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)