Bertha K Madras, PhD Professor, Psychobiology Department of Psychiatry McLean Hospital

Bertha K Madras, PhD Professor, Psychobiology Department of Psychiatry McLean Hospital

I disclose the following relationships with entities that may be relevant to the content I am presenting: Rivermend Health, Scientific Advisory Board National Football League, Advisory Board (-2015) World Health Organization U.S. Department of Justice

Marijuana Opioids New Psychoactive Drugs Hallucinogens As Medicines All Drugs Legal

Scientific evidence INCREASING MARIJUANA IS UNSAFE! Pro-Marijuana MORE VOCAL SAFE, HARMLESS, BENEFICIAL

Is it only a plant? How does it work? Does marijuana kill? Is marijuana safe? Safe for Children? Is it addictive? Safer than alcohol? A marijuana-opioid nexus? Possible results if legal? Marijuana is a medicine? What can you do?

How Does Marijuana Act?

D 9 -TetraHydroCannabinol (THC ) highest OH O ~104 Phytocannabinoids, 200-300 terpenoids Synthetic cannabinoids: 1,000 s made by chemists Endocannabinoids: Made by brain, body

Endocannabinoids in Brain Organs and Blood Cells CB1 receptors BRAIN Heart Pancreas Muscle Testis, ovaries Uterus Prostate Vascular tissue Immune cells CB2 receptors CB2 receptors BLOOD CELLS IMMUNE CELLS Brain Heart Adrenal Intestinal tract Pancreas Bone Smooth muscle Reproductive organs

100 billion nerve cells Cannabinoids implicated in brain development promote birth of new brain cells tell cells what type to become guide them to their targets help them form connections 1 trillion supporting cells

Is Marijuana Safe? More pronounced in early initiators or during adolescence COGNITIVE DEGRADATION Acute Long term ADDICTION MOTIVATION PSYCHOSIS MEDICAL PROBLEMS E.R. use Psychiatry Child Neglect Traffic fatalities Exacerbation of alcohol, tobacco effects Workplace

Impairs learning, working memory Reduces attention span and concentration Reduces ability to plan Reduces organizational skills Reduces problem solving Reduces decision making Reduces perception of facts Reduces emotional control Reduces behavioral control Impairs motor coordination Increases impulsivity Increases hunger

No THC THC Fewer cannabinoid targets (receptors) Targets move inside cells Function reduced Dudok et al, Cell-specific STORM super-resolution imaging reveals nanoscale organization of cannabinoid signaling. Nature Neuroscience 18: (1) 75-86. 2015; Hirvonen et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Molecular Psychiatry (2012) 17, 642 649;

Impairs learning memory: Verbal IQ, Memory Word associations Perseveration Impairs motor function: Balance, coordination Sports, driving, working Impairs decision making Risky sexual behavior Driving impaired Executive function Psychosis Crean RD, Crane NA, Mason BJ. An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions. Journal of Addiction Medicine 2011;5:1-8;Pope HG Jr, et al. Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug Alcohol Depend. 2003 Apr 1;69(3):303-10.; (Pope and Yurgelun-Todd (1996) Solowij et al. 2002, Fletcher et al., 1996,McHale and Hunt,2008; Porter, & Frampton, 2007 et al., 2002; Harvey et al, 2007; Solowij & Pesa, 2010 ; Novaes et al. 2008; Battisti et al., 2010

IQ drop most: if use before age 18, addicted at 38 IQ drop associated: with length of time addicted IQ still reduced: if use before 18 and then quit IQ reduced: if did not quit use at age 38 est. 13 yr 18 yr 21 yr 32 yr 38 yr Meier et al, Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc. Natl. Acad. Sci USA, 2012 Oct 2;109(40):E2657-64.

Marijuana Addiction Marijuana Pain Killers Cocaine Heroin Stimulants Tranquilizers Hallucinogens Inhalants Sedatives Addiction risk 4.3 million people Ratio % All 1 in 10 10%-30.5% Mid-teen 1 in 6 17% Daily use 1 in 2-3 30-50% 0 1000 2000 3000 4000 Thousands SAMHSA, Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-48, HHS Publication No. (SMA) 14-4863. Rockville, MD: SAMHSA, 2014. Hasin et al., Prevalence of Marijuana UseDisorders in the United States Between 2001-2002 and 2012-2013. JAMA Psychiatry. 2015 Dec 1;72(12):1235-42.

Percent with Outcome 60 50 40 30 On Welfare Unemployed Bachelor's Degree 20 10 0 Never 001-099 100-199 200-299 300-399 400+ Number of times used marijuana as a teen Source: Fergusson and Boden, Addiction, 103, pp. 969-976, 2008.

A d ju s te d o d d s r a tio 2 0 1 5 Addiction C.U.D Other O e r illicit illiic it drugs d g use u s e Suicide attempt S u ic id e a tte m p t 1.2 1 Completed high school or college degree 1 0 0.8 5 0.6 0.4 0 N e v e r L e s s th a n m o n th ly M o n th ly o r m o r e W e e k ly o r m o r e D a ily 0.2 0 F r e q u e n c y o f U s e Silins et al, Lancet Psychiatry 1: 286 93, 2014; n= 2537-3765; 13-30 years

8 7 6 5 Before 15 After 15 Risk 4 3 2 1 0 Schizophrenia Psychosis Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002 Nov 23;325(7374):1212-3. *PDI: Psychiatric Diagnostic Interview McGrath J, et al. Arch Gen Psychiatry. 2010 May;67(5):440-7van Os et al, 2002; Zammit et al., 2002; Henquet et al., 2005; Stefanis et al., 2004; Rubino and Parolaro, 2008; Konings et al., 2008; Andreasson et al., 1987; Moore et al, 2007

Hash: THC 4%+ Skunk: THC: 16% Di Forti et al Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. The Lancet Psychiatry 2:233-238, 2015

Age When Psychosis Emerged Di Forti et al. Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophr Bull. 2014 Nov;40(6):1509-17; Kelley ME, et al, Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders. Schizophr Res. 2016 Jan 16. [Epub ahead of print] 32 31 30 29 28 27 26 25 Age of Onset of Psychosis Depends on frequency of use and potency of marijuana THC: 16% THC: 4%+

Is Marijuana Safe for Children? Addiction; addiction to other drugs Marijuana poisoning Brain changes IQ loss; cognitive impairment Poor grades at school (drop-out) Psychosis

Is Marijuana Safer than Alcohol?

ISSUE MARIJUANA ALCOHOL Parent, teacher, supervisor relationships Education Worse Palamar et al Am J Drug Alcohol Abuse, 2014; 40(6): 438 446 Better Worse (direct link) Better (No direct link) Energy Worse Better Interest in activities Worse Better Work, school Worse Better Adverse psychological Worse Better Burden of disease Better Worse Adverse psychosocial Better Worse

N=2,179-3,678; longitudinal study between 13-25 years Marijuana weekly Alcohol weekly 2 1.8 1.6 1.4 1.2 1 0.8 Did not complete high school Did not enroll university Did not obtain degree E. Silins et al. Drug and Alcohol Dependence 156 (2015) 90 96; previous research (Esch et al., 2014; Macleod et al., 2004; Maggs et al., 2015; Silins et al., Lancet Psychiatry, 2014; Townsend et al., 2007).

MARIJUANA IMMEDIATE EFFECTS: up to 6 hours SUB-ACUTE EFFECTS: can last 6-20 days LONG-TERM EFFECTS: more than 20 days Even if not using now, learning ability may be compromised for many days THC dissolves in fat and leaks out slowly ALCOHOL One drink clears the body within ~3 hours OH O Sources: Hall W & Degenhard L (2009). Adverse health effects of non medical cannabis use. Lancet, 374:1383 1391. Jager and Ramsey, 2008

Marijuana Use During Adolescence Marijuana Use During Pregnancy Marijuana Use Before Conception

Legalization? Traffic deaths Driving under the influence Marijuana-related emergency room visits Marijuana-related hospitalizations Marijuana-only related poison exposures THC production lab explosions 32% increase 45% increase; and fatalities 29% increase 38% increase (46% in 3 years) 72% increase (800% increase in 5 years, younger than 12) 167% increase The Legalization of Marijuana in Colorado: The Impact Vol. 3/September 2015 Executive Summary P a g e 2; AA. Monte; RD. Zane. K J. Heard, The Implications of Marijuana Legalization in Colorado JAMA. 2015;313(3):241-242.

12 10 12-17 year olds,(past month) 2013/2014 Age 12-17: National vs CO use rates Nationally 8 % Use 6 4 2 5.99 National Colorado Age 18-25: National 8.52 vs CO use rates 11.31 0 Non-MMJ MMJ MMJ/Legal Source: NSDUH, 2014, Issued 2015

Impact of non-medical marijuana use on health Improve, no change or worsen? Evidence strength Psychosis, psychotic symptoms Worse Very strong Brain function Worse Strong Psychosocial function Worse Strong Addiction Worse Very Strong Addiction other drugs Worse Strong Schizophrenia Worse [Fair] Anxiety Worse Fair Depression Worse Fair Health Impact Assessment: Marijuana Regulation in Vermont; Vermont Dept of Health 2016 HealthVermont.gov; BK Madras

Impact of non-medical marijuana use on health Improve, no change or worsen? Evidence strength Motor vehicle accidents Worse Very strong Child poisoning Worse Some evidence Bronchitis Worse Strong Pregnancy Worse Strong Stroke, heart attack Worse Fair Cancer? Limited Health Impact Assessment: Marijuana Regulation in Vermont; Vermont Dept of Health 2016 HealthVermont.gov: BK Madras

Health Impact Assessment: Marijuana Regulation in Vermont; Vermont Dept of Health 2016 HealthVermont.gov; BK Madras Impact of non-medical marijuana use on health Does condition improve, no change or worsen? Evidence strength Academic performance Worse Strong Welfare Worse Strong Life Satisfaction Worse Good Employment economic Worse Good Workplace Worse Limited

SCHEDULE 1 Marijuana has high potential for abuse Marijuana has no currently accepted medical use in treatment U. S. Lack of accepted safety for use of marijuana under medical supervision

World Health Organization Report http://www.who.int/medicines/access/controlledsubstances/6_2_cannabis_update.pdf

Opioid Use fell dramatically from 1907/08 to 2006 Rx hydrocodone fell dramatically from 2014 4 3.5 3 2.5 2 1.5 1 1907/08 2006 % USERS 0.5 0 Asia Source: UN Office on Drugs and Crime, 2008 Report World Jones et al.,effect of US DEA Rescheduling of Hydrocodone Combination Analgesic Products on Opioid Analgesic Prescribing JAMA Intern Med. 2016 Jan 25 [Epub ahead of print]

FULL ACCESS SAFE Pleasure Victimless Civil right Only a plant Beneficial Alcohol worse No addiction Patients suffering FDA cumbersome Difficult to patent Cheap alternative Easy access SCIENTIFIC EVIDENCE WILL PREVAIL RESTRICT UNSAFE No accountability Circumvents FDA Public health issue Impaired function Addiction -ve health -ve Psychiatric -ve Behaviors -ve Brain effects Adolescents at risk Parents at risk Public Safety