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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cannabinoid Receptors © AMSP 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

CB1 Receptors in The Brain © AMSP

CB1 Receptors in The Brain © AMSP

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

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

Psychosocial Rx for CUD © AMSP 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

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

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

Some Definitions © AMSP 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

Some Definitions – 2 © AMSP 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

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

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

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

© AMSP 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

© AMSP 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

© AMSP 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

© AMSP 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

© AMSP 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

Rehabilitation/Relapse Prevention © AMSP 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

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

© AMSP 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

© AMSP 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

© AMSP 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

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

Future Directions © AMSP 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

Summary © AMSP 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