Cannabinoid Biology and

Marijuana Policy Sharon Levy, MD, MPH

Assistant Professor of Pediatrics Boston Children’s Hospital

Harvard Medical School

Director, Adolescent Substance Abuse Program Division of Developmental Behavioral Pediatrics

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MMaarriijjuuaannaa PPoolliicy

Brain Weight by Age

Source: Dekaban, A.S. and Sadowsky, D. Annals of Neurology, 4:345-356, 1978

New

born

FemalesMales

Age

Adult size

Source: Gogtay et al. PNAS. 2004:101(21):8174-8179.

motivationemotion

CerebellumAmygdala

Nucleus Accumbens

Prefrontal cortex

Planning, Organizing, Impulse control Physical

coordination,Sensory processing

Slide adapted from Ken Winters, PhD.

Toddler milestones:

balance, walking,

coordinationPreschool milestones:

emotional regulationSchool age

milestones:

achievement

Adolescent

milestones: impulse

control

Casey BJ, et al., Development Reviews. 2008; 28: 62-77.

Nucleus Accumbens

Prefrontal

Cortex

Adult Adolescent

Fu

nct

ion

al

De

velo

pm

en

t

Age

Source: Galvan A, Hare AT, Parra, CE, Penn J, Voss H, Glover G, Casey BJ, Earlier Development of the Accumbens Relative to Orbitofrontal

Cortex Might Underlie Risk-Taking Behavior in Adolescents. Journal of Neuroscience, 2006,26(25):6885–6892

Children ages 7-11 Teens ages 13-17 Adults ages 23-29

marijuana

Source: NIDA

“Taken together, we found no significant

substitution effect between alcohol and

marijuana. Rather, an uptick in availability

seems to increase the prevalence of

concurrent use of alcohol and marijuana.”

-Guohua Li, MD, PhD

Mailman School professor of Epidemiology

Article accessed at: http://www.mailman.columbia.edu/news/half-young-victims-fatal-crashes-nine-us-states-used-either-alcohol-or-marijuana

In reference to: Keyes KM, Brady JE, Li G. Effects of minimum legal drinking age on alcohol and marijuana use: evidence from toxicological

testing data for fatally injured drivers aged 16 to 25 years. Inj Epidemiol. 2015;2(1):1.

Delta-9-

tetrahydrocannabinol Anandamide

Cannabinoid Binding Sites

Source: NIDA

FrontBack

In 1988 researchers Allyn Howlett and William Devane

discovered cannabinoid receptors in the brain and called them

cannabinoid 1 receptors (CB1) (Devane et al., 1988). In 1992

researchers discovered an endogenous cannabinoid and called

it anandamide (Devane et al., 1992).

17

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

The neuron’s “volume control”: dials

down neuron activity when too strong

Source: Kraft, U. Scientific

Receptor binding in brain tissue

Compound Potency relative to THC

(-)-Delta9-THC 1

Anandamide .47*

*The affinity of anandamide for cannabinoid receptors ranges from about one-fourth to

one-half that of THC . The differences depend on the cells or tissue that are tested and on

the experimental conditions, such as the binding assay used.

Joy J, Watson SJ, Benson JJ, eds. Cannabinoids and animal physiology. In: Marijuana and Medicine: Assessing the Science Base. Washington DC:

Division of Neuroscience and Behavioral Health - Institute of Medicine. National Academies Press; 1999:288

Source: Iversen L. How cannabis works in the brain. In Marijuana and Madness. Ed. Castle & Murray, 2004.

Oxford University Press.

Source: Meier et al. Proceedings of the National Academy of Sciences. 2012. Available at:

www.pnas.org/cgi/doi/10.1073/pnas.1206820109

The Dunedin Study

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

The Dunedin Study

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

Never used

Mj dependent 2 yrs

Mj dependent 1 yr

Used, never diagnosed

Mj dependent 3+ yrs

Average IQ change:

•“Never used”

• 99.8 to 100.6

•“Mj dependent 3+ yrs”

• 99.7 to 93.9

Source: Meier et al. PNAS, 2012

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

Healthy non user Daily MJ user Schizophrenic patient

A meta-analysis of 6 studies found an increased risk of psychotic

outcome among those who used cannabis most frequently, compared

with non-users. (Adjusted odds ratio: 2.09, 95% CI: 1.54-2.84) Moore THM, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic

review. Lancet. 2007;370(9584):319–28. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17662880.

Marijuana Use and Psychotic Disorders

* Adjustments for: prior personality disorders at conscription, IQ, disturbed behavior in childhood, social adjustment, risky use of alcohol, smoking, early adulthood socioeconomic position, use of other drugs, brought up in a city. The category “Ever used cannabis” includes all individuals who reported cannabis use, including those who reported “>50 times”.

Griffith-Lendering, Addiction, 108(4), 733-740.

Manrique-GarciaBMC Psychiatry, 12, 112.

# Exposure # Cases HR Crude HR adjusted*

Never used

cannabis 39, 978 47 1 1

Ever used

cannabis 5,109 12 2.1 (1.1-3.8) 0.8 (.2-2.9)

>50 times 855 7 7.5 (3.4- 16.7) 7.4 (1.0 – 54.3)

Association between cannabis use and

schizoaffective disorder

Kuepper R, van Os J, Lieb R, Wittchen H-U, Höfler M, Henquet C. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-

up cohort study. BMJ. 2011;342(mar01_1):d738. Available at: http://www.bmj.com/content/342/bmj.d738. Accessed May 8, 2015.

Conclusion: Cannabis use is a risk factor for the

development of incident psychotic symptoms. Continued

cannabis use might increase the risk for psychotic disorder

by impacting on the persistence of symptoms.

The evidence is consistent with the view that cannabis

increases risk of psychotic outcomes independently of

confounding and transient intoxication effects ....

Marijuana Policy

“Medical Marijuana” v. Cannabinoids

IOM poses

“compassionate” use

to relieve suffering in

terminally ill patients.

CA passes “medical

marijuana ballot

initiative

1990

1996

History of “Medical Marijuana”

CNN documentary

supporting “medical

marijuana”

2013

20 states and DC have

“medical marijuana

laws”

2014

Limited evidence of therapeutic efficacy of

medical marijuana

Condition Level of Evidence

Chemotherapy induced Nausea and

Vomiting in Adults Modest evidence1

Chronic Pain Insufficient evidence2

HIV/Aids and Anorexia associated with Aids Insufficient evidence3

Neurological Problems Insufficient evidence4

1. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33(2):195–209..

2. Martín-Sánchez E, Furukawa TA, Taylor J, Martin JLR. Systematic review and meta-analysis of cannabis treatment for chronic pain.

3. Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane database Syst. Rev..

4. Koppel BS, Brust JCM, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development

Subcommittee of the American Academy of Neurology. Neurology. 2014;82(17):1556–63.

*Not one single study has ever included children

Marijuana is NOT a medication

Effects of State Medical Marijuana

Laws on Health Outcomes Relevant

for Youth

From Dr. Rosalie Pacula. “Effect of Medical Marijuana on the Health of the Young” at

Pediatric Academic Societies on April 28th, 2015

Any MML Law Source

Prevalence of youth MJ use NS Pacula,

2015

Effects of State Laws on Health

Outcomes Relevant for Youth

From Dr. Rosalie Pacula. “Effect of Medical Marijuana on the Health of the Young” at

Pediatric Academic Societies on April 28th, 2015

Any MML

Law

Legal

Dispensaries Source

Prevalence of youth

MJ use NS NS

Pacula,

2015

Youth Treatment

Admissions for MJ

disorders

Decreased Increased Pacula,

2015

Effects of State Laws on Health

Outcomes Relevant for Youth

From Dr. Rosalie Pacula. “Effect of Medical Marijuana on the Health of the Young” at

Pediatric Academic Societies on April 28th, 2015

Any MML

Law

Legal

Dispensaries Source

Alcohol Treatment

Admissions Decreased Increased

Pacula, 2013

Heaton, 2015

Youth Alcohol

Involved Fatality Decreased Increased

Pacula, 2013

Sevigny, 2015

Youth Opioid

Treatment

Admissions

NS NS Powell, 2015

The problem with R&D

• mid 19th century: <1% of tobacco

consumed as smoked cigarettes

Kluger, Richard. (1996). Ashes to Ashes. New York: Knopf; Ford, Barry. (1994). Smokescreen. Perth, Australia: Halcyon

• 1880: Flue curing made tobacco inhalable

• Bonsack Machine could produce 70,000 cigs/day

• American Tobacco Co. created monopoly

• 1900: 1 out of 3 tobacco users smoked cigs

• 1947: 45% American adults smoked

• 1950: asbestos filter and ammonia free-base

introduced

• 1957: First Surgeon General Report

Source: Malone DT et al. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Brit J

Pharmacol. 2010;160:511-522

0%

2%

4%

6%

8%

10%

199419951996199719981999200020012002200320042005200620072008

1

9

9

4

2

0

0

8

Year

<4%

9%

Content of THC in marijuana has

increased over time

Effects of State Laws on Health

Outcomes Relevant for Youth

From Dr. Rosalie Pacula. “Effect of Medical Marijuana on the Health of the Young” at

Pediatric Academic Societies on April 28th, 2015

Any MML

Law

Legal

Dispensaries Source

Potency of marijuana

(%THC) NS Increased

Sevigny,

2014

Serving size: 1 cookie

Serving size: 1/4 cookie

• Pure cannabis oils (100%) THC are now available.

• “Because they're so potent, you don't need a large

amount to get high.”

– The Wire, May 15, 2013

• “Reduces exposure to other

toxins.”

Research on high potency THC

• Increases risk of psychosis Br J Psychiatry. 2009 Dec;195(6):488-91

• Decreases age of onset psychosis Schizophr Bull. 2014 Nov;40(6):1509-17.

• Impairs “creative thinking” Psychopharmacology (Berl). 2014 Oct 7.

Exclusive: “Skinnygirl Marijuana”, a Strain of Pot

That Won’t Cause the Munchies!

Skinnygirl cocktails creator:

“She read about how profitable the cannabis

industry is and wants to get in on that.”

-US Magazine online

Sk

“

in

3. The AAP opposes legalization marijuana … and

supports studying the effects of recent laws to

better understand the impact and define best

policies to, reduce adolescent marijuana use.

0500

1,0001,5002,0002,5003,0003,5004,0004,5005,000

Suspensions

Expulsions

http://www.cde.state.co.us/cdereval/suspend-expelcurrent

Drug-related School Suspensions and

Expulsions in Colorado, 2004-2014

Summary

• Marijuana use during adolescence is associated with increased mental health disorders and cognitive decline.

• There is enough evidence to suggest some of these relationships are causal.

• New products are driving up THC exposure for users.

• Surveillance infrastructure may be insufficient as harms are not typically medical.