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Steven Wright, MD Littleton, CO

Family Medicine 1982

Addiction Medicine 1987

Medical Pain Management 2003

Big Sky, MT

January 21, 2020

North Dakota Academy of Family Physicians

Family Medicine Update Conference 2020

Breakin ’ Good ? or

Breakin ’ Bad ?

The Cannabis Conundrum

Disclosures

• Alliance for Benzodiazepine Best Practices

• BioDelivery Sciences, Inc Belbuca

• Daiichi Sankyo Movantik, Morphabond ER, Oxybond

• Gerson Lehrman Group Addiction

• Indivior Opioid addiction, Suboxone, Sublocade

• NEMA Research Benzodiazepine book, Opioid Induced Constipation

• US World Meds Lucemyra

Disclosures

3

Much of the potential medical use information

is off – label

There is no label for cannabis !!

Objectives

1) Describe CB pharmacology, neuropharmacology

2) Outline major negative consequences of CB use

3) Outline evidence for potential CB, cannabinoid medical use

4) Discuss approach to patients using CB medically, non-medically

CB = Cannabis

Earliest Records

Medical use: 2737 BCE Emperor Sheng Neng

Adverse effects: 77 CE Pliny the Elder

Kaneh bosem of the Hebrew Bible ??

And keep invention

in a noted weed.

- Sonnet #76

And keep invention

in a noted weed.

- Sonnet #76

Thackeray. Pipes showed CB. S Afr J Sci. 2001;97:19-21 PD-US

1 2

3 4

5 6

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PD-US

PD-US

We don’t see things

as they are,

we see them

as we are.

- Anais Nin

Steve Veals: Used with Permission

• ~ 40%

• 14%

• 9%

• 6 million

• 7,000

Have tried cannabis 1,2

Used last year 2002 4% 3,4

Used last month 3

Use daily 2006 3 million 1

New users daily 5

1 SAMHSA. 2013 National Survey on Drug Use and Health. HHS Pub # (SMA) 14-4863. 2014 2 Degenhardt. Global view of alcohol, tobacco, CB, cocaine use. PLoS Med. 2008;5(7):e141

Cannabis Use Epidemiology

Adult Americans

3 NSDUH: 2014-2015 to 2015-2016 Substance Use Comparisons for US and by states4 Hasin. US CUD prevalence between 2001-2002 and 2012-2013. JAMA Psych. 2015;72(12):1235-425 Azofeifa. MJ use & related indicators - NSDUH 2002-14. MMWR. 2016;65(11):1-25

Last Year

Louisiana 11%

Mississippi 9%

• Ever used cannabis by 8th grade: 16% 1

• Ever used cannabis by 12th grade 1

1979 60%

1993 35%

2014 44%

• Last month cannabis use in 12th grade: 21% 1

• Average age 1st use: 18 years old 2

1 Johnston. Monitoring the Future National Survey on Drug Use 1975-2014. 2015 2 ONDCP. National Drug Strategy: Data Supplement 2014 Accessed 3/20/16

Cannabis Use Epidemiology

School-Age Americans

7 8

9 10

11 12

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• “Safer than alcohol” 1-5 "Substitute for alcohol" 6

Alcohol use in Colorado ↑ 4% 7

Alcohol without impairment at directed dose 4

Alcohol measurement allows impairment management 8

• “Natural" “Herb” 10,11 Strychnine, tobacco also natural

• Black market elimination Hasn’t happened 12

• √ Tax revenue 12 BUT For each $1 received → $4.50 to mitigate adverse outcomes 13

• Personal liberty arguments 14

Faces off with harm / potential harm arguments

1 Pedersen. Perceived substance harm. Scand J Pub Health. 2015;43(4):385-92 2 Reynaud. Drug damage-benefit. J Psypharm. 2013;27(&):590-9 3 O'Keefe. Alcohol, CV. Mayo Clin Proc. 2014;89:382-93 4 Lachenmeier. Substance comparative risk. Sci Rep. 2015;5:8126 5 van Amsterdam. Substance physical harm. Regul Tox Pharm. 2013;66(1):83-7 6 Subbaraman. Can CB be considered substitute for alcohol? Alc Alc. 2014; 49:292-8 7 Rocky Mountain High Intensity Drug Trafficking Area. Colorado MJ legalization Impact. 20178

9 Palamar. Alcohol, MJ adverse psychsocial. Am J Drug Alc Abuse. 2014;40(6)438-46 10 Yahoo Answers. Is MJ a drug or herb? Accessed 8/14/15 11 Willie Nelson, Bob Marley, Arnold Schwarzenegger, Timothy Leary 12 Rocky Mountain High Intensity Drug Trafficking Area. Legalization of MJ in CO Impact. 2018 13 Centennial Institute: Economic, Social Costs of Legalized MJ (Colorado). November 15, 2018 14 Blumenson. MJ law reform moral case. Ind Law J. 2010;85(1) 15 Pew Research Center survey. 2017 16 Quinnipiac University Poll. August 3, 2017

Better described as a different safety profile 9

Recreational Use Legalization Arguments

61% Americans

Favor legalization 15,16

34

10

Legal Positions on Cannabis

• FDA: Cannabis Schedule I 1970 1 Reaffirmed 2006 2

Abuse potential, no medical use, unsafe

• 2005 Gonzales v Raich

Federal agents can act despite state law 3

• 2009 Ogden Memo 4 Reaffirmed 2013 5

Department of Justice won’t prosecute if in compliance with state law

• 2018 Sessions essentially rescinds the Ogden memo 6

• 2018 Agriculture Improvement Act allows hemp research & production 7

• >> 50% states allow CB medical use 8

• 17 states allow high CBD:THC ratio products 8

LaetrileOnly other substance

to circumvent FDA

with state approval 9

1 21 USC Sec. 812 Controlled Substance Act Accessed 8/14/15 2 FDA. Regarding claims smoked MJ is medicine. 2006 Accessed 8/14/15 3 Gonzales v Raich (previously Ashcroft v Raich), 545 US 1. 2005 Accessed 8/14/15 4 Ogden. Investigations, prosecutions in states authorizing MMJ. US DOJ. October 19, 2009 Accessed 8/14/15

5 Cole. Guidance regarding MJ enforcement. US DOJ. August 29, 2013 Accessed 8/15/15 6 Sessions J. Memorandum for US Attorneys: Marijuana Enforcement. January 4, 2018 7 Agricultural Improvement Act of 2018. Sec. 7129, 7501, 7605, 10113, 10114, 126198 Mead. Legal status of CB, CBD under US law. Epilepsy Behav. 2017;70(Pt B):288-919 American Cancer Society. Unproven cancer management. CA Cancer J Clin. 1991;41(3):187-92

There are three

kinds of men:

The ones that learn by reading

The few who learn by observation

The rest of them have to

pee on the electric fence

- Will Rogers

• Many studies observational, small sample size

• Many studies conflate results of different cannabinoid products

• Most studies examine smoked cannabis, not other routes of delivery

• Problems quantifying cannabis / THC used

• Variable dose, frequency, duration, smoking technique

• Variable THC quantities in products

• Higher THC levels today: ↑ 2-3 times since 1996 CBD levels ↓ 3 times since 1996 2-4

• Medical users tend to use lower doses than recreational users

• Confounding effects of other drugs - tobacco used by 40-90% of cannabis users 5

• Cumulative effects may be masked by acute effects

1 Russell. CB routes of administration for cannabis use. Int J Drug Policy. 2018;52:87-962 ONDCP. National Drug Strategy: Data Supplement 2014. Table 70, pg. 84 Accessed 3/20/163 Burgdorf. Heterogeneity in MJ composition seized in California. Drug Alc Dep. 2011;117(1):59-61

Cannabis Use Challenges

4 ElSohly. Changes in US CB potency 1995-2014. Biol Psych. 2016;79(7):613-95 Peters. Co-occurring CB, tobacco use. Addiction. 2012;107(8):1404-17

Smoking is

most common ROA 1

13 14

15 16

17 18

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Receptors Affected by Cannabinoids

Cannabinoid receptors: CB1 CB2 GPR55 GPR119 GPR55940 1,2

GABA 1,3

NMDA 3

Serotonin 4,5

Dopamine 5-7

Opioid Mu1 Kappa Delta 6,8,9

Potassium channel 9

Sodium channel 1

Calcium channel 10

TRPV1 channel 11

PPAR-alpha PPAR-gamma 12

1 Pertwee. CB1, CB2 pharmacology. Br J Pharm. 2008;153(2):199-215 2 Sharir. GPR55 characterization. Pharm Ther. 2010;126(3):301-13 3 Pazos. CB neuroanatomy. Pharm Biochem Behav. 2005;81(2):239-47 4 Braida. CB, 5-HT1A receptor in rats. Eur J Pharm. 2007;555(2-3)156-83 5 Tzavara. CB antagonist, monoamines. Br J Pharm. 2003;138:544-53 6 Tanda. CB, heroin mu activation. Science. 1997;276:2048-50

7 Urban. CB, DA release. Biol Psych. 2012;71(8):677-83 8 Berrendero. Opioid system, THC anxiolysis. Psychopharm. 2002;163:111-7 9 Marin. Kappa, CP 55,940, rats. Pharm Biochem Behav. 2003;74:567-73 10 Demuth. Cannabinoid signaling. Life Sci. 2006;78(6):549-63 11 De Petrocellis. CB, TRPV. Acta Physiol (Oxf). 2012;204(2):255-66 12 Esposito. CBD, IBD. Phytother. Res. 2013;27(5):633-6

∆9 Tetrahydrocannabinol (THC)

Appears to cause the primary safety

problems with cannabis

1 Wright. Recreational cannabinoid use hazards. J Fam Pract. 2016;65(11):770-9 2 Crean. MJ, executive function. J Addict Med. 2011;5(1):1-83 Morrison. Frontal theta coherence disruption by THC associated with psychotic Sxs. Neuropsychopharm. 2011;36(4):827-36 4 Englund. Can we make cannabis safer? Lancet Psych. 2017;4(8):643-8

∆9 Tetrahydrocannabinol (THC)

CB1 CB2 partial agonist 1

Intoxication 2

Analgesic 3

Anti-inflammatory 4

Appetite stimulant 4,5

Impaired immune response 6

Anti-neoplastic (mixed results) 6

Sedative 7

Memory impairment 8

Mixed results : Anxiety 7-10

Decreased IOP 11

Anti-emetic 10

Worse psychomotor control 12

Increased risk of psychosis 13

Neuroprotective, Neurotoxic 8,14

1 Pertwee. CB1, CB2 pharmacology. Br J Pharm. 2008;153(2):199-215 2 Gorelick. THC tolerance. J Anal. Tox. 2013;37(1):11-6 3 Cooper. Dronabinol, MJ, pain. Neuropsychopharm. 2013;38(10):1984-92 4 Alhamoruni. CB, inflammation. Br J Pharm. 2012;165(8):2598-610 5 Engeli. CB, food intake, body weight. Handb Exp Pharm. 2012;209:357-81 6 Hall. CB, cancer. Lancet Oncol. 2005;6(1):35-42 7 Martin-Santos. Acute THC, CBD. Curr Pharm Des. 2012;18(32):4966-79

8 Bhattacharyya. THC, CBD opposite. Neuropsychopharm. 2010;35(3):764-74 9 Berrendero. Opioid system, THC anxiolysis. Psychoharm. 2002;163:111-7 10 Whiting. Medical cannabinoids. JAMA. 2015;313(24):2456-73 11 Merritt. THC, glaucoma. J Clin Pharm. 1981;21(8-9 Suppl):467S-471S 12 Ramaekers. THC, cognition, motor. Drug Alc Dep. 2006;85(2):114-22 13 D’Souza.THC in schizophrenia:. Biol Psych. 2005;57(6):594-608 14 Hampson. CBD, THC neuroprotect. Proc Ntl Acad Sci. 1998;95:8268-73

Association

Does Not Necessarily Mean

Causal

• Overall physical health: mixed results 1,2

• ↓ overall mental health 1

• 455,000 ER visits yearly 3

• Overall effect on mortality indeterminate 4

• No OD deaths recorded

• Mortality associated with cancer, cardiac, CVA, MVA, hyperemesiswhich are associated with CB use 5-9

1 Gruber. Attributes of long-term heavy CB users. Psychol Med. 2003;33(8):1415-22 2 Hill. Minimal physical health risk with LT CB. JAMA. 2016;315(21):2338-9 3 SAMHSA, DAWN, 2011: Drug related emergency department visits. HHS Pub (SMA) 13-4760, DAWN Series D-39. pp.15,25 4 Calabria. Does CB use increase risk of death? Systematic review. Drug Alcohol Rev. 2010;29(3):318-30

Recreational Cannabis Use

Health Outcome Associations

5 Ashbridge. Acute CB, MVA. BMJ. 2012;344:e53 6 Tomar. Evidence on carcinogenicity of CB smoke. Accessed 3/21/16 7 Yankey. MJ & CV, cerebrovascular mortality. Eur J Prev Card. 2017;24(17):1833-408 Rocky Mountain High Intensity Drug Trafficking Area. Colorado MJ legalization Impact. 2017 Accessed 1/8/18 9 Nourbakhsh. Cannabinoid hyperemesis fatal cases. J Forensic Sci. 2019;64(1):270-4

• ↓ Quality of life 1

• ↓ EducaLonal achievement 1-3

• ↓ Work success 4

• ↓ Income 1-3

• ↑ School delinquency 1

• ↑ Youth crime 1,5

• ↑ RelaLonship problems 1-3

1 Gruber. Attributes of long-term heavy CB users. Psychol Med. 2003;33(8):1415-22 2 Palamar. Drug use psychosocial outcomes in HS seniors. Am J Drug Alc Abuse. 2014;40(6):438-46 3 Fergusson. CB & later life outcomes. Addiction. 2008;103:969-76

4 Brook. CB & work, financial, social. Subst Abus. 2013;34:298-305 5 ONDCP. National Drug Strategy: Data Supplement 2014 Accessed 3/20/16

Recreational Cannabis Use

Socioeconomic Associations

19 20

21 22

23 24

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• Eyes

• Mouth

• Cardiac

• GI

• Endo

• Neuro

• Skin

Conjunctival injection 1

Caries Stomatitis Periodontal disease 2,3

↑ HR ↓ BP ↑ MI ↑ Cardiomyopathy Heart failure 4-9

Cannabinoid Hyperemesis Syndrome >2 million events annually 10-15

Gynecomastia Hypogonadism Sexual dysfunction 16,17

↑ stroke frequency (mixed results) 5,6,18-24

Burns from butane THC extraction 25 Less likely in the future b/o CO2 extraction

1 Yazulla. Endocannabinoids in retina. Prog Retin Eye Res. 2008;27(5):501-26 2 Cho. General, oral health of CB users. Aust Dent J. 2005;50(2):70-4 3 Hill. Minimal physical health risk with LT CB. JAMA. 2016;315(21):2338-9 4 Gorelick. No THC tolerance to CV effects. J Anal Tox Adv. 2012;00:1-6 5 Thomas. CB & CV, cerebrovascular, PV events. Am J Card. 2014;113(1):187-96 Kalla. CB predicts heart failure, CV. J CV Med (Hagerstown). 2018;19(9):480-47 Hall. Adverse health effects of recreational CB. Addiction. 2015;110(1):19-35 8 Mukamal. MJ-related mortality after MI. Am Heart J. 2008;155(3):465-70

18 Barber. CB & CVA and TIA. Stroke. 2013;44(8):2327-9 19 Singh. CB-related stroke. J Stroke CV Dis. 2012;21(7):555-60 20 Wolff CB-related stroke: myth or reality? Stroke. 2013;44(2):558-63 21 Yankey. MJ & CV, cerebrovascular mortality. Eur J Prev Card. 2017;24(17):1833-40 22 Rumalla. Recreational MJ & acute ischemic stroke. J Neurol Sci. 2016;364:191-6 23 Falkstedt. CB, tobacco, alcohol & risk of early stroke. Stroke. 2017;48(2):265-70 24 Barber. CB, ischemic stroke, TIA: case-control study. Stroke. 2013;44(8):2327-925 Bell. Butane hash oil burns. J Med Toxicol. 2015;11(4):422-5

9 Franz. MJ use & CV disease. Cardiol Rev. 2016;24(4):158-62 10 Warner. CB hyperemesis relieved by bathing. Clin Med. 2014;14(1):86-711 Wallace. CB hyperemesis syndrome. South Med J. 2011;104(9):659-64 12 Schreck. CB hyperemesis review. Drug Alc Dep. 2018;182:27-32 13 Kim. Cyclic vomiting, MJ liberalization. Acad Emerg Med. 2015;22(6):694-9 14 Habboushe. CB Hyperemesis prevalence. Basic Clin Pharm Tox. 2018;122(6):660-2 15 Nourbakhsh. Cannabinoid hyperemesis fatal cases. J Forensic Sci. 2019;64(1):270-4 16 Harmon. Gynecomastia in MJ users. NEJM. 1972;287(18):936 17 Gorzalka. CB gonadal hormone, sex. Horm Behav. 2010;58(1):91-9

Recreational Cannabis Effects

• ↑ appetite 1

• ↑ carbohydrate preference 2

• ↑ young adult obesity 3

• Adults overall with chronic use 4

↓ BMI

Better lipid parameters

↓ frequency of diabetes

3 Huang. Adolescent substance use & obesity in young adulthood. Addict Behav. 2013;38(11):2653-604 Rajavashisth. Decreased DM prevalence in CB users. BMJ Open. 2012;2:e000494

Recreational Cannabis Effects: Metabolic

1 Ashton. CB pharmacology, effects. Br J Psych. 2001;178(2):101-6 2 Muniyappa. Metabolic effects of chronic CB smoking. Diabetes Care. 2013;36(8):2415-22

• Acute use: Bronchodilation lasting 1 hour 1

• Chronic use:

• ↑ FEV1 or no change 2-4

• ↑ Lung volumes, large airway obstruction 2,4 not COPD 4

• Apical emphysema “Marijuana Lung” 5

• Chronic bronchitis → resolves with discontinuation 4

• Bronchial inflammation 1

• Respiratory infection 1 Fungal contaminants 1,6

• Lung cancer risk: not settled 4,7-11

1 Gates. CB smoking and respiratory health. Respirology. 2014;19(5):655-82 2 Pletcher. CB exposure, pulmonary function over 20y. JAMA. 2012;307:173-81 3 Hancox. CB effects on lung function. Eur Respir J. 2010; 35:42-47 4 Tashkin. CB effects on lung. Ann Am Thorac Soc. 2013;10(3):239-7 5 Beshay. Emphysema, pneumothorax in young adults smoking CB. Eur J Cardiothorac Surg. 2007;32(6):834-8 6 Verweij. Fungal contamination of tobacco, MJ. JAMA 2000;284:2875

7 Callaghan. CB, lung cancer risk. Cancer Causes Control. 2013;24(10):1811-20 8 Hashibe. CB and cancer risk. Alcohol. 2005;35(3):265-759 Tomar. Evidence on carcinogenicity of CB smoke. Accessed 3/21/16 10 Yayan. Damaging effects of CB on lungs. Adv Exp Med Biol. 2016;952:31-3411 Underner. CB smoking and lung cancer. Rev Mal Respir. 2014;31(6):488-98

Recreational Cannabis Effects: Pulmonary

• E -cigarette, or Vaping, product use-Associated Lung Injury

• Any THC-product use: 86% Exclusive THC-product use: 34% 1

• Any nicotine-product use: 64% Exclusive nicotine-product use: 11% 1

• Both THC-product and nicotine-product use: 52% 1

• Risk factors for EVALI: THC-containing products Informal sources 2

• Risk factors for EVALI mortality: Older age 1

• Etiology: Vaping product excipients? Vitamin E acetate ? 3

• Pathology: Pulmonary infiltrates on CXR Opacities on CT scan 4

• Intervention: Hospitalize for SaO2 <95% or respiratory distress 4

Antibiotics / Steroids depending on clinical circumstances 4

Respiratory support 4 Lung transplant

E V A L I

1 Moritz. E-cigarette, or vaping, product use-associated lung injuries. MMWR. 2019;68(43):985-92 Navon. Risk factors for EVALI. MMWR. 2019;68(45):1034-9

3 Taylor. Characteristics of EVALI and products seized by law enforcement - Minnesota. MMWR. 2019;68(47):1096-1004 Siegel. Interim guidance for EVALI. MWR. 2019;68(41):919-27

Carcinogens: Cannabis vs Tobacco

1 Wu. Pulmonary hazards of CB v tobacco. NEJM. 1988;318(6):347-512 Moir. MJ tobacco smoke comparison. Chem Res Tox. 2008;21(2):494-502 3 Sullivan. Pesticide residues in CB smoke. J Toxicol. 2013; 2013: 378168

4 Cai. Pyrathroid residues inn cigarette smoke. J Chromatogr A. 2002;964(1-2):205-11 5 Stone. CB, pesticides conflicting laws. Regul Tox Pharmacol. 2014;69(3):264-8 6 Tomar. Evidence of carcinogenicity of CB smoke. Accessed 3/21/16

• Adult cancers: Prostate1-3 Testes1,3,4 Brain2,3,5

• Childhood cancers due to parental exposure:

Astrocytoma3 Rhabdomyosarcoma3 Neuroblastoma3 Leukemia3

• Mixed or borderline results:

Lung1,6 Bladder1,6-8 Cervical6,3 NH lymphoma1,9 AML3 Head-neck SCC1,10,11

• Possibly protective of NH lymphoma9 Head-neck SCC12 Bladder7

Recreational Cannabis Effects: Cancer

8 Thomas. CB, bladder cancer. Urology. 2015;85(2):388-92 9 Chacko. MJ, transitional cell cancer. Urology. 2006;67(1):100-4 10 Holly. Non-Hodgkin lymphoma risk. Am J Epidemiol. 1999;150(4):375-89 11 Zhang. MJ risk head/neck SCC. CA Epidemiol Biomark Prevent. 1999;8:1071-8 12 Rosenblatt. MJ w/o risk oral SCC. CA Res. 2004;64:4049-54 13 Liang. MJ, head/neck SCC. Cancer Prev Res. 2009;2:759-68 14 Dariš. Cannabinoids in cancer Rx. Bosn J Basic Med Sci. 2018 Sep 2

1 Sidney. MJ, cancer incidence. CA Causes Control. 1997;8(5):722-8 2 Hashibe. MJ, cancer risk. Alcohol. 2005;35(3):265-75 3 Tomar. Evidence on carcinogenicity of CB smoke. Accessed 3/21/16 4 Gurney. CB & testicular cancer meta-analysis. BMC Cancer. 2015;15:897 5 Trabert. MJ, testicular cancer. Cancer. 2011;117(4):848-536 Efird. Risk for adult glioma. J Neurooncol. 2004;68(1):57-69 7 Hall. Cannabinoids, cancer. Lancet Oncol. 2005;6(1):35-42

Certain cannabinoids

are anti-tumor 14

25 26

27 28

29 30

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• Helps morning sickness 1,2 Not Recommended

• Used by 2-22% of pregnant women 3-8

Prenatally exposed neonatal associations

• Certain rare cancers 9

• Certain rare birth defects: VSD Anencephaly Gastroschisis 10

• Mild (if any) withdrawal 11 ↓ Birth weight 12 ↑ Mortality 12

Prenatally exposed childhood associations

• Behavioral and cognitive problems 10,11,13-15

• Limited educational achievement 11 No effect on language or IQ 4

• Increased risk for teen cannabis and cigarette use 11

1 Westfall. CB for morning sickness. Complement Ther Clin Pract. 2006;12(1):27-33 2 Curry. Hyperemesis gravidarum & CB. J Cannabis Ther. 2002;2(3-4):63-83 3 SAMHSA. 2013 National Survey Drug Use & Health. HHS Pub 14-4863. 2014 4 Fergusson. Maternal MJ, pregnancy outcome. BJOG. 2002;109(1):21-7 5 Lozano. CB gestational exposure. Acta Pediatr. 2007;96(12):1734-76 Williamson. Drug misuse prevalence by meconium. Arch Dis Child Neonatal Ed. 2006;91:F291-27 El Marroun. Maternal CB use by self-report, UA. Eur Addict Res. 2011;17(1):37-43

8 Oga. Cigarette smoking, substance use in pregnancy. Matern Child Health J. 2018 Jun 79 Tomar. Evidence on carcinogenicity of CB smoke. Accessed 3/21/16 10 CO Dept Health & Environment. Possible MJ Health Effects. 2014 Accessed 9/5/15 11 Behnke. Perinatal substance abuse effects. Pediatrics. 2013;131:e1009-24 12 Howard. CB use association with infant birth weight. J Addict Med. 2019;13(6):436-41 13 Jacques. CB, pregnant women, children. J Perinatol. 2014;34(6):417-24 14 Julvez. Maternal CB, childhood cognition. Int J Epidemiol. 2007;36(4):825-32 15 Huizink. Prenatal CB, infants. Prog Neuropsychopharm Biol Psych. 2014;52:45-52

Recreational Cannabis Effects: Pregnancy

1 Hser. CB ↓ improves anxiety, depression, sleep. J Subst Abuse Treat. 2017;81:53-8 2 Jiang. CB, anxiety, depression. J Clin Invest. 2005;115(11):3104-16 3 Cairns. Adolescent depression risk. J Affect Disord. 2014;169:61-75 4 Denson. CB & decreased depression. Addict Behav. 2006;31(4):738-42 5 Copeland. Mental health youth CB impact. Curr Opin Psych. 2013;26(4):325-9 6 Chadi. Depressive, suicidality in adolescents using e-cig, MJ. J Addict Med. 24 Jan 2019. 7 Fergusson. CB, youth adjustment. Addiction. 2002;97(9):1123-35 8 Price. CB, suicide. Br J Psych. 2009;195(6):492-7 9 Grucza. CB policy, suicide. Drug Alc Dep. 2015;152:68-72

19 Englund. CBD inhibits THC-paranoia. J Psychopharm. 2013;27(1):19-27 20 Griffith-Lendering. Inhibitory control & CB. J Clin Exp Neuropsych. 2012;34(7):688-9721 Lane. Acute MJ effects on risk taking. Neuropsychopharm. 2005;30(4):800-9 22 Moreno. Impulsivity: CB, binge drinkers in college. Drug Alc Dep. 2012;124(3):355-62 23 Barrett. Violence in comorbid SUD, PTSD. Addict Behav. 2011;36(7):721-8 24 Friedman. CB violence non-delinquent v delinquents. J Addict Dis. 2003;22(3):63-78 25 Norstrom. CB use, violence. Scand J Pub Health. 2014;42(4):358-63 26 Wilkinson. CB & PTSD symptoms, violence. J Clin Psych. 2015;76(9):1174-80 27 Gillet. Acting out &psychoactive substances. Encephale. 2001;27(4):351-9 28 Shishko. Medical MJ for PTSD review. Ment Health Clin. 2018;8(2):86-94

10 Silins. CB, young adult sequelae. Lancet Psych. 2014;1(4):286-93 11 Woolridge. MJ for HIV Sxs. J Pain Symp Manag. 2005;29(4):358-67 12 Nelemans. CB, youth SAD. Eur Child Adol Psych. 2015 Aug 8 13 Buckner. Antecedents of MJ use. J Behav Ther Exp Psych. 2012; 43(1): 647-55 14 Turna. CB Rx for anxiety, mood, related disorders. Depress Anxiety. 2017;34(11):1006-1715 Le Bec. CB & psychosis: systematic review. Encephale. 2009;35(4):377-85 16 Murray. CB, synthetic CBs increasing risk for psychosis. World Psych. 2016;15(3):195-204 17 De Hert. CB & age onset schizophrenia, bipolar. Schizophr Res. 2011;126(1-3):270-6 18 Zorrilla. Quitting CB during manic episode improves outcome. Acta Psych Scand. 2015;131(2):100-10

• Depression: Mixed results 1-6

• Suicidality: Mixed results 4-10

• Anxiety: Mixed results 1,2,11-14

• Psychosis: Probably causal 15-17

Recreational Cannabis Effects: Psychiatric

• Bipolar disorder: Earlier onset, worse function 17,18

• Paranoia 19

• Impulsivity 20-22

• Violence: Mixed results 23-27

PTSD data

poor / conflicting 28

My friends who smoke pot

don’t do anything bad.

In fact,

they don’t do anything

at all !

- Kathleen Madigan

• 8-14% users develop CUD 1-4

• 4% Americans (14 million) 5

• 17% if initiated before age 17 3,6,7

• 25-50% daily non-medical users are addicted 8,9

• Withdrawal well defined 10,11,12 Fear of WD is barrier to cessation 13

Nabilone, CBD, gabapentin may help 14-16

• CUD treatable 2,12,17-19

Gabapentin, N-acetylcysteine, CBD, naltrexone may help 14-16,20,21

• Gateway to other drugs uncertain 22-24

1 Kandel. Dependence prevalence. Drug Alc Dep. 1997;44:11-29 2 Lopez-Quintero. Transition to dependence. Drug Alc Dep. 2011:115:120-30 3 Ehlers. CB dependence. Addict Behav. 2010;35(2):102-10 4 von Sydow. Natural course of CB use, abuse, dependence. Drug Alc Dep. 2001;64(3):347-6 5 Budney. MJ dependence, treatment. Addict Sci Clin Pract. 2007;4(1):4-16 6 Wagner. Dependence risk periods. Neuropsychopharm. 2002;2(3):244-68 7 CASA. Early MJ use related to later illicit drug use Accessed 8/7/15 8 Hall. CB non-med health effects. Lancet. 2009;374(9698):1383-91 9 Zaman. Adolescent substance, mental health. JAMA. 2015;9(4):317-21 10 Gorelick. CB WD Dx criteria. Drug Alc Dep. 2012;123(1-3):141-7 11 Vandrey. CB, tobacco WD. Drug Alc Dep. 2008;92(1-3):48-54

12 Benyamina. CB WD, dependence Rx. Expert Rev Neurother. 2008;8(3):479-91 13 Zvolensky. Perceived barriers for CB cessation. Addict Behav. 2018;76:45-5114 Haney. Nabilone decreases MJ WD. Neuropsychopharm. 2013;38(8):1557-65 15 Mason. Gabapentin effect on CB use, WD, executive function in CUD. Neuropsychopharm. 2012;37(7):1689-98 16 Mandolini. CBD in Rx psych disorders. Epidem Psych Sci. 2018;27(4):327-3517 McRae. MJ dependence Rx. J Sub Abuse Treat. 2003;24:369-76 18 Danovitch. CB dependence Rx. Psych Clin North Am. 2012;35(2):309-26 19 Gates. CUD psychosocial interventions. Cochrane Rev. 2016;(5):CD00533620 Balter. Pharmacologic approaches to Rx CUD. Curr Addict Rep. 2014;1(2):137-4321 Notzon. Pilot of injectable NTX for CUD. Am J Drug Alc Abuse. 2018;44(6):619-2722 Degenhardt. Drug gateway theory. Drug Alc Dep. 2010;108(1-2):84-97 23 Mayet. Adolescent tobacco-CB transitions. Addict Behav. 2011;36(11):1101-5 24 Degenhardt. Evaluating gateway drug theory. Drug Alc Dep. 2010;108(1-2):84-97

Cannabis Use Disorder (CUD)

Big Bong

Theory

• Psychomotor function worse with acute 1-3 and chronic use 4

• Increased non-traffic, occupational injuries 5-7

• ↑ MVAs 2-3 times 8-11 ↑ Fatal MVAs 1.3-2 times 8,12,13

Dose dependent 8,9

14x worse if combined with alcohol 10

More problematic with routine than complex driving 8

Risk persists at least 4-6 hours after smoking 8 Longer with edibles

96% of drugged driving in youth presenting to ED 14

1 Hunault. Acute CB cognitive-motor. Psychopharm. 2009;204(1):85-95 2 Weinstein. Acute THC cognitive-motor. J Psychopharm. 2008;22(4):441-51 3 Ramaekers. THC level, cognitive-motor. Drug Alc Dep. 2006;85(2):114-22 4 Ramaekers. THC, neurocognition. J Psychopharm. 2009;23(3):266-77 5 Barrio. MJ, non-traffic injuries. Accid Anal Prev. 2012;47:172-6 6 Khashaba. Non-fatal occupational injuries in construction. Toxi Ind Health. 2018;34(2):83-907 Choi. Older adult MJ use, injuries, ED visits. Am J Drug Alc Abuse. 2018;44(2):215-23

8 Macdonald. CB, cocaine injury risk. Drug Alc Dep. 2003;72(2):99-115 9 Grotenherman. CB driving limits. Addiction. 2007;102(12):1910-7 10 Ramaekers. CB dose, MVA risk. Drug Alc Dep. 2004;73(2):109-19 11 Goullé. THC PK, synthetic CBs, road safety. Bull Acad Natl Med. 2015;198(3):541-56 12 Ashbridge. Acute CB, MVA. BMJ. 2012;344:e53 13 Martin. CB, alcohol & fatal road accidents. PLoS One. 2017;12(11):e018732014 Bonar. Drugged driving of emerging adults presenting to ED. Addict Behav. 2018;78:80-84 15 Sartor. Perceived safety and controllability of events. Addict Behav. 2017;66:114-7

Recreational Cannabis Effects: Psychomotor

Some users lack awareness

of impairment or risks 15

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Couch

Locked

Couch

Locked

• Worse with acute 1-3 and chronic use 4

• Multiple domains affected negatively 1-6

• Worse if start younger 6-8

• Worse if use more or for longer 6,9

• Reversibility of dyscognition with abstinence likely 6,10,11

• Problematic chemical: THC 5

1 Hunault. Acute CB cognitive-motor. Psychopharm. 2009;204(1):85-95 2 Weinstein. Acute THC cognitive-motor. J Psychopharm. 2008;22(4):441-51 3 Ramaekers. THC level, cognitive-motor. Drug Alc Dep. 2006;85(2):114-22 4 Ramaekers. THC, neurocognition. J Psychopharm. 2009;23(3):266-77 5 Barrio. MJ, non-traffic injuries. Accid Anal Prev. 2012;47:172-6

6 Macdonald. CB, cocaine injury risk. Drug Alc Dep. 2003;72(2):99-115 7 Grotenherman. CB driving limits. Addiction. 2007;102(12):1910-7 8 Ramaekers. CB dose, MVA risk. Drug Alc Dep. 2004;73(2):109-19 9 Sewell. CB, alcohol, driving. Am J Addict. 2009;18(3):185-93 10 Ashbridge. Acute CB, MVA. BMJ. 2012;344:e53 11 Schreiner. Neurocog performance after CB abstinence. Exp Clin Psychopharm. 2012;20(5):420-9

Recreational Cannabis Effects: Cognition

Cognitive Functions Improved with Cannabis ??

Attention / Concentration

Mixed results 1

• Among chronic users CB improves focus 2

• Among occasional users CB worsens focus 3

1 Crean. MJ and executive function effects. J Addict Med. 2011;5(1):1-8 2 Hart. Effects of acute smoked MJ on complex cognitive performance. Neuropsychopharm. 2001;25(5):395-404 3 Morrison. IV THC effects on psychosis, mood, cognition. Psychol Med. 2009;39(10):1607-16

Hashish …

gives the power of imagination

and takes away the ability

to profit from it.

Baudelaire. Les Paradis Artificiel, 1860

Hashish …

gives the power of imagination

and takes away the ability

to profit from it.

Baudelaire. Les Paradis Artificiel, 1860

PD: Triddle

• Amotivational Syndrome uncertain 1-4

• Absenteeism ↑ 75% if pre-employment THC positive 5

• ↓ work commitment 6

• ↓ energy and interest in adolescents 7

1 Barnwell. MJ, motivation, life satisfaction. Sub Abuse Treat. 2006;1(1):2 2 Fried. Neurocognitive consequences of MJ. Neurotoxicol Teratol. 2005;27:231-9 3 Schmits. MJ, amotivational syndrome. Rev Med Liege. 2013;68(5-6):281-6 4 Lawn. CB effort-related decision-making, amotivational hypotheses. Psychopharm (Berl). 2016;233(19-20):3537-52

5 NIDA. MJ research series. Pub #10-3859 Accessed 8/13/156 Brook. MJ & work commitment / financial stability / social effect. Sub Abuse. 2013;34(3):298-305 7 Palamar. Adverse psychosocial CB v alcohol. Am J Drug Alc Abuse. 2014;40(6):438-46

Recreational Cannabis Effects: Motivation

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Photo: Steve Wright

Potential recognized but needs more research

• Literature in general 1,2

• American Academy of Family Physicians 3

• American Society of Addiction Medicine 4

• American College of Physicians 5

• Institute of Medicine 6

Included in some guidelines 7

• American Academy of Neurology Medical MJ Guidelines 2014 8,9

• Canadian Fibromyalgia Guidelines 2012 10

1 Martin-Sanchez. CB chronic pain meta-analysis. Pain Med. 2009;10(8):1353-68 2 Wilsey. CB in neuropathic pain. J Pain. 2008;9(6):506-21 3 American Academy of Family Physicians Policies: Marijuana. 2014 Accessed 8/2/15 4 American Society of Addiction Medicine position paper. 2012 Accessed 11/7/155 American College of Physicians MMJ position paper. 2008 Accessed 10/19/15

6 Watson. 1999 IOM report: MJ & medicine. Arch Gen Psych. 2000;57(6):547-52 7 Guideline Clearinghouse Accessed 8/17/15 8 American Academy of Neurology Medical MJ Guidelines 2014 Accessed 10/19/15 9 American Academy of Neurology: CAM for MS 2014 Accessed 8/17/15 10 Canadian Fibromyalgia Guidelines. 2012;2.3.3 Recommendation 31 Accessed 10/19/15

Cannabis Medical Use

• Evidence with variable support:

Acute 1,2 Post-op 3 Chronic 2-4 Cancer 3,5,6

Neuropathic 3,5-10 Spasm-associated 3,11-15

Headache, migraine 16,17 Fibromyalgia 3,18,19

• Dronabinol may work as well, last longer, less euphoria 20

• Studies limited, show modest benefit, concern about harms 2,3,10,21-23

1 Wallace. MJ, capsaicin pain. Anes. 2007;107:785-96 2 Campbell. CB, pain review. BMJ. 2001;323(7303):13 3 Aviram. CB-based meds for pain: meta-analysis. Pain Phys. 2017;20(6):E755-96 4 Martin-Sanchez. CB, chronic pain. Pain Med. 2009;10(8):1353-68 5 Hall. CB, cancer. Lancet Oncology. 2005;6(1):35-42 6 Abrams. CB in cancer care. Clin PharmTher. 2015;97(6):575-86 7 Marcotte. CB, neuropathic pain. J Pain. 2008;9(6):506-218 Rog. CB, central MS pain. Neurology. 2005;65(6):812-9

16 Rhyne. CB & migraine frequency. Pharmacother. 2016; 36(5):505-10 17 Cuttler. Effects of cannabis on HA, migraine. J Pain. 2019 Nov 9. pii: S1526-5900(19)30848-X18 van de Donk. CB in chronic pain patients with FM. Pain. 2019;160(4):860-9 19 Sagy. Safety, efficacy of medical CB in FM. J Clin Med. 2019;8(6). pii: E80720 Cooper. Dronabinol, MJ, pain. Neuropsychopharm. 2013;38:1984-92 21 Whiting. Medical cannabinoids. JAMA. 2015;313(24):2456-73 22 Hill. Medical MJ. JAMA. 2015;313(24):2474-83 23 Metts. Medical MJ: Rx worth trying? J Fam Pract. 2016;65(3):178-85

Excludes

Mono-CBD StudiesCannabis-Based Medicines

for Pain

9 Petzke. CB efficacy, tolerability, safety for chronic neuropathic pain. Schmerz. 2016;30(1):62-88 10 Nugent. Effects of CB with chronic pain, general harms review. Ann Int Med. 2017;167(5):319-3111 Yadav. Complementary MS meds. Neurology. 2014;82(12):1083-92 12 Zajicek. CB, MS symptoms. Lancet. 2003;362:1517-20 13 Leussink. CB, MS spasticity. Ther Adv Neuro Disord. 2012;5(5):255-66 14 Borgelt. Medical CB. Pharmacother. 2013;33(2):195-209 15 Weber. THC, ALS. J Neuro Neurosurg Psych. 2010;81(10):1135-40

Pain conditions with best support

• Brain tumors: Potential benefit in early trials 1

• Parkinson’s disease: ↓ symptoms in surveys 2,3

• DemenLa: ↓ symptoms in limited trials (mixed) 4,5

• ToureRe’s Syndrome: ↓ symptoms in limited trials 6-8

• Amyotrophic Lateral Sclerosis: ↓ symptoms in small trials 9

• Glaucoma: ↓ IOP for 4 hours in uncontrolled trials 10,11

• MulLple sclerosis: Significant ↓ symptoms No limitaLon of disease progression 12-21

Excludes

Mono-CBD Studies

Cannabis-Based Medicines

for Neurologic Disease

1 Lewis. Pharmacological foundations of CB chemovars. Planta Med. 2018;84(4):225-33 2 Venderová. CB use in Parkinson's: subjective improvement of motor Sxs. Mov Disord. 2004;19(9):1102-63 Finseth. Self-reported efficacy of CB in Parkinson's. Evid Based Comp Alt Med. 2015;2015:8748494 Volicer. Dronabinol effects on anorexia, disturbed behavior in Alzheimer's. Int J Ger Psych. 1997;12(9):913-95 van den Elsen. THC in behavioral disturbances in dementia. Am J Ger Psych. 2015;23(12):1214-246 Curtis. Cannabinoids for Tourette's. Cochrane Rev. 2009;(4):CD0065657 Whiting. Medical cannabinoids. JAMA. 2015;313(24):2456-73 8 Muller-Vahl. Treatment of tics in Tourette Syndrome. J Clin Psych. 2003;64(4):459-65 9 Carter. CB and ALS: hypothetical, practical applications. Am J Hosp Palliat Care. 2010;27(5):347-5610 Panahi. Arguments for / against cannabinoids in glaucoma. Biomed Pharmacother. 2017;86:620-711 Tomida. Effect of SL cannabinoids on IOP. J Glaucoma. 2006;15(5):349-53

12 Amato. CB in MS, neuropathic pain, chemotherapy. Epidem Prev. 2017;41(5-6):279-93 13 Torres-Moreno. Medicinal cannabinoids in MS. JAMA Network Open. 2018;1(6):e183485 14 Solaro. Pharmacological management of pain in MS. Drugs. 2010;70(10):1245-5415 Langford. THC/CBD oromucosal spray for neuropathic pain in MS. J Neuro. 2013;260(4):984-9716 Rog. Oromucosal THC/CBD for neuropathic pain in MS. Clin Ther. 2007;29(9):2068-79 17 Collin. CB-based medicine in spasticity in MS. Eur J Neuro. 2007;14(3):290-618 Flachenecker. LT effectiveness, safety of nabiximols for spasticity in MS. Eur Neurol 2014;72(1-2):95-10219 Flachenecker. Nabiximols in clinical practice for MS spasticity. Eur Neuro. 2014;71(5-6):271-920 Wade. CB-based meds for Sxs in MS. Mult Scler. 2004;10(4):434-4121 Zajicek. Dronabinol, MS progression. Lancet Neuro. 2013;12(9):857-65

CBD probably

more beneficial

Except for glaucoma

• Anxiety: Studies mixed, not encouraging 1-8

• Post Traumatic Stress Disorder: Studies mixed, insufficient, generally unsupportive 9-14

• Insomnia: Studies mixed 13-18

• Cancer chemo-induced N/V: Effective – similar to other antiemetics 18-20

• Cancer / HIV wasting: Studies limited, megestrol better 8,17,18,21-24

• Inflammatory Bowel Disease: ↓ symptoms but ↑ surgeries 25-28

• Diabetes: ↓DPN pain 17,29 ↓insulin resistance 30,31 ↓DM prevalence 32

Excludes

Mono-CBD StudiesCannabis-Based Medicines

for Non-Neurologic Disease

Not ready for

prime time !!

Except as 3rd line for

Cancer chemo N/V

Cancer / HIV wasting

1 Tambaro. Cannabinoids in anxiety disorders. Recent Pat CNS Drug Discov. 2012;7(1):25-402 Buckner. SAD is risk for CUD. J Psychiatr Res. 2008;42(3):230-93 Crippa. CB & anxiety review. Hum Psychopharm. 2009;24(7):515-234 Hser. CB ↓ improves anxiety, depression, sleep. J Subst Abuse Treat. 2017;81:53-8 5 Jiang. CB, anxiety, depression. J Clin Invest. 2005;115(11):3104-16 6 Woolridge. MJ for HIV Sxs. J Pain Symp Manag. 2005;29(4):358-67 7 Nelemans. CB, youth SAD. Eur Child Adol Psych. 2015 Aug 8 8 Buckner. Antecedents of MJ use. J Behav Ther Exp Psych. 2012; 43(1): 647-55 9 Shishko. Medical MJ for PTSD review. Ment Health Clin. 2018;8(2):86-9410 Betthauser. Cannabinoids in vets with PTSD. Am J Health Syst Pharm. 2015;72(15):1279-8411 Papini. Chronic CB associated with impaired fear extinction. J Abnorm Psychol. 2017;126(1):117-24

23 Badowski. Dronabinol in anorexia, weight loss in AIDS, cancer. Ther Clin Risk Manag. 2018;14:643-5124 Abrams. CB in cancer care. Clin Pharm Ther. 2015;97(6):575-8625 Hoffenberg. CB and pediatric IBD. J Ped Gastroent Nutr. 2017;64(2):265-7126 Naftali. CB response in Crohn's. Clin Gastroent Hepatol. 2013;11(10):1276-80.e127 Ravikoff. MJ use in IBD. Inflamm Bowel Dis. 2013;19(13):2809-1428 Storr. CB Sx relief but worse prognosis in Crohn's. Inflamm Bowel Dis. 2014;20(3):472-8029 Wallace. Inhaled CB efficacy in DPN. J Pain. 2015;16(7):616-2710 Penner. MJ impact on glucose, insulin, insulin resistance. Am J Med. 2013;126(7):583-931 Sidney. MJ & type 2 diabetes mellitus review. Curr Diab Rep. 2016;16(11):11732 Rajavashisth. Decreased DM prevalence in CB users. BMJ Open. 2012;2:e000494

12 O'Neil. Benefits, harms of plant-based CB for PTSD review. Ann Int Med. 2017;167(5):332-4013 Bonn-Miller. CB for sleep: heightened frequency in PTSD. Drug Alc Dep. 2014;136:162-5 14 Mizrachi Zer-Aviv. Cannabinoids and PTSD. Behav Pharm. 2016;27(7):561-915 Belendiuk. CB choice in sleep-disturbed CB users. Addict Behav. 2015;50:178-8116 Gates. Effects of cannabinoids on sleep review. Sleep Med Rev. 2014;18(6):477-87 17 Mücke. Cannabinoids in palliative care. Schmerz. 2016;30(1):25-3618 Whiting. Medical cannabinoids. JAMA. 2015;313(24):2456-73 19 Smith. Cannabinoids for N/V in adult CA chemotherapy. Cochrane Rev. 2015;(11):CD00946420 Phillips. Antiemetics for chemo-induced N/V in childhood. Cochrane Rev. 2016;2:CD00778621 DeJesus. Dronabinol ↑ appetite, weight in HIV/AIDS. J Int Assoc Phys AIDS Care (Chic). 2007;6(2):95-10022 Lutge. CB & morbidity / mortality in HIV/AIDS. Cochrane Rev. 2013;(4):CD005175

Cannabidiol Clinical Effects

• Seizures 1-3

Intractable Rx-resistant seizures of Dravet / Lennox-Gastaut Syndrome 4,5

• Parkinson’s Disease 6

• Psychiatric: Anxiety 3,7-11 PTSD 11,12 Psychosis 3,11,13 ? Depression 11

• Insomnia 10,14

• Cannabis Use Disorder 3,15-17

• Nausea and vomiting 18

• Cancer 19.20

• Adverse reactions: Fatigue Diarrhea ∆ appetite / weight 21,22

Minimal to no impairment 23

1 O'Connell. Cannabinoids in Rx-resistant epilepsy review. Epilepsy Behav. 2017;70(Pt B):341-82 Blair. Cannabinoid potential Rx in epilepsy? Expert Opin Pharmacother. 2015;16(13):1911-4 3 Devinsky. CBD pharmacology, role in epilepsy, neuropsych disorders. Epilepsia. 2014;55(6):791-8024 Thiele. CBD in seizures associated with Lennox-Gastaut RCT. Lancet. 2018;391(10125):1085-965 Devinsky. CBD trial in Dravet syndrome. Neuro. 2018;90(14):e1204-11 6 Crippa. CBD for non-motor Parkinson’s. Eur Arch Psych Clin Neurosci. 2019;269(1):121-337 Corroon. Cross-sectional study of CBD users. Cannabis Cannabinoid Res. 2018;3(1):152-618 Soares. Anti-panic actions of CBD. Curr Neuropharm. 2017;15(2):291-99 Schier. CBD as anxiolytic. Rev Bras Psiquiatr. 2012;34 Suppl 1:S104-1010 Shannon. CBD in anxiety, sleep. Perm J. 2019;23:18-041

11 Campos. Mechanisms of CBD in psych disorders. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3364-7812 Elms. CBD in PTSD case series. J Altern Complement Med. 2018 Dec 13. [Epub]13 Zuardi. Antipsychotic effects of CBD. Curr Pharm Des. 2012;18(32):5131-40 14 Kuhathasan. Cannabinoids for sleep. Exp Clin Psychopharmacol. 2019 15 Solowij. CBD Rx of psych, cognitive Sxs in CB users. Cannabis Cannabinoid Res. 2018;3(1):21-3416 McRae. MJ dependence Rx. J Sub Abuse Treat. 2003;24:369-76 17 Balter. Pharmacologic approaches to Rx CUD. Curr Addict Rep. 2014;1(2):137-4318 Parker. Regulation of nausea, vomiting by cannabinoids. Br J Pharm. 2011;163(7):1411-2219 Ramer. Cannabinoids as anticancer drugs. Adv Pharm. 2017;80:397-436 20 Velasco. Cannabinoids as anticancer agents. Prog Neuropsychopharm Biol Psych. 2016;64:259-6621 Iffland. CBD safety, AEs. Cannabis Cannabinoid Res. 2017;2(1):139-5422 Berfamaschi. CBD safety, AEs. Curr Drug Saf. 2011;6(4):237-49 23 Morgan. Acute THC, CBD psychotomimetic memory effects. Transl Psych. 2018;8(1):181

CBD

A different animal …

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Cerdá et al 1

• States with legalization vs States without legalization 2008-2016

Survey (self-report) NSDUH data: >500,000 respondents

• Relative to states not enacting permissive legislation:

• Age group 12-17 years old: 25 % ↑ Cannabis Use Disorder

• Age group 18-25 years old: No change

• Age group > 25 years old: 36 % ↑ Cannabis Use Disorder

Cannabis Use Disorder OutcomesRelated to

Cannabis Recreational Use Legalization

1 Cerdá. Recreational MJ legalization & MJ use, CUD 2008-2016. JAMA Psych. 13 Nov 2019

Colorado Traffic Deaths Related to Cannabis

0

30

60

90

120

150

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Ogden Memo“Commercialization”

Recreational UseFull Legalization

Adapted from Rocky Mountain Intensity Drug Trafficking Area. Legalization of MJ in Colorado Impact. September 2016 Accessed 9/4/16

Correlation to legalization unclear

PopulaLon, traffic ↑

Incomplete drug testing

Incomplete data collection

More officers trained to identify drug use

Colorado Outcomes: Medical

• ↑ CB-involved MVAs / fatalities - trend accuracy questionable 1-3

• CB-involved injuries - extent unknown 1

• ↑ CB-involved ED visits / for cyclic vomiting by 1.5-2x 1,4-6

• ↑ CB-related hospitalizations, poison center calls by 2x 1-3,7-9

• Unchanged: # of people admitted for CUD treatment 1

• ↑ Accidental CB ingesHon by children by 2 Hmes 11

• ↑ Pet ingesHon of CB products – extent unknown 12

• Burns due to THC extraction from cannabis

Expected to decline as CO2 is supplanting butane for extraction 2,3

1 Centennial Institute: Economic and Social Costs of Legalized Marijuana (Colorado). November 15, 20182 Rocky Mountain High Intensity Drug Trafficking Area. Legalization of MJ in Colorado Impact. 2018;5 3 Colorado Dept Public Safety, Division of Criminal Justice. Impacts of MJ Legislation. October 20184 Wang. MJ and acute health care contacts in Colorado. Prev Med. 2017;104:24-305 Monte. Implications of CB legalization in Colorado. JAMA. 2015;313(3):241-26 Wang. Impact of CB legalization in Colorado on adolescent ED, urgent care. J Adolesc Health. 2018;63(2):239-41

7 Davis. Public health effects of medical MJ legalization in Colorado. Am J Prev Med. 2016;50(3):373-98 Colorado Dept Public Safety, Division of Criminal Justice. MJ Legalization in Colorado: Early Findings. March 20169 Colorado Dept Public Health & Environment. MJ Poison Center Calls 2000-2017 10 Kim. Cyclic vomiting following MJ liberalization in Colorado. Acad Emer Med. 2015;22(6):694-911 Wang. Unintentional pediatric MJ exposures in Colorado, 2009-2015. JAMA Ped. 2016;170(9):e16097112 Meola. MJ toxicosis in dogs living in Colorado 2005-2010. J Vet Emer Crit Care. 2012;22(6):690-6 13 Bachhuber. CB law, opioid mortality. JAMA Int Med. 2014;174(10:1668-73

Red Text

Negative Outcomes

Blue Text

Positive Outcomes

Black Text

Neutral or Undetermined relation

↓ opioid

OD deaths ?? 13

Colorado Outcomes: Economic

• ↓ Unemployment in Colorado overall

• ↑ Unemployment among CB users 18,000 employed in CB industry 3

• ↑ Total gross CB sales 1,2

• CB industry credited with 5.5% of employment growth (1st half 2017) 3

• CB industry jobs typically have good benefits 4

• ↑ State tax revenue: $247 million in 2017 5

• For every $1 in tax revenue → $4.50 cost to mitigate adverse effects 6

• ↑ Commercial real estate valuation in areas allowing sales

• ↑ Residential real estate valuation in areas allowing sales by $15,600 7

• ↑ Housing / commercial / rental costs and renter CB-related evictions 6

• ↑ Employer costs: workplace policies and employee CB use violations 6

• Income diverted to CB purchases 6

1 Colorado Department of Revenue: MJ Sales Reports2 Market Size and Demand for MJ in Colorado 2017 Market Update: MJ Policy Group3 Feliz. Economic effects of MJ industry in Colorado. Federal Reserve Bank of Kansas City. April 16, 2018

4 Walters. Work and Well-Being in the CB Industry. 20175 Colorado Department of Revenue: MJ Tax Data6 Centennial Institute: Economic and Social Costs of Legalized Marijuana (Colorado). November 15, 20187 Cheng. Effect of legalizing retail MJ on housing values Colorado. Economic Inquiry. 2018;56(3):1585-601

↓ CB price 1

Blue Text

Positive Outcomes

Black Text

Neutral or Undetermined relation

Red Text

Negative Outcomes

Colorado Outcomes: Socio-Environmental

• ↓ Educational achievement among CB users 1

• ↑ CB-related student disciplinary incidents 1,2

• ↑ CB-related energy use 1

• ↑ CB-related environmental degradation 3

• ↑ CB plastic packaging: >18 million pieces (2017) 1

• ↑ CO2 emissions = CO2 produced by 38,000 cars (2016) 1

• ↑ Water use: 480 gallons per plant 4

• ↑ CB-containing parcels seized in mail service by 5 times (2013-2017) 5

• ↑ Non-mail-service interdictions of CB transported to other states, now trending down 5

• ↑ Public land plant seizures 5

Blue Text

Positive Outcomes

Black Text

Neutral or Undetermined relation

Red Text

Negative Outcomes

1 Centennial Institute: Economic and Social Costs of Legalized Marijuana (Colorado). November 15, 20182 Rosa. Colorado K-12 student discipline incidents: 2015-2016 school year. Colorado Dept Ed.3 Hammon. Impacts of outdoor growth of CB in Colorado. Colorado State Univ Extension. 20154 Chaitanya. CB cultivators’ report on water usage. Marijuana Venture. September 23, 20155 Rocky Mountain High Intensity Drug Trafficking Area. Legalization of MJ in Colorado Impact. 2018;5

Recommending Cannabis-Based Medicines

• Learn about cannabis 1

• Treat cannabis seriously

Do not tell patients simply “if it helps, take it”

• In the recommendation process 2-5 use same steps as

Controlled substance prescribing 6

Off-label prescribing 7,8

Consider cannabis off OFF label

1 Beaulieu. Medical CB considerations. Can J Anes. 2016;63(5):608-242 Metts. Medical MJ: Rx worth trying? J Fam Prac. 2016;65(3):178-85

3 Hill. Medical MJ for chronic pain & other problems. JAMA. 2015;313(24):2474-83 4 Aggarwal. Dosing medical MJ. Med Gen Med. 2007;9(3):52

Just say KNOW !

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Cannabinoid Family of Products

Cannabis plant / plant parts 1

3x ↑ potency over Lme 2,3 ↑ THC:CBD raLo over Lme 4

Hemp: < 0.3% THC 5

THC / THC congeners

Marinol® Casemet® Namisol®

Butane extraction: “shatter” “dab” “wax” 6

Synthetic street cannabinoids 7-10

“Spice” “K2” “Incense”

Desired effects: empathy, euphoria, well being

Adverse effects: panic, psychosis, violence, ARF, death

Cannabidiol-enriched products 11

Sativex® Canador® Epidiolex®

Charlotte’s Web 12,13

1 Hazekamp. MJ use survey. J Psychoactive Drug. 2013;45(3):199-210 2 Cascini. THC content in MJ increasing. Curr Drug Abuse Rev. 2012;5(1): 32-40 3 Mehmedic. MJ potency 1993-2008. J Forensic Sci. 2010;55(5):1209-17 4 Burgdorf. Composition of MJ seized in California. Drug Alc Dep. 2011;117(1):59-615 Larsen. The Illustrated History of Cannabis in Canada. 19716 You Tube. Hash honey butane extraction method Accessed 8/14/15

7 Gurney. Synthetic CBs. Forensic Sci Rev. 2014;26(1):53-78 8 Mustata. Spice: CBs as new designer drugs. Adicciones. 2009;21(3):181-6 9 Fattore. CB designer drugs. Front Behav Neurosci. 2011;5:60 10 Ghosh. Severe illness with synthetic MJ, Colorado. MMWR. 2013;62:1016-7 11 Scott. Enhancing CBD activity. Anticancer Res. 2013;33(10):4373-80 12 Maa. The case for MJ in epilepsy. Epilepsia. 55(6):783-6 13 Gupta. Charlotte's Web on CNN. 2014 Accessed 8/8/15

FDA Approved Cannabinoids

Nabilone (Cesamet®) Approved 1985 Schedule II

Synthetic cannabinoid similar to THC

FDA-approved indication: Cancer chemo-related N/V 1-3

Dronabinol (Marinol®) Approved 1986 Schedule III

Synthetic THC

FDA-approved indication: AIDS anorexia 4,5 Cancer chemo-related N/V 3,6-9

Versus smoked CB: Similar psychoactive effects 10

Cannabidiol (Epidiolex®) Approved 2018 Scheduling pending

Cannabidiol mono agent

FDA-approved indication: Seizures associated with Lennox-Gastaut or Dravet syndrome in patients >2yo 11,12

1 Pomeroy. Nabilone v domperidone. CA Chemother Pharm. 1986;17(3)285-8 2 Maida. Nabilone in CA symptoms. J Support Onc. 2008;6:119-2 3 Whiting. Medical cannabinoids. JAMA. 2015;313(24):2456-73 4 Struwe. Dronabinol, nutrition, HIV. Ann Pharmacother. 1993;27(7-8):827-31 5 Lutge. Medical CB HIV/AIDS. Cochrane Rev. 2013;4: CD005715 6 Meiri. Dronabinol v ondansetron. Curr Med Res Opin. 2007;23(3):533-43

7 McCabe. THC for refractory N/V. Invest New Drugs. 1988;6(3):243-6 8 Cotter. MJ, THC for chemo nausea. Onc Nurs Forum. 2009;36(3):345-52 9 Narang. Dronabinol & chronic opioids. J Pain. 2008;9(3):254-64 10 Issa. Psychoactive effects of po dronabinol studied in pain. Clin J Pain. 2014;30(6):472-811 Thiele. CBD in seizures associated with Lennox-Gastaut RCT. Lancet. 2018;391(10125):1085-9612 Devinsky. CBD trial in Dravet syndrome. Neuro. 2018;90(14):e1204-11

• Smoking 1

• Vaporization 1,2

• Oral-mucosal 1 Tinctures

• Oral “Edibles” 1,5,6

• Dermal 1

Cannabis-Based Products

By Route of Delivery

1 Russell. CB routes of administration for cannabis use. Int J Drug Policy. 2018;52:87-96 2 Spindle. PK profile of CB smoked, vaporized. J Anal Tox 2019 Jan 7. [Epub]3 Moritz. E-cigarette, or vaping, product use-associated lung injuries. MMWR. 2019;68(43):985-94 Navon. Risk factors for EVALI. MMWR. 2019;68(45):1034-9 5 Vandrey. PK profile of po CB, PD outcomes. J Anal Tox. 2017;41(2):83-99 6 Bruni. Cannabinoid delivery systems for pain, inflammation. Molecules. 2018;23(10). pii: E2478

Rapid onset 1

Rapid onset EVALI risk 3,4

Intermediate onset

Delayed onset, longer duration

Slow onset, Lower systemic levels

Products in dispensaries available up to 90% THC 2

• By plant source

• Cannabis sativa – more psychoactive, less sedating 1,2

• Cannabis indica – less psychoactive, more sedating 1,2

• Hybrids

1 Pearce. Discriminating the effects of C sativa, indica. J Altern Complement Med. 2014;20(10):787-912 Brunt. Satisfaction with different CB strains. J Clin Psychopharm. 2014;34(3):344-9 3 Vandrey. Dose, label accuracy in edible medical CB products. JAMA. 2015;313(24):2491-3

• By cannabinoid composition

• THC CBD THC:CBD ratio 1.2

• Stated dose not always accurate 3

• Other constituents often listed

THC CBD

H

Y

B

R

I

D

THC 20:1 2:1 1:1 1:2 1:20 CBD

Cannabis-Based Products

By Composition

1 Jensen. Medical MJ and chronic pain. Curr Pain Headache Rep. 2015;19:502 Aggarwal. Dosing medical MJ. Med Gen Med. 2007;9(3):523 Carter. Medicinal CB rational guidelines for dosing. IDrugs. 2004;7(5):464-704 MacCallum. Medical CB administration and dosing. Eur J Int Med. 2018;49:12-195 Michael Lewis, MD. Personal communication. 2/17/19

THC starting dose uncertain: 5-10 mg reasonable 1-3

Maximum recommended dose: 30 mg 4

Cannabis-Based Medicines

Dosing

Adjust according to efficacy or side effects

CBD starting dose uncertain: 5-15 mg 5

Maximum recommended dose: 60 mg 5

Medical Cannabis Products

AK-47

Blue Dream

Headband

Lemon Skunk

Qrazy Train

Northern Lights

Purple God

Sour Diesel

Train Wreck

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Photo: Steve Wright

Don’t put the cart

before the horse !

Don’t put the joint

before the science !

Screen all patients for all potentially addicting substances 1-4

Counsel patients evidence does not support safe recreational CB use 5,6

Screen CB users with validated screener for problematic use 7,8

Diagnose presence or not of CB addiction - refer as necessary 4

If CB addiction present, collaborate with addiction therapy team 4,9

Continue to monitor and respond to CB use 10

1 Strobbe. Prevention, Substance use SBIRT in 1º care. Prim Care. 2014;41(2):185-213 2 Guidance on Marijuana Screening: Colorado Health TeamWorks Accessed 8/5/15 3 Newton. ED alcohol/drug misuse detection. Pediatrics. 2011;128(1):e180-92 4 Turner. CB primary care approach. Can Fam Phys. 2014;60(9):801-9 5 Carney. BIs, substance-using adolescents. Cochrane Rev. 2014 Feb 4;(2):CD008969

6 Patnode. Behavioral interventions to reduce illicits in youth. AIM. 2014;160(9):612-20 7 CUDIT-R scale Accessed 7/30/15 8 Piontek. Short scales to assess CB-related problems. Sub Abuse Treat Prev Pol. 2008;3:25 9 Copeland. CB use disorder. Int Rev Psych. 2009;21(2):96-103 10 Lubman. CB, mental health. Aust Fam Phys. 2010;39(8):554-7

Practice Recommendations: CannabisPractice Recommendations: Cannabis-Based Medicines

Contraindications

Cannabis Use Disorder 1

Active addiction to other substances

Patient < 25 years old 1 (SORT B), excepting CBD

Women pregnant or planning to become pregnant 1

Working in a safety sensitive job 2

Significant respiratory, cardiac, vascular disease 1

Significant dyscognition, depression, anxiety 1

Presence or high risk for psychosis 1

Concurrent opioids, benzodiazepines, alcohol 1

Tobacco smoking 1

1 Kahan. Smoked CB for chronic noncancer pain. Can Fam Phys. 2014;60(12):1083-90 2 Phillips. MJ workplace guidance. JCOEM. 2015;57(4):459-75

Determine diagnosis, need for treatment

Determine approved treatments insufficient 1

Determine risk / benefit for CB-based medicines 2,3

Determine FDA approved cannabinoids insufficient

Patient education, informed consent for CB-based medicines

Follow law, regulations, guidelines, policy

Follow-up to ensure safety and efficacy per risk management 4,5

1 Joy. MJ as Medicine: Institute of Medicine Report. 1999 Accessed 2/1/162 Hill. Medical MJ for chronic pain & other problems. JAMA. 2015;313(24):2474-83 3 Kahan. Smoked CB for chronic noncancer pain. Can Fam Phys. 2014;60(12):1083-90 4 Sehgal. Opioid abuse predictors & strategies to curb opioid abuse in chronic pain. Pain Phys. 2012;15:ES67-92 5 Wright. REMS not 4-letter word. Colo Med Mag. 2017;114(5):43-4

Practice Recommendations: Cannabis-Based MedicinesPractice Recommendations: Medical Cannabis

Indications: Cannabis Plant

Oral, vaporized - not smoked

Neuropathic pain 1-13

Multiple sclerosis spasticity, central pain 1,2,13-15

Cancer chemotherapy nausea / vomiting 16-18

Cancer / HIV-AIDS wasting / weight loss 19-21

Not 1st line for

any indication

1 Metts. Medical MJ: Rx worth trying? J Fam Pract. 2016;65(3):178-85 2 Hill. Medical MJ. JAMA. 2015;313(24):2474-83 3 Dworkin. Pharmacological Rx neuropathic pain. Mayo Clin Proc. 2010;85(3 Suppl):S3-14 4 Nugent. CB effects, harms in chronic pain. Ann Intern Med. 2017 ;167(5):319-315 Petzke. Efficacy, tolerability, safety CBs for chronic neuropathic pain. Schmerz. 2016;30(1):62-88 6 Lynch. Cannabinoids for chronic non-cancer pain. Br J Clin Pharm. 2011;72(5):735-44 7 Mücke. CB-based medicines for chronic neuropathic pain. Cochrane Rev. 2018;3:CD012182

8 Selvarajah. Sativex in painful diabetic neuropathy. Diabetes Care. 2010;33(1):128-309 Wallace. Efficacy of inhaled CB on painful diabetic neuropathy. J Pain. 2015;16(7):616-27 10 Lynch. CB extract for chemo-induced neuropathic pain. J Pain Symp Manage. 2014;47(1):166-7311 Abrams. CB in painful HIV-associated sensory neuropathy. Neurology. 2007;68:515-2112 Ellis. Smoked CB for neuropathic pain in HIV. Neuropsychopharmacology. 2009;34(3):672-8013Amato. CB in MS, neuropathic pain, chemotherapy. Epidem Prev. 2017;41(5-6):279-9314 Torres-Moreno. Medicinal cannabinoids in MS. JAMA Network Open. 2018;1(6):e183485 15 Solaro. Pharmacological management of pain in MS. Drugs. 2010;70(10):1245-54

16 Mücke. Cannabinoids in palliative care. Schmerz. 2016;30(1):25-3617 Smith. Cannabinoids for N/V in adult CA chemotherapy. Cochrane Rev. 2015;(11):CD00946418 Phillips. Antiemetics for chemo-induced N/V in childhood. Cochrane Rev. 2016;2:CD00778619 DeJesus. Dronabinol ↑ appetite, weight in HIV/AIDS. J Int Assoc Phys AIDS Care . 2007;6(2):95-10020 Lutge. CB & morbidity / mortality in HIV/AIDS. Cochrane Rev. 2013;(4):CD005175 21 Badowski. Dronabinol in anorexia, weight loss in AIDS, cancer. Ther Clin Risk Manag. 2018;14:643-5122 Abrams. CB in cancer care. Clin Pharm Ther. 2015;97(6):575-86

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A calm and placid beatitude - every philosophical problem is resolved - Baudelaire

Marihuana … often makes the smoker vicious with a desire to fight and kill - Scientific American, 1936

I pay the saxophone because you don’t inhale

- Bill Clinton

68

Supplemental

Slides

69

• Medical Marijuana Laws by State https://healthcare.findlaw.com/patient-rights/medical-marijuana-laws-by-state.html

• Wright. Recreational CB use: hazards. J Fam Pract. 2016;65(11):770-3, 778-9. https://www.mdedge.com/jfponline/article/116578/addiction-medicine/recreational-cannabinoid-use-hazards-behind-high

• Wright. Recreational CB use: hazards. J Fam Pract. 2016;65(11):770-3, 778-9. https://www.mdedge.com/jfponline/article/116578/addiction-medicine/recreational-cannabinoid-use-hazards-behind-high

Resources

Cannabis Use Initiation Risk Factors

Younger age, especially adolescent initiation 1

Cannabis availability and peer use / pressure 2

Perception that cannabis risk is low 3,4

Other addiction-prone substance use 1,2,5

Personal mental health problems 6

Fun seeking 5

Lower religious involvement 5

Childhood maltreatment 7

Lax parenting style 8

Low family income 1

Medical cannabis advertising 9

1 Chen. Who becomes CB dependent soon after onset of use? Drug Alc Dep. 2005;79(1):11-22 2 Von Sydow. CB use, addiction prediction in youth. Drug Alc Dep. 2002;68(1):49-64 3 Merrill. CB use & risk perceptions. Am J Health Behav. 2015;39(3):308-17 4 ONDCP. National Drug Strategy: Data Supplement 2014 Accessed 3/20/165 Silins. Factors associated with CB use in young adulthood. Drug Alc Dep. 2013;133(2):452-86 Crane. Neuropsych sex differences & age CB initiation. J Clin Exp Neuropsych. 2015;37(4):389-401 7 Dubowitz. Child maltreatment & adolescent CB use. Child Maltreat. 2016;21:16-25 8 Choquet. Parenting & tobacco, alcohol, CB use among. Alc Alc. 2008;43(1):73-809 D’Amico. Medical CB ads & use during middle school. J Addict Behav. 2015;29(2)

Cannabis Addiction Risk Factors

Younger age, especially adolescent initiation 1-5

Use of other addiction-prone substances 1-6

Heavier cannabis use 5,7

Personal mental health problems 7

Family history of cannabis 4 or alcohol 5 addiction

Parental death before 15 yo 6 Trauma exposure 8

Poor social coping 8

Low family income 1,6

Non-white ethnicity 2

Lower education 2

1 Chen. Who becomes CB dependent soon after onset of use? Drug Alc Dep. 2005;79(1):11-22 2 Swendsen. Socio-demographic risk factors for alcohol and drug dependence. Addiction. 2009;104(8):1346-55 3 Behrendt. Transitions from 1st substance use to SUD in adolescence. Drug Alc Dep. 2009;9(1-3):68-78 4 Ehlers. CUD in San Francisco Family Study. Addict Behav. 2010;35(2):102-10 5 Perkonigg. Course of CB use, abuse dependence 1st decades of life. Addiction. 2008;103(3):439-49 6 von Sydow. CB use, addiction prediction in youth. Drug Alc Dep. 2002;68(1):49-64 7 Swift. Adolescent CB users at 24 years. Addiction. 2008;103(8):1361-70 8 Werner. Trauma experience & CB initiation, problem use. Drug Alc Dep. 2016 [Epub before print] 9 Sussman. 1y SUD prospective prediction in high-risk adolescents. J Subst Abuse. 2000;12(4):373-86

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Cannabis-Based Medicines

for Neuropathic Pain

• Multiple reviews conclude evidence of efficacy and harms 1-8

• Cochrane review: 16 RCTs 2-26 week duration 1,750 participants 7

• NNTB 11 for >30% pain ↓ NNTB 20 for >50% pain ↓

• NNTH 3 for CNS adverse events NNTH 10 for psych disorders

• “Potential benefits … might be outweighed by potential harms”

• Diabetic peripheral neuropathy 9,10

• Cancer chemotherapy neuropathy 8,11

• HIV neuropathy 12,13

1 Metts. Medical MJ: Rx worth trying? J Fam Pract. 2016;65(3):178-85 2 Hill. Medical MJ. JAMA. 2015;313(24):2474-83 3 Dworkin. Pharmacological Rx neuropathic pain. Mayo Clin Proc. 2010;85(3 Suppl):S3-14 4 Nugent. CB effects, harms in chronic pain. Ann Intern Med. 2017 Aug 15. [Epub ahead of print]5 Petzke. Efficacy, tolerability, safety CBs for chronic neuropathic pain. Schmerz. 2016;30(1):62-88 6 Lynch. Cannabinoids for chronic non-cancer pain. Br J Clin Pharm. 2011;72(5):735-44

7 Mücke. CB-based medicines for chronic neuropathic pain. Cochrane Rev. 2018;3:CD012182 8 Amato. CB in MS, neuropathic pain, chemotherapy. Epidem Prev. 2017;41(5-6):279-939 Selvarajah. Sativex in painful diabetic neuropathy. Diabetes Care. 2010;33(1):128-3010 Wallace. Efficacy of inhaled CB on painful diabetic neuropathy. J Pain. 2015;16(7):616-27 11 Lynch ME. Oral mucosal CB extract for chemo-induced neuropathic pain. J Pain Symp Manage. 2014;47(1):166-7312 Abrams. CB in painful HIV-associated sensory neuropathy. Neurology. 2007;68:515-2113 Ellis. Smoked CB for neuropathic pain in HIV. Neuropsychopharmacology. 2009;34(3):672-80

Fair-Quality RCTs

Mixed Results

Excludes

Mono-CBD Studies Cannabis-Based Medicines and Opioids

• Same neural pathways mediate physiologic dependence / addiction 1,2

• Cannabinoids-opioid CNS systems interact 3-5

• Cannabinoids & opioids might have analgesic synergy 2,6-12 Contested 13,14

• Cannabinoids might reduce opioid tolerance, dose used 11,12,15-18 Contested 13,14

• Cannabinoids are used as alternative to opioids for pain 19,20 Contested 13,14,21

• Cannabinoids can help opioid-resistant pain 22

• Mood worse: CB + opioids vs opioids alone 23

• States with medical CB with 25% fewer opioid OD deaths 24 Confirmation bias ?? 25

• CB use predictive of subsequent Opioid Use Disorder 26,27

• Recent CB use associated with ↓ opioid use by opioid injectors 28

19 Abuhasira. Medical cannabis in the elderly. Eur J Int Med. 2018;49:44-50 20 Lucas. Medical CB substitution for Rx opioids. Int J Drug Pol. 2017;42:30-5 21 Liang. Medical CB legalization & opioid Rx 1993-2014. Addict. 2018;113(11):2060-7022 Johnson. THC:CBD & THC extract in intractable CA pain. J Pain Symp Manage. 2010;39(2):167-79 23 Rogers. Opioid + CB relations to substance misuse, MH, pain. J Addict Med. 2018 December 13. [Epub]24 Bachhuber. CB law, opioid mortality. JAMA Int Med. 2014;174(10:1668-73 25 Hall. Access to medicinal CB in hopes of solving opioid crisis. JAMA. 2018;113(6):987-826 Olfson. CB use & OUD risk. Am J Psych.2018;175(1):47-53 27 Butelman. NMU CB self-exposure predicts OUD. Front Psych. 2018 27;9:28328 Kral. CB, opioid use in people who inject drugs. Drug Alc Dep. 2015;153:236-41

1 Manzanares. Interactions between opioids & CBs. Trends Pharm Sci. 1999;20(7):287-94 2 Welch. Interaction of CB & opioid systems in nociception. Int Rev Psych. 2009;21(2):143-513 Scavone. CB & opioid interactions. Neuroscience. 2013;248:637-544 Cichewicz. Synergistic interactions between CB & opioids. Life Sci. 2004;74(11):1317-24 5 Desroches. Opioid-CB interactions in pain management. Curr Drug Targets. 2010;11(4):462-736 Abrams. MJ-opioid interaction. Clin Phrm Ther. 2011;90(6):844-51 7 Roberts. THC, morphine synergy. Eur J Pharm. 2006;530(1-2):54-8 8 Welch. CB, opioid analgesic synergy. Int Rev Psych. 2009;21(2):143-51 9 Cooper. Co-admin OXC & smoked CB on analgesia. Neuropsychopharm. 2018;43(10):2046-55

10 Nielsen. Opioid-sparing effect of cannabinoids meta-analysis. Neuropsychopharm. 2017;42(9):1752-6511 Lynch. CB reduces opioid dose. J Pain Symp Manage. 2003;25(6):496-8 12 Karst. CBs pain efficacy, strategies to reduce psychoactivity. Expert Opin Invest Drugs. 2009;18(2):125-33 13 Campbell. CB effect in people with chronic nonCA pain Rxd opioids. Lancet Public Health. 2018;3(7):e341-5014 Humphreys. Should physicians recommend replacing opioids with CB? JAMA. Online February 1, 201915 Boehnke. Medical CB use associated with decreased opiate. J Pain. 2016;17(6):739-4416 Vigil. Medical CB & Rx opioid use in chronic pain. PLoS One. 2017;12(11):e0187795 17 Stith. Legal access to CB & Scheduled II-V drug Rxs. J Am Med Dir Assoc. 2018;19(1):59-64.e118 Boehnke. Medical CB associated with decreased opiate med. J Pain. 2016;17(6):739-44

Cannabis-Based Medicines

for Multiple Sclerosis

• Reviews conclude evidence of efficacy and harms 1-3

• Symptomatic benefit significant 2-9

• Pain

• Spasticity

• Bladder dysfunction

• Adverse events limited, manageable 2,9

• No effect on disease progression 10

8 Amato. CB in MS, neuropathic pain, chemotherapy. Epidem Prev. 2017;41(5-6):279-93 2 Torres-Moreno. Medicinal cannabinoids in MS. JAMA Network Open. 2018;1(6):e183485 3 Solaro. Pharmacological management of pain in MS. Drugs. 2010;70(10):1245-544 Langford. THC/CBD oromucosal spray for neuropathic pain in MS. J Neuro. 2013;260(4):984-975 Rog. Oromucosal THC/CBD for neuropathic pain in MS. Clin Ther. 2007;29(9):2068-79

Well-designed RCTs

Good Results

Excludes

Mono-CBD Studies

6 Collin. CB-based medicine in spasticity in MS. Eur J Neuro. 2007;14(3):290-67 Flachenecker. LT effectiveness, safety of nabiximols for spasticity in MS. Eur Neurol 2014;72(1-2):95-1028 Flachenecker. Nabiximols in clinical practice for MS spasticity. Eur Neuro. 2014;71(5-6):271-9

9 Wade. CB-based meds for Sxs in MS. Mult Scler. 2004;10(4):434-4110 Zajicek. Dronabinol, MS progression. Lancet Neuro. 2013;12(9):857-65

• Coined in 1998 by Raphael Mechoulam and Ben-Shabat 1

• Involves “cross-talk” between and among biological pathways 2

• Synergy: Effect is greater than the sum of individual effects

• Due to various cannabinoids in cannabis – for example nabiximols 3,4

• Postulated opioid-cannabinoid analgesic synergy 5

• Entourage: Effect amplified by compound not known to have that effect by itself 1

• Due to various terpenoids in cannabis 1,6,7

• Research may show compounds do have such effects, e.g., myrcene “couch lock” 7

• Foundation for argument for medical use of plant / plant extracts

As opposed to medical use of isolated cannabinoids

The Entourage Effect

1 Ben-Shabat. Entourage : inactive endogenous fatty acid glycerol esters ↑ 2-AG activity. Eur J Pharm. 1998;353(1):23-31 2 Lex. Entourage: relationships between biological pathways. IEEE Trans Vis Comput Graph. 2013;19(12):2536-453 Schoedel. Effects of oromucosal sprays containing cannabinoids. Curr Pharm Des. 2012;18(32):5008-14

4 Lewis. Pharmacological foundations of CB chemovars. Planta Med. 2018;84(4):225-335 Nielsen. Opioid-sparing effect of cannabinoids meta-analysis. Neuropsychopharm. 2017;42(9):1752-656 Russo. CB pharmacology. Adv Pharm. 2017;80:67-1347 Russo. Potential CB synergy, phytocannabinoid-terpenoid entourage. Br J Pharm. 2011;163(7):1344-64

Future of Cannabis-Based Medicines

Cannabidivarin: Seizures 1

Tetrahydrocannabidivarin: Seizures 2

Cannabichromene: Anti-inflammatory 3

Cannabigerol: Inflammatory bowel disease 4

Glaucoma 5

1 Davis. CBs in pain: CB1, CB2, non-classic receptor ligands. Expert Opin Invest Drugs. 2014;23(8):1123-402 Hill. Cannabidivarin anticonvulsant in mouse, rat. Br J Pharm. 2012;167(8):1629-42 3 Hill. Tetrahydrocannabivarin suppresses epileptiform activity in rats. Epilepsia. 2010;51(8):1522-32 4 DeLong. Cannabichromene pharmacology. Drug Alc Dep. 2010;112(1-2):126-33 5 Borelli. Cannabigerol in experimental IBD. Biochem Pharm. 2013;85(9):1306-16 6 Tomida. Cannabinoids and glaucoma. Br J Ophthalmol. 2004;88:708-13

CB2 agonists 1

CB1 antagonists 1

CB1 selective agonists 1

Cannabinoid bifunctional ligands 1

Regionally-restricted cannabinoids 1

Peripherally-restricted cannabinoids 1

• 2000 Amendment 20 to the state constitution

Allows medical use in defined ways

• 2009 Commercialization of medical use

Increased expansion of medical use with the Ogden memo

Which stated the federal government would not prosecute when state laws followed

• 2012 Amendment 64 to the state constitution

Allowed recreational use in defined ways

• 2014 Full implementation of rule making allowing recreational use

Colorado Cannabis Legalization

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Past Month Cannabis Use

• Before medical commercialization v After recreational legalization 1

Youth ↑ 32% College age ↑ 42% Adults ↑ 127%

• However in 2016 youth use prevalence came returned to 2008 level 1

• However from 2005 to 2015 adolescent ED, urgent care visits more than doubled 2

• Colorado ranks 3rd in US for cannabis use prevalence 1

Colorado Outcomes

Healthy Kids Colorado survey:

No change in frequency of use

by high school age youth 3,4

1 National Survey on Drug Use and Health – 20172 Wang. Colorado CB legalization & adolescent ED, urgent care visits. J Adolesc Health. 2018;63(2):239-41 3 CDPHE. Monitoring Health Concerns Related to Marijuana in Colorado. 2018. Accessed 1/8/18

4 Healthy Kids Colorado, Colorado Youth MJ Use Survey 2017. 2018

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