Sion Kim Harris, PhDAssociate Professor of PediatricsHarvard Medical School

The State of the Science:

Teen Brain Development and

the Impact of Marijuana Use

State Marijuana Laws, March 2019

http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx

• 46 states legalized in some form• 24 legalized medical marijuana only• 10 legalized adult recreational use• 12 low THC/high CBD only• Still Schedule 1 drug at federal level

Images about marijuana that young people see today…

The Next ‘Big Tobacco’

4Slide courtesy of Kevin Sabet, PhD; www.learnaboutsam.com

Social Media Marketing

Perceived Risk of Harm and Marijuana UseU.S. 12th graders: 1975-2018

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%Great Risk of HarmGreat Risk of Harm

27%

Source: National Monitoring the Future Survey, 2017

Perceived risk is at historic

low!

Perceived Risk of Harm and Marijuana UseU.S. 12th graders: 1975-2018

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%Great Risk of Harm Past Month Use

27%22%

Source: National Monitoring the Future Survey, 2017

Perceived risk is at historic

low!

50%

30%31%

8%10%

6%0

10

20

30

40

50

60

70

80

9020

00

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

Alcohol

Tobacco

Percent of U.S. 12th Graders Using Substance in Past Month, 2000-2018

Source: National Monitoring the Future Survey, 2017

Illicit drugs other than marijuana

50%

30%31%

8%

21% 22%

10%6%

0

10

20

30

40

50

60

70

80

9020

00

2001

2002

2003

2004

2005

2006

2007

2008

2009

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2011

2012

2013

2014

2015

2016

2017

2018

2019

Alcohol

Tobacco

Percent of U.S. 12th Graders Using Substance in Past Month, 2000-2018

Marijuana

Source: National Monitoring the Future Survey, 2017

Illicit drugs other than marijuana

Colorado allows commercial marijuana

industry

50%

30%31%

8%

21% 22%

10%6%

21%

0

10

20

30

40

50

60

70

80

9020

00

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

Alcohol

Tobacco

Percent of U.S. 12th Graders Using Substance in Past Month, 2000-2018

Marijuana

Source: National Monitoring the Future Survey, 2017

Illicit drugs other than marijuana

Colorado allows commercial marijuana

industry

Vaping

“Liquid shatter” pen“Premium wax vaporizer”

More than 1/4 of e-cigarette users say they also vape marijuana…

Source: Monitoring the Future Survey, 2018

30%

14%

20%

4%3% 1%0

5

10

15

20

25

30

3520

00

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

Binge drinking* in past 2 weeks*5+ drinks in a row

Daily cigarette smoking

Percent of U.S. 12th Graders Reporting Behavior in Past Month, 2000-2018

Source: National Monitoring the Future Survey, 2017

Daily alcohol use

30%

14%

20%

4%

6%6%

3% 1%0

5

10

15

20

25

30

3520

00

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

Binge drinking* in past 2 weeks*5+ drinks in a row

Daily cigarette smoking

Percent of U.S. 12th Graders Reporting Behavior in Past Month, 2000-2018

Daily marijuana use

Source: National Monitoring the Future Survey, 2017

Daily alcohol use

So what?

Common Marijuana Myths

• It’s not addictive• It’s harmless and natural

Let’s look at the science…

Is marijuana addictive?

Studying the Addictiveness of Drugs

The Reward Pathway

Ventral-TegmentalAreaSource: NIDA

Striatum

marijuana

Marijuana (THC) is no exception…

Marijuana is especially addictive for teens …

15%10%

1%5%

0%

10%

20%

30%

40%

50%

60%

70%

Alcohol Heroin/Opiates Cocaine Meth/OtherStimulants

Marijuana

Source: SAMHSA National Treatment Episode Data Set, 2014

15%10%

1%5%

65%

0%

10%

20%

30%

40%

50%

60%

70%

Alcohol Heroin/Opiates Cocaine Meth/OtherStimulants

Marijuana

Source: SAMHSA National Treatment Episode Data Set, 2014

• Among adolescents, marijuana accounts for more treatment admissions than all other substances combined

Is marijuana harmless?

Not for the teen brain!

30

Adolescence is a sensitive period in brain development.

The brain is still developing until about mid-20’s!!

What we now know…

Slide courtesy of Ken Winters, PhD.

Critical PeriodDefinition:“Window” in brain development when a part of the brain … • develops rapidly • is highly sensitive to

being shaped by environmental exposures and experiences

Brain Development

Genes Exposures

Key Brain DevelopmentProcesses until Mid-20s

“Pruning” “Myelination”

Source: Lubman DI, Cheetham A, Yücel M. Cannabis and adolescent brain development. Pharmacol Ther 2015;148:1–16. http://www.sciencedirect.com/science/article/pii/S0163725814002095

Neurons

35

Around age 12, brain cell connections start to undergo pruning based on “use it or lose it” (connections that are not used are pruned away)

Construction Ahead

Source: Giedd J., et al., Neuropsychopharmacology Reviews (2015) 40, 43–49. Available at: http://www.nature.com/npp/journal/v40/n1/full/npp2014236a.html

Slide courtesy of Ken Winters, PhD.

Construction Ahead

• At the same time, myelin starts to cover axons and thicken

• Helps neuron signals travel 100 times faster

39

Myelinated axons = White Matter TractsThe Brain’s Information Superhighway

Source: Dr. Gordon J. Harris, MGH, 2008.

• Faster, but fewer, connections in the brain

• A speedier, more efficientbrain

Source: Baker STE, Lubman DI, Yücel M, et al. Developmental Changes in Brain Network Hub Connectivity in Late Adolescence. Journal of Neuroscience 2015;35:9078–87. Available at: http://www.jneurosci.org/content/35/24/9078.long

The result of pruning and myelination…

41Image source: Dr. Van J. Wedeen, MGH, 2011Source: Stevens MC, Skudlarski P, Pearlson GD, et al. Age-related cognitive gains are mediated by the effects of white matter development on brain network integration. Neuroimage 2009;48:738–46.

The Brain’s Connectome

Source: Neuropsychopharmacology Reviews advance online publication 22 October 2014. doi:10.1038/npp.2014.236

Pruning and myelination happeninto the mid-20s…

It’s speeding up the commute time…

43

The Gas Pedal

The Brakes

To go from this…

To being able to do this…

Diekhof EK, Gruber O. When desire collides with reason: functional interactions between anteroventral prefrontal cortex and nucleus accumbens underlie the human ability to resist impulsive desires. The Journal of Neuroscience. 2010;30(4):1488-1493.

The teen brain is highly “neuroplastic”It’s a double-edged sword…

Vulnerability

Opportunity

Renard J, Vitalis T, Rame M, Krebs MO, Lenkei Z, Le Pen G, Jay TM. Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex. Eur Neuropsychopharmacol. 2016 Jan;26(1):55-64. http://www.europeanneuropsychopharmacology.com/article/S0924-977X(15)00355-7/abstract

Adolescence is a great time for getting good at something!

The teen brain is more vulnerable to being harmed by alcohol and drugs than the adult brain

The Teen Brain on Marijuana

51

What is in Marijuana?• Contains many cannabinoid chemicals …

– delta-9-tetrahydrocannabinol (THC)– cannabidiol (CBD)– cannabinol– cannabichromene– cannabigerol– Etc.

Source: Mechoulam R, Hanus L, The cannabinoid system from the point of view of a chemist. In Marijuana and Madness. ed. Castle, Murray. Cambridge University Press, 2004

THC Properties• Crosses the blood-brain barrier and the

placenta

• Highly absorbed in fat tissue, resulting in long elimination time (several days to 1 week)

• Acts on the body’s cannabinoid receptors, present in the central (CB1 receptors) and peripheral nervous system (CB2 receptors)

Source: Mechoulam R, Hanus L, The cannabinoid system from the point of view of a chemist. In Marijuana and Madness. ed. Castle, Murray. Cambridge University Press, 2004

53

THC Binding Sites

Source: NIDA

FrontBack

Cannabinoid receptors in our brains?

Why?

Fooling the brain…

55

Source: NIDA

The Brain’s “Endocannabinoid”

System

“Endo” = “within” or “inside”

Basic Neuron Structure

Axon

Synapse

Electrical signal

Cell body

Dendrites

58

Source: Kraft, U. Scientific American Mind, 2006, p. 62-65

Endocannabinoid System Functions• The neuron’s “volume control” system

• dials down neuron activity and neurotransmitter release when too strong

• regulates levels of many brain chemicals (affects pleasure, mood, pain, appetite, motivation, memory, growth and reproductive hormones)

THC vs. Anandamide

• Both dial down neuron activity to change neurotransmitter release

• THC has a MUCH STRONGER, LONGER effect than anandamide on brain cells

• THC interferes with our own brain’s system for protecting neurons and keeping brain activity in balance

61

Anandamide THC

Repeated THC exposure causes brain to scale back CB receptors, causing “cannabinoid deficiency”

Marijuana Withdrawal Symptoms(symptoms of an “out-of-whack” brain)

• Restlessness, anxiety• Increased irritability, anger, aggression• Difficulty falling and staying asleep,

nightmares/strange dreams• Boredom• Decreased appetite

Source: Budney et al. Arch Gen Psych 58(10):917-924, 2001.

Marijuana-relatedamotivational syndrome

Source: Lawn, W., et al. (2016). Acute and chronic effects of cannabinoids on effort-related decision-making and reward learning: an evaluation of the cannabis ‘amotivational’ hypotheses. Psychopharmacology, 233(19–20), 3537–3552; Silveira, M. M., et al. (2016). Δ9-Tetrahydrocannabinol decreases willingness to exert cognitive effort in male rats. Journal of Psychiatry & Neuroscience : JPN, 41(6), 150363.

Endocannabinoid System cont’d

• Shapes brain development by…

– guiding neurons to grow to the right places in the brain for correct function

– controlling neuron activity, thereby affecting pruning and brain wiring

– supporting myelin growth on neurons

Source: Galve-Roperh I, Palazuelos J, Aguado T, Guzman M. Eur Arch Psychiatry Clin Neurosci. 2009;259:371-382.

Neuropsychopharmacology Reviews advance online publication 22 October 2014. doi:10.1038/npp.2014.236

Pruning and myelination happen throughout adolescence…

If the adolescent brain is regularly exposed to THC, it could alter development of the connectome

Longitudinal brain imaging studies provide confirmation:

Brain connectivity over time in adolescent regular marijuana users

compared to non-users

Source: Camchong J et al., Cerebral Cortex (2016)

Anterior cingulate cortex

Orbitofrontal cortex

Using marijuana once or twice associated with brain structure differences in 14-year-olds

Source: Orr, C., et al., J. Neurosci 2019; 10.1523/JNEUROSCI.3375-17.2018

72

What else is affected by THC?

Source: NIDA

73

The Hippocampus (the key to learning)

Marijuana and Memory

• THC suppresses activity of hippocampal cells below the level needed to trigger memory formation

• With chronic THC exposure, neuron connections involved in memory aregradually lost due to continual suppression

Source: Ranganathan M, D’Souza DC. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl) 2006;188:425–44; Broyd SJ, van Hell HH, Beale C, et al. Acute and Chronic Effects of Cannabinoids on Human Cognition-A Systematic Review. Biol Psychiatry 2016;79:557–67.

Marijuana and Hippocampal Size

Sources: Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C, Lubman DI. Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry. 2008 Jun;65(6):694-701. Rubino T, Realini N, Braida D, et al. Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood. Hippocampus. 2009;19:763-772.

Marijuana usersNon-users

Marijuana Use and IQThe Dunedin Study (New Zealand)

(N=1,037)

1 2 3 4 5

Assessment ages

13 yrs(Pre-initiation) 18 yrs 21 yrs 32 yrs 38 yrs

Source: Meier et al. PNAS, 2012

Dose-related IQ change

Never used

Regular mj use - 2 yrs

Regular mj use - 1 yr

Used infrequently

Regular mj use - 3+ yrs

Marijuana and Psychosis

The Health Effects of Cannabis and Cannabinoids: Current State of Evidence and Recommendations for Research (2017)

Citation: National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research. Washington, DC: The National Academies Press.

Strong evidence for link between marijuana and psychotic disorders

Marijuana is very different today from what it was 20 years

ago, bringing greater risks…

Avg. % THC Content among Confiscated Cannabis Products in U.S. (1995-2014)

*Source: ElSohly et al., Biological Psychiatry, 2016.

0%

2%

4%

6%

8%

10%

12%

14%

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

*38,681 samples

~4%

~12%

Avg. % THC Content among Confiscated Cannabis Products in U.S. (1995-2014)

*Source: ElSohly et al., Biological Psychiatry, 2016.

0%

2%

4%

6%

8%

10%

12%

14%

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

*38,681 samples

~4%

~12%% Cannabidiol (CBD)(antipsychotic)

Forms of Butane Hash Oil

“Shatter”“Dabs”

“Vaping””

“Budder”

“Earwax”

– contain up to 90% THC!

As THC increases, we see more negative effects:• Paranoia • Anxiety and panic• Hallucinations• Erratic mood swings• Aggressive behavior• Hyperemesis syndrome

Marijuana and Cardiovascular

Risks

Acute and Long-term Cardiovascular Risks of Marijuana Use

• Tachycardia (rapid heartbeat)• Increased blood pressure• Atrial fibrillation (arrythmic heartrate)• Myocardial infarction (heart attack)• Increased risk of death after heart attack• Cardiac arrest• Stroke, transient ischemic attack

Soruce: Thomas G, et al., Am J Cardiol 2014:113:187-190

96.2 94.6 97.4102.4

123.1 122.7

149.0146.2

40

60

80

100

120

140

160

2004 2005 2006 2007 2008 2009 2010 2011

Emergency Department Visits Caused by Marijuana Use (Rate per

100,000 people)

Source: National Drug Abuse Warning Network, 2011

The Colorado Experience

https://www.nytimes.com/2019/03/25/well/eat/marijuana-edibles-may-pose-special-risks.html

Time Course of Marijuana Effects by Ingestion Method

Source: Grotenherman, F. Clin Pharmacokinet 2003; 42 (4): 327-360

First death in Colorado after legalized recreational marijuana

Levy Thamba-Pongi, 19-year-old college

student on Spring Break

Jumped out of 4th floor window after eating

whole pot cookie

A Lethal Combination

Marijuana and PsychosisGenetic Risk: AKT1 Gene

Source: Di Forti et al. Biol Psychiatry. 2012.

If people have the AKT1 C/C variant, daily use increases

their odds of developing psychosis 7 times higher

compared to no use

Other things teens say:

“My parents smoked pot when they were growing up, so why

shouldn’t I?”

Useful Responses

• Because today’s pot is much more potent and dangerous

• We know SO much more today about the harms for teens (other examples: harms of tobacco, trans fats, concussions, etc.)

Potential Epigenetic Effects on Future Generations

Source: Murphy SK, et al., Epigenetics, 13:12, 1208-1221, 2018.

103

Take-Home Points based on latest science

1. Adolescence/emerging adulthood is a time of critical brain development

2. Repeated exposure to marijuana suggests there may be lasting effects on brain structure and function (e.g., memory and IQ),

104

3. Today’s marijuana is a lot more potent, so it’s more addictive and carries more risks to physical and mental health

4. Risk of psychotic disorders greater, especially for those starting use in adolescence and for those with family risk

Take-Home Points cont’d.

Advise DELAYING use

“To help you reach your goals and dreams, give yourself the best chance possible by delayingalcohol and drug use until your brain is fully developed”

Useful Message

Useful Review

Blohm, E., Sell, P., & Neavyn, M. (2019). Current Opinion in Pediatrics, 31(2), 256–261.

Marijuana and the Teen Brain: Recent Research Reviews

• Lubman DI et al., Cannabis and adolescent brain development. Pharmacology & Therapeutics. 2015;148:1-16

• Lisdahl KM et al. Considering Cannabis: The Effects of Regular Cannabis Use on Neurocognition in Adolescents and Young Adults. Curr Addict Rep. 2014 Jun 1;1(2):144-156.

• Volkow ND et al., Effects of Cannabis Use on Human Behavior, Including Cognition, Motivation, and Psychosis: A Review. JAMA Psychiatry. 2016;73(3):292-7

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Questions:Sion.harris@childrens.harvard.edu

www.crafft.orgwww.teen-safe.org