MS, cannabis and cognitive dysfunction: Insights from brain imaging

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1 MS, cannabis and cognitive dysfunction: Insights from brain imaging Anthony Feinstein Department of Psychiatry University of Toronto

2 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

3 Disclosure Funding for my MS-cannabis work comes from the Multiple Sclerosis Society of Canada

4 Additional disclosure When I was in medical school I smoked a joint once. I may have inhaled (I honestly cannot remember )

5 Summary of my talk Cannabis-101 Cannabis and cognition in healthy subjects Pharmaceutically manufactured cannabis Cannabis, MS and cognition

7 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.

8 Sabur ibn Sahl, Persia, 9 th 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.

9 Rene Descartes ( ) philosopher, mathematician, physicist

10 Inspiration from cannabis I think therefore I am.

11 Carolinus Linnaeus, narcotica, phantastica, dementans, anodyna repellens.

Marshall, C.R. 1897. The active principle of Indian hemp: A preliminary communication. Lancet 1:235-238.

12 Marshall, C.R The active principle of Indian hemp: A preliminary communication. Lancet 1: First described oromucosal use of a cannabis extract. Extract of cannabis resin g sublingual: Onset of effects at 45 minutes Obviously intoxicated Offset at 2.5 hours Recovery at 3 hours

13 Empirical Medicine of the 19 th Century Combines morphine, cannabis, and capsicum Arguably provided better outpatient pain relief than is currently available in the 21 st century

14 Sir William Osler, Cannabis indica is probably the most satisfactory remedy. The Principles and Practice of Medicine, New York and London: Appleton and Co.

15 Cannabis-101 Herbal cannabis = marijuana Derived from air dried flowering or fruiting tops and leaves of the cannabis plant THC concentration: % from leaves/stems THC concentration: 5 14% from flowering tops Typically smoked as a joint Joint usually contains g of cannabis (THC concentration can vary from 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%

16 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 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

17 Cannabis-101 Most widely used drug in the world % of the world population aged has tried it at least once North American prevalence: 10.5% Canada: 14.1% ages 15 years

18 Cannabis-101: neuroprotection Cannabinoids are anti-inflammatory and immunomodulating. Cerebral insult (trauma, ischemia, exitotoxic stress) stimulates the synthesis of endocannabinoids by immune cells

19 Cannabis-101: Cannabinoid Receptors CB 1 CB 2 CNS Testis Uterus Modulates pain, movement, emotion, emesis, seizure threshold Spleen Tonsils Lymphoid tissues Modulates immune function

21 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.

22 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

23 Healthy subjects, cannabis and cognition

24 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?

25 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)

26 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

27 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

28 Inhaled THC vs Sativex : Comparison of pharmacokinetic profiles 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 THC 76, 77 (red trace). Note that the mean THC plasma concentration with Sativex never exceeds 2 ng/ml. From: Russo EB The solution to the medicinal cannabis problem. In: Schatman ME (ed.). Ethical issues in chronic pain management. Boca Raton, FL: Taylor & Francis.

30 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

31 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

34 Cannabis, multiple sclerosis and cognition

35 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

36 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 $ per month

37 Cognitive dysfunction affects % of people with MS Information processing speed Working memory Visual-spatial memory Executive function

38 Study 1

39 Cannabis and cognition in MS subjects. Naturally grown cannabis

40 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

42 Cannabis and cognition in MS subjects. Naturally grown cannabis

43 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

44 Study 2

46 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

47 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 x 2 p Age: mean (SD) 43.6 (11.7) 43.6 (9.8) t = Sex: F/M 11/14 12/13 x 2 = Education in years (SD) 13.5(2.8) 14.6(2.8) t = ANART: mean (SD) (9.7) (7.1) t = Employment status: n 7 (28.0) 14 (56.0) x 2 = (%) currently employed Marital status: n (%) 16 (64.0) 17 (68.0) x 2 = married/ common-law Disease duration in 11.4 (7.6) 12.7 (11.0) t = years, mean (SD) Disease course (n) Relapsing Remitting x 2 = Primary/ 3/5 2/4 Secondary Progressive EDSS: median (range) 3.0 (0-8.5) 2.0 (0-8.0) t = Disease-modifying 11 (44.0) 9 (36.0) x 2 = drugs: n (%) Alcohol: number/week, median (range) 2.5 (0-12) 1.0 (0-8) t =

48 Cognitive comparisons cannabis users vs. cannabis naive Table 3. Cognitive test comparisons between MS cannabis users and non-users. Cognitive Domain Learning and Memory Verbal fluency Visuospatial perception Cognitive test CVLT-II Immediate Recall CVLT-II Long Delay Recall BVMT-R Total Recall BVMT-R Delay Recall COWAT Total Score Cannabis users Mean (SD) Non-users Mean (SD) t or x (10.9) 52.5 (11.2) t = (3.6) 11.2 (2.7) t = (8.3) 22.8 (7.6) t = (3.1) 8.7 (3.1) t = (11.9) 33.7 (10.8) t = JLO Score* 23.9 (4.7) 26.7 (3.5) t = p Executive functioning D-KEFS Sorting score D-KEFS Description Score 8.4 (2.4) 10.3 (2.7) t = (9.5) 37.4 (10.4) t = Information processing speed PASAT (12.0) 44.0 (11.4) t = PASAT (7.6) 35.0 (11.7) t = SDMT Total 42.4 (11.4) 50.4 (12.9) t = Global Cognitive Impairment 1.5 SD on 2 or more of 11 cognitive tests: n (%) 16 (64.0) 8 (32.0) x 2 =

49 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 Visuospatial perception JLO Score HADS Anxiety MFIS (-5.115, 8.779) (0.545, 5.263) Executive functioning D-KEFS Sorting score D-KEFS Description Score Education Alcohol consumption Education EDSS Alcohol consumption (0.274, 3.077) (-0.663, ) Information processing speed PASAT-3.0 Gender (-2.600, ) Education Alcohol consumption HADS Anxiety PASAT-2.0 Education (2.347, 3.667) Global Cognitive Impairment SDMT Total 1.5 SD on 2 or more of 11 cognitive tests: n (%) EDSS (0.337, ) Alcohol consumption Education (1.265, ) 0.020

50 Psychiatric comparisons cannabis users vs. cannabis naive Table 2. Comparison of MS cannabis users and non-users on psychiatric measures. Variable SCID- I Major depression, lifetime: n (%) SCID- I Anxiety disorder, lifetime: n (%) Antidepressants: n (%) taking HADS - Depression subscore HADS - Anxiety subscore Modified Fatigue Impact Scale Cannabis users Mean (%/sd) Non-users Mean (%/sd) t or x 2 p 15 (60.0) 13 (52.0) x 2 = (40.0) 8 (32.0) x 2 = (40.0) 12 (48.0) x 2 = (4.4) 6.7 (4.9) t = (4.7) 7.00 (5.7) t = (16.2) 40.4 (24.2) t =

51 Cannabis use and global cognitive impairment Global cognitive impairment was not significantly correlated with: urine cannabinoid levels (r= , p= 0.118), age of cannabis use onset (r= , p= 0.118) duration of cannabis use (r= 0.158, p= 0.451).

52 Study 3

54 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; mild to moderate; > 66 severe).

55 Sample Characteristics MS CANNABIS Mean (SD)/ Frequency (%) (N = 20) MS NON CANNABIS MEAN(SD)/ Frequency (%) (N = 19) t-test/x 2 Age, years (11.28) (9.085) t = -.79 p = 0.44 Females, % 6 (30.0) 6 (31.6) x 2 = p = 0.92 P 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 = p = 0.54 Currently employed 10 (50.0) 10 (52.6) x 2 = 0.27 p = 0.87 Disease-Modifying Drugs (%) Disease Course RRMS PPMS SPMS Disease duration, years Urine concentration of cannabis metabolite (ug/l) 7 (35.0) 9 (47.4) x 2 = 0.62 p = x 2 = 0.67 p = (7.24) 9.9 (9.6) t = p = (90.0) 0 - -

56 TEST MS Cannabis Mean (SD)/ Frequency (%) (N = 20) MS Non-cannabis Mean (SD)/ Frequency (%) (N = 19) t-test/x 2 p WTAR Predicted (9.13) (8.21) t = 0.97 p = 0.92 Purdue Peg Test, Both hands, No. of pegs Selective Reminding Test Long Term Storage 8.63 (1.77) 8.75 (2.0) t = P = (16.6) (13.6) t = p = /36 Spatial Test Total Correct (7.4) (4.1) t = p = 0.03 Word Fluency Test (Total) PASAT (2 Sec), No. correct (13.4) 39.9 (9.5) t = 0.50 p = (13.3) (15.35 t = p = 0.02 SDMT, No. correct (9.7) (10.0) t = p = 0.54 Global Cognitive Impairment, No. of subjects 8 (40.0) 3 (16.8) x 2 = 2.82 p = 0.09 HADS Score >= 8 Anxiety Depression 13(65.0) 11(55.0) 11(58.0) 8(40.0) x 2 = 0.21 x 2 = 0.85 p = 0.65 p = 0.42 MFIS Total 42.9 (20.1) (20.13) t = 0.58 p = 0.57

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

58 0-Back ZERO BACK - Patients are asked to hit TARGET (green button) when an X appears and NOT- TARGET (red button) for other letters..

59 1-Back 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

60 2-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

61 Behavioral Results: N-back fmri Cognitive Tasks MS Cannabis Mean (SD)/ Frequency (%) (N = 20) MS Noncannabis Mean (SD)/ Frequency (%) (N = 19) t-test p zero-back, targets correct zero-back Reaction time (ms) 14.3 (1.2) 14.8 (0.54) t = p = (259.3) (120.5) t = 0.98 p = Back, targets correct 1-Back Reaction time (ms) 2-Back, targets correct 2-Back Reaction time (ms) 8.25 (0.79) 8.53 (0.61) t = p = (230.7) (181.2) t = 1.46 p = (1.54) 6.32 (1.4) t = p = (196.3) (264.8) t = 1.02 p = 0.31

62 Within-group activation maps for the zero-back (a) and 2-Back (b) tasks

63 Between-group activation maps for the zero-back (a) and 2-Back (b) tasks.

64 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.

65 What about information processing speed? SDMT Block design 11 blocks of 6 symbol-digit pairs Button box response

SDMT 2800 2600 2400 2200 Non Cannabis Cannabis 2000 1800 Block 1 Block 2 Block 3 Block 4 Block 5 Block 6 Block 7 Block 8 Block 9 Block 10 Block 11

66 SDMT Non Cannabis Cannabis Block 1 Block 2 Block 3 Block 4 Block 5 Block 6 Block 7 Block 8 Block 9 Block 10 Block 11 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)

67 Within-group activation maps for the during the SDMT

68 Between-group activation maps during the SDMT

69 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)

71 Study 4

72 Effects of cannabis use on gray matter, white matter and cognition in patients with MS MS cannabis (n=20) MS noncannabis (n=19) Gray Matter (76.50) (52.38) 0.81 White Matter (71.52) (50.41) 0.31 Lesions (21.19) (21.82) 0.31 p Total brain tissue/lesion volume ml

73 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.

74 Imaging Data Set behavior (or task) brain-behavior brain-behavior brain

75 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

76 Effects of cannabis use on gray matter and cognition in patients with MS: Partial Least Squares analysis

77 Effects of cannabis use on white matter and cognition in patients with MS: Partial Least Squares analysis

78 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.

79 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

80 Quo Vadis?

81 Cannabis and the Law Introduced to the West in 1611: the plant brought to Virginia for use in hemp production Mid 19 th century-widely used medicinally (analgesia, appetite enhancer, antiemetic, muscle relaxant, anticonvulsant). United States Pharmacopeia, 1850 Recreational use increased quickly in the early 20 th 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

85 The future of cannabis?

87 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

88 References Breivogel CS, Childers SR. Neurobiology of Disease 5: (1998) Consroe P, et al. European Neurology 38:44-8 (1997) Yadav V, et al. Neurology 82: (2014) Wright MJ, et al. British Jnl. Pharmacology 170: (2013) Mechoulam R & Parker L. British Jnl Pharmacology 170: (2013) Meier MH et al. PNAS 109(40): E (2012) Rogeberg O. PNAS 110(11): (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: (2011) Pavisian B, et al. Neurology 82:1-9 (2014)

Marijuana and Adolescents: Truth and Consequences. Disclosure Statement OBJECTIVES. Secondary Objectives. State of Marijuana in US

Marijuana and Adolescents: Truth and Consequences Clinical Advances in Pediatrics Symposium Children s Mercy Park September 28, 2017 Disclosure Statement I have no actual or potential conflict of interest