Percentage of Past Month Marijuana Users Aged 12 or Older: Annual - - PowerPoint PPT Presentation

Wilson M. Compton, M.D., M.P.E. Deputy Director National Institute on Drug Abuse

Marijuana: Science in the Context of a

Shifting Social and Legal Environment

• An estimated 2.4

million Americans used it for the first time in 2013

2013 National Survey on Drug Use and Health, SAMHSA, 2014.

Marijuana is the Most Commonly Used Illicit Drug In the U.S.

Tetrahydrocannabinol (THC) Active Ingredient in Marijuana

• Over 115 million Americans have tried it

at least once

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

Age in Years

1.0 5.8 14.2 20.3 18.3 13.7 11.7 7.0 5.6 5.2 5.5 4.4 3.1 0.9

5 10 15 20 25

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+ Percent Using in Past Month Source: SAMHSA, 2013 National Survey on Drug Use and Health (September 2014).

1 to 2 Days 23% 3 to 5 Days 17% 6 to 19 Days 19%

20 or More Days 41%

Among Current Marijuana Users, Two In Five Are Daily or Almost Daily Users

Source: SAMHSA, 2013 National Survey on Drug Use and Health (September 2014).

19.8 Million Past Month Users of Marijuana in 2013

Number of Days Used Marijuana in the Past Month

10 20 30 40 50 60

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

Percentage of U.S. 12th Grade Students Reporting Past Month Use of Cigarettes, Alcohol, and Marijuana

University of Michigan, 2015 Monitoring the Future Study.

Cigarettes Marijuana Alcohol

5 10 15 20 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12

∆-9 THC

∆-9 THC

Marijuana Potency (% Δ-9 THC) Tripled in Past 20 Years

SOURCE: University of Mississippi Marijuana Project (potency data)

%

2 4 6 8 10 12 10 20 30 40 50 60 70 80 90

Daily Use (Percent) Perceived Risk (Percent)

Perceived Risk Daily Use

SOURCE: University of Michigan, 2014 Monitoring the Future Study.b

Percent 12th Grade Students Reporting Daily Marijuana Use vs. Perceived Risk of Regular Use

2 4 6 8 10 12 10 20 30 40 50 60 70 80 90

Daily Use (Percent) Perceived Risk (Percent)

Perceived Risk Daily Use

SOURCE: University of Michigan, 2014 Monitoring the Future Study.b

Percent 12th Grade Students Reporting Daily Marijuana Use vs. Perceived Risk of Regular Use

Status of Marijuana Laws in the USA (2015)

Cerda M et al. Drug and Alcohol Dependence 2012; 120: 22 – 27. NESARC: National Epidemiologic Survey on Alcohol and Related Conditions

1.81 1.92 1.03 0.5 1 1.5 2 2.5

Past Year MJ Abuse/Dependence Past Year MJ Use Past Year MJ Abuse/Dependence Among Current Users Map of States that Legalized Medical Marijuana by 2004

passed laws legalizing medical MJ

Odds Ratio

States that Legalized Medical Marijuana Use Have Higher Rates Of Marijuana Use and of Marijuana Abuse and Dependence

Source of Marijuana* among 12th Graders in 2012 and 2013, by State Policy

20 40 60 80 100

Medical Marijuana States Non-Medical Marijuana States ** **

*Categories not mutually exclusive ** Statistically significant difference SOURCE: University of Michigan, 2013 Monitoring the Future Study

%

Methods of Using Marijuana Among 12th Grade Past Year Users, 2014

0.0 20.0 40.0 60.0 80.0 100.0

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
• 0.5

0.0 0.5 1.0

z-score

Controls (n=34) Marijuana Users (n=31)

Medina, Hanson, Schweinsburg, Cohen-Zion, Nagel, & Tapert, 2007

Verbal Memory

50 60 70 80

Marijuana Users Controls

50 60 70 80

*

*

*p<.01

~Age18 N=46

Mean CBF (ml/100g/min)

Left Insula

Medial Frontal Gyrus Brain blood flow after 28 days monitored abstinence

Recovery of Cognition and CBF with Abstinence

Tapert, 2016

Non-users used 1 Dx used 2 Dx used 3 Dx

• 8
• 6
• 4
• 2

2

Average Point Difference in IQ score (IQ at age 38 – IQ at age 13)

Persistent Marijuana Users Show A Significant IQ Drop between Childhood and Midlife

Source: Meier MH et al., PNAS Early Edition 2012

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

Silins, et al., Lancet Psychiatry 2014;1:286-293

HS Complete Never < Monthly Monthly + Weekly + Daily 0.2 0.4 0.6 0.8 1 1.2 HS Complete

O.R.

5 10 15 20 Cannabis Depend

O.R.

2 4 6 8 10 Other Illicit Drug

O.R.

2 4 6 8 Suicide Attempt

O.R.

More Teenage Use of Cannabis Associated with Worse Outcomes in 20’s (3 Australia/New Zealand Studies)

Marie O, Zollitz U, IZA Discussion Paper No. 8900, March 2015

When MJ Sales Were Restricted in The Netherlands, University Grades Improved

61 49 47 20 24 10 9 14 21 27 21 20 16 17 4 3 2 1 4 5 9 4

10 20 30 40 50 60 70

Percent

High Rates of Mood & Anxiety Disorders Among Respondents with Marijuana Dependence

Marijuana Dependence General Population

Source: NESARC Study; Conway KP et al., J Clin Psychiatry 2006; 67(2): 247-257.

Marijuana-Associated Psychosis

Andréasson et al Lancet, 1987.

1 2 10 <50 >50

30 20 10 No of times marijuana taken

Cases of Sz per 1,000

4.5 1.6 1 2 3 4 5 6 7 8 9

Cannabis users by age 15 years Cannabis users by age 18 years

Arseneault et al BMJ 2002

Risk of schizophrenia-like psychosis at age 26 years

Odds ratio

MARIJUANA AND SCHIZOPHRENIA

Study of Swedish Conscripts (n=45570)

MARIJUANA AND SCHIZOPHRENIA-Like

Longitudinal prospective Dunedin study (n=1037)

Regular Marijuana Use Increases Schizophrenia Risk in those with AKT1 rs2494732 genotype

Di Forti et al., Biological Psychiatry, 2012.

AKT1 genotype does not predict History of Cannabis use (p=0.772) GXE multiplicative model: p*=0.014

Never used cannabis History of cannabis use Never used cannabis Used cannabis at week ends or less Used cannabis everyday

Odds Ratio

AKT1(T/T) AKT1(C/T) AKT1(C/C) AKT1(T/T) AKT(C/T) AKT1(C/C)

Odds Ratio

31.4 31.1 29.5 26.5* 25.2*

None ≤ Weekly Hash Daily Hash ≤ Weekly Skunk Daily Skunk

High Potency Marijuana and Earlier Onset of Psychosis

Di Forti M et al. Schizophr Bull 2013;schbul.sbt181

Hippocampus/Amygdala volumes correlated with psychosis in schizophrenics (closed) and bipolar patients (open)

Schizophrenics have Smaller Hippocampus and Amygdala: Marijuana might exacerbate this

Watson et al., Brain Imaging Behav. 2012.

Areas in Hippocampus and Amygdala where volumes were smaller in schizophrenics than controls

Prestia et al., Am J Geriatr Psychiatry 2015.

delta-9-tetrahydrocannabinol delta-9-tetrahydrocannabivarin delta-8-tetrahydrocannabinol cannabigerol cannabinol cannabichromene cannabidiol

Marijuana contains ~100 cannabinoids plus other chemicals in varying concentrations

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

PET images of [11C]-NE40 (CB2R radioligand)

Ahmad et al., Mol Imaging Biol. 2013 A Terry et al., Eur J Nucl Med Mol Imaging. 2010

Whole Body Distribution of CB1 Receptors (2, 25, and 100 min

after injection of 11C-MePPEP)

Cannabinoid Receptors Are Also Located Throughout the Body

Source: Mackie K. Ann Rev Pharmacol Toxicol., 2006

Endocannabinoids are produced on demand. They travel back to the transmitting neuron to dampen further activity.

Cannabinoid CB1 Receptors in Human Brain are Lower in Marijuana Abusers

Van Loere et al., 2007. Hirvonen et al., Mol Psychiatry 2013

Marijuana Abusers Controls

ACC/CBL

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

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.

Precuneus to splenium Fimbria of hippocampus, hippocampal commissure and Splenium

Adolescents – White Matter

Alcohol Effects Marijuana 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

Adolescent Brain Cognitive Development National Longitudinal Study

NIDA, NIAAA, NCI, NICHD, NIMHD, ORWH, NIMH, NINDS, OBSSR

Ten year longitudinal study of 10,000 children from age 10 to 20 years to assess effects of drugs on individual brain development trajectories

Other Marijuana-related Health Concerns

• Driving under the influence of marijuana

(or the combination of marijuana and alcohol)

• Overdose/acute toxicity (especially with

edibles)

• Exposure during pregnancy
• Second hand exposure

5 10 15 20

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Percent Who Reported

12th Graders Who Drove After Smoking Marijuana or Drinking Alcohol, 2001-2014

Source: University of Michigan, 2014 Monitoring the Future study, Unpublished special tabulations (December 2014).

During the LAST TWO WEEKS, have you driven a car, truck, or motorcycle after …

… drinking alcohol … smoking marijuana Since 2009, more high school seniors reported driving after smoking marijuana than driving after drinking alcohol.

Key Question: Is marijuana addictive?

ADDICTION: A developmental brain disease expressed as compulsive behavior through continued use of a drug despite negative consequences.

ACG OFC SCC Hipp NAcc VP Amyg

REWARD INHIBITORY CONTROL MEMORY/ LEARNING EXECUTIVE FUNCTION

PFC

Becomes severely disrupted in

ADDICTION

MOTIVATION/ DRIVE

The fine balance in connections that normally exists between brain areas active in reward, motivation, learning and memory, and inhibitory control

Natural and Drug Reinforcers Increase Dopamine in NAc

VTA/SN nucleus accumbens frontal cortex Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction

100 200 300 400 500 600 700 800 900 1000 1100 1 2 3 4 5 hr

AMPHETAMINE

% of Basal Release 50 100 150 200 60 120 180

Time (min)

% of Basal Release Empty Box Feeding Di Chiara et al., 1997

FOOD

150 125 100

0 20 40 60 80

MARIJUANA

% of Basal Release Tanda, et al, Scienceb 1997 Di Chiara et al., 1997

67.5% 22.7% 20.9% 8.9% 0% 50% 100% Nicotine Alcohol Cocaine Cannabis

Estimated Prevalence of Dependence Among Users

NO—Use is NOT the Same as Addiction Key Question: Do All Users Become Addicted?

• C. Lopez-Quintero et al. Drug and Alcohol Dependence (2011)

Note that heavy use and teenage onset are associated with a higher rate of Dependence.

Environment

ADDICTIONS as Diseases of Gene-Environment-Development

Addiction

DRUG/ALCOHOL Brain Mechanisms Biology

Genes/Development

Age

There are Multiple Environmental Influences

Laws/Culture Neighborhood/ Community Family/Peers Biology Individual/ Genes

Time/Age

Parents are Powerful and Can Reduce Drug Use Onset

Substance Use Rate of Increase

Involved-Supportive Parenting

Low High

High supportive parenting decreased substance use risk in those with low serotonin transporter expressing valiants (high risk alleles)

No Genetic Risk (l-l allele) Genetic Risk (s-s or s-l allele)

• G. Brody et al. J Consulting Clinical Psychol (2009)

How Prevention Interventions Work

MODIFIABLE RISK and PROTECTIVE FACTORS Background Factors

Age Gender Race/ethnicity Poverty level Genotype Early aggression Social skills deficits Academic problem Misperceived drug use norms Association with deviant peers Neighborhood availability Media glamorization Parental monitoring and support

INTERVENTIONS

Parent skills training Social skills training Self-regulation Impulse control Tutoring Norms training Refusal skills Community policing Health literacy

• Prevention Approaches Should

Enhance Protective Factors & Reduce Risk Factors Reduce these Elevate these

PROSPER (Community/University Partnership) Reduces Illicit Substance Use

Sum of six lifetime illicit use measures (methamphetamines, Ecstasy, inhalants, Vicodin, prescription drug misuse overall,

• ther illicit drug use); Intervention vs. Control difference in slope is statistically significant, as are differences at multiple time

points, including 11th and 12th grades.

Reduced Increase in Use Through 6½ Years Past Baseline

0.00 0.50 1.00 1.50 2.00 2.50 Grade 6 Grade 7 Grade 8 Grade 9 Grade 10 Grade 11 Grade 12

Control Intervention

Source: Spoth, Redmond, Shin, Greenberg, Feinberg, et al. (2013). PROSPER community-university partnerships delivery system outcomes through 6½ years past baseline.

Higher Risk = Lifetime initiation of alcohol, cigarette or marijuana use at baseline; Lower Risk = No initiation at baseline. Intervention effects are significantly stronger for the Higher-Risk subgroup, as compared to the Lower-Risk Subgroup.

Greater Impact of PROSPER on High Risk Youth Through 6½ Years Past Baseline

0.00 0.50 1.00 1.50 2.00 2.50 3.00 Grade 6 Grade 7 Grade 8 Grade 9 Grade 10 Grade 11 Grade 12 Higher-Risk in Control Lower-Risk in Control Higher-Risk in Intervention Lower-Risk in Intervention

PROSPER (Community/University Partnership) Reduces Illicit Substance Use

Source: Spoth, Redmond, Shin, Greenberg, Feinberg, et al. (2013). PROSPER community-university partnerships delivery system outcomes through 6½ years past baseline.

Marijuana as Medicine?

• Promise lies in purified ingredients
• r synthetic compounds with more

selectivity, less adverse effects

• Applications: pain, nausea,

wasting, obesity, muscle spasticity, addiction, inflammatory conditions, HIV

NIH research (across NIDA, NCI, NINDS, NIAID, etc.) focuses on THC, CBD, and compounds that alter the function of the endocannabinoid system.

• Exogenous compounds
• Phytocannabinoids
• THC, CBD, combinations
• Synthetic cannabinoids
• Dronabinol
• Endogenous manipulation
• FAAH inhibitors
• MAGL inhibitors
• Allosteric modulators
• Receptor targets
• CB1, CB2, TRPV1, PPAR, 5-HT, peripheral, others…

Enzyme Inhibitors (e.g., AEA degradation)

Indirect enhancers of CB activity—more selective, less side effects What have we learned?

Very mild side effect profile in animals and humans

Reduce nicotine addiction Reduce anxiety-like behaviors Enhance social behavior in ASD models Reduce depression-like behaviors May be effective for cannabis use disorder FAAH inhibitors

ECB

Piomellli, 2016

Epidiolex (Cannabidiol) in Tx Resistant Epilepsy

Devinsky O et al., Poster presented at the 2015 Annual Meeting of the American Epilepsy Society. Research funding from GW Pharmaceuticals, the company developing the tested formulation of cannabidiol (Epidiolex)

State of Science: What we know… Where we need more research… Policy Research

Source: Pacula, March 2016

Source: Glantz and Barry, 2016

Policy Research: The Details Matter

• How to minimize harm, prevent underage use,

use during pregnancy…..

• Marijuana is most commonly used illicit drug in U.S.
• Marijuana use generally begins in adolescence
• Use of marijuana can have a wide range of effects on an

individual’s brain, body and behavior including short and long term effects on such functions as:

 Brain development 

Memory and cognition



Motivational systems and reward



Addiction



Lung health

• Research on the impact of marijuana on the developing

adolescent brain is important.

• Medical uses of marijuana are most likely from plant

cannabinoid constituents

Summary

Web interactive

Drugs + Your Body: It Isn't Pretty

Includes graphics, videos, quizzes and much more on the wide-ranging harmful effects

• f drugs on the brain and body.

www.drugabuse.gov

Science = Solutions