Marijuana : Science in the Context of a Shifting Social and Legal Environment Wilson M. Compton, M.D., M.P.E. Deputy Director National Institute on Drug Abuse
Marijuana is the Most Commonly Used Illicit Drug In the U.S. • Over 115 million Americans have tried it at least once • An estimated 2.4 million Americans used it for the first time in 2013 Tetrahydrocannabinol (THC) Active Ingredient in Marijuana 2013 National Survey on Drug Use and Health, SAMHSA, 2014.
Percentage of Past Month Marijuana Users Aged 12 or Older: Annual Averages, 2002-2003
Percentage of Past Month Marijuana Users Aged 12 or Older: Annual Averages, 2012-2013
Past Month Marijuana Use among Persons Aged 12 or Older, by Age Percent Using in Past Month 25 20.3 20 18.3 15 14.2 13.7 11.7 10 7.0 5.6 5.8 5.5 5.2 4.4 5 3.1 0.9 1.0 0 12-13 14-15 16-17 18-20 21-25 26-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65+ Age in Years Source: SAMHSA, 2013 National Survey on Drug Use and Health (September 2014).
Among Current Marijuana Users, Two In Five Are Daily or Almost Daily Users Number of Days Used Marijuana in the Past Month 6 to 19 Days 19% 20 or More 3 to 5 Days 17% Days 41% 1 to 2 Days 23% 19.8 Million Past Month Users of Marijuana in 2013 Source: SAMHSA, 2013 National Survey on Drug Use and Health (September 2014).
Percentage of U.S. 12 th Grade Students Reporting Past Month Use of Cigarettes, Alcohol, and Marijuana 60 50 Alcohol 40 30 Marijuana 20 10 Cigarettes 0 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 University of Michigan, 2015 Monitoring the Future Study.
Marijuana Potency (% Δ -9 THC ) Tripled in Past 20 Years ∆ -9 THC 20 15 % 10 5 0 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 ∆ -9 THC SOURCE: University of Mississippi Marijuana Project (potency data)
Percent 12 th Grade Students Reporting Daily Marijuana Use vs. Perceived Risk of Regular Use Perceived Risk 12 90 Daily Use Perceived Risk (Percent) 80 10 Daily Use (Percent) 70 8 60 50 6 40 4 30 20 2 10 0 0 SOURCE: University of Michigan, 2014 Monitoring the Future Study.b
Percent 12 th Grade Students Reporting Daily Marijuana Use vs. Perceived Risk of Regular Use Perceived Risk 12 90 Daily Use Perceived Risk (Percent) 80 10 Daily Use (Percent) 70 8 60 50 6 40 4 30 20 2 10 0 0 SOURCE: University of Michigan, 2014 Monitoring the Future Study.b
Status of Marijuana Laws in the USA (2015)
States that Legalized Medical Marijuana Use Have Higher Rates Of Marijuana Use and of Marijuana Abuse and Dependence Map of States that Legalized Medical Marijuana by 2004 2.5 1.92 2 1.81 Odds Ratio 1.5 1.03 1 passed laws legalizing medical MJ 0.5 0 Past Year MJ Past Year MJ Use Past Year MJ Abuse/Dependence Abuse/Dependence Among Current Users NESARC: National Epidemiologic Survey on Alcohol and Related Conditions Cerda M et al. Drug and Alcohol Dependence 2012; 120: 22 – 27.
Source of Marijuana* among 12 th Graders in 2012 and 2013, by State Policy 100 Medical Marijuana States Non-Medical Marijuana States 80 60 % 40 ** 20 ** 0 *Categories not mutually exclusive SOURCE: University of Michigan, 2013 Monitoring the Future Study ** Statistically significant difference
Methods of Using Marijuana Among 12th Grade Past Year Users, 2014 100.0 80.0 60.0 40.0 20.0 0.0 Smoking In Food In Drink Other Non-MMJ States MMJ States SOURCE: University of Michigan, 2014 Monitoring the Future Study
Does marijuana use negatively affect the brain?
Marijuana: Worsens Memory 1.0 Controls (n=34) Marijuana Users (n=31) 0.5 z-score 0.0 -0.5 -1.0 Medina, Hanson, Schweinsburg, Cohen-Zion, Nagel, & Tapert, 2007
Recovery of Cognition and CBF with Abstinence Brain blood flow after 28 days Verbal Memory monitored abstinence 80 Mean CBF (ml/100g/min) 70 Marijuana 60 Users 50 Controls * p <.01 * 80 ~Age18 * 70 N=46 60 50 Tapert, 2016 Medial Frontal Gyrus Left Insula
Persistent Marijuana Users Show A Significant IQ Drop between Childhood and Midlife Followed 1,037 individuals from birth to age 38. Tested marijuana use at 18, 21, 26, 32 and 38. Tested for IQ at ages 13 and 38 Average Point Difference in IQ score 2 (IQ at age 38 – IQ at age 13) 0 -2 -4 -6 -8 used used used Non-users 1 Dx 2 Dx 3 Dx Source: Meier MH et al., PNAS Early Edition 2012
More Teenage Use of Cannabis Associated with Worse Outcomes in 20’s (3 Australia/New Zealand Studies) Never 1.2 8 < Monthly 1 O.R. O.R. 6 Monthly + 0.8 10 Weekly + 4 0.6 8 Daily O.R. 2 0.4 6 0 0.2 20 4 HS Complete O.R. Suicide 0 15 2 Attempt HS Complete 0 10 Other Illicit 5 Drug 0 Cannabis Depend Silins, et al., Lancet Psychiatry 2014;1:286-293
When MJ Sales Were Restricted in The Netherlands, University Grades Improved Marie O, Zollitz U, IZA Discussion Paper No. 8900, March 2015
High Rates of Mood & Anxiety Disorders Among Respondents with Marijuana Dependence 70 61 60 Marijuana Dependence General Population 49 50 47 Percent 40 27 30 24 21 21 20 20 20 17 16 14 10 9 9 10 5 4 4 4 3 2 1 0 Source: NESARC Study; Conway KP et al., J Clin Psychiatry 2006; 67(2): 247-257.
Marijuana-Associated Psychosis MARIJUANA AND SCHIZOPHRENIA-Like MARIJUANA AND SCHIZOPHRENIA Longitudinal prospective Dunedin study (n=1037) Study of Swedish Conscripts (n=45570) 9 Cases of Sz Risk of schizophrenia-like 8 per 1,000 psychosis at age 26 years 7 30 6 4.5 5 4 20 3 Odds ratio 1.6 2 10 1 0 Cannabis users by Cannabis users by 0 0 1 2 10 <50 >50 age 15 years age 18 years No of times marijuana taken Arseneault et al BMJ 2002 Andréasson et al Lancet, 1987.
Regular Marijuana Use Increases High Potency Marijuana and Schizophrenia Risk in those with Earlier Onset of Psychosis AKT1 rs2494732 genotype Never used cannabis History of cannabis use Odds Ratio 31.4 31.1 29.5 AKT1(T/T) AKT1(C/T) AKT1(C/C) 26.5* Never used cannabis Used cannabis at week ends or less Odds Ratio 25.2* Used cannabis everyday None ≤ Daily ≤ Daily AKT1(T/T) AKT(C/T) AKT1(C/C) Weekly Hash Weekly Skunk AKT1 genotype does not predict History of Cannabis use Hash Skunk (p=0.772) GXE multiplicative model: p*=0.014 Di Forti M et al. Schizophr Bull 2013;schbul.sbt181 Di Forti et al., Biological Psychiatry, 2012.
Schizophrenics have Smaller Hippocampus and Amygdala: Marijuana might exacerbate this Hippocampus/Amygdala Areas in Hippocampus and Amygdala volumes correlated with psychosis where volumes were smaller in in schizophrenics (closed) and schizophrenics than controls bipolar patients (open) Prestia et al., Am J Geriatr Psychiatry 2015. Watson et al., Brain Imaging Behav. 2012.
Marijuana contains ~100 cannabinoids plus other chemicals in varying concentrations delta-9-tetrahydrocannabinol delta-9-tetrahydrocannabivarin delta-8-tetrahydrocannabinol cannabigerol cannabinol cannabichromene cannabidiol
Cannabinoid Receptors Are Located Throughout the Brain Regulation of: • Brain Development • Memory and Cognition • Movement Coordination • Pain Regulation & Analgesia • Immunological Function • Appetite • Motivational Systems & Reward
Cannabinoid Receptors Are Also Located Throughout the Body Whole Body Distribution of PET images of CB1 Receptors (2, 25, and 100 min [11C]-NE40 after injection of 11C-MePPEP) (CB2R radioligand) Terry et al., Eur J Nucl Med Mol Imaging. 2010 Ahmad et al., Mol Imaging Biol. 2013 A
Endocannabinoids are produced on demand. They travel back to the transmitting neuron to dampen further activity. Source: Mackie K. Ann Rev Pharmacol Toxicol., 2006
Cannabinoid CB1 Receptors in Human Brain are Lower in Marijuana Abusers Marijuana Abusers ACC/CBL Controls Van Loere et al., 2007. Hirvonen et al., Mol Psychiatry 2013
Subcortical structures evaluated for group differences between daily marijuana users and nonusers. Weiland B J et al. J. Neurosci. 2015;35:1505-1512
Early (<18y) Long-Term Cannabis Use Decreases Axonal Fiber Connectivity Precuneus to splenium Fimbria of hippocampus, hippocampal commissure and Splenium Axonal paths with reduced connectivity (measured with diffusion-weighted MRI) in cannabis users (n=59) than in controls (N=33). Zalesky et al Brain 2012.
Adolescents – White Matter Marijuana Effects Alcohol Effects Hutchison, 2016
Adolescents & Marijuana What We Know: • Adversely influences learning • Effects on memory and attention outlast intoxication Appear worse with earlier age of onset, more chronic use • • Some neuroimaging data support these effects What We Need to Know: • Does cognitive ability (and corresponding brain alterations) recover with abstinence? • What are the parameters of cannabis use sufficient to produce cognitive impairment? • How does other drug use (e.g., alcohol, nicotine) influence outcomes? • Are there individual/gender/other differences in susceptibility? How might dose/strain/potency differences affect cognitive impairment? • Need large longitudinal study to disentangle multiple interacting factors and examine individual differences. Meier, Tapert, Hutchison, 2016
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