1 Cannabis Workshop: Changing Landscape of Marijuana (Cannabis): What’s Real, What’s Not??????Alan J. Budney, Ph.D. Dartmouth College, Geisel School of Medicine ATTC Conference Workshop Lebanon, NH July 20, 2016

2 Disclosures Funded by National Institute on Drug Abuse - NIH has supported my research and conference attendance for about 25 yrs Copy of Slides, Articles, or Other:

3 - THINK HARD ABOUT THESE ISSUES -Learning Objectives 1. Describe and discuss the potential impact of changes in cannabis laws and regulations 2. Describe the limitations of the evidence for cannabis as a therapeutic substance 3. Describe the primary concerns related to adolescents’ use of cannabis, and how the changing landscape interacts with these issues - THINK HARD ABOUT THESE ISSUES -

4 DO YOU THINK… Cannabis has addictive potential?Cannabis withdrawal is clinically important? Quitting Cannabis is relatively easy? Cannabis adversely impacts learning? Cannabis adversely impacts motivation? Cannabis adversely impacts decision-making? Cannabis has benefit for ADHD, PTSD, Anxiety? Cannabis has benefit for Epilepsy? Cannabis has therapeutic benefit for Pain? Cannabis use increases risk of psychosis?

5 DO YOU THINK … Vaping is a safe way to use Cannabis?Eating is a safe way to use Cannabis? Cannabis is as dangerous as Alcohol? We should legalize Cannabis? Medical? Recreational? Just One, Both? 18 year olds should be able to use Cannabis?

6 Reefer Madness 2015 Cannabis Products: Smoking / Vaping

7 Reefer Madness: 2015 Edibles

8 Reefer Madness: 2015 Devices

9 Reefer Madness 2015: The Market

10 Reefer Madness 2015: The Market

11 Are the Products What They Appear? Vandrey et al. (2015)Edible cannabis products (N=75) purchased from medical dispensaries 3 quasi-randomly selected stores in San Francisco, Los Angeles, and Seattle State-approved patients given budget of $400 to purchase variety of products

12 Accurate Under Over #, % Products 12 (17%) 17(23%) 45 (60%) THC, mg - label - actual < Discrepancy (Mean, SD) (Max) -3 (4) 9 28 (13) 55 - 47 (29) -99

13 Current Marijuana “Laws”Legal “Medical” Marijuana: 24 States, plus Washington, D.C. At least 3 States have Pending legislation 5 States have legalized recreational use of cannabis Federal Status: ILLEGAL

14 Medical Marijuana Laws (USA) “chaos”Fees to get “approval”: Range: $15-$200 Reciprocal approvals with other States: n=6 Minnesota and New York’s rules do not allow smoking of cannabis Allow dispensaries (n~15) Possession Limits Vary Tremendously: 1oz – 24oz (n=19 states) 30-60 day supply (n=5 states) plants: (mature, immature, seedlings?) Most States discuss plants and ounces, but don’t mention oils, wax, shatter, or even edibles No mention of potency

15 Approved Medical Conditions across StatesCachexia, cancer, chronic pain, epilepsy and other disorders characterized by seizures, glaucoma, HIV or AIDS, multiple sclerosis and other disorders characterized by muscle spasticity, and nausea, Hepatitis C, ALS, Crohn's disease, Alzheimer's disease, anorexia, arthritis, migraine, Parkinson's disease, posttraumatic stress disorder, decompensated cirrhosis, muscular dystrophy, severe fibromyalgia, spinal cord disease (including but not limited to arachnoiditis), Tarlov cysts, hydromyelia syringomyelia, Rheumatoid arthritis, fibrous dysplasia, spinal cord injury, traumatic brain injury and post concussion syndrome, Arnold-Chiari malformation and Syringomelia, Spinocerebellar Ataxia (SCA), Parkinson's Disease, Tourette Syndrome, Myoclonus, Dystonia, Reflex Sympathetic Dystrophy, RSD (Complex Regional Pain Syndromes Type I), Causalgia, CRPS (Complex Regional Pain Syndrome Type II), Neurofibromatosis, Chronic inflammatory Demyelinating Polyneuropathy, Chronic Inflammatory Demyelinating Polyneuropathy, Sjogren's Syndrome, Lupus, Interstitial Cystitis, Myasthenia Gravis, Hydrocephalus, nail-patella syndrome or residual limb pain; terminal illness with a life expectancy of under one year, one or more injuries that significantly interferes with daily activities as documented by the patient's provider, Huntington's disease

16 Addiction Science & Clinical Practice (2015)

17 Belendiuk et al., 2015 Common conditions shared by > 80% of MML states: - Alzheimer’ s disease - amyotrophic lateral sclerosis - Cachexia/wasting synd. - cancer - Crohn’ s disease - epilepsy and seizures - Glaucoma, - Hepatitis C - HIV/AIDS, - MS / muscle spasticity - Severe & chronic pain - severe nausea. - Post-traumatic stress disorder (PTSD) *… for the majority of these conditions, there is insufficient evidence to support the recommendation of medical marijuana at this time

18 California Society of Addiction Medicine“Medical marijuana” is a flawed concept for 3 reasons: A) administering any medication via drawing hot smoke into the lungs is inherently unhealthy; B) although use of vaporizers, sprays, and tinctures solves problems inherent in smoking, treatment of illness without standardized dose or content of the medication remains a safety issue; C) if the public wants to legalize marijuana, there is no reason to force physicians to be gatekeepers in a manner that enables liberal access to marijuana but generally fails to uphold accepted standards of practice for recommending a potentially addicting medication.

19 Challenges and Needs Cannabis studied in context of illicit not medical use Cannabinoids more so than cannabis studied Highly variable plant(s) over 100 “active” compounds Education needed for clinicians and patients Data needed to determine effects, side-effects & risks

20 Seizures / Epilepsy Animal studies - anticonvulsant effects and reduce seizure-related mortality - lower threshold for seizures; withdrawal increases convulsions Survey Studies % of patients with epilepsy smoke cannabis - some report positive effects and belief that it is therapeutic - others reporting increased seizure frequency and intensity RCTs (total of 48 patients) Cochrane Review (2014) - only assess cannabidiol / no follow-up longer than 6 months - reduction in seizure frequency (2 studies) - no effect compared to placebo (1 study)

21 NH Medical Society Clinical Cannabis Survey How would you rate your knowledge of marijuana/cannabis effects? (Savage, 2014)

22 Additional Suggested Reading: Medical Marijuana: Review of the Science and Implications for Developmental-Behavioral Pediatric Practice Hadland, SE, Knight, JR, Harris, SK. J Dev Behav Pediatr 36:115–123, (2015)

23 Recreational MJ Laws Better / More Appropriate Alternative than “Medical” Marijuana Legalization??

24 Changing World of Cannabis What Will Legal / Regulatory Changes BringPotential for Positive and Negative Impact - Higher Potency / New Products / New Delivery Systems - Impact on Use, Attitudes, Perceived Risk - Impact on Health, Public Safety - Addiction / Problematic Use - Science: Understanding of Cannabis

25 Impact on Addiction ScienceWindfall! Jackpot! Gold Mine! Opportunities Abound! Science needed at all levels - Define Safe Use - Marketing / Labeling - Measure Intoxication - Dosing/Potency - Test Drug Interactions - Methods of Admin. - Prevention & Intervention - Reduction - Test Medical Applications - Product Content

26 How Science and Scientific Reporting Works

27 Little More About... Potency Methods of AdministrationYouth Consequences

28 Potency

29 Potency / Dose Basic Behavioral and Clinical Pharmacology - Potency (Dose) matters! With Cannabis it’s all about THC dose …or is it? • Cannabidiol? • Over 100 compounds; over 70 phytocannabinoids

30 THC Potency Lab studies have not gone above 8% THC, and only one study has gone that high. - confiscated cannabis averaged 12.8% in 2012 Existing data on lab and epidemiological studies capture results from use of much lower THC levels than now used Need to learn more about higher % THC products! Unlike alcohol, we do not have current norms on a standard dose (drink) and how much you can use before becoming “intoxicated”, or in medical danger Unlike alcohol – different methods of administration

31 Cannabidiol (CBD) Cannabis plants have varying amounts of CBDSuggestive data that it moderates effects of THC - Potential as an anxiolytic? - Potential as an antipsychotic? - Marketed (like marijuana) as a medication for multiple problems: e.g., epilepsy, SUDs! - 1:1 ratio with THC in Sativex (approved medication) Recent lab study suggests effects are not so clear? - appeared almost inert when studied carefully in experienced cannabis users Schubart et al. (2013); Neisink et al. (2013) Haney et al., (2015)

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33 QUIZ Report in Medscape on an ongoing study of cannabidiol for children with epilepsy What is wrong with this sentence? “The US Food and Drug Administration (FDA) has given approval for studies to begin on a medicinal form of marijuana for the treatment of intractable epilepsy in children.”

34 Summary: Potency Cannabis is not just THC Need data on higher % THCNeed data on Cannabidiol and THC/Cannabidiol Cannabis combination products ---- What about with synthetic cannabinoids? How dose interacts with method of use

35 Route of AdministrationSmoking vs. Vaping vs. Eating Basic behavioral and clinical pharmacology route influences effects and thus interacts with with dose - onset, timecourse, euphoric effects, adverse effects

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37 Vaping “Vaping” is the slang term for the vaporization of substances (e.g., flavors, nicotine, or cannabis products) whereby liquid, oil, or plant material is heated to a temperature that releases an aerosolized mixture of water vapor and active ingredients (e.g., nicotine in e-cigs and THC in cannabis), which is then inhaled. Avoids combustion of the substance and the inhaling of smoke, which contains carbon monoxide and other by-products of combustion.

38 Vaping: Knowns and UnknownsBenefits - Clear harm reduction impact with respect to respiratory / lungs / carcinogenic factors. - Facilitate use of cannabis for medical purposes (titrate, no combustible smoke, etc.). Concerns - long-term effects of frequent vaping are unknown. - may have a positive impact on cannabis initiation, problem development and maintenance? - better tasting, more efficient high, more discreet use, combined with flavors or nicotine, attractive packaging, part of an evolving vaping culture, perceived as safe (Budney et al., 2015 Addiction)

39 Facebook Survey Study (almost under review)Distributed to pro-cannabis interest groups NORML, Legalize Marijuana, Medical Marijuana Popular music associated with such groups Liked / Interest marijuana N= 2932

40 Cannabis Use Characteristics% of Sample Lifetime Prevalence Smoking 99.6% Vaping 61.3% Age of initiation M (SD) 15.6 (4.1) 24.2 (12.2) Daily cannabis smokers were more likely to report vaping compared to occasional smokers (73% vs. 41%, p<.001)

41 Reasons for vaping More safe for my health Better taste/less harshBetter effects Discreet Cool?

42 Current (past 30 days) Cannabis UseThis graph shows days of current use (past 30 days) by route of administration. Again, the categories for current use are on the x-axis, and % of valid sample on the y-axis. As you can see, smoking was again the most common route of administration (especially among frequent users). Very few people vaped cannabis regularly.

43 Differed by School and Age (younger more likely )High School (5 in CT): E-cigs and Cannabis Vaping (Morean et al., 2015) Lifetime Use (%) Total n= 3847 E-cig Users n=1075 Cannabis Users n=1123 Dual Users n=724 e-cigs 27.9 ---- 64.5 cannabis 29.2 67.3 use e-cigs to vape 5.4 18.0 18.4 26.5 Differed by School and Age (younger more likely )

44 Youth Concerns: Vaping CultureFLAVORS, NICOTINE, CANNABIS, CAFFEINE Earlier Initiation? Combine Products Initiation by Youth at Lower Risk? More frequent use? More problematic use? Health Concerns?

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46 Edibles - Onset much slower, eventually similar effects - “overdose” concerns - Increase access and ease of use - Discreet - Reinforcing taste in addition to drug effect

47 Edibles: Concerns Labels related to dose and onset of effects?Why are all these cannabis products needed? - alcohol lollipops, alcohol in chocolate? - caffeine??? What is their purpose.... Marketing to youth, easier to ingest, sell as much as possible? Child protective packaging?

48 “The unfortunate aspect of this (cannabis) arms race is that they’re finally turning the drug into everything the U.S. government once said it was….It used to be we could say the government exaggerated the threat of this ‘crazy weed,’ but these new potent strains (and methods of use) belie that.” Robert MacCoun, behavioral scientist, marijuana policy expert U.C. Berkeley

49 National Data: Risk – Use ?

50 Concerns about Youth Cannabis UsePoor academic performance Interferes with brain development Increased risk of accidents Relationship problems Health/mental health problems Delinquent behavior High risk sexual behavior Gateway / Associated with use of Multiple Substances Addiction / Use Disorders / Problematic Use Data supportive of all these things, but definitive answers about correlation vs. causation, remain…… Like to change gears a little and get back to the one consequence that isn’t up there, Dependence…Does marijuana lead to dependence and what is its potential

51 NHSDH 2012

52 NSDUH 2012 AGE Marijuana abuse among adolescents is a growing problem.Summarize stats from slide….. AGE

53 NSDUH 2011 (Wu et al., 2013) Marijuana abuse among adolescents is a growing problem. Summarize stats from slide…..

54 NSDUH 2011 (Wu et al., 2013) Marijuana abuse among adolescents is a growing problem. Summarize stats from slide…..

55 Epidemiology Take HomesUse and frequency are moving in an increasing direction, although not as clear for frequency Start paying attention to types of cannabis/cannabinoids and how they are administered Distinguish between use and problematic use Examine full range of frequency Look more carefully at more narrow age ranges Subgroups Differences (vulnerable populations) - Disadvantaged populations can least afford an increase in use/misuse

56 Adolescent Treatment Admissions TEDS Data SetMarijuana abuse among adolescents is a growing problem. Summarize stats from slide…..

57 Admissions x Criminal Justice Involvement TEDS Data SetMarijuana abuse among adolescents is a growing problem. Summarize stats from slide…..

58 Health Services Take Home:Youth are using a substantial amount of substance use treatment services, most of which are related to problematic use of cannabis Legalization will not likely reduce this; may increase it?

59 Cannabis / Mental Illness: Positive Association- Psychotic Disorders - Affective Disorders - Anxiety Disorders / PTSD - ADHD Causal Factor or Impact on Existing Illness? Product of third variable

60 Risk of being a Psychotic Case(OR adjusted for gender, age, ethnicity, Stimulants, level of Ed) Frequent Use of High-Potency Cannabis May Drive the Increased Probability of Psychosis in Cannabis Users (Di Forti et al., 2014)

61 Suggested Reading: Does Cannabis Cause, Exacerbate or Ameliorate Psychiatric Disorders? An Over-simplified Debate Discussed. M. Haney, A.E. Evins Neuropsychopharmacology, August 2015

62 Australian Adolescent Health Cohort Study (n=1756)Degenhardt et al., 2012

63 Australian Adolescent Health Cohort Study (n=1756)

64 Cannabis and Mental Illness SummaryCannabis use is associated with increased levels of mental illness; this relationship may be moderated by frequency of use and potency of the cannabis Growing evidence that cannabis use may have causal impact on lowering of the age of onset of Psychotic Disorders; related to age of onset of cannabis use, frequency and potency. * Probability of occurrence is “low” in low risk samples Cannabis use can probably be considered a risk factor for poor outcomes in functioning across mental illnesses. Data do not support use of cannabis to treat any type of mental illness

65 Impact on Brain, Brain Development, Cognitive FunctioningSUGGESTED READINGS Dare to delay? The impacts of adolescent alcohol and marijuana use onset on cognition, brain structure, and function. Lisdahl KM, Gilbart ER, Wright NE, et al. Front Psychiatry. 2013;4:53. Medical Marijuana: Review of the Science and Implications for Developmental-Behavioral Pediatric Practice. Hadland, SE, Knight, JR, Harris, SK. J Dev Behav Pediatr 36:115–123, (2015) The effects of regular cannabis use on neurocognition in adolescent and young adults. Lisdahl KM, Wright NE, Kirchner-Medina C, Maple KE, Shollenbarger S. Curr Addict Rep (2):

66 Regular Cannabis Use / Brain Summary* Cannabis Use ~ abnormal brain structure/cognition - Gray matter: Limbic (amygdala, hippocampus), reward (nucleus accumbens), cerebellum, parietal, PFC - White matter: reduce integrity - Cognitive: negative impact: IQ, verbal memory, psychomotor speed, complex attention, executive function (cognitive inhibition, decision-making) - small to medium effect sizes - higher dose-exposed and early age onset ~ higher risk Limitations: Preexisting conditions, environment, genetics, sampling 66

67 Early Initiation = Bad

68 Prevention Prevention Messages??Perceived Risk on the Decline -- Worrisome Not as bad as alcohol (accidents, adverse events, etc.) Putative “Medical” benefits are numerous Vaping or Eating --- no respiratory issues Some argue that maybe cannabis will replace or reduce alcohol consumption -- that would be a net benefit?

69 What Do We Tell Parents / KidsCommunicate Clear Disapproval Not OK for teens; just like alcohol State the Concerns / Risks Does not matter if you used to do it or even if you currently use it Find a way to present risks / benefits information

70 Kushexpo.com

71 Irony is, as we move toward legalization cannabis appears to be on a trajectory towards becoming a class of substance with more potential for harm (enticing products including edibles, increased potency products, more efficient methods of delivery, and surely other modifications that will increase its allure).

72 - more objective, thoughtful contemplation of pros and cons Silver Lining - stimulating thoughtful and important science and discourse related to cannabis and drug policy - more objective, thoughtful contemplation of pros and cons In the end, more rational policy and regulation… One can only hope!

73 Take Home Messages “The Times They are a Changing”Science and Common Sense Policy is Needed Now More than Ever Educate yourself through traditional means: read the scientific literature!

74 Thank you!! For your time and attention today!To NIDA for funding my scientific endeavors To my colleagues, trainees, and research staff, particularly: Dustin Lee, Catherine Stanger, John Hughes, Ryan Vandrey Jim Sargent, Ben Crosier, Jacob Borodosky, Mary Brunette, Gray Norton, Samantha Auty, Jennifer Darsie, Lisa Marsch, Mark Milam, Stanley See, Hao Yang, Bonita Bosnyat

75 ncpic.org.au drugabuse.gov/drugs-abuse/marijuana