Chris Bundy, MD, MPH Medical Director Washington Physicians Health Program Clinical Associate Professor of Psychiatry University of Washington School of Medicine

2017 MARRCH Annual Conference October 31, 2017

Disclosure:

No commercial interests or conflicts to report

No conflicts of interest to report

1. Analyze the clinical and public health implications of cannabis legalization and commercialization

2. Summarize the neurobiology and evidence regarding risks and benefits of cannabis use

3. Formulate strategies for counseling patients and advising colleagues about cannabis use and health

484 known biological compounds

At least 84 brain-active cannabinoids

Flowers, seeds, leaves and stems are consumed

Most widely used illicit substance in Western culture

Longest recorded history of human use

Medicinal effects (unrelated to psychoactive properties) recognized in Chinese texts 3000 BC

Psychoactive properties introduced to the America’s through the Arab world in the 19th century

Marihuana Tax Act 1937: fear of recreational use among Mexican immigrants “spreading” to the general population stigmatizing label

Pacher et al. Pharmacol Rev. 2006

Receptors: CB1 (CNS) and CB2 (immune); (Matsuda 1990)

Natural ligand: Anandamide (fatty acid neurotransmitter)

CB1 is the most abundant receptor in the mammalian brain

Master Neurotransmitter: tonic neuromodulation of multiple systems and subsystems

Influences dendritic pruning: critical to adolescent adult brain development

Pacher et al. Pharmacol Rev. 2006

∆9-tetrahydrocannabinol (Gaoni, Mechoulam 1964)

Structural analogue to anandamide, binds to CB1

Primary psychoactive constituent in cannabis

Localization of THC binding sites (CB1 Receptors)

THC binds CB1 receptors in VTA DA release in NA

40% of the plant’s phytochemical extract

Charlotte’s Web (0.3%THC /high CBD hemp product)

Negligible affinity at CB1/CB2 receptors

May be an indirect antagonist

Powerful anti-oxidant, possible anticonvulsant and antipsychotic properties

Significant interest in developing medical uses Nabiximols: 1:1 CBD:THC aerosol for pain 2/2 MS

Epidiolex: CBD oil in clinical trials for refractory epilepsy

Dense concentration of cannabinoid receptors in the amygdala (Katona,Rancz et al.2001)

Responds to THC by quickly downregulating receptors

14 days of daily use reduces receptors by 24% (Romero, Berrendero et al.1998)

CB1 downregulation = less novelty (boredom, amotivational syndrome?), less forgetting painful memories (PTSD), less buffering capacity

Downregulation may contribute to the cannabis withdrawal syndrome on cessation of regular use

Decrimininalization: treats possession of small amounts of cannabis for personal use as a civil, rather than criminal offense

Legalization: creates a legal, regulated market for the sale and distribution

Medicalization: special decriminalization for medical users

Commercialization: product development including advertising, sales promotion, and marketing to encourage and increase product adoption and demand

By 2001 10 states had decriminalized cannabis Alaska

California

Colorado

Nebraska

New York

North Carolina

Maine

Minnesota

Ohio

Oregon

1996: California (Prop 215)

1998: Alaska, Oregon, Washington

1999: Maine

2000: Colorado, Hawaii, Nevada

2004: Montana

2006: Rhode Island

2007: New Mexico, Vermont

2008: Michigan

2010: Arizona, New Jersey

2011: Delaware, Washington, D.C.

2012: Connecticut, Massachusetts

2013: New Hampshire, Illinois

2014: Maryland, Minnesota

29 States including DC Guam, Puerto Rico 2018 Campaigns in MI, MO, SD, OK, UT

FY2015 WA

Sales

$ 259,522,322;

Excise Tax

$64,880,581

FY2016 WA

Sales

$786,449,599

Excise Tax

$185,678,648

Initial excise tax forecast projections (2013)

FY 2015 $36.3 million FY 2016 $80.0 million FY 2017 $119.8 million FY 2018 $160.2 million FY 2019 $193.5 million

Current excise tax forecast projections* (Feb. 2016) n/a FY 2016 $164.0 million FY 2017 $268.7 million FY 2018 $329.5 million FY 2019 $361.8 million

0

20000

40000

60000

80000

100000

120000

Jul-14 Aug-14 Sep-14 Oct-14 Nov-14 Dec-14 Jan-15 Feb-15 Mar-15 Apr-15 May-15 Jun-15

Un

its

Jul-14 Aug-14 Sep-14 Oct-14 Nov-14 Dec-14 Jan-15 Feb-15 Mar-15 Apr-15 May-15 Jun-15

Solid Edibles 0 1520 4099 7661 21938 41249 45226 55516 73056 89153 107093 112825

Liquid Edibles 0 0 22 3165 8114 10733 20417 13470 27656 25607 30191 32762

Extract for Inhalation 1740 13929 5926 11355 15324 24425 31415 41875 58354 75397 97379 114264

Topicals 0 0 0 0 66 245 277 520 924 1730 2936 3963

Marijuana Concentrate and Infused Product Sales

1960

1965

1970

1974

1978

1980

1983

1984

1985

1986

1990

1992

1993

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

THC 0.2 0.2 0.4 0.5 1 1 1.5 3.3 3.3 3.5 3.5 3.1 3.1 4 4.5 5.2 5 4.7 5.4 6.2 7.3 7.2 8.3 8.1 9.1 10 10 9.9 11 11CBD 0.3 0.3 0.4 0.4 0.3 0.3 0.4 0.4 0.4 0.4 0.5 0.5 0.4 0.5 0.5 0.5 0.5 0.5 0.4

0

2

4

6

8

10

12

14

MA

RIJ

UA

NA

PO

TE

NC

Y

CBD: NON-

Psychoactive Ingredient

Average THC and CBD

Mehmedic et al., 2010

THC: Psychoactive

Ingredient

19

Recreational Legalized

Courtesy Of Ben Cort: Smart Approaches to Marijuana

Highest Measured

Highest Strains (Indica/Sativa Hybrids): • Cali Kush Farms Emperor

Cookie Dough - 31.1% • Chem D.O.G. - 32.13%

“Budder” “Shatter”

“Ear Wax” “Green Crack” wax

Hash Oil Capsules

Butane Hash Oil (BHO)

10 mg is a legal dose or “serving size”

Packaging and dosing in retails is regulated

Unintentional ingestion by children 2.82 x calls for children 6 or younger to poison control in states with legal MM 2000-2013*

*The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academy of SEM 2017.

Most commonly used illicit drug in US: 22.2 million current users

Lifetime prevalence 42%

Past year 12%

Current (past mo): Increased 6.2% 8.3% 2002-2014

Johnson et al. Monitoring the Future Survey 1975-2013

http://monitoringthefuture.org/pubs/monographs/mtf-overview2013.pdf

Courtesy Bertha Madras, PhD, Harvard Medical School

www.rmhidta.org

www.rmhidta.org

www.rmhidta.org

Cannabis: Health Effects

CONDITION VOLKOW NEJM 2014 REVIEW RISKS/BENEFITS

WHITING JAMA 2015 79 RCT’s BENEFITS

NATIONAL ACAD SCI 2017 10k ABSTRACTS RISKS/BENEFITS

MJ ADDICTION HIGH YES

ABNL BRAIN DEV MOD

COG IMPAIRMENT CURRENT USERS; LIMITED IN PAST USERS

GATEWAY MOD

SCHIZOPHRENIA MOD LIKELY INCR RISK

DEP/ANXIETY MOD INC RISK

ACHIEVEMENT HIGH LIMITED

MVA/DEATH/OD IN KIDS HIGH INC RISK

CH BRONCHITIS HIGH INC RISK

LUNG CA LOW NO EVIDENCE

PAIN EFFECTIVE MODERATE EFFECTIVE

SPASTICITY EFFECTIVE MODERATE EFFECTIVE

CINV NAUS>VOM LOW LOW

HIV/AIDS ANOREXIA YES BUT NO EFFECT ON MORTALITY

LOW LOW

GLAUCOMA INSUFF EVIDENCE NONE LOW

Devinsky et al. Cannabidiol in patients with treatment resistant epilepsy. Lancet Neurology 2016; 15: 270-78

Multisite trial, n=214

76% (162) completed 12wk safety/tolerability trial

64% (137) completed efficacy trial

79% of safety group had adverse effects (somnolence 25%, dec appetite 19%, diarrhea 19%, fatigue 13%, convulsions 11%)

30% serious adverse effects (1 death – unrelated to CBD, 12% related to drug with half status epilepticus)

3% (5) discontinued due to AE

Median monthly motor szs decreased from 30 to 15.8 at 12 weeks; median change was -36.5%

Open trails needed; high placebo response rate in children

CO: unpurified CBD migrants vs resident responders (47% v 22% had 50% reduction in szs)

Ann Intern Med. 2017;167:319-331. doi:10.7326/M17-0155

Ann Intern Med. 2017;167:332-340. doi:10.7326/M17-0477

Hasin et al. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2015.1858

NESARC 2001 vs 2012 (large epidemiologic survey)

Past year MJ use: 4.1% vs. 9.5%

Past year MJ use disorder: 1.5% vs. 3.0%

• The adolescent brain is especially susceptible to marijuana use.

• When kids use, they have a greater chance of developing addiction.

Wagner, F.A. & Anthony, J.C. , 2002; Giedd. J. N., 2004 Szutorisz et al. Neuropsychopharmacology, 2014

• 1 in 10 adults and 1 in 6 adolescents who try marijuana will become addicted to it.

• Early exposure to cannabis increases risk for later opioid seeking

• Rodents of fathers exposed to THC seek opioids much more than those whose fathers were never exposed

These data are largely based on studies in which THC content was <12%

Adolescent brain development continues until age 25

Children/adolescents at far greater risk for developing addiction

Impact on brain function is greater than in adults Cognition impaired to a greater degree and longer after last use

Poorer educational attainment, greater IQ drops

Impact on brain structure is greater than in adults EC system is central to pruning that occurs in adolescence

Changes in the size and internal structure of multiple areas of the brain, with greater impact when exposure occurs earlier in life

Impact on emotions and reasoning greater than in adults

Impact of Marijuana on Children and Adolescents, CSAM 2009

New Zealand Longitudinal birth cohort N=1265 25 yrs follow-up Fergusson et al. Addiction 2008

Little doubt about association between MJ and psychotic illness (Moore, Zammit et al. 2007; Kuepper, van Os et al. 2011; Large 2011)

Six longitudinal studies in 5 countries: regular MJ use confers twofold risk for later schizophrenia (Zammit, Allebeck et al. 2002)

Cannabis use is also associated with an earlier age at onset of psychotic disorders, particularly schizophrenia (Veen, Selten et al. 2004; Semple, McIntosh et al. 2005)

410 1st episode psychosis vs 370 never-psychotic controls

Andréasson et al Lancet, 1987

0 1 2 10 <50 >50

30

20

10

0

No of times cannabis taken

Ca

ses

of

Sz

pe

r 1,

00

0

4.5

1.6

0

1

2

3

4

5

6

7

8

9

Cannabis users byage 15 years

Cannabis users byage 18 years

Arseneault et al BMJ 2002

Risk of schizophrenia-like psychosis at age 26 years

Od

ds

rati

o

CANNABIS AND SCHIZOPHRENIA Study of Swedish Conscripts (n=45570)

CANNABIS AND SCHIZOPHRENIA-Like Longitudinal prospective Dunedin study (n=1037)

Fact or Fantasy?

Literature is inconsistent regarding long-term, chronic effects, reversibility, etc.

Acute impairment in cognitive function (memory, processing speed, attention) and motor function is not controversial

Studies have had difficulty separating acute from chronic effects

Intoxication and carry-over effects last for hours if not days Pilots impaired 24 hours after smoking one 19 mg joint (Yesavage, AJP 1985)

Abnl EEG, PET, and fMRI findings persist hours and days after MJ use (Ball, Lancet 2009)

WPHP cannabis referrals usually unfit for duty by cog testing

Question: Isn’t brain function important and delicate enough to assume that cannabis, like all other intoxicants, may impair function until proven otherwise?

Courtesy Bertha Madras, PhD, Harvard Medical School

Voluntary

Physicians, Physician Assistants, Advanced Practice Nurses

Requires certifying professionals to enroll in state registry, patients are certified via entry into the registry

Qualifying conditions: cancer, glaucoma, HIV/AIDS, Tourette, ALS, IBS incl Crohn’s, seizures, muscle spasm/MS, terminal illness with life expectancy less than one year, intractable pain

Must have a bona fide medical relationship with patient sufficient to diagnose the qualifying condition, be available for ongoing treatment of the condition, and determine if disability requiring a caregiver is present

Must complete surveys as requested from the OMC

Does not legalize use of plants or edibles (must be oils, capsules, vaporized products)

Eight dispensaries (Minnesota Medical Solutions, LeafLine Labs)

No tax on medical cannabis sales

Can lead to impairment and risks to patient safety

Health habits of professionals predict treatment recommendations and adherence (Frank 2008; Duperly 2009; Frank 2013)

Employers, medical staff bylaws, and malpractice carriers may have prohibitions against use

Cannabis remains federally illegal, schedule I controlled substance

MN law specifically forbids practice under influence of cannabis

Termination for use has been upheld in the courts despite legalization (Colorado Supreme Court, Coats vs. Dish Network, 2015)

Recreational legalization is probably inevitable

How will you maintain your highly regulated medical market in the face of a practical recreational market (botanicals, edibles, etc?).

Protecting tax revenue to meaningfully offset harms through education, early evaluation, and treatment.

What about “safe-limits” for driving or employment?

Who are your most vulnerable populations and how will you protect them?

Cannabis use has well-established serious risks: addiction, psychosis, abnormal adolescent development, cognitive impairment, and motor vehicle accidents.

Medical cannabis is legislated cannabis, not medicine.

Cannabis did not become safer with legalization. It became more dangerous.

Clear heads and science must prevail amidst social and political forces that are motivated only by the desire to liberate recreational use and create markets for profit.

We’ve been down this path with tobacco and opioids. Medicine should not unwittingly collude again.

Chris Bundy, MD, MPH Medical Director Office: 206-583-0127 www.wphp.org