Marijuana 101, 102 and 103

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1 Marijuana 101, 102 and 103 Andrew Kowal, MD, FASAM Director, Pain Management Center Assistant Clinical Professor of Anesthesiology, Tufts Medical School Lahey Hospital & Medical Center Burlington, MA

2 Why drink and drive, when you can smoke and fly. If we all had a bong, we d all get along.

3 I Have Nothing To Disclose

4 Agenda A brief history of the medicinal use of marijuana A review of the pharmacology/physiology of the endocannabinoid system Does marijuana actually have good (any?) data supporting its utilization medically Adverse effects of marijuana Legal considerations for the clinician Everyone please grab a free brownie on way out

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7 Cannabis sativa or Cannabis indica Subspecies of hemp plant Common throughout world

8 Listed in U.S Pharmacopeia marijuana & hashish extracts were the 1 st, 2 nd, or 3 rd most prescribed meds in the US from s

9 neuralgia gout rheumatism tetanus hydrophobia epidemic cholera convulsions chorea hysteria mental depression delirium tremens insanity uterine hemorrhage

10 California's Proposition First statewide medical marijuana ballot initiative to pass in the USA allow possession and cultivation of cannabis for debilitating medical conditions if recommended by a physician provide a defense against prosecution under state criminal laws

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12 Venice Beach, CA The Clevelenad Clinic of Medical THC

13 Common Forms of Cannabis Hashish - dried resin and compressed flowers 9 -THC content ranged from 3 to 7% with rare increases as high as about 20% Accounted for < 1% of all confiscated marijuana samples in the past ten years Marijuana - dried flowering tops and leaves Wide range of 9 -THC content with increases as high as about 30% most common form

14 > 400 chemicals, NaturalCBs neurotransmitterrelease Endogenous Anandamide ( bliss ) Exogenous Sativa plant (marijuana) Tetrahydrocannabinol (THC) psychoactive Cannabidiol (CBD) PERIPHERAL

15 In 1960s-70s potency ~1-2%THC Today, up to 20-25%THC

16 Butane Hash Oil (BHO) Dab, Shatter, Wax

17 Primary psychoactive constituent Endocannabinoid system Brain development Mimics anandamide Dial down neuron activity THC longer and stronger

18 Opiates / Marijuana Papaver somniferum (poppy) opium Endorphins Mu, kappa Percocet Cannabis Sativa (marijuana) THC, Cannebediol Anandamide CB1, CB2?Sativex

19 THC activates the CB1 and CB2 cannabinoid receptors: CB1 has high density in cerebellum, basal ganglia, hippocampus, cerebral cortex. CB1 has low density in the brainstem, hence low risk of respiratory depression. CB2 is found in spleen, hematopoietic cell lines, mast cells. 41

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21 CB1 CNS site of CB binding Memory, learning, problem solving, coordination Activated by anandamide, other CBs Modulates neurotransmitters CB2 immune cells outside CNS Anti-inflammatory effects

22 Dopamine (DA) - euphoria, reward, pleasure GABA - muscle relaxation, sleepiness Glutamate - relaxation, memory

23 Mild euphoria and relaxation The giggles Increased sensitivity to external stimuli: Colors seem brighter Smells are more pungent Distortion of time perception 16

24 Smoked marijuana: Reaches the brain in minutes. Effects last 1-3 hours. Delivers a lot of THC into the bloodstream. Eating or drinking marijuana: Routes of Administration Takes ½ - 1 hour to have an effect Effects last up to 4 hours. Delivers significantly less THC into the bloodstream. SMOKED VAPORIZED EATEN/DRUN K Smoked in a pipe, bowl, cigarette Inhaled through machine that converts active compounds into inhalable form. Rapid effects Rapid effects Consumed as ingredient in baked goods, candies, sodas Takes time to reach brain, so effects are delayed 19

25 Adrenergic look-alike: Tachycardia Hypertension (but orthostatic hypotension) Tachypnea Dry mouth Conjunctival injection Appetite increase

26 Short-term memory impairment Judgment impairment leading to risky sexual behaviors Motor coordination impairment interfering with driving skills 24

27 AcuteTHC Peripheral vision Motor coordination reaction time time/distance judgment #1 reported illicit drug in accidents/fatalities 2x accident risk 3-7x risk of causing accident

28 THC impairs primarily automatic driving functions Can be compensated with behavioral strategies Alcohol impairs complex tasks requiring conscious control Combining THC withalcohol Eliminates the compensatory strategies that help withthc Results in impairment even at doses that would be insignificant for either drug alone

29 Mental slowing Planning ability Judgment, concentration,memory Apathy, pursuit of goals

30 Ability to learn Attention,concentration Abstract reasoning anddecision-making Memory

31 Respiratory Function Infections Stroke/Temporary brain blood constriction

32 Endocannabinoid system plays a role in the control of brain maturation, particularly emotional responses Babies exposed tothc: Neurological development effects Children exposed tothc: Problem-solving skills, memory, attention THC-specific vs. associated environmental factors hard to sort out

33 Anxiety Acute THC anxiety Long-termTHC anxiety Depression Psychosis

34 Percent (SE) 70 Marijuana General Population NESARC, 2005; slide courtesy of Dr. Frances Levin.

35 MeasuresTHC Casual use: Up to 10 days in urine 50% positive in hair samples Heavy use: Up to 30 days in urine 85% positive in hair samples Weight loss gives serial UTox spike Dronabinol gives positive test Passive inhalation gives negative test

36 3 grams of synthetic cannabinoids sprayed on vegetable matter, herbal incense or meditation potpourris Labeled not for human consumption No age restriction Sold in stores or on the Internet as legal high

37 Cannabimimetic Agents are Schedule I. Unless specifically exempted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of cannabimimetic agents, or which contains their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. 7

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41 22 million users in past month 13% users have CUD 305,000 sought Rx forcud

42 In SameYear, 2 of: Tolerance Withdrawal Use more/longer Unable to use Use despite problems Craving Failed roles Hazardous use Social problems Activities Lots time use

43 9% of people who use marijuana will become addicted. The risk increases to 17% in people who start using in their teens. The risk increases to 25 to 50% in people who are daily users (most of whom started using marijuana early in adolescence). 11

44 MonitoringTheFuture.org; Volkow, NEJM, 2014.

45 36% of teens think MJ harmless 43% favor legalization 80s: 15% 90s-00s: 30% Harm perception lowest in 40yrs Often precedes prevalence

46 Ever tried ~17% 8th graders ~50%12th graders Past year use 12% 8th graders 35% 12th graders Current use (past month) 7% 8th graders 21% 12th graders Surpasses current alcohol and tobacco use

47 Cancer Cannabis has up to 70% more carcinogens than tobacco However, evidence of causality is inconclusive Bronchitis and chronic cough Warning for Coronary ArteryDisease Amotivational syndrome debate

48 Adverse Effects: Long Term or Heavy Use Addiction (in about 9% of users overall, 17% of those who begin use in adolescence,and 25 to 50% of those who are daily users) Altered brain development Poor educational outcome, with increased likelihood of dropping out of school Cognitive impairment, with lower IQ among those who were frequent users during adolescence Volkow et al,n engl j med 370;23 nejm.org june 5, 2014

49 Adverse Effects: Long Term or Heavy Use Diminished life satisfaction and achievement (determined on the basis of subjective and objective measures as compared with such ratings in the general population) Increased risk of chronic psychosis disorders (including schizophrenia) in persons with a predisposition to such disorders Symptoms of chronic bronchitis Volkow et al,n engl j med 370;23 nejm.org june 5, 2014

50 Memory Learning & retaining new information Attention and concentration Response speed & variability Executive functioning Working memory Verbal fluency

51 Meier, Proc. Natl. Acad. Sci., 2012.

52 Meier, Proc. Natl. Acad. Sci., 2012.

53 Biological markers normalize ~4wks CB receptor density in brain Cortical blood volumes Especially in cognitive areas

54 Apparent after a few days of abstinence Complete return-to-baseline by 30 days

55 Size, shape and function of brain regions Important for: Reward and motivation Cognition Efficiency of inter-region connectivity

56 CB1 Receptors from infancyto age 30 Most and latest change in areas of: Reward and motivation Cognition

57 Contradictory and controversial findings Some suggest no lasting deficits Others find persistent deficits in 1+ domains Most show at least partial recovery by 30d Recovery likely, though longer than adults

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59 Pain (cancer, multiple sclerosis) Nausea (cancer) Loss of appetite and wasting (HIV/AIDS) Increased ocular pressure (glaucoma) Inflammation (rheumatoid arthritis, Crohn s disease, ulcerative colitis) Epilepsy

60 The Players (forms of MJ available) Oral Tab Formulations: dronabinol (marinol), nabilone (casamet), cannabis extracts Oral Spray: nabixemols (sativex) Marijuana Plant : smoked, vaporized, ingested in brownies

61 Nabixemols (Sativex) Oral spray containing 1:1 ratio of THC:CBD Approved in 24 countries for spasticity from MS, neuropathic pain, cancer pain Phase 3 trials in US for cancer pain (Fast Track) 20 times lower peak plasma THC Absorption through buccal mucosa and metered dosing may mimic smoked marijuana without as many psychotropic effects New Studies: NO BETTER THAN PLACEBO

62 Glaucoma May cause transient decrease in IOP, provide neuroprotective effect THC but not CBD lowered IOP in rabbits Currently available therapies are more effective Volkow et al,n engl j med 370;23 nejm.org june 5, 2014

63 Inflammation CBD has shown potential to be anti-inflammatory by its effect on reducing cytokine production and cell proliferation ANIMAL studies have shown promise in RA and Crohns/UC Rev Bras Psiquiatr 2008;30: Phytother Res 2013;5:633-6.

64 Neurologic Disorders AAN Koppel etal 34 studies found that met criteria with 8 Class 1 stringent criteria Spasticity in MS: cannabis extract works for reducing patient reported scores, ineffective for objective measures at 15 weeks, maybe at 1 year. Smoked uncertain efficacy Pain in MS: extracts/nabiximols probably effective. Smoked uncertain efficacy Some efficacy in epilepsy,tremors Neurology 82 April 29, 2014

65 Epidiolex Recommemded by FDA Panel for Pediatric Epilepsy (pure CBD)

66 Chronic Pain Smoked THC MAY be effective in neuropathic pain syndromes through central and peripheral modulation of nociceptive pathways. No long term studies beyond 3 months Worrisome population prone to exposure to multiple addictive/sedating substances 94% of RX in Colorado for chronic pain, yrs old J Pain 2008;9: Anesthesiology 2007;107:785-96

67 Does Marijuana Decrease Opioid Abuse? Dr. Sanjay Gupta of CNN says yes AJP 2018 Olfson etal: adults who use THC 6x more likely to misuse opioids, 8x to have opioid use d/o after 3 years Marijuana use tends to increase rather than decrease risk for opioid abuse or dependence Pain Medicine 2017;0:1-12 : pts using thc and opioids concurrently for chronic pain have higher rates of opioid misuse Some states initially showed decline (CO), but now back to increasing OD rates, in addition to cocaine and methamphetamine use exploding Marijuana a companion drug not a replacement

68 MA Medical Marijuana Law It is ILLEGAL for a physician to write for/ prescribe a Schedule 1 drug (heroin, thc), doing so one can lose DEA number and be banned from Medicare patients etc Physicians can recommend or certify patients for Marijuana, under the belief that this is not a prescription Case Law: Pearson vs. McCaffery 2001, federal court determined a physician recommending marijuana is writing a prescription for marijuana and a violation of federal law

69 MA Medical Marijuana Law The MA law does not require healthcare providers or hospitals to provide written recommendations for medical marijuana The MA law DOES NOT protect someone from being terminated or the refusal to hire someone because they use medical marijuana No protection against federal prosecution The use of medical marijuana is not protected under the Americans With Disabilities Act ONE provider breaking federal law can cause entire health system to lose Medicare eligibility

70 What do the Big Boys Say about Medical THC procon.org Johns Hopkins: no position MGH: did not respond Mayo: consider risks Cleveland Clinic: does not recommend use of illegal substances UCLA: we have no stated position UCSF: no position BWH: no position Duke: we will not be participating

71 Cannabis includes marijuana plants and synthetic cannabinoids Cannabis use is common, risk of a use disorder increases with earlier onset of use Marijuana contains more THC now than in the past, which likely impacts risk for psychosis, anxiety, and negative consequences Marijuana effects cognition, but this is reversible in adults, impacts on adolescents less clear Cannabis may or may not reduce opioid consumption

72 THANK YOU!

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