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Sion Kim Harris, PhDAssociate Professor of PediatricsHarvard Medical School
The State of the Science:
Teen Brain Development and
the Impact of Marijuana Use
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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
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Images about marijuana that young people see today…
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The Next ‘Big Tobacco’
4Slide courtesy of Kevin Sabet, PhD; www.learnaboutsam.com
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Social Media Marketing
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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!
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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!
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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
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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
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
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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
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“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
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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
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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
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So what?
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Common Marijuana Myths
• It’s not addictive• It’s harmless and natural
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Let’s look at the science…
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Is marijuana addictive?
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Studying the Addictiveness of Drugs
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The Reward Pathway
Ventral-TegmentalAreaSource: NIDA
Striatum
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marijuana
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Marijuana (THC) is no exception…
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Marijuana is especially addictive for teens …
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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
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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
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Is marijuana harmless?
Not for the teen brain!
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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.
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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
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Brain Development
Genes Exposures
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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
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Neurons
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35
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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
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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
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39
Myelinated axons = White Matter TractsThe Brain’s Information Superhighway
Source: Dr. Gordon J. Harris, MGH, 2008.
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• 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…
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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
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Source: Neuropsychopharmacology Reviews advance online publication 22 October 2014. doi:10.1038/npp.2014.236
Pruning and myelination happeninto the mid-20s…
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It’s speeding up the commute time…
43
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The Gas Pedal
The Brakes
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To go from this…
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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.
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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
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Adolescence is a great time for getting good at something!
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The teen brain is more vulnerable to being harmed by alcohol and drugs than the adult brain
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The Teen Brain on Marijuana
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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
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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
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53
THC Binding Sites
Source: NIDA
FrontBack
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Cannabinoid receptors in our brains?
Why?
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Fooling the brain…
55
Source: NIDA
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The Brain’s “Endocannabinoid”
System
“Endo” = “within” or “inside”
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Basic Neuron Structure
Axon
Synapse
Electrical signal
Cell body
Dendrites
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Source: Kraft, U. Scientific American Mind, 2006, p. 62-65
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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)
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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
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Anandamide THC
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Repeated THC exposure causes brain to scale back CB receptors, causing “cannabinoid deficiency”
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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.
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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.
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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.
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Neuropsychopharmacology Reviews advance online publication 22 October 2014. doi:10.1038/npp.2014.236
Pruning and myelination happen throughout adolescence…
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If the adolescent brain is regularly exposed to THC, it could alter development of the connectome
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Longitudinal brain imaging studies provide confirmation:
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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
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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
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What else is affected by THC?
Source: NIDA
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The Hippocampus (the key to learning)
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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.
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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
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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
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Dose-related IQ change
Never used
Regular mj use - 2 yrs
Regular mj use - 1 yr
Used infrequently
Regular mj use - 3+ yrs
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Marijuana and Psychosis
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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.
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Strong evidence for link between marijuana and psychotic disorders
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Marijuana is very different today from what it was 20 years
ago, bringing greater risks…
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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%
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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)
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Forms of Butane Hash Oil
“Shatter”“Dabs”
“Vaping””
“Budder”
“Earwax”
– contain up to 90% THC!
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As THC increases, we see more negative effects:• Paranoia • Anxiety and panic• Hallucinations• Erratic mood swings• Aggressive behavior• Hyperemesis syndrome
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Marijuana and Cardiovascular
Risks
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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
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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
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The Colorado Experience
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https://www.nytimes.com/2019/03/25/well/eat/marijuana-edibles-may-pose-special-risks.html
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Time Course of Marijuana Effects by Ingestion Method
Source: Grotenherman, F. Clin Pharmacokinet 2003; 42 (4): 327-360
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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
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A Lethal Combination
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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
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Other things teens say:
“My parents smoked pot when they were growing up, so why
shouldn’t I?”
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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.)
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Potential Epigenetic Effects on Future Generations
Source: Murphy SK, et al., Epigenetics, 13:12, 1208-1221, 2018.
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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),
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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.
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Advise DELAYING use
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“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
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Useful Review
Blohm, E., Sell, P., & Neavyn, M. (2019). Current Opinion in Pediatrics, 31(2), 256–261.
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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
108