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Marijuana Update – From

Antepartum to Adolescence

Elizabeth Meade, MD, FAAP

Chief of Pediatrics, Swedish Medical Center

Swedish Pediatrics Symposium

January 26, 2018

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Disclosures

• No financial disclosures

• Brief discussion of off-label use of

cannabinoids

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Objectives

• Review trends in legalization and use

• Review current AAP policy statement

• Discuss recent literature on exposure across the age spectrum

• Update on newer synthetic cannabinoids

• Brief discussion of recent case reports and of medical indications

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The Legal Landscape

• CA – MM 1996• WA – recreationally

legal since 2014• 2017 changes:

• NH decriminalized• WV medical use

• Suspected in 2018:• Vermont• New Jersey• Michigan

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Trends In Use• Most commonly used illicit drug

• National (2014):• 7.5% of those ≥12 years within last month

• 7,000 new users each day

• Increased use in adults, but not adolescents

• Past-year use: 9.4% of 8th graders, 23.9% of 10th graders, 35.6% of 12th graders (6% daily)

• Teen perception of risk of using steadily decreased over last 10 years

• Washington:• Similar <18y usage; but increase in all groups >18y

• 21% of 18-24y report current use

• 73% increase in related poison control calls from 2011-13 to 2014-16 (40% pediatric)

• Colorado: • Same usage but >2x ED/UC visits in <18y

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AAP Policy• Opposes use by children/adolescents

• Opposes use outside of the FDA process• Recognizes option for life-limiting or severely

debilitating conditions and inadequate current therapies

• Advocates for more research & development of cannabinoid pharmaceuticals

• Advocates against legalization, but for decriminalization

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PRENATAL EXPOSURE

“Studies have shown that the babies of cannabis-consuming

mothers are more advanced and less irritable than the babies of

mothers who do not use cannabis… [it] is also extremely…

nutritious… as a food source… In the future (when real research is

allowed) cannabis supplements will be as common for pregnant

women as prenatal vitamins.” – Serra Frank, Founding Director of

www.momsformarijuana.org

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Prenatal Exposure• Most common illicit drug used in pregnancy

• Existing US data:– 2002-2014, self-reported past-month use increased 2.4% 3.9%

– 14.6% of pregnant adolescents

• Kaiser Permanente Northern California 2009-2016:– Pregnant females ≥ 12y (310,085 pts)

– Use increased from 4.2% 7.1%• Highest in 12-24y - ~10% ~20%

– Higher based on toxicology than self-report

– This was after medical use legalized, but before recreational use!

• 79% of pregnant women 2007-2012 reported perceiving little to no harm

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Risks of Prenatal Exposure

• Alters neurotransmitters, decreases synthesis of protein/nucleic acid/lipids

• Smoking – may alter fetal oxygenation and uterine blood flow (>cigarettes)

• Increased tremor/startle in newborns, inattention/impulsivity at age 10, academic underachievement

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2016 meta-analysis• 24 studies; various outcomes (maternal, fetal,

neonatal) up to 6 weeks postpartum– 1.4x risk of anemia

– 1.77x risk of low birth weight

– 2x risk of NICU admission

• Difficult to determine cannabis-only effect given frequent co-use of tobacco/EtOH

• Small studies with unique outcomes

• Often relies on self-report

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Spontaneous Preterm Birth• International study – 2004-2011 (5588 women)

– Excluded high risk of pre-eclampsia, SGA, or preterm birth

• Interviewed at 15 and 20 weeks

• Categories: never, quit prior to pregnancy, quit prior to 15 weeks, still using at 15 weeks, still using at 20 weeks

• 5.6% using marijuana, 26.4% using tobacco

• Over 2x risk of PTB with any MJ use three months prior to/during pregnancy – regardless of cigarette use– Especially true if using past 20 weeks (5x risk)

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THC and Breastfeeding• AAP considers chronic/heavy use to be a contraindication

(accumulates in human milk)

• Infants exposed to marijuana through breastmilk tested + in urine for 2-3 weeks

• Reported effects include:– Increased tremor

– Poor suck

– Decreased feeding time/slow weight gain

– Changes in visual responses

– Delayed motor development

• Other studies have not shown differences, especially among infrequent/light users

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YOUNG CHILDREN

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Not your grandma’s pot…• Potency (% of THC) in 1978 – avg 1.37%

– 1998 – avg 4.43%

– 2009 – avg 8.52%

– 2014 – avg 12%

– CBD declining

• Edibles – Delayed onset

– Potential for accidental ingestion

• Vaping– Concentrates can be up to 90% THC

• Synthetics

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Young Children

• Where legalization does = increased “use”– CO: no reported

toddler ingestion <2009

– 2009-2015: 81 reported, 21% admitted, 15% PICU

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OLDER CHILDREN

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Mental Health• Previous studies:

– 2012 large prospective study NZ – decrease 6-7 IQ points if use started in adolescence

– 2014 case control study Sweden – increased risk of schizophrenia with prior cannabis abuse (even among sibling/twin pairs)

– Onset of use <age 16 poorer attention, executive functioning, memory performance, verbal IQ

– Elevated risk of developing other substance use disorders

– Subclinical psychotic symptoms (even after 1 year abstinence)

– Poor school performance and leaving school early

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Hypomania• 2017 study in UK

– Birth cohort study; 3370 participants

– Cannabis use at age 17 associated with hypomania at age 22-23• Dose-response relationship – any use (OR 1.82) vs 2-3x weekly (OR 2.87)

– Predicted depression (OR 2.48) & psychotic symptoms (OR 3.33)

– Dose-response relationship

– Independent of gender, environmental risk factors, alcohol/other drug use, depression, psychotic symptoms at age 18

• Observational study, self-reporting

• Dopaminergic signaling increases during adolescence – cannabis may compound this, leading to hypomania

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Case

• 18 y/o healthy male found agitated and diaphoretic at a party aggressive in the ED

• T 37.6, HR 131, RR 24, BP 131/89, O2 98%

• Pupils 3-4mm, sluggishly reactive. Mild conjunctival injection. Nonfocal physical exam.

• Utox, EtOH negative. Lytes normal.

• Returned to baseline over several hours

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Synthetic Cannabinoids• K2, Spice, Aroma, Mr. Smiley…

• Plant/herbal materials sprayed with active chemical

• Recently classified as schedule 1 substances

• Similar to marijuana + diaphoresis, agitation, restlessness

• Do not result in + THC screen

• Treat with benzos (+ diphenhydramine if dystonic)

• Reports of association with immunomodulation, carcinogenicity, memory loss, psych disease, dependence

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Synthetic Cannabinoids• Who’s using them?

– 2.9% of HS seniors, currently

– 1.4% of HS seniors ≥3 days in past month

• More likely to use LSD, cocaine, heroin, and/or nonmedical use of opioids (compared to marijuana-only users) – and to engage in other risky behaviors

• Risk factors: depressive symptoms, marijuana use, EtOH use

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Why are teens so at risk?• Period of rapid brain development – well into 20s

• Earlier onset of use = higher rates of addiction– Overall – 9%

– Starting in adolescence – 17%

– Teens who smoke daily – 25-50%

• Episodes of lifetime use correlated with lower cognitive functioning

• Mental health – already tricky time

• Decreased odds of H.S. completion/degree attainment

• Increased risk of use of other substances and suicide attempts

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CASE REPORTS

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Myocarditis and Death• 11 m/o male in CO presented with CNS depression

cardiac arrest unable to resuscitate

• Preceded by 24-48 hours irritability, decreased activity

• Workup significant only for + THC

• Autopsy – severe, diffuse, lymphocytic myocarditis and no infection

• Motel living; parental disclosure of drug possession

• Myocardial complications and cannabis toxicity well-documented in adolescents/adults

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“Cookie death”

• 19 y/o in CO (visiting from WY – exchange student from Republic of Congo)

• No h/o drug use or mental illness

• Died after eating 6x recommended dose of marijuana cookie jumped off 4th story

• 1 cookie was 6 servings

• Inexperienced users, unclear packaging, latency of onset = trouble

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MEDICAL USE

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Washington State

• Medical marijuana

– <18, requires parent and physician

authorization

• Terminal/debilitating conditions

– >18, requires physician authorization (no

parent)

– >21y legal recreationally

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Products Generic

(Brand)

Cannabinoid

Content

Administration

Formulation and

Dosage

FDA Approval Indications Approved

Countries

Dronabinol (Marinol

and Syndros)

Synthetic δ-9-THC Oral capsule or solution Approved in 1985,

Schedule III controlled

substance

CINV (pediatric and

adult), anorexia

associated with

weight loss in AIDS

(adult)

United States,

Australia, Germany,

New Zealand, and

South Africa

5–15 mg/m2 per dose,

up to 6 doses daily

Nabilone (Cesamet) Synthetic δ-9-THC Oral capsule Approved in 1985,

Schedule II controlled

substance

CINV United States,

Canada, Ireland,

Mexico, and United

Kingdom

1 or 2 mg twice a day,

up to 6 mg daily (adult)

Nabiximols (Sativex) Ratio of 2.7 δ-9-

THC to 2.5 CBD,

plant derived

Oromucosal spray Phase III trials Neuropathic pain,

cancer pain, multiple

sclerosis spasticity

Canada, Czech

Republic, United

Kingdom, Denmark,

Germany, Poland,

Spain, and Sweden

1 spray daily, up to 12

sprays daily with at least

15 min between sprays

(adult)

CBD (Epidiolex) CBD, plant derived Oral solution Phase III trials, fast-

track designation

Epilepsy None

2 up to 50 mg/kg per d

(research trials)

Cannabis plant

products (eg,

marijuana and oral

cannabis extracts)

Varying

concentration of

plant-derived THC

to CBD

Includes smoking

(marijuana) and oral

(cannabis extracts)

None, Schedule I

controlled substance

None approved Medically and

recreationally legal in

certain states via

physician certification

Wong SS, Wilens TE. Medical Cannabinoids in Children and Adolescents: A Systematic Review. Pediatrics. 2017;140(5):e20171818.

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Medical Use• Adult patients - use in nausea/vomiting from chemo, reducing pain in

chronic neuropathic pain

• 2017 systematic review peds literature– 2743 citations 22 studies met criteria (795 pts)

• Seizures (11) – strongest evidence in Dravet syndrome; promising data in smaller studies of refractory epilepsy, Sturge-Weber,

• CINV (6) – reduced CINV across multiple trials

• Spasticity (2)

• Tics (1)

• PTSD (1)

• Neuropathic pain (1)

• Adult patients – use in nausea/vomiting from chemo, reducing pain in chronic neuropathic pain

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Our Role• Counteract perception of use as “benign”

• Tobacco literature: teens alter use with detrimental association between use and current health, cost, athletic performance

• Recommend avoidance until mid-20s

• Minimize collateral damage (ingestions, secondhand smoke)

• Know alternatives/synethetics

• Screen adolescents – AAP recommends SBIRT assessment as part of routine care• 2017: <1/3 adolescents reported being asked by MD/RN

• Address use/dependence/addiction

• Provide guidance on medical use

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Now we need…

• More research, especially in

pregnancy/breastfeeding

• Improved packaging/warnings

• Continue to collect case reports/data

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References• Ammerman S, Ryan S, Adelman WP., THE COMMITTEE ON SUBSTANCE ABUSE, THE COMMITTEE ON ADOLESCENCE. The Impact of Marijuana Policies on Youth:

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• Gonzalez R, Swanson JM. Long-term effects of adolescent-onset and persistent use of cannabis. Proc Natl Acad Sci USA.2012;109(40):15970–15971

• Gunn JKL, Roseales CB, Center KE, et al. Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open. 2016;6:e009986.

• Ko JY, Farr SL, Tong VT, Creanga AA, Callaghan WM. Prevalence and patterns of marijuana use among pregnant and nonpregnant women of reproductive age. Am J Obstet Gynecol. 2015;213(2):201.e1-201.e10.

• Leemaqz SY, Dekker GA, McCowan LM, et al. Maternal marijuana use has independent effectson risk for spontaneous preterm birth but not other common late pregnancy complications. Reproductive Toxicology. 2016;62:77-86.

• 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):319–328. Available at:www.ncbi.nlm.nih.gov/pubmed/17662880.

• Nappe TM, Hoyte CO. Pediatric Death Due to Myocarditis After Exposure to Cannabis. Clin Pract Cases Emerg Med. 2017;1(3):166-170.

• Ninnemann AL, Choi HJ, Stuart GL, Temple JT. Longitudinal Predictors of Synthetic Cannabinoid Use in Adolescents. Pediatrics. 2017;139(4):e20163009.

• Palamar JJ, Barratt MJ, Coney L, et al. Synethic Cannabinoid Use Among High School Seniors. Pediatrics. 2017;140(4):e20171330.

• Reiss J, Rhee KE, Kumar M. Changing Physician Approaches to Marijuana Use in a New Era of Legalization. JAMA Pediatr. 2017;171(12):1137-1138.

• Ryan SA, Ammerman SD, COMMITTEE ON SUBSTANCE USE AND PREVENTION. Counseling Parents and Teens About Marijuana Use in the Era of Legalization of Marijuana. Pediatrics Mar 2017, 139 (3) e20164069

• Schepis TS, Adinoff B, Rao U. Neurobiological processes in adolescent addictive disorders. Am J Addict. 2008;17(1):6–23. Available at: www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2274940&tool=pmcentrez&rendertype=abstract.

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• Young-Wolff KC, Tucker L, Alexeeff S, Armstrong MA, Conway A, Weisner C, Goler G. Trends in Self-reported and Biochemically Tested Marijuana Use Among Pregnant Females in California From 2009-2016. JAMA. 2017;318(24):2490–2491.