1. 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

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

3. 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.

4. Changing marijuana landscape

6. What do we know?

7. 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)

8. 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

9. Targeted Brain Areas

10. 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: /nature20153

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

12. Neural changes in rat brain
Journal of Neurochemistry Volume 73, Issue 6, pages , 18 JAN 2002 DOI: /j x

13. 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  , e17-e31DOI: ( /j.biopsych )

14. Studying Marijuana and the Brain

15. Marijuana users in these studies
N males
Mean age ± ± 8.3
Mean use (days per week) ± ± 0.6
Mean use (occasions per day) ± ± 1.6
Mean duration in years of regular use ± ± 8.0
Non-users
N males
Mean age ± ± 7.4

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

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

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

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

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

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

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

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

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

26. 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

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

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

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

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

31. Leif Parsons, NY Times

32. Cue exposure task: marijuana vs. natural rewardOR

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

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

35. 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)

36. What about motivation?

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

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

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

40. 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

41. What about learning and memory?

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

43. 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 .

44. Who are at risk?

45. 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).

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

47. 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)

48. Childhood adversities and substance use
N=46, year old non-using youth

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

50. Response during stress positively correlated with Marijuana Problem Scale

51. 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

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

53. 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

54. 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?

55. 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