1. Potential Pharmacotherapy for Cannabis Use Disorders Leslie H. Lundahl, Ph.D. Department of Psychiatry and Behavioral Neurosciences Wayne State University School of Medicine

2. Cannabis Use Disorders (CUDs) are Common 22 million users in past mo 13% users have CUD 305,000 sought Rx for CUD Changing legal landscape → ↑ Rx need © AMSP 20162

3. Cannabis Use is Risky → Physical problems (e.g., respiratory) → Mental health challenges (e.g., mood) → Cognitive impairment → CUDs © AMSP 20163

4. Rx for CUD is Challenging Few data-supported approaches ~ 50% achieve abstinence ~ 70% relapse No FDA-approved medications © AMSP 20164

5. This Lecture Covers Consequences of cannabis use How cannabis works Potential medications for CUD Rx © AMSP 20165

6. This Lecture Covers Consequences of cannabis useConsequences of cannabis use How cannabis works Potential medications for CUD Rx © AMSP 20166

7. Impaired Driving Acute THC –→ ↓ 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 © AMSP 20167

8. Amotivational Syndrome Mental slowing ↓ Planning ability ↓ Judgment, concentration, memory Apathy, ↓ pursuit of goals © AMSP 20168

9. Impaired Cognition ↓ Ability to learn ↓ Attention, concentration ↓ Abstract reasoning and decision-making ↓ Memory © AMSP 20169

10. Physical Health Respiratory –↓ Function –↑ Infections ↑ Stroke/Temporary brain blood constriction © AMSP 201610

11. Mental Health Anxiety –Acute THC → ↓ anxiety –Long-term THC → ↑ anxiety ↑ Depression ↑ Psychosis © AMSP 201611

12. Substance Use Disorder In Same Year, ≥2 of: Tolerance Withdrawal Use more/longer Unable to ↓ use Use despite problems Craving 12 Failed roles Hazardous use Social problems ↓ Activities Lots time use © AMSP 2016

13. Substance Use Disorder In Same Year, ≥2 of: Tolerance WithdrawalWithdrawal Use more/longer Unable to ↓ use Use despite problems CravingCraving 13 Failed roles Hazardous use Social problems ↓ Activities Lots time use © AMSP 2016

14. Cannabis Withdrawal Irritability Anxiety Sleep problems Restlessness ↓ Appetite/weight loss Depressed Mood © AMSP 201614 Causing distress & ≥ 3 of the following: AND ≥ 1 of the following: Abdominal pain Sweating Shakiness/tremors Fever/chills Headache

15. This Lecture Covers Consequences of cannabis use How cannabis worksHow cannabis works Potential medications for CUD Rx © AMSP 201615

16. Cannabinoids (CBs) © AMSP 201616 > 400 chemicals, ↓ neurotransmitter release Natural CBs Endogenous – Anandamide (“bliss”) Exogenous – Sativa plant (marijuana) Tetrahydrocannabinol (THC) – psychoactive Cannabidiol (CBD) – no effects ↓

17. Cannabinoid Receptors © AMSP 201617 CB 1 – CNS site of CB binding Memory, learning, problem solving, coordination Activated by anandamide, other CBs Modulates neurotransmitters CB 2 – immune cells outside CNS Anti-inflammatory effects

18. CB1 Receptors in The Brain © AMSP 201618

19. CB1 Receptors in The Brain © AMSP 201619

20. Neurotransmitter Modulation © AMSP 201620 Dopamine (DA) - euphoria, reward, pleasure GABA - muscle relaxation, sleepiness ↓ Glutamate - relaxation, ↓ memory ↓ ↓ ↓ ↓

21. This Lecture Covers Consequences of cannabis use How cannabis works Potential CUD Rx medications © AMSP 201621

22. Psychosocial Rx for CUD © AMSP 201622 Goal: Prepare for life without drugs Cognitive Behavioral Therapy (CBT) Basic idea: thoughts = feelings and behaviors Identify and correct problem thoughts and behaviors Explore positive and negative CB consequences Identify craving quickly to avoid CB use

23. Psychosocial Rx for CUD - 2 © AMSP 201623 Relapse Prevention Therapy (RPT) Identify, avoid, cope Effective coping skills Pt’s belief he/she can change Keep CB use lapses “short” ↓ ↓

24. We Need To Do More © AMSP 201624 ~ 50% achieve abstinence ~ 70% relapse Medications treat other SUDs, may help CUD Pharmacotherapy adjunct to psychosocial Rx Developing CUD meds based in CB effects

25. Some Definitions © AMSP 201625 Agonist – creates an action Drug binds to and stimulates receptors E.g., heroin - opioid agonist; THC - CB 1 agonist Partial agonist – partially activates Drug binds to receptors, but “ceiling” effect E.g., buprenorphine - opioid partial agonist Produces mild euphoria Allows opioid cessation with ↓ withdrawal

26. Some Definitions – 2 © AMSP 201626 Inverse agonist – opposite effect Binds to receptor, not absence of agonist E.g., rimonabant (Accomplia) reverses appetite Antagonist – blocks agonist drugs Binds to receptor, but no “high” E.g., naltrexone for opioids, prevents drug effects

27. © AMSP 201627 Treatment targets Overdose Detoxification/Withdrawal Rehabilitation/Relapse Prevention Investigational CUD Medications

28. © AMSP 201628 Rx Goal: Block drug effects CB OD not fatal Possible Rx: CB inverse agonist rimonabant Overdose

29. Detoxification and Withdrawal © AMSP 201629 Rx Goal: Treat acute effects of cessation (Partial) Agonist Rx – replacement Pros: Safer form, ↓ craving, focus on Rx Cons: Develop tolerance/dependence

30. © AMSP 201630 Dronabinol (Marinol) – synthetic THC Partial agonist of CB 1 receptors Chemo-related nausea, AIDs wasting Pros: ↓ anxiety, misery, irritability, craving Cons: ↑ drug liking, did not ↓ use, poor bioavailability, slow onset of action Detox & Withdrawal: Agonist

31. © AMSP 201631 Nabilone (Cesamet) – synthetic THC CB 1 receptor agonist Pros: ↓ irritability, ↑ sleep & appetite; ↓ relapse Cons: ↑ mood, not ↑ abstinence initiation Clinical trial ongoing Detox & Withdrawal: Agonist - 2

32. © AMSP 201632 Nabiximols (Sativex) – 1:1 THC/Cannabidiol (CBD) CBD in cannabis, nonpsychoactive, indirect agonist CBD might block pleasurable effects of THC MS, epilepsy, neuropathic pain Pros: ↓ withdrawal severity, ↑ Rx retention Cons: 69% relapse, diversion, impaired driving Detox & Withdrawal: Agonist - 3

33. © AMSP 201633 Gabapentin (Neurontin) - restore GABA fx ↑ GABA biosynthesis → “quiets” brain Anticonvulsant & ↓ neuropathic pain Pros: ↓ withdrawal/use Cons: 72% drop out rate; suicidal thoughts Ongoing clinical trial Detox & Withdrawal: Non-agonist

34. © AMSP 201634 Fatty acid amide hydrolase (FAAH) inhibitors Inhibiting FAAH → ↑ CB levels + CB activation In animals: FAAH inhibitors ↓ withdrawal Pros: Acts indirectly on receptors → safer Clinical trial ongoing Detox & Withdrawal: Non-agonist - 2

35. Rehabilitation/Relapse Prevention © AMSP 201635 Rx Goal: Block pleasurable drug effects Antagonist Rx – binds and blocks E.g., opioids– naltrexone (Revia) ↓ craving Pros: No tolerance, not → dependence Cons: +/- effect on craving

36. © AMSP 201636 Cannabidiol (CBD) - CB antagonist In cannabis; 5HT partial agonist, FAAH inhibitor Antidepressant, anxiolytic, antipsychotic Preclinical studies: ↓ THC effects Human studies just begun Rehabilitation: Antagonist

37. © AMSP 201637 Naltrexone (opioid antagonist) Opioid/CB receptor system interaction Animal: ↓ THC administration; human: mixed Acute Rx: ↑ “high” and cardiovascular effects Repeated Rx: ↓ subjective effects and use Clinical trials needed Rehabilitation: Antagonist - 2

38. © AMSP 201638 Rimonabant (Accomplia) CB 1 inverse agonist; “reverses” CB 1 activity Obesity Rx (Europe) Pros: ↓ rapid HR, ↓ “high” Cons: withdrawn from market (safety concerns) Inhibit transmission at CB 1 → serious side effects Rehabilitation: Non-antagonist

39. © AMSP 201639 N-acetylcysteine (NAC) Amino acid derivative, OTC supplement Acetaminophen OD, cystic fibrosis, COPD Restores normal glutamate activity Pros: ↓ use in adolescents Cons: did not ↓ craving Ongoing multi-site clinical trial Rehabilitation: Non-antagonist - 2

40. © AMSP 201640 Target: Detox (achieve initial abstinence) Gabapentin (Neurontin) NAC Target: Rehabilitation ( ↓ relapse) CB agonists (agonist replacement) Nabilone (Cesamet) Dronabinol (Marinol) Promising Results

41. Future Directions © AMSP 201641 Large RCTs to test efficacy Safety trials for FDA approval Consider novel approaches – CB 1 antagonist without serious side effects – Rx that ↑ CB signaling – Drug combinations ↑ Understanding of endocannabinoid system Rx of co-morbid disorders

42. Summary © AMSP 201642 CUDs are common: 13% of US population CB use has adverse consequences Impaired driving, ↓ learning and memory ↑ risk for respiratory and cardiovascular problems ↑ risk for depression, anxiety, psychosis Existing Rx ineffective No magic bullet – behavioral/pharmacotherapy Promising: nabilone, gabapentin, NAC, dronabinol Awaiting results on: CBD, FAAH inhibitors