategy. Since such an effect would be
limited at the site of damage and at the exact time of the endocannabinoid release, the therapeutic
effect would be maximized and a disruption of cognitive networks elsewhere in the brain would be less
likely to take place. The caution that we presently express involves not only acute psychotropic
phenomena resulting from potent CB receptor activation, but more urgently the receptor downregulation and impaired synaptic plasticity affecting cognitive systems after long-term administration of
cannabis. In any case, safer and more valid conclusions will have to await the results of long-term, largescale systematic clinical trials of cannabinoid-based medicinal extracts (CBMEs). Toward this end, a
large-scale, multicenter trial is now underway in the United Kingdom, known as CUPID (cannabinoid use
in progressive inflammatory brain disease), which will evaluate the effects of oral THC on 500 individuals
with multiple sclerosis over a 3-year period.20 It remains to be determined what type of cannabinoid
agent and what route of administration are the most suitable to maximize the beneficial effects and
minimize the incidence of undesirable side effects.
In conclusion, studies on cannabinoids and multiple sclerosis as well as on cannabinoids and cognition
provide important new data, but all have their limitations with respect to the study design and
interpretability of outcome. Furthermore, despite the enthusiasm about the reported clinical value of
cannabinoids in multiple sclerosis, many issues remain unresolved in this area. Therefore, a balanced
assessment of the risk-benefit ratio for cannabinoids in multiple sclerosis is still difficult to make. As long
as the relevant evidence is not conclusive, clinical trials with cannabinoids that will provide more
substantial clinical data, both about the efficacy of cannabinoids and about their long-term adverse side
effects, are warranted.

REFERENCES

1. Ben Amar M: Cannabinoids in medicine: a review of their therapeutic potential. J

Ethnopharmacol 2006; 105:125[CrossRef][Medline]
2. Baker D, Pryce G, Giovannoni G, et al: The therapeutic potential of cannabis. Lancet Neurology
2003; 2:291298[CrossRef][Medline]
3. Iversen L: Cannabis and the brain. Brain 2003; 126:12521270[Abstract/Free Full Text]
4. Pryce G, Baker D: Emerging properties of cannabinoid medicines in management of multiple
sclerosis. Trends Neurosci 2005; 28:272276[CrossRef][Medline]
5. Clark AJ, Ware MA, Yazer E, et al: Patterns of cannabis use among patients with multiple
sclerosis. Neurology 2004; 62:20982100[Abstract/Free Full Text]
6. Brady CM, DasGupta R, Dalton C, et al: An open-label pilot study of cannabis-based extracts for
bladder dysfunction in advanced multiple sclerosis. Mult Scler 2004; 10:425
433[Abstract/Free Full Text]
7. Fox P, Bain PG, Glickman S, et al: The effect of cannabis on tremor in patients with multiple
sclerosis. Neurology 2004; 62:11051109[Abstract/Free Full Text]
8. Killestein J, Hoogervorst EL, Reif M, et al: Safety, tolerability, and efficacy of orally administered
cannabinoids in MS. Neurology 2002; 58:14041407[Abstract/Free Full Text]
9. Rog DJ, Nurmiko T, Friede T, et al: Randomized controlled trial of cannabis based medicine in
central neuropathic pain due to multiple sclerosis. Neurology 2005; 65:812
819[Abstract/Free Full Text]
10. Russo EB: Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology
2003; 60:729730[Free Full Text]
11. Svendsen KB, Jensen TS, Bach FW: Does the cannabinoid dronabinol reduce central pain in
multiple sclerosis? Randomised double blind placebo controlled crossover trial. Bri Med J 2004;
329:253[CrossRef]
12. Vaney C, Heinzel-Gutenbrunner M, Jobin P, et al: Efficacy, safety and tolerability of an orally
administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a
randomized, double-blind, placebo-controlled, crossover study. Mult Scler 2004; 10:417
424[Abstract/Free Full Text]
13. Wade DT, Makela P, Robson P, et al: Do cannabis based medicinal extracts have general or
specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebocontrolled study on 160 patients. Mult Scler 2004; 10:434441[Abstract/Free Full Text]

14. Wade DT, Makela PM, House H, et al: Long-term use of cannabis-based medicine in the
treatment of spasticity and other symptoms of multiple sclerosis. Mult Scler 2006; 12:639
645[Abstract/Free Full Text]
15. Zajicek J, Fox P, Sanders H, et al: Cannabinoids for the treatment of other symptoms related to
multiple sclerosis (CAMS study): multicentre, randomized, placebo-controlled trial. Lancet 2003;
362:15171526[CrossRef][Medline]
16. Zajicek J, Fox P, Sanders HP, et al: Cannabinoids in multiple sclerosis (CAMS study): safety and
efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 2005; 76:1664
1669[Abstract/Free Full Text]
17. Pertwee RG: Cannabinoids and multiple sclerosis. Pharmacol Ther 2002; 95:165
174[CrossRef][Medline]
18. Jackson SJ, Diemel LT, Pryce G, et al: Cannabinoids and neuroprotection in CNS inflammatory
disease. J Neurol Sci 2005; 233:2125[CrossRef][Medline]
19. Smith PF: The safety of cannabinoids for the treatment of multiple sclerosis. Expert Opin Drug
Saf 2005; 4:443456[CrossRef][Medline]
20. Bowling A: Cannabinoids in MS: are we any closer to knowing how best to use them? Mult Scler
2006; 12:523525[Free Full Text]
21. Russo EB, Guy GW: A tale of two cannabinoids: the therapeutic rationale for combining
tetrahydrocannabinol and cannabidiol. Med Hypotheses 2006; 66:234246[CrossRef][Medline]
22. Grant I, Gonzalez R, Carey CL, et al: Non-acute (residual) neurocognitive effects of cannabis use:
a meta-analytic study. J Int Neuropsychol Soc 2003; 9:679689[CrossRef][Medline]
23. Messinis L, Kyprianidou A, Malefaki S, et al: Neuropsychological deficits in long-term frequent
cannabis users. Neurology 2006; 66:737739[Abstract/Free Full Text]
24. Solowij N, Michie PD: Cannabis and cognitive dysfunction: parallels with endophenotypes of
schizophrenia? J Psychiatry Neurosci 2007; 32:3052[Medline]
25. Bovasso GB: Cannabis abuse as a risk factor for depressive symptoms. Am J Psychiatry 2001;
158:20332037[Abstract/Free Full Text]
26. Johns A: Psychiatric effects of cannabis. Br J Psychiatry 2001; 178:116
122[Abstract/Free Full Text]
27. Nunez LA, Gurpegui M: Cannabis-induced psychosis: a cross-sectional comparison with acute
schizophrenia. Acta Psychiatry Scand 2002; 10:173178
28. Iversen L: Long-term effects of exposure to cannabis. Curr Opin Pharmacol 2005; 5:69
72[CrossRef][Medline]

29. Budney AJ, Hughes JR, Moore BA, et al: Review of the validity and significance of cannabis
withdrawal syndrome. Am J Psychiatry 2004; 161:19671977[Abstract/Free Full Text]
30. Budney AJ, Hughes JR: The cannabis withdrawal syndrome. Curr Opin Psychiatry 2006; 19:233
238[Medline]
31. Smith NT: A review of the published literature into cannabis withdrawal symptoms in human
users. Addiction 2002; 97:621632[CrossRef][Medline]
32. Crowley TJ, Macdonald MJ, Whitmore EA, et al: Cannabis dependence, withdrawal, and
reinforcing effects among adolescents with conduct symptoms and substance use disorders.
Drug Alcohol Depend 1998; 50:2737[CrossRef][Medline]
33. Roffman RA, Klepsch R, Wertz JS, et al: Predictors of attrition from an outpatient marijuanadependence counselling program. Addict Behav 2003; 18:553566[CrossRef]
34. Soellner R: Dependence on cannabis: an everlasting issue. Subst Use Misuse 2005; 40:857
867[CrossRef][Medline]
35. Matsuda LA, Lolait SJ, Brownstein MJ, et al: Structure of a cannabinoid receptor and functional
expression of the cloned CDNA. Nature 1990; 346:561564[CrossRef][Medline]
36. Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for
cannabinoids. Nature 1993; 365:6165[CrossRef][Medline]
37. Begg M, Pacher P, Batkai S, et al: Evidence for novel cannabinoid receptors. Pharmacol Ther
2005; 106:133145[CrossRef][Medline]
38. Mechoulam R, Ben-Shabat S, Hanus L, et al: Identification of an endogenous 2-monoglyceride,
present in canine gut that binds to cannabinoid receptors. Biochem Pharmacol 1995; 50:83
90[CrossRef][Medline]
39. Mechoulam R, Parker LA, Gallily R: Cannabidiol: an overview of some pharmacological aspects. J
Clin Pharmacol 2002; 42:11S-19S.
40. Schlicker E, Kathmann M: Modulation of neurotransmitter release via presynaptic cannabinoid
receptors. Trends in Pharmacol Sci 2001; 22:565572[CrossRef]
41. Gong JP, Onaivi ES, Ishiguro H, et al: Cannabinoid CB2 receptors: immunohistochemical
localization in the rat brain. Brain Res 2006; 107:110123
42. Piomelli D: The molecular logic of endocannabinoid signaling. Nat Rev Neurosci 2003; 4:873
884[CrossRef][Medline]
43. Pertwee RG: The therapeutic potential of drugs that target cannabinoid receptors or modulate
the tissue levels or actions of endocannabinoids. AAPS J 2005; 7:E625-E654

44. Bahr BA, Karanian DA, Makanji SS, et al: Targeting the endocannabinoid system in treating brain
disorders. Expert Opin Investig Drugs 2006; 15:351365[CrossRef][Medline]
45. Louw DF, Yang FW, Sutherland GR: The effect of 9tetrahydrocannabinol on forebrain ischemia
in rat. Brain Res 2000; 857:183187[CrossRef][Medline]
46. Nagayama T, Sinor AD, Simon RP, et al: Cannabinoids and neuroprotection in global and focal
cerebral ischemia and in neuronal cultures. J Neurosci 1999; 19:2987
2995[Abstract/Free Full Text]
47. Panikashvili D, Simeonidou C, Ben-Shabat S, et al: An endogenous cannabinoid (2arachidonylglycerol) is neuroprotective after brain injury. Nature 2001; 413:527
531[CrossRef][Medline]
48. Dirnagl U, Costantino L, Moskowitz P: Pathobiology of ischemic stroke: an integrated view.
Trends Neurosci 1999; 22:391397[CrossRef][Medline]
49. Nicotera P, Leist M, Manzo L: Neuronal cell death: demise with different shapes. Trends
Pharmacol Sci 1999; 20:4651[CrossRef][Medline]
50. Marsicano G, Goodenough S, Monory K, et al: CB1 cannabinoid receptors and on-demand
defence against excitoxicity. Science 2003; 302:8488[Abstract/Free Full Text]
51. Shen M, Piser TM, Seybold US, et al: Cannabinoid receptor agonists inhibit glutamatergic
synaptic transmission in rat hippocampal cultures. J Neurosci 1996; 16:4322
4334[Abstract/Free Full Text]
52. Baker D, Pryce G, Croxford JL, et al: Endocannabinoids control spasticity in a multiple sclerosis
model. FASEB J 2001; 15:300302[Free Full Text]
53. Witting A, Chen L, Cudaback E, et al: Experimental autoimmune encephalomyelitis disrupts
endocannabinoid-mediated neuroprotection. Proc Natl Acad Sci USA 2006; 103:6362
6367[Abstract/Free Full Text]
54. Gorelick DA, Heishman SJ: Methods for clinical research involving cannabis administration.
Methods Molec Med 2006; 123:235253
55. Pope HG Jr, Gruber AJ, Hudson JI, et al: Neuropsychological performance in long-term cannabis
users. Arch Gen Psychiatry 2001; 58:909915[Abstract/Free Full Text]
56. Bolla KI, Brown K, Eldreth D, et al: Dose-related neurocognitive effects of marijuana use.
Neurology 2002; 59:13371343[Abstract/Free Full Text]
57. Solowij N, Stephens RS, Roffman RA, et al: Cognitive functioning of long-term heavy cannabis
users seeking treatment. JAMA 2002; 287:11231131[Abstract/Free Full Text]
58. Fletcher JM, Page JB, Francis DJ, et al: Cognitive correlates of long-term cannabis use in Costa

Rican men. Arch Gen Psychiatry 1996; 53:10511057[Abstract/Free Full Text]

59. Ehrenreich H, Rinn T, Kunert HJ, et al: Specific attentional dysfunction in adults following early
start of cannabis use. Psychopharmacology 1999; 142:295301[CrossRef][Medline]
60. Pope HG Jr, Gruber AJ, Hudson JI, et al: Early-onset cannabis use and cognitive deficits: what is
the nature of the association? Drug Alcohol Depend 2003; 69:303310[CrossRef][Medline]
61. Huestegge L, Radach R, Kunert HJ, et al: Visual search in long-term cannabis users with early age
of onset. Prog Brain Res 2002; 140:377394[Medline]
62. Wilson WH, Mathew RJ, Turkington TG, et al: Brain morphological changes and early marijuana
use: a magnetic resonance and positron emission tomography study. J Addict Dis 2000; 19:1
22[Medline]
63. Macleod J, Oakes R, Copello A, et al: Psychological and social sequelae of cannabis and other
illicit drug use by young people: a systematic review of longitudinal, general population studies.
Lancet 2004; 363:15791588[CrossRef][Medline]
64. Tzilos GK, Cintron CB, Wood JB, et al: Lack of hippocampal volume change in long-term heavy
cannabis users. Am J Addict 2005; 14:6472[CrossRef][Medline]
65. Solowij N: Cannabis and Cognitive Functioning. Cambridge, UK, Cambridge University Press,
1998
66. Struve FA, Patrick G, Straumanis JJ, et al: Possible EEG sequelae of very long duration marihuana
use: pilot findings from topographic quantitative EEG analyses of subjects with 15 to 24 years of
cumulative daily exposure to THC. Clin Electroencephalogr 1998; 29:3136[Medline]
67. Block RI, OLeary DS, Ehrhardt JC, et al: Effects of frequent marijuana use on brain tissue volume
and composition. Neuroreport 2000; 11:491496[Medline]
68. Matochik JA, London EL, Eldreth DA, et al: Altered brain tissue composition in heavy marijuana
users. Drug Alcohol Depend 2005; 77:2330[CrossRef][Medline]
69. Block RI, OLeary DS, Hichwa RD, et al: Effects of frequent marijuana use on memory-related
regional cerebral blood flow. Pharmacol Biochem Behav 2002; 72:237250[CrossRef][Medline]
70. Eldreth DA, Matochik JA, Cadet JL, et al: Abnormal brain activity in prefrontal brain regions in
abstinent marijuana users. Neuroimage 2004; 23:914920[CrossRef][Medline]
71. Bolla KI, Eldreth DA, Matochik JA, et al: Neural substrates of faulty decision-making in abstinent
marijuana users. Neuroimage 2005; 26:480492[CrossRef][Medline]
72. Kanayama G, Rogowska J, Pope HG, et al: Spatial working memory in heavy cannabis users: a
functional magnetic resonance imaging study. Psychopharmacology 2004; 176:239
247[CrossRef][Medline]

73. Jacobsen LK, Mencl WE, Westerveld M, et al: Impact of cannabis use on brain function in
adolescents. Ann N Y Acad Sci 2004; 1021:384390[CrossRef][Medline]
74. Jager G, Kahn RS, Van Den Brink W, et al: Long-term effects of frequent cannabis use on working
memory and attention: an fMRI study. Psychopharmacology 2006; 185:358
368[CrossRef][Medline]
75. Respondek C, Solowij N, Ward P: Functional magnetic resonance imaging indices of memory
function in long-term cannabis users. World J Biol Psychiatry 2004; 5(S1):S131
76. Compston A, Coles A: Multiple sclerosis. Lancet 2002; 359:12211231[CrossRef][Medline]
77. Calabrese P: Neuropsychology of multiple sclerosis: an overview. J Neurology 2006; 253:10
15[CrossRef]
78. Rao SM, Leo GJ, Ellington L, et al: Cognitive dysfunction in multiple sclerosis: impact on
employment and social functioning. Neurology 1991; 41:692696[Abstract/Free Full Text]
79. Zakzanis KK: Distinct neurocognitive profiles in multiple sclerosis subtypes. Arch Clin
Neuropsychol 2000; 15:115136[CrossRef][Medline]
80. Denney DR, Sworowski LA, Lynch SG: Cognitive impairment in three subtypes of multiple
sclerosis. Arch Clin Neuropsychol 2005; 20:967981[Abstract]
81. Nocentini U, Pasqualetti P, Bonavita S, et al: Cognitive dysfunction in patients with relapsingremitting multiple sclerosis. Mult Scler 2006; 12:7787[Abstract/Free Full Text]
82. Hoffmann S, Tittgemeyer M, Yves von Cramon D: Cognitive impairment in multiple sclerosis.
Curr Opin Neurol 2007; 20:275280[Medline]
83. Henry JD, Beatty WW: Verbal fluency deficits in multiple sclerosis. Neuropsychologia 2006;
44:11661174[CrossRef][Medline]
84. Olivares T, Nieto A, Sanchez MP, et al: Pattern of neuropsychological impairment in the early
phase of relapsing-remitting multiple sclerosis. Mult Scler 2005; 11:191
197[Abstract/Free Full Text]
85. Litvan J, Grafman J, Vendrell P, et al: Multiple memory deficits in patients with multiple
sclerosis: exploring the working memory system. Arch Neurol 1988; 45:607
610[Abstract/Free Full Text]
86. Pelosi L, Geesken JM, Holl M, et al: Working memory impairment in early multiple sclerosis:
evidence from an event-related potential study of patients with clinically isolated myelopathy.
Brain 1997; 120:20392058[Abstract/Free Full Text]
87. Achiron A, Barak Y: Cognitive impairment in probable multiple sclerosis. J Neurol Neurosur
Psychiatry 2003; 74:443446[Abstract/Free Full Text]

88. Baddeley : Working memory. Science 1992; 255:556559[Abstract/Free Full Text]

89. Paulesu E, Frith CD, Frackowiak RSJ: The neural correlates of the verbal component of working
memory. Nature 1993; 362:342344[CrossRef][Medline]
90. Lazeron RH, Boringa JB, Schouten M, et al: Brain atrophy and lesion load as explaining
parameters for cognitive impairment in multiple sclerosis. Mult Scler 2005; 11:524
531[Abstract/Free Full Text]
91. Rovaris M, Filippi M, Falautano L, et al: Relation between MR abnormalities and patterns of
cognitive impairment in multiple sclerosis. Neurology 1998; 50:1601
1608[Abstract/Free Full Text]
92. Zivadinov VR, De Masi D, Nasuelli LM, et al: MRI techniques and cognitive impairment in the
early phase of relapsing-remitting multiple sclerosis. Neuroradiology 2001; 43:272
278[CrossRef][Medline]
93. Audoin B, Ibarrola JP, Ranjeva S, et al: Compensatory cortical activation observed by fMRI during
a cognitive task at the earliest stage of MS. Hum Brain Mapp 2003; 20:5158[CrossRef][Medline]
94. Staffen WA, Mair H, Zauner A, et al: Cognitive function and fMRI in patients with multiple
sclerosis: evidence for compensatory cortical activation during an attention task. Brain 2002;
125:12751282[Abstract/Free Full Text]
95. Feinstein A: The neuropsychiatry of multiple sclerosis. Can J Psychiatry 2004; 49:157
163[Medline]
96. Ghaffar O, Feinstein A: The neuropsychiatry of multiple sclerosis: a review of recent
developments. Curr Opin Psychiatry 2007; 20:278285[Medline]
97. Demaree HA, Gaudino E, DeLuca J: The relationship between depressive symptoms and
cognitive dysfunction in multiple sclerosis. Cognit Neuropsychiatry 2003; 8:161
171[CrossRef][Medline]
98. Feinstein A: Mood disorders in multiple sclerosis and the effects on cognition. J Neurol Sci 2006;
245:6366[CrossRef][Medline]
99. Lazeron RH, Rombouts SA, Scheltens PH, et al: An fMRI study of planning-related brain activity in
patients with moderately advanced multiple sclerosis. Mult Scler 2004; 10:549
555[Abstract/Free Full Text]
100.
Au Duong MV, Boulanouar K, Audoin B, et al: Modulation of effective connectivity inside
the working memory network in patients at the earliest stage of multiple sclerosis. Neuroimage
2005; 24:533538[CrossRef][Medline]
101.
Mesulam M: Brain, mind, and the evolution of connectivity. Brain Cogn 2000; 42:4
6[CrossRef][Medline]

102.
Langdon DW, Thompson AJ, Johnson KP, et al: The psychological effects of cannabis in
MS: impact on cognition, pain, mood and fatigue (abstract). Mult Scler ECTRIMS 2003; 9:S27
103.
Karst M, Salim K, Burstein S, et al: Analgesic effect of the synthetic cannabinoid CT-3 on
chronic neuropathic pain. JAMA 2003; 290:17571762[Abstract/Free Full Text]
104.
Wissel J, Haydn T, Muller J, et al: Low dose treatment with the synthetic cannabinoid
nabilone significantly reduces spasticity-related pain: a double blind placebo-controlled crossover trial. J Neurol 2006; 253:13371341[CrossRef][Medline]
105.
Kurzthaler I, Bodner T, Kemmler G, et al: The effect of nabilone on neuropsychological
functions related to driving ability: an extended case series. Hum Psychopharmacol 2005;
20:291293[CrossRef][Medline]
106.
Muller-Vahl KR, Prevedel H, Theloe K, et al: Treatment of Tourette syndrome with delta9-tetrahydrocannabinol (delta 9-THC): no influence on neuropsychological performance.
Neuropsychopharmacology 2003; 28:384388[CrossRef][Medline]
107.
Sim-Selley LJ: Regulation of cannabinoid CB1 receptors in the central nervous system by
chronic cannabinoids. Crit Rev Neurobiol 2003; 15:91119[CrossRef][Medline]
108.
Hampson RE, Simeral JD, Kelly EJ, et al: Tolerance to the memory disruptive effects of
cannabinoids involves adaptation by hippocampal neurons. Hippocampus 2003; 13:543
556[CrossRef][Medline]
109.
Kelleher LM, Stough C, Sergejew AA, et al: The effects of cannabis on informationprocessing speed. Addict Behav 2004; 6:12131219
110.
Hoffman AF, Oz M, Caulder T, et al: Functional tolerance and blockade of long-term
depression at synapses in the nucleus accumbens after chronic cannabinoid exposure. J
Neurosci 2003; 23:48154820[Abstract/Free Full Text]
111.
Robbe G, Alonso O, Manzoni J: Exogenous and endogenous cannabinoids control
synaptic transmission in mice nucleus accumbens. Ann N Y Acad Sci 2003; 1003:212
225[CrossRef][Medline]
112.
Mato S, Robbe D, Puente N, et al: Presynaptic homeostatic plasticity rescues long-term
depression after chronic delta 9-tetrahydrocannabinol exposure. J Neurosci 2005; 25:11619
11627[Abstract/Free Full Text]
113.
Hampson RE, Deadwyler SA: Cannabinoids reveal the necessity of hippocampal neural
encoding for short-term memory in rats. J Neurosci 2000; 20:8932
8942[Abstract/Free Full Text]
114.
Kim D, Thayer SA: Cannabinoids inhibit the formation of new synapses between
hippocampal neurons in culture. J Neurosci 2001; 21:RC146

115.
DIntino G, Paradisi M, Fernandez M, et al: Cognitive deficits associated with cholinergic
and nerve growth factor down-regulation in experimental allergic encephalomyelitis in rats.
Proc Natl Acad Sci USA 2005; 102:30703075[Abstract/Free Full Text]
116.
White DA, Heaton RK, Monsch AU: Neuropsychological studies of asymptomatic human
immunodeficiency virus-type-1 infected individuals. The HNRC Group. HIV Neurobehavioral Res
Center. J Int Neuropsychol Soc 1995; 1:304315[Medline]
117.
Ernst T, Chang L, Jovicich J, et al: Abnormal brain activation on functional MRI in
cognitively asymptomatic HIV patients. Neurology 2002; 59:13431349[Abstract/Free Full Text]
118.
Cristiani SA, Pukay-Martin ND, Bornstein RA: Marijuana use and cognitive function in
HIV-infected people. J Neuropsychiatry Clin Neurosci 2004; 16:330335[Abstract/Free Full Text]
119.

Fernandez UD: Treatment of multiple sclerosis. Neurologia 1999; 14(S6):1-12

120.
Henze T, Rieckman P, Toyka KV: Symptomatic treatment of multiple sclerosis. Eur
Neurol 2006; 56:78105[CrossRef][Medline]
121.
Kendrick M, Johnson KI: Long-term treatment of multiple sclerosis with interferon-beta
may be cost effective. Pharmacoeconomics 2000; 18:4553[CrossRef][Medline]
122.
Kappos L, Polman CH, Freedman MS, et al: Treatment with interferon beta-1b delays
conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
Neurology 2006; 67:12421249[Abstract/Free Full Text]
123.

Smith PF: Sativex (GW-1000). Curr Opin Investig Drugs 2004; 5:748754[Medline]

124.
Wade DT, Robson P, House H, et al: A preliminary controlled study to determine
whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin
Rehabil 2003; 17:2129[Abstract/Free Full Text]
125.
Mestre L, Correa F, Arevalo-Martin O: Pharmacological modulation of the
endocannabinoid system in a viral model of multiple sclerosis. J Neurochem 2005; 92:1327
1339[CrossRef][Medline]
126.
Hentges ST, Low MJ, Williams JT: Differential regulation of synaptic inputs by
constitutively released endocannabinoids and exogenous cannabinoids. J Neurosci 2005;
25:97469751[Abstract/Free Full Text]