Marijuana and the Brain: From Addiction to Neuroscience Francesca Filbey, PhD Center for BrainHealth School of Behavioral and Brain Sciences University of Texas at Dallas President’s Dream Colloquium Simon Fraser University February 23, 2017

Oldest marijuana: 2,700 years old Journal of Experimental Botany, 2008

Marijuana is the most prevalent illicit drug In 2010, more than 29 million Americans (11.5%) aged 12 or older reported abusing marijuana within the past year. ~9-10% who use marijuana become dependent. PREVALENCE OF USE TREATMENT RATES SAMHSA, Center for Behavioral Health Statistics and Quality, National Survey on Drug Use and Health, 2013.

Changing marijuana landscape

What do we know?

Cannabis has psychoactive ingredients ~483 chemical compounds 113 cannabinoids Tetrahydrocannabinol (THC) – CB1 receptors in central nervous system Cannabidiol (CBD) – indirect effects on CB1 and CB2 Cannabinol (CBN ) - CB2 receptors in peripheral organs (immune system)

The Endocannabinoid System (ECS) ECS regulates various physiological processes. higher order cognitive functions, pain, appetite, immune system response, mood, reward and motivation. Types of cannabinoids: Endocannabinoid – Brain-derived Anandamide (AEA), 2-Arachidonoylglycerol (2-AG) Phytocannabinoids – Plant-derived THC, CBD, CBN, etc. Synthetic cannabinoids – Laboratory-derived Marinol, K2 or Spice

Targeted Brain Areas

M A P Bloomfield et al. Nature 539, 369–377 (2016) doi:10 M A P Bloomfield et al. Nature 539, 369–377 (2016) doi:10.1038/nature20153

Short and Long-term Changes Curran et al., Nature Reviews Neuroscience 17, 293–306 (2016) doi:10.1038/nrn.2016.28

Neural changes in rat brain Journal of Neurochemistry Volume 73, Issue 6, pages 2447-2459, 18 JAN 2002 DOI: 10.1046/j.1471-4159.1999.0732447.x http://onlinelibrary.wiley.com/doi/10.1046/j.1471-4159.1999.0732447.x/full#f2

Changes in human neuroanatomy Neuroanatomical alterations in cannabis users CB1R density Overlap between alterations and CB1R density Non-overlap between alterations and CB1R density Biological Psychiatry 2016 79, e17-e31DOI: (10.1016/j.biopsych.2015.11.013)

Studying Marijuana and the Brain

Marijuana users in these studies N males 57 33 Mean age 24.5 ± 8.6 29.3 ± 8.3 Mean use (days per week) 6.2 ± 3.8 6.9 ± 0.6 Mean use (occasions per day) 4.5 ± 11.3 3.1 ± 1.6 Mean duration in years of regular use 6.8 ± 8.4 9.8 ± 8.0 Non-users 27 80 N males 5 39 Mean age 30.32 ± 10.1 30.04 ± 7.4

Magnetic Resonance Imaging (MRI) Functional MRI (fMRI) Structural MRI (sMRI) Diffusion Tensor Imaging (DTI) Astolfi et al., (2004)

Smaller Hippocampal and Amygdala Volumes Schacht ,Filbey et al., Neuropsychopharmacology 2012

Smaller OFC volume in MJ users Filbey et al., PNAS (in press)

Orbitofrontal cortex is part of the Brain’s Reward System Dopamine

Magnetic Resonance Imaging (MRI) Structural MRI (sMRI) Diffusion Tensor Imaging (DTI)

Measure of white matter integrity Fractional isotropy (FA) High FA Low FA

Lower FA in MJ users Orbitofrontal cortex Forceps minor Filbey et al., PNAS (2014)

Conclusions Gray and white matter alterations in marijuana users, particularly in the orbitofrontal cortex

Magnetic Resonance Imaging (MRI) Functional MRI (fMRI) Structural MRI (sMRI) Diffusion Tensor Imaging (DTI) Astolfi et al., (2004)

Role of craving in addiction Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association Criterion DSM IV DSM 5 Failure to meet obligations Recurrent use Legal problems Social problems Tolerance Withdrawal Loss of control Unsuccessful quit attempts Time spent Give up activities Continued use despite harm Craving 1 = abuse 4-5 = moderate >6 = severe 2-3 = mild 3 = dependence

Cue exposure task in the MRI scanner Filbey et al., PNAS (2009)

Greater response to pipe Filbey et al., PNAS (2009)

Positive correlations Marijuana Problem Scale Age of onset High FA Filbey et al., PNAS (2009)

Conclusions Gray and white matter alterations in marijuana users, particularly in the orbitofrontal cortex Greater reward response to marijuana cues in marijuana users

Leif Parsons, NY Times

Cue exposure task: marijuana vs. natural reward OR

Response to MJ, food and neutral cues Pipe > Pencil Fruit > Pencil MJ > NU NU > MJ

Response to MJ, food and neutral cues Pipe > Fruit MJ NC MJ NU

Conclusions Gray and white matter alterations in marijuana users, particularly in the orbitofrontal cortex Greater reward response to marijuana cues in marijuana users Greater reward response to marijuana cues suggests incentive sensitization (vs. reward deficiency)

What about motivation?

Incentive motivation in the reward circuit N=14 healthy males Wrase et al, NeuroImage (2007)

Monetary Incentive Delay Task Knutson et al., NeuroImage(2000)

Positive and negative motivation MJ users Non-users Filbey et al., PLOS One (2013)

Conclusions Gray and white matter alterations in marijuana users, particularly in the orbitofrontal cortex Greater reward response to marijuana cues in marijuana users Greater reward response to marijuana cues suggests incentive sensitization (vs. reward deficiency) MJ users are sensitive to positive reinforcers, but not negative reinforcers

What about learning and memory?

Neural effort (EEG alpha and beta) Serial Reaction Time (SRT) Task

Conclusions Gray and white matter alterations in marijuana users, particularly in the orbitofrontal cortex Greater reward response to marijuana cues in marijuana users Greater reward response to marijuana cues suggests incentive sensitization (vs. reward deficiency) MJ users are sensitive to positive reinforcers, but not negative reinforcers MJ users exhibit impaired learning associated with low alertness .

Who are at risk?

Onset of use Individuals with a history of childhood abuse have been found to have earlier onsets of substance abuse (Dembo et al. 1988; Harrison et al. 1997; Widom et al. 1999).

Earlier onset = less activation in control areas ACG mid-FG

Early life stress Physical and sexual abuse during childhood is highly associated with MJ use in adulthood (hazard ratio =2.16) (Duncan et al., 2008). Prospective studies show that levels of stress in adolescents are predictive of greater severity of substance abuse (Kaplan et al. 1986; Newcomb and Bentler, 1988; Kaplan and Johnson 1992; Wills et al. 1996) monkeys with stress have less binding in dopamine D2 receptors in receptors  Morgan et al. Nat Neurosci. (2002)

Childhood adversities and substance use N=46, 12-17 year old non-using youth

Response to acute stress 4 x 10/5 = ? TIMEOUT! 1 2 3 4 5 6 7 8 9

Response during stress positively correlated with Marijuana Problem Scale

Genes regulate neurobiology Pet study (Hirvonen et al., 2011) 20% reduction of CB1 receptors in cannabis smokers compared to controls Amount of CB1 receptors correlated with duration of years

CNR1 is associated with differences in brain volume Schacht ,Filbey et al., Neuropsychopharmacology 2012

FAAH C + CNR1 G = greater response Striatum Orbitofrontal cortex (OFC) Activation Activation 1 2 1 2 Number of Risk Alleles Striatum OFC Filbey et al., Neuropsychopharmacology, 2010

Chicken or Egg? Conclusions Gray and white matter alterations in marijuana users, particularly in the orbitofrontal cortex Greater reward response to marijuana cues in marijuana users Greater reward response to marijuana cues suggests incentive sensitization (vs. reward deficiency) MJ users are sensitive to positive reinforcers, but not negative reinforcers MJ users exhibit impaired learning associated with low alertness Factors increase vulnerability to MJ’s effects: age of onset, stress, genetics Chicken or Egg?

Thank you! This research is supported by NIDA KO1 , NIDA RO1 Special thanks to all of the participants (NM, TX)! Joseph Dunlop, PhD Derek Beaton Herve Abdi, PhD Sina Aslan, PhD Sam DeWitt Ariel Ketcherside Shikha Prashad, PhD Filbey lab Sherwood Brown, MD Bryon Adinoff, MD Sarah Feldstein Ewing, PhD Ursula Myers Kent Hutchison, PhD Vince Calhoun, PhD Joseph Schacht, PhD Mike Doty, MS www.filbeylab.com