department of psychiatry university of toronto · 2018-04-02 · cannabis-101 herbal cannabis =...
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MS, cannabis and cognitive dysfunction: Insights from brain imaging
Anthony Feinstein Department of Psychiatry
University of Toronto
MS, Cannabis and Cognition
Aims:
To appreciate the link between cannabis (smoked) and cognition in MS
To understand how brain function and structure can explain, at least in part, the association between cannabis and cognition in MS
Disclosure
Funding for my MS-cannabis work comes from the Multiple Sclerosis Society of Canada
Additional disclosure
When I was in medical school I smoked a joint once.
I may have inhaled (I honestly cannot remember…)
Summary of my talk
Cannabis-101
Cannabis and cognition in healthy subjects
Pharmaceutically manufactured cannabis
Cannabis, MS and cognition
Cannabis
Derived from the plants Cannabis Sativa and Indica
Contains 60+ cannabinoids
Most abundant is ∆ -9-tetrahydracannabinol (∆9-THC). It is psychoactive (and was first isolated in the Weizmann Institute of Science in Rehovot, Israel, in 1964).
Cannabidiol is the second most common cannabinoid. It does not have psychoactive properties.
Sabur ibn Sahl, Persia, 9th Century
An intranasal base preparation of juice from cannabis seeds was mixed with a variety of other herbs to treat migraine, calm uterine pains, prevent miscarriage, and preserve fetuses in their mothers’ abdomens.
Rene Descartes (1595 – 1650) philosopher, mathematician, physicist
Inspiration from cannabis “I think therefore I am.”
Carolinus Linnaeus, 1772.
“narcotica, phantastica, dementans,
anodyna repellens.”
Marshall, C.R. 1897. The active principle of Indian hemp: A
preliminary communication. Lancet 1:235-238.
First described oromucosal use of a cannabis extract.
Extract of cannabis resin 0.1-0.15 g sublingual:
• Onset of effects at 45 minutes
• Obviously intoxicated
• Offset at 2.5 hours
• Recovery at 3 hours
Empirical Medicine of the 19th Century
Combines morphine, cannabis, and capsicum
Arguably provided better outpatient pain relief than is currently available in the 21st century
Sir William Osler, 1915.
“Cannabis indica is probably the most satisfactory remedy.”
The Principles and Practice of
Medicine, New York and London: Appleton and Co.
Cannabis-101
Herbal cannabis = marijuana Derived from air dried flowering or fruiting tops and leaves of the cannabis plant
THC concentration: 0.5 – 5.0% from leaves/stems
THC concentration: 5 – 14% from flowering tops
Typically smoked as a joint
Joint usually contains 0.5 – 1.0 g of cannabis (THC concentration can vary from 5 – 150 mg).
Euphoria produced by 2-3 mg
Cannabis resin = hashish THC concentration: 2 – 8%
Cannabis oil = concentrate of herbal cannabis or cannabis resin THC concentration: 16-60%
Cannabis-101
Most common is inhalation
Marijuana often smoked in combination with tobacco.
Hashish can be smoked.
Marijuana, hashish and hashish oil consumed through a water pipe called a “bong” – maximises potency
Smoking leads to rapid absorption (maximum brain effects within 15-30 minutes, but rapid decline in THC too – 50% less after 15 minutes)
Effects (psychological and physiological) last 2-4 hours
Marijuana and hash can be ingested - slower absorption, concentrations 2-30% of the inhaled compound, less intense high
Cannabis-101
Most widely used drug in the world
3.3 – 4.4% of the world population aged 15-64 has tried it at least once
North American prevalence: 10.5%
Canada: 14.1% ages ≥ 15 years
Cannabis-101: neuroprotection
Cannabinoids are anti-inflammatory and immunomodulating .
Cerebral insult (trauma, ischemia, exitotoxic stress) stimulates the synthesis of endocannabinoids by immune cells
Cannabis-101: Cannabinoid Receptors
CB1 CB2
CNS
Testis
Uterus
Modulates pain, movement,
emotion, emesis, seizure threshold
Spleen
Tonsils
Lymphoid tissues
Modulates immune
function
Cannabis-101: metabolites
Primary metabolites of THC are 11 hydroxy THC (11-OH-THC) and 11-Nor-9 –carboxy THC (THC-COOH)
20% of THC excreted in the urine
THC lipophilic – deposited in fatty tissue for days to weeks and gradually released.
Cannabis-101: dependence
Inability to reduce use despite wanting too
Considerable time spent procuring cannabis
Disruption of social/occupational pursuits
Escalating use
Persistent use despite unwanted effects
Tolerance
Withdrawal symptoms
Reduced concentration
Irritability
Loss of appetite
Depression
Insomnia
Healthy subjects, cannabis and cognition
Healthy subjects, cannabis and cognition
Acute effects (ingestion to a few hours)
Strong evidence of cognitive decline
Short term residual effects (abstinence of hours to several days)
Evidence suggests deficits linger, but are less apparent
Long term residual effects (abstinence exceeding several weeks)
Data equivocal
Many potential confounders across all studies:
Frequency of cannabis use?
Duration of use?
Strength of cannabis?
In abstinent group are deficits linked to residual cannabis or withdrawal effects?
Cognition in chronic heavy users
Harmful New Zealand Study Meier et al (2012) 25 year follow-up Prospective study, birth cohort,
1037 subjects Index cognitive assessment: 13
yrs. of age Cannabis assessments at 18,
21, 26, 32, and 38 years of age Assessed 25 years later with a
wide array of neuropsychological tests
If use began in adolescence + smoking regularly (>4 times per week), many deficits.
Not harmful Did not control for the time varying
effects of socio-economic status on IQ (Rogeberg, 2013)
Cannabis use and brain imaging: healthy subjects
Functional (n=33) Structural (n=8)
PET/SPECT (n=16)
fMRI(n=1) Volumetric (n=5)
DTI (n= 3)
Resting state Acute effects (n=10) Chronic effects (n=6) Lower global and prefrontal blood flow compared to cannabis naive subjects
Chronic effects Lower global and prefrontal activity compared to cannabis naive subjects
Reduction in medial temporal lobe structure volumes (n=2)
Changes in MD the anterior portion of the corpus callosum (n=1)
Activation Task specific results in 16 studies with increased activation in frontal and anterior cingulate regions
From Martin-Santos et al (2010) Psychological Medicine
Pharmaceutically manufactured cannabis
Generic Trade Availability Route Content Indications
Nabilone Cesamet USA, Canada oral THC nausea
Dronabinol Marinol USA, Canada oral THC Nausea,
anorexia
Nabiximols Sativex USA, Canada, Europe
Oromucosal
(spray)
THC and CBD Spasticity,
neuropathic
pain
Smoked
cannabis
Figure 2: Comparison of pharmacokinetic peaks of Sativex® oromucosal spray containing 10.8
mg THC and 10 mg CBD (purple trace), vaporized Tetranabinex® with 6.65 mg THC (GWPK0114,
data on file, GW Pharmaceuticals, blue trace), and smoked cannabis from a cigarette containing
an estimated 34 mg THC76, 77 (red trace). Note that the mean THC plasma concentration with
Sativex never exceeds 2 ng/ml.
From: Russo EB. 2007. The solution to the medicinal cannabis problem. In: Schatman ME (ed.). Ethical issues in chronic pain management. Boca Raton, FL: Taylor & Francis.
Inhaled THC vs Sativex®: Comparison of pharmacokinetic profiles
Synthetic cannabis, cognition and MS
A single study in which cognition was among the primary outcome
measures
8 week, randomized, double blind, placebo controlled, crossover trial
17 cannabis naive subjects: Sativex vs. Placebo
Outcome measure: MSFC
This includes the 3 second PASAT
No between group differences on the PASAT
Critique: single measure of cognition, small sample
Cannabis and cognition in MS subjects. Synthetic cannabis
Of the 8 remaining studies, none had cognition has a primary outcome measure
7 of these were randomized, double blind placebo controlled studies investigating cannabis treatment for pain or spasticity.
3 studies reported cognitive problems: verbal memory, learning, long term memory storage, cognitive flexibility, attention, psychomotor speed.
2 studies found no deleterious cognitive effects
1 study did not look at cognition
1 study documented baseline, but no follow-up data
1 open label trial with Sativex: 6 subjects reported subjective cognitive problems, but there were no objective data
Cannabis, multiple sclerosis and cognition
Cannabis use (smoked/ingested) in MS patients:
~40% of MS patients have used cannabis at some point
Over half these date their first use post diagnosis
Of those who have never used cannabis ¾ would do so if the drug was legal
Most smoke cannabis in cigarettes and pipes
Ingestion is more frequent in patients whose use is medicinal
Cannabis use in MS patients: demographics and patterns of use
Male
Tobacco users
Mobility difficulties
Higher self rating of disability
Duration: ~ 6 years
2-3 x per day, 5-6 days per week (Consroe et al, 1997), most often as a hypnotic
$50-500 per month
Cognitive dysfunction affects 40-70-% of people with MS
Information processing speed
Working memory
Visual-spatial memory
Executive function
Study 1
Cannabis and cognition in MS subjects. Naturally grown cannabis
Computerized SDMT
• 8 trials of 9 symbols
• Measures: - mean time per trial (sec) - total time for all trials (sec) - mean time per item (total time / 72 items) • Excellent Test-retest reliability
Cannabis and cognition in MS subjects. Naturally grown cannabis
Cannabis and cognition in MS subjects. Naturally grown cannabis
Study limitations:
Small sample
Limited cognitive battery
Absence of biochemical confirmation of cannabis presence and absence
No premorbid IQ data
Study 2
Cannabis and cognition: a neuropsychological study
Two groups of 25 subjects each
Cannabis smokers vs. cannabis naïve
Cannabis users were defined as regular users (had to have used cannabis within the past month, but not in the 12 hours preceding testing).
Matched for demographic variables including years of education, pre-morbid IQ (ANART).
Matched for disease variables including EDSS, duration of symptoms, disease course
Urine tested for cannabis metabolites
Demographic comparisons cannabis smokers vs.cannabis naive
Table 1. Demographic and neurological variables for MS cannabis users and non-users.
Sample Characteristic
Cannabis users
Non-users
t or x2 p
Age: mean (SD) 43.6 (11.7) 43.6 (9.8) t = 0.000 1.000 Sex: F/M 11/14 12/13 x
2 = 0.081 0.777
Education in years (SD) 13.5(2.8) 14.6(2.8) t = -1.482 0.145 ANART: mean (SD) 108.6 (9.7) 112.5 (7.1) t = -1.581 0.120 Employment status: n (%) currently employed
7 (28.0) 14 (56.0) x2 = 4.023 0.045
Marital status: n (%) married/ common-law
16 (64.0) 17 (68.0) x2 = 0.089 0.765
Disease duration in years, mean (SD)
11.4 (7.6) 12.7 (11.0) t = -0.479 0.634
Disease course (n)
Relapsing-Remitting
17 19 x
2 = 0.422
0.810
Primary/ Secondary Progressive
3/5 2/4
EDSS: median (range) 3.0 (0-8.5) 2.0 (0-8.0) t = 1.186 0.241 Disease-modifying drugs: n (%)
11 (44.0) 9 (36.0) x2 = 0.333 0.564
Alcohol: number/week, median (range)
2.5 (0-12) 1.0 (0-8) t = 1.870 0.068
Cognitive comparisons cannabis users vs. cannabis naive
Table 3. Cognitive test comparisons between MS cannabis users and non-users.
Cognitive Domain
Cognitive test Cannabis users Mean (SD)
Non-users Mean (SD)
t or x2 p
Learning and Memory
CVLT-II Immediate Recall
49.5 (10.9) 52.5 (11.2) t = -0.969 0.337
CVLT-II Long Delay Recall
10.6 (3.6) 11.2 (2.7) t = -0.681 0.499
BVMT-R Total Recall
22.1 (8.3) 22.8 (7.6) t = -0.284 0.777
BVMT-R Delay Recall
8.2 (3.1) 8.7 (3.1) t = 0.545 0.588
Verbal fluency COWAT Total Score
31.0 (11.9) 33.7 (10.8) t = -0.845 0.403
Visuospatial perception
JLO Score* 23.9 (4.7) 26.7 (3.5) t = -2.417 0.020
Executive functioning
D-KEFS Sorting score
8.4 (2.4) 10.3 (2.7) t = -2.704 0.009
D-KEFS Description Score
31.4 (9.5) 37.4 (10.4) t = -2.127 0.039
Information processing speed
PASAT-3.0 36.0 (12.0) 44.0 (11.4) t = -2.402 0.020
PASAT-2.0 26.1 (7.6) 35.0 (11.7) t = -3.188 0.003
SDMT Total 42.4 (11.4) 50.4 (12.9) t = -2.329 0.024
Global Cognitive Impairment
≤1.5 SD on 2 or more of 11 cognitive tests: n (%)
16 (64.0) 8 (32.0) x2 = 5.128 0.024
Predictors of individual test performance cannabis users vs. cannabis naive
Table 4. Linear regression analyses for significant cognitive tests and cannabis use. *
Cognitive Domain Cognitive test indices Covariates† B (95% CI) p
Verbal fluency COWAT Total Score Gender Education EDSS HADS Anxiety MFIS
1.832 (-5.115, 8.779) 0.533
Visuospatial perception
JLO Score HADS Anxiety MFIS
2.904 (0.545, 5.263) 0.017
Executive functioning
D-KEFS Sorting score Education Alcohol consumption
1.676 (0.274, 3.077) 0.020
D-KEFS Description Score Education EDSS Alcohol consumption
4.943 (-0.663, 10.548) 0.083
Information processing speed
PASAT-3.0 Gender Education Alcohol consumption HADS Anxiety
4.355 (-2.600, 11.310) 0.214
PASAT-2.0 Education 8.007 (2.347, 3.667) 0.007
SDMT Total EDSS Alcohol consumption
7.116 (0.337, 13.895) 0.040
Global Cognitive Impairment
≤1.5 SD on 2 or more of 11 cognitive tests: n (%)
Education
-1.468 (1.265, 14.887) 0.020
Psychiatric comparisons cannabis users vs. cannabis naive
Table 2. Comparison of MS cannabis users and non-users on psychiatric measures.
Variable Cannabis users Mean (%/sd)
Non-users Mean (%/sd)
t or x2
p
SCID- I Major depression, lifetime: n (%)
15 (60.0) 13 (52.0) x2 = 0.325 0.569
SCID- I Anxiety disorder, lifetime: n (%)
10 (40.0) 8 (32.0) x2 = 0.347 0.556
Antidepressants: n (%) taking
10 (40.0) 12 (48.0) x2 = 0.325 0.569
HADS - Depression subscore
7.0 (4.4) 6.7 (4.9) t = 0.182 0.856
HADS - Anxiety subscore
8.8 (4.7) 7.00 (5.7) t = 1.225 0.227
Modified Fatigue Impact Scale
46.3 (16.2) 40.4 (24.2) t = 1.022 0.322
Cannabis use and global cognitive impairment
Global cognitive impairment was not significantly correlated with: urine cannabinoid levels (r= -0.321, p= 0.118),
age of cannabis use onset (r= -0.321, p= 0.118)
duration of cannabis use (r= 0.158, p= 0.451).
Study 3
Cannabis group
Not acutely intoxicated: participants were asked to refrain from using cannabis for 12 hours prior to testing.
Before proceeding with the protocol, saliva samples from were screened for Delta9- tetrahydrocannabinol using NarcoCheck©, 9 which detects cannabis use within the last 4-6 hours.
The mean score on the Cannabis Withdrawal Scale was 15 (SD=18.4). (< 51 none; 52 - 66 mild to moderate; > 66 severe).
Sample
Characteristics MS CANNABIS
Mean (SD)/
Frequency (%)
(N = 20)
MS NON
CANNABIS
MEAN(SD)/
Frequency (%)
(N = 19)
t-test/x2 P
Age, years 41.30 (11.28) 43.89 (9.085) t = -.79 p = 0.44
Females, % 6 (30.0) 6 (31.6) x2 = 0.011 p = 0.92
Years of education 14.3 (1.8) 15.2 (2.0) t = -1.5 p = 0.14
EDSS, mean
median(range)
2.83 (2.2)
3.0 (0 – 8.0)
2.47 (1.52)
2.0 (0 – 8.5)
t = -0.62 p = 0.54
Currently employed 10 (50.0) 10 (52.6) x2 = 0.27 p = 0.87
Disease-Modifying
Drugs (%)
7 (35.0) 9 (47.4) x2 = 0.62 p = 0.43
Disease Course
RRMS
PPMS
SPMS
16
2
2
17
1
1
x2 = 0.67
p = 0.88
Disease duration,
years
9.5 (7.24) 9.9 (9.6) t = -0.79 p = 0.44
Urine concentration
of cannabis
metabolite (ug/L)
246 (90.0) 0 - -
TEST MS Cannabis
Mean (SD)/
Frequency (%)
(N = 20)
MS Non-cannabis
Mean (SD)/
Frequency (%)
(N = 19)
t-test/x2 p
WTAR Predicted 110.85 (9.13) 110.57 (8.21) t = 0.97 p = 0.92
Purdue Peg Test,
Both hands, No. of
pegs
8.63 (1.77) 8.75 (2.0) t = -0.20 P = 0.85
Selective Reminding
Test
Long Term Storage
44.30(16.6)
45.37 (13.6)
t = -0.22
p = 0.83
10/36 Spatial Test
Total Correct
16.40 (7.4)
20.79 (4.1)
t = -2.29
p = 0.03
Word Fluency Test
(Total)
41.75 (13.4) 39.9 (9.5) t = 0.50 p = 0.62
PASAT (2 Sec), No.
correct
28.35 (13.3) 39.47 (15.35 t = -2.41 p = 0.02
SDMT, No. correct 41.55 (9.7) 43.53 (10.0) t = -0.63 p = 0.54
Global Cognitive
Impairment, No. of
subjects
8 (40.0) 3 (16.8) x2 = 2.82 p = 0.09
HADS Score >= 8
Anxiety
Depression
13(65.0)
11(55.0)
11(58.0)
8(40.0)
x2 = 0.21
x2 = 0.85
p = 0.65
p = 0.42
MFIS Total 42.9 (20.1) 39.16 (20.13) t = 0.58 p = 0.57
N-back
Large n-back fMRI literature in healthy subjects
Oral and button-box versions of the fMRI compatible version
Functional neuroanatomy has been well defined
0-Back
ZERO BACK - Patients are asked to hit TARGET (green button) when an X appears and NOT-TARGET (red button) for other letters. .
ONE-BACK - Patients are asked to hit TARGET when a letter presented matches a letter presented 1 letter back, and NOT TARGET for all other letters
1-Back
TWO BACK - Patients are asked to hit TARGET for letters that match letters presented two letters back, and NOT-TARGET for all other letters
2-Back
Behavioral Results: N-back
fMRI Cognitive
Tasks
MS Cannabis
Mean (SD)/
Frequency (%)
(N = 20)
MS Non-
cannabis Mean
(SD)/
Frequency (%)
(N = 19)
t-test p
zero-Back,
targets correct
14.3 (1.2) 14.8 (0.54) t = -1.66 p = 0.10
zero-Back
Reaction time
(ms)
691.7 (259.3) 628.9 (120.5) t = 0.98 p = 0.34
1-Back, targets
correct
8.25 (0.79) 8.53 (0.61) t = -1.23 p = 0.23
1-Back Reaction
time (ms)
817.7 (230.7) 720.8 (181.2) t = 1.46 p = 0.15
2-Back, targets
correct
4.95 (1.54) 6.32 (1.4) t = -2.89 p = 0.006
2-Back Reaction
time (ms)
1072.31 (196.3) 995.7 (264.8) t = 1.02 p = 0.31
Within-group activation maps for the zero-Back (a) and 2-Back (b) tasks
Between-group activation maps for the zero-Back (a) and 2-Back (b) tasks.
Conclusions
The cannabis group performed significantly more poorly during the 2-second PASAT and the 10/36 spatial recall test.
Cannabis users had a more diffuse pattern of cerebral activation across all N-back trials.
They also made more errors on the 2-Back task (p < 0.006) during which they displayed increased activation relative to non-users in parietal (p < .007) and anterior cingulate (p < .001) regions implicated in working memory.
What about information processing speed?
SDMT
Block design
11 blocks of 6 symbol-digit pairs
Button box response
SDMT
1800
2000
2200
2400
2600
2800
Block 1 Block 2 Block 3 Block 4 Block 5 Block 6 Block 7 Block 8 Block 9 Block 10 Block 11
Non Cannabis
Cannabis
No differences in accuracy of response. Overall time slower in the cannabis group (p=.087). Cannabis group was slower in 9 of the 11 blocks (p=.0001)
Within-group activation maps for the during the SDMT
Between-group activation maps during the SDMT
Conclusions
There was a trend for the cannabis group to have a slower reaction time during the SDMT
No differences in accuracy of response
Both groups activated a prefrontal-parietal neural circuit that has ben well described in tests of information processing speed.
The main between group difference was the absence of thalamic activation in the cannabis group.
Previous studies in cannabis naïve subjects have demonstrated that relative to healthy controls people with MS show greater activation in the thalamus, insula and anterior cingulate linked to slower response times.
Add cannabis, and the thalamic and insula activation are no longer discernible.
Pavisian et al. Multiple Sclerosis Journal-ETC (in press)
Study 4
Effects of cannabis use on gray matter, white matter and cognition in patients with MS
MS cannabis (n=20)
MS non-cannabis (n=19)
p
Gray Matter 680.37 (76.50) 675.18 (52.38) 0.81
White Matter 514.26 (71.52) 493.76 (50.41) 0.31
Lesions 25.87 (21.19) 18.52 (21.82) 0.31
Total brain tissue/lesion volume mL
Partial Least Squares
PLS is optimized to explain the relation between two or more blocks of data.
It looks to find if there are latent (hidden) variables that maximally correlate two matrices, which in the present study are the brain data (grey and white matter for every voxel) and cognitive performance (every neuropsychological test score).
Because we are comparing two groups (cannabis and non-cannabis) we can observe whether the correlations differ across the groups.
Permutation testing is carried out to assess the significance of the extracted latent variables.
The entire process is carried out in one step, so you do not need to correct for multiple comparisons.
behavior (or task)
brain-behavior
brain-behavior
brain
Imaging Data Set
Anatomical correlates of cognition
Grey matter volume
thalamus and basal ganglia
medial temporal regions (hippocampus, amygdala)
inferior and superior temporal gyri, fusiform gyrus
posterior parietal lobes
lateral and medial prefrontal cortex
White matter volume
fornix continuing into the left
fimbria,
superior parietal region
middle frontal region
Effects of cannabis use on gray matter and cognition in patients with MS: Partial Least Squares analysis
Effects of cannabis use on white matter and cognition in patients with MS: Partial Least Squares analysis
Effects of cannabis use on gray matter, white matter and cognition in patients with MS
In the presence of cannabis, volume reduction in certain brain regions is more closely linked to cognitive compromise: not just information processing speed, but memory too.
This interpretation fits with the fMRI-working memory findings in this group.
Failed to find absolute differences between groups. This may reflect modest sample size.
Conclusions
Cannabis further compromises cognitive function in some MS patients
Cannabis here refers to street cannabis and not Sativex, Marinol or Cesamet
No evidence that cannabis compromises mood or anxiety. No evidence of psychosis.
The potentially deleterious cognitive effects should be weighed against benefits in other areas (pain, spasticity, urinary problems etc).
Limitations of our studies: modest sample sizes, cross sectional design
Romero et al (2015). Neuroimage Clinical
Quo Vadis?
Cannabis and the Law
Introduced to the West in 1611: the plant brought to Virginia for use in hemp production
Mid 19th century-widely used medicinally (analgesia, appetite enhancer, antiemetic, muscle relaxant, anticonvulsant).
United States Pharmacopeia, 1850 Recreational use increased quickly in the early 20th century Sensational accounts of changed behavior together with the
development of other drugs (eg. Aspirin) led to a ban on cannabis in Canada in 1923 (Opium and Drug Act). Similar ban in the USA (Marijuana Tax Act).
By 1942 cannabis had been removed from the pharmaceutical manuals Single Convention on Narcotic Drugs policy in Canada (1961)
cultivation could lead to 7 years in jail. This did not deter the youth of the 1960’s.
Both the CMA and AMA recognized that cannabis not a narcotic (1970’s)
Controlled Substance Act (1977)-cannabis is currently classified as a Schedule 1 controlled substance in the USA
The debate continues
The future of cannabis?
Acknowledgments
MS Society of Canada
Canadian Institute of Health Research
Bennis Pavisian
Jordon Ellis
Viral Patel
Kris Romero
Brad McIntosh
Richard Staines
Paul O’Connor
Liesly Lee
References
Breivogel CS, Childers SR. Neurobiology of Disease 5:417-31 (1998)
Consroe P, et al. European Neurology 38:44-8 (1997)
Yadav V, et al. Neurology 82:1083-92 (2014)
Wright MJ, et al. British Jnl. Pharmacology 170:1365-73 (2013)
Mechoulam R & Parker L. British Jnl Pharmacology 170: 1364-4 (2013)
Meier MH et al. PNAS 109(40): E2657-64 (2012)
Rogeberg O. PNAS 110(11): 4251-4 (2013)
Akbar N, et al. J. Neurology 258:373-9 (2011)
Ghaffar O & Feinstein A. Neurology 71:164-9 (2008)
Honarmand K, et al. Neurology 76: 1153-60 (2011)
Pavisian B, et al. Neurology 82:1-9 (2014)
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