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October 4, 2018
The State of the Science: Teen Brain Development and the Impact of Marijuana Use
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Dr. Sion Kim Harris
Today’s Presenter
Sion Kim Harris, PhD Associate Professor of Pediatrics Harvard Medical School
The State of the Science:
Teen Brain Development and
the Impact of Marijuana Use
State Marijuana Laws, 2018
• 46 states legalized in some form
• 31 legalized medical marijuana or recreational
• 15 low THC/high CBD only
• Still Schedule 1 drug at federal level
Source: http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx
Marketing Marijuana
Images about marijuana that young people see today…
Perceived Risk of Harm and Marijuana Use U.S. 12th graders: 1975-2017
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%Great Risk of Harm Past Month Use
29%
23%
Source: National Monitoring the Future Survey, 2017
Perceived risk is at historic
low!
50%
33% 31%
11% 10% 7%
0
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Alcohol
Tobacco
Percent of U.S. 12th Graders Using
Substance in Past Month, 2000-2017
Source: National Monitoring the Future Survey, 2017
Illicit drugs other than marijuana
50%
33% 31%
11%
21% 23%
10% 7%
17%
0
10
20
30
40
50
60
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80
90200
0
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Alcohol
Tobacco
Percent of U.S. 12th Graders Using
Substance in Past Month, 2000-2017
Marijuana
Source: National Monitoring the Future Survey, 2017
Illicit drugs other than marijuana
Colorado allows
commercial marijuana
industry
Vaping
30%
16%
20%
5%
6% 6%
3% 1% 0
5
10
15
20
25
30
35200
0
200
1
200
2
200
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201
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201
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201
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201
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201
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201
8
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, 2000-2017
Daily marijuana use
Source: National Monitoring the Future Survey, 2017
Daily alcohol use
Percent Using Marijuana in Past Month, Ages 12-17, by State (2014-2015)
0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 10% 11% 12% 13% 14% 15%
UTALIALA
MSNEOKVATNNCOHWV
HIMNNDKSKYSDAKARIDIL
MOSC
WYFLNJ
GATXPADENVNYWIAZINMICACT
NMMTMAMDWANHORME
RIVTCO
Source: National Survey on Drug Use and Health, 2014-2015
States with Legalized Marijuana in 2014-2015 (Medical or
Recreational)
Top 3 states: CO 11.1%* VT 10.9% RI 10.2%
*Note: CO was ranked #14 in 2005-2006, #4 in 2011-2012, and became #1 starting in 2013-2014
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-Tegmental
Area Source: 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 Period Definition:
“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 Experiences
Key Brain Development Processes 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
34
Neurons
Basic Neuron Structure
Axon
Synapse
Electrical signal
Cell body
Dendrites
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
The Brain’s Information Superhighway:
Myelinated axons = White Matter Tracts
Source: Dr. Gordon J. Harris, MGH, 2008.
Result when pruning and myelination are complete: faster, but fewer, connections in the brain
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
41 Image source: Dr. Van J. Wedeen, MGH, 2011 Source: 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 happen
into the mid-20s…
It’s speeding up the commute…
43
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
52
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
54
THC Binding Sites
Source: NIDA
Front Back
Cannabinoid receptors in our brains?
Why?
Fooling the brain…
56
Source: NIDA
The Brain’s “Endocannabinoid”
System
“Endo” = “within” or “inside”
Basic Neuron Structure
Axon
Synapse
Electrical signal
Cell body
Dendrites
59
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
62
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.
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
White matter differences in brains of those starting regular use in adolescence vs. not
Source: Arnone D, Barrick TR, Chengappa S et al. Corpus callosum damage in heavy marijuana use: Preliminary
evidence from diffusion tensor tractography and tract-based spatial statistics. NeuroImage, 2008; 41:1067-1074
Non-user Daily user
Recent longitudinal brain imaging studies provide confirmation:
70
What else is affected by THC?
Source: NIDA
71
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 during adolescence, neuron connections involved in memory are gradually 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 users Non-users
National Academies of Sciences
Report on Marijuana, 2017
Available at: https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state
Comprehensive Review of Scientific Research
• 16-member Expert Panel from all areas of medicine, public health, social sciences
• Reviewed >10,700 scientific papers published between 1999-2016
• Generated nearly 100 conclusions about cannabis/cannabinoids’ effects and risks
• Rated strength of scientific evidence for each as substantial, moderate, limited, none
National Academy of Sciences report conclusion:
Moderate evidence for harmful effects of frequent marijuana
use on memory and IQ
Volkow ND, Swanson JM, Evins AE, et al.: Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry 2016; 73:292–297
Marijuana Use and IQ The 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
IQ at Age 13 by Mj Use during Follow-up
99.8 99.7
13 yrs old
Ne
ve
r u
sed
mari
juan
a
Reg
ula
r u
se f
or
3+
yrs
Change in IQ from 13 to 38 yrs old
99.8 99.7 100.6
93.6
13 yrs old 38 yrs oldN
ev
er
used
mari
juan
a
Nev
er
used
mari
juan
a
Reg
ula
r u
se f
or
3+
yrs
Reg
ula
r u
se f
or
3+
yrs
Source: Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, McDonald K, Ward A, Poulton R, Moffitt TE. Persistent
cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct
2;109(40):E2657-64. Available at: http://www.pnas.org/content/109/40/E2657.long
Dose-related IQ change
Never used
Regular mj use - 2 yrs
Regular mj use - 1 yr
Used infrequently
Regular mj use - 3+ yrs
Adult Social Outcomes
Fergusson, D. M., & Boden, J. M. (2008). Cannabis use and later life outcomes. Addiction, 103(6), 969–976.
Longitudinal New Zealand study of 1003 youth from birth to age 25
Marijuana-related amotivational syndrome is real…
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.
Marijuana and Psychosis
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%
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
*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%
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
*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
The Danger of THC Edibles
Time Course of Marijuana Effects by Ingestion Method
Source: Grotenherman, F. Clin Pharmacokinet 2003; 42 (4): 327-360
96.2 94.6 97.4 102.4
123.1 122.7
149.0 146.2
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
2004-2011 Change in Rate of ED Visits Caused by Marijuana Only (no
other substance involved), by Age Group
79
164
123
92 75
43
17 1
159
226
172
114 95
55
29
3 0
50
100
150
200
250
12-17 18-20 21-24 25-29 30-34 35-44 45-64 65+
Emergency Department Visits Caused by Marijuana Only (Rate per 100,000 people)
2004
2011
Source: Zhu H, Wu LT. Trends and Correlates of Cannabis-involved Emergency Department
Visits: 2004 to 2011. J Addict Med. 2016 Nov/Dec;10(6):429-436.
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 Psychosis
Genetic 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.)
100
Take-Home Points based on latest science
1. Adolescence/emerging adulthood is a time of critical brain development
2. Repeated exposure to marijuana has been shown to have lasting effects on cognitive function (e.g., memory and IQ), brain structure and function
101
3. Today’s marijuana is a lot more potent, so it’s more addictive and carries more risks to physical and mental health
4. Marijuana increases the risk for car crashes
5. Risk of psychotic disorders greater for those starting use in adolescence, especially for those with family risk
Take-Home Points cont’d.
Advise DELAYING use until 21+
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
105
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