Cannabis Use Disorder: Endocannabinoid System, Side Effects, Risks & Therapies

1. Cannabis Use Disorder Presentation provided by Selene Etches MD, FRCPC IWK Health Centre, Halifax, Nova Scotia

2. No conflict of interest to declare No pharmaceutical industry support No support from cannabis producers DISCLOSURE

3. Endocannabinoid System Cannabis and methods of cannabis intake Epidemiology of cannabis use disorders Synthetic Cannabinoids Cannabis intoxication and withdrawal Driving Mental Health and Cognitive Effects Use in pregnancy and breast feeding Psychotherapeutic and pharmacological treatments Therapeutic Benefits ? OBJECTIVES

4. Regulate the action of neurotransmitters that play roles in cognition, emotion, and memory • Critical role in brain development and maturation especially in adolescence and young adulthood ENDOCANNABINOIDS

5. CB1 receptors • CNS • Responsible for euphoric and anticonvulsive effects of cannabis • Endocannabinoidanandamide binds as partial agonist • CB2 receptors • Periphery • Highly inducible following inflammation and injury, play a role in immune response • Endocannabinoidarachidonoylglycerol (2-AG) binds as full agonist ENDOCANNABINOIDS

6. Around 500 compounds, 80+ are phytocannabinoids • Chief cannabinoid is Δ 9-tetrahydrocannabinol (THC) • Partial agonist to CB1 receptor • Another key component is cannabidiol (CBD) CANNABIS THC

7. Cannabis sativa Stimulating, hallucinogenic Higher THC:CBD ratio Often daytime use Cannabis indica Lower THC:CBD ratios Calm, relaxation, sleep aid

11. www.ccsa.ca • www.cclt.ca Cannabis is the most widely used illicit drug in Canada - 10.6% of Canadians aged 15+ years (CTADS, 2013)

12. 1/10 who ever use 1/6 who start in adolescence ¼ - ½ who use daily Large proportion self-discontinue EPIDEMIOLOGY – USE DISORDERS

13. Pharmacological research tools to study endocannabinoid system Synthetic cannabinoids sprayed on herbal plants No cannabidiol Super agonist at CB1 receptor Can cause acute renal failure, hypertension, myocardial infarction, seizures, psychosis, death Not detected in standard urine drug screens SYNTHETIC CANNABINOIDS

14. CANNABIS EFFECTS Mild euphoria Relaxation Increased perceptual experiences Distortion of time perception ↑ HR, ↑ RR, orthostatic hypotension Conjunctival injection Appetite increase https://www.drugabuse.gov/publications/drugfacts/marijuana

15. Chronic cannabis use and: • Recurrent nausea and vomiting • Abdominal pain (periumbilical/epigastric, colicky or crampy) • Relief of symptoms with hot bathing • Improvement of symptoms with cannabis cessation • Acute renal failure can occur in these patients CYCLIC VOMITING/CANNABIS HYPEREMESIS

16. Cannabis smoke contains 3 x more tar and 5 x more carbon monoxide than standard cigarette • 1 bong/joint = 3-5 cigarettes in terms of lung damage • Bongs do not reduce exposure to tar or carbon monoxide • If use a plastic bong, have exposure to byproducts and chemicals from heating the plastic • Vaporizers lead to exposure of potentially neurotoxic levels of ammonia • Mixed evidence linking cannabis to COPD or lung cancer • Case reports of aspergillious pneumonia RESPIRATORY EFFECTS

17. Case reports of acute coronary syndromes and strokes • Secondary to reversible cerebral vasoconstriction • Reports of ischemic strokes in young people using synthetic cannabinoids • 4 x increased risk of MI in patients with recent MI in hour after smoking cannabis • Compared to cannabis users without history of MI CARDIOVASCULAR EFFECTS

18. PsychosisBipolar DisorderDepressionAnxietySuicideSleepPTSDCognition

19. Associated with depersonalization, hallucinations, anxiety, paranoia • Responds well to treatment • Low dose antipsychotics, benzodiazepines, reassurance • Exception: synthetic cannabinoid-induced psychosis CANNABIS-INDUCED PSYCHOTIC DISORDER

20. SUBSTANCE-INDUCED PSYCHOTIC DISORDER ALGORITHM Hallucinations, delusions, or grossly disorganized thoughts/behaviours? Has the patient used substances over the past 4 weeks or currently under the influence? YES Could psychotic symptoms be a direct result of substance use or withdrawal? Do psychotic symptoms go into remission with 4 weeks after the patient discontinues use of offending substance? YES YES NO NO NO YES NO • The patient does not have psychotic symptoms at this time • Evaluate for • Substance use • Affective disorders • Other disorders • Psychotic symptoms are less likely to be a direct result of substance use/withdrawal • Evaluate for • Schizophrenia spectrum disorders • Affective disorders with psychotic features • Psychosis due to GMC • Brief psychotic disorder • Psychotic symptoms appear to be a direct result of substance use/withdrawal • Evaluate for • Substance-induced psychotic disorder • Another disorder that explains symptoms better

21. Overall, at least a 2 fold increased risk of developing a psychotic disorder in regular cannabis users • Even higher risk in areas where THC is higher potency • Stronger association with: • Early age at first cannabis use • Frequent daily use • Use of high potency cannabis • Risk factors for psychosis CANNABIS USE AND PSYCHOSIS

22. Cannabis is seen as a preventable risk factor for schizophrenia • Prevention, early identification and treatment of cannabis use may delay onset of psychotic illness in those at high risk • Advise siblings of those with psychosis not to use cannabis • Advise those with a family history of psychosis not to use cannabis CANNABIS AND PSYCHOSIS

23. Cannabis is the most commonly used illicit substance in patients with schizophrenia • Increased number of hospitalizations • Increased length of hospital stays • Stopping cannabis after onset of psychosis: • Decreased positive symptoms • Improved mood and anxiety • Improved global functioning • Increased medication adherence • Decreased relapse CANNABIS USE AFTER ONSET OF PSYCHOTIC DISORDER

24. Earlier age of onset of bipolar disorder • Greater length and number of affective and manic episodes • More rapid cycling • More suicide attempts • Increased overall disability • More hospitalizations • More severe course of illness • Patients with bipolar disorder who stopped using cannabis had similar outcomes after 2 years to those who did not use cannabis BIPOLAR DISORDER AND CANNABIS

25. People who use cannabis, particularly early, regular and heavy use, are more likely to develop depression • Young women appear to be more likely affected • Estrogen’s effects on development of female nervous system depends on well-regulated functioning of endocannabinoid system DEPRESSION AND CANNABIS

26. Appears to be an increased risk of suicidal ideation and suicide attempts although evidence is mixed Risk factor (OR = 2-3) may be heavy use under age 15 SUICIDE AND CANNABIS

27. Social anxiety disorder is associated with 6.5 x increased risk of developing a cannabis use disorder THC, especially at doses >5%, can induce fear, panic attacks Formulations with high THC:CBD increase anxiety scores Formulations with low THC:CBD may decrease anxiety scores ANXIETY AND CANNABIS

28. Individuals with PTSD have increased rates of substance use disorders • Cannabis use in PTSD is associated with: • Increased symptom severity • Increased violent behaviour • Greater alcohol and other substance use • Exacerbations of PTSD impairments in memory, concentration, and information processing • No RCT’s have been completed, currently insufficient evidence to recommend its use PTSD AND CANNABIS

29. Decreased executive function and impulse control • Processing speed, working memory, and attention can show mild long term effects • Improves with days-weeks of abstinence • IQ decline among persistent cannabis use in adolescence • Drop from 50th% to 29th% (5-8 points) • Similar to high doses of lead exposure COGNITIVE EFFECTS OF CANNABIS USE IN ADOLESCENCE

30. More frequent, earlier and persistent cannabis use correlated with increased impairment • ABCD study – started fall 2015 • 11,000+ youth ages 9-10 • Will follow into early adulthood • Integrating brain imaging with genetics, neuropsychological, behavioral, and other health assessments COGNITIVE EFFECTS OF CANNABIS USE INADOLESCENCE

31. Growing evidence that cannabis directly decreases motivation Question: what effect does disruption of sleep have on overall malaise and motivation? EFFECTS ON MOTIVATION

32. Decreased REM sleep Shorter sleep onset time Increased stage 4 sleep Sedative effects can persist into the next day CANNABIS AND SLEEP

33. Cannabis is the most frequently used illicit drug in pregnancy Crosses placenta to the fetus Impaired intrauterine growth Lower birth weight Increased infant anemia Increased risk of NICU stay Transferred into breast milk

34. Executive dysfunction and attention deficits in offspring Increased impulsivity Adverse effects on cognitive development and academic achievement Increased risk of use of cannabis in adolescence and young adulthood MATERNAL CANNABIS USE DURING PREGNANCY AND BREAST FEEDING

35. Cessation of cannabis use that has been heavy or prolonged • 3 or more of the following signs and symptoms within ~ 1 week of cannabis discontinuation: • Irritability, anger, aggression • Nervousness or anxiety • Sleep difficulty • Decreased appetite or weight loss • Restlessness • Depressed mood At least one of the following physical symptoms causing significant discomfort: • Abdominal pain • Shakiness/tremors • Sweating, fever, chills • Headache CANNABIS WITHDRAWAL

36. Most intense in first week, peak day 4, can last a month Often use nicotine and cannabis together so have withdrawal from both Among adolescents and adults engaged in treatment or in heavy cannabis use, 50-95% report withdrawal symptoms In clinical laboratory studies, aggression is frequently seen in withdrawal CANNABIS WITHDRAWAL

37. Cannabis is the most common illicit drug identified in MVA’s and fatalities Among young drivers, driving after using cannabis is greater than rate of driving after drinking alcohol Cannabis appears to be an independent risk for MVA with a 2-7 x increased risk of accident Don’t have simple, accurate roadside behavioural impairment test DRIVING AND CANNABIS

38. Delayed reaction time Decreased hand-eye coordination Decreased eye tracking and visual function Altered time perception and problems with time estimation Decreased short term memory Decreased ability for divided attention and ability to handle unexpected events DRIVING AND CANNABIS

39. 4 hours after inhalation • 6 hours after oral ingestion • 8 hours if patient experiences euphoria • More impairment when combine alcohol and cannabis than when either used at low doses alone ADVISE NO DRIVING UNTIL:

40. www.ncpic.org.au • Cannabis Use Problems Identification Test (CUPIT) • Severity of Dependence Scale • Cannabis Problems Questionnaire • Adolescent and adult version • CRAFFT ASSESSMENT OF CANNABIS USE DISORDER

41. CASUAL USE: • Urine results positive for 7-10 days • HEAVY USE • Weeks to months • THC is lipophilic and distributes in fat • Weight loss gives positive test as is released from fat stores • Passive inhalation – negative test DRUG TESTING

42. Motivational Enhancement Therapy • Cognitive Behavioural Therapy • Contingency Management • Family-based Programs • Exercise • Internet assisted therapy/telephone assisted therapy • Apps • Computer-delivered CBT/MET/CM PSYCHOSOCIAL TREATMENTS

43. APP!

44. Sleep-inducing agents: • Zolpidem x 3 days • Decreased nocturnal awakenings and improved sleep quality • No difference in withdrawal symptoms or cravings for cannabis • Nabiximols • Extract of cannabis sativa • Each spray contains 2.7 mg THC and 2.5 mg CBD • Agonists • Dronabinol (Marinol) • Nabilone (Cesamet) WITHDRAWAL MANAGMENT

45. Antagonists: • Rimonabant • Smoke cannabis, don’t feel positive effect • +++ dysphoria, marked suicidality • Anticonvulsants: • Lithium – no effect • Divalproex – no effect RELAPSE PREVENTION

46. Gabapentin • 12 week RCT of 1200 mg OD • Decreased use, decreased withdrawal, decreased craving, improved sleep • N- acetyl-cysteine • 1200 mg BID + contingency management • Currently a large trial (ACCENT) evaluating effectiveness of NAC RELAPSE PREVENTION

47. Assess and treat concurrent mental health disorder(s) if present CONCURRENT DISORDERS Mental illness Concurrent Disorder Substance Use

48. Neuropathic pain Spasticity in Multiple Sclerosis Dyskinesias in late-stage Parkinson’s Disease Increasing appetite in HIV/AIDS Reducing chemotherapy-induced nausea and vomiting Decreasing ocular pressure (i.e. glaucoma) Decreasing seizures (specifically CBD) THERAPEUTIC POTENTIAL

49. History of cannabis use disorder Active substance use disorder Age <25 Personal or strong family history of psychosis Cardiovascular disease Severe respiratory disease Pregnant, planning to become pregnant, or breastfeeding CONTRAINDICATIONS

50. Cannabis is not an approved medication by Health Canada • Little evidence for benefit and typically benefit is modest and below conventional therapies • Only current indication is for neuropathic pain • As a 3rd or 4th line therapy • There are clear harms associated with cannabis use • There are contraindications for its use CURRENT STANCE