Transcript this Presentation - Alcohol Medical Scholars Program

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
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Cannabis Use is Risky
• → Physical problems (e.g., respiratory)
• → Mental health challenges (e.g., mood)
• → Cognitive impairment
• → CUDs
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Rx for CUD is Challenging
• Few data-supported approaches
• ~ 50% achieve abstinence
• ~ 70% relapse
• No FDA-approved medications
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This Lecture Covers
• Consequences of cannabis use
• How cannabis works
• Potential medications for CUD Rx
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This Lecture Covers
• Consequences of cannabis use
• How cannabis works
• Potential medications for CUD Rx
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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
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Amotivational Syndrome
• Mental slowing
• ↓ Planning ability
• ↓ Judgment, concentration, memory
• Apathy, ↓ pursuit of goals
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Impaired Cognition
• ↓ Ability to learn
• ↓ Attention, concentration
• ↓ Abstract reasoning and decision-making
• ↓ Memory
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Physical Health
• Respiratory
– ↓ Function
– ↑ Infections
• ↑ Stroke/Temporary brain blood constriction
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Mental Health
• Anxiety
– Acute THC → ↓ anxiety
– Long-term THC → ↑ anxiety
• ↑ Depression
• ↑ Psychosis
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Substance Use Disorder
In Same Year, ≥2 of:
• Tolerance
• Failed roles
• Withdrawal
• Hazardous use
• Use more/longer
• Social problems
• Unable to ↓ use
• ↓ Activities
• Use despite problems
• Lots time use
• Craving
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Substance Use Disorder
In Same Year, ≥2 of:
• Tolerance
• Failed roles
• Withdrawal
• Hazardous use
• Use more/longer
• Social problems
• Unable to ↓ use
• ↓ Activities
• Use despite problems
• Lots time use
• Craving
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Cannabis Withdrawal
Causing distress & ≥ 3 of the following:
•
•
•
•
• ↓ Appetite/weight loss
Irritability
Anxiety
• Depressed Mood
Sleep problems
Restlessness
AND ≥ 1 of the following:
• Abdominal pain
• Sweating
• Fever/chills
• Headache
• Shakiness/tremors © AMSP 2016
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This Lecture Covers
• Consequences of cannabis use
• How cannabis works
• Potential medications for CUD Rx
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Cannabinoids (CBs)
↓ neurotransmitter release
↓
• > 400 chemicals,
• Natural CBs
• Endogenous – Anandamide (“bliss”)
• Exogenous – Sativa plant (marijuana)
• Tetrahydrocannabinol (THC) – psychoactive
• Cannabidiol (CBD) – no effects
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Cannabinoid Receptors
• 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
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CB1 Receptors in The Brain
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CB1 Receptors in The Brain
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Neurotransmitter Modulation
↓
↓
GABA -
↓
•
Dopamine (DA) - euphoria, reward,
↓
•
pleasure
muscle relaxation, sleepiness
• ↓ Glutamate - relaxation, ↓ memory
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This Lecture Covers
• Consequences of cannabis use
• How cannabis works
• Potential CUD Rx medications
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Psychosocial Rx for CUD
• 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
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Psychosocial Rx for CUD - 2
• Relapse Prevention Therapy (RPT)
• Identify, avoid, cope
Effective coping skills
↓
•
↓
•
Pt’s belief he/she can change
• Keep CB use lapses “short”
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We Need To Do More
• ~ 50% achieve abstinence
• ~ 70% relapse
• Medications treat other SUDs, may help CUD
• Pharmacotherapy adjunct to psychosocial Rx
• Developing CUD meds based in CB effects
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Some Definitions
• Agonist – creates an action
• Drug binds to and stimulates receptors
• E.g., heroin - opioid agonist; THC - CB1 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
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Some Definitions – 2
• 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
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Investigational CUD Medications
• Treatment targets
• Overdose
• Detoxification/Withdrawal
• Rehabilitation/Relapse Prevention
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Overdose
• Rx Goal: Block drug effects
• CB OD not fatal
• Possible Rx: CB inverse agonist rimonabant
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Detoxification and Withdrawal
• Rx Goal: Treat acute effects of cessation
• (Partial) Agonist Rx – replacement
• Pros: Safer form, ↓ craving, focus on Rx
• Cons: Develop tolerance/dependence
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Detox & Withdrawal: Agonist
• Dronabinol (Marinol) – synthetic THC
• Partial agonist of CB1 receptors
• Chemo-related nausea, AIDs wasting
• Pros: ↓ anxiety, misery, irritability, craving
• Cons: ↑ drug liking, did not ↓ use, poor
bioavailability, slow onset of action
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Detox & Withdrawal: Agonist - 2
• Nabilone (Cesamet) – synthetic THC
• CB1 receptor agonist
• Pros: ↓ irritability, ↑ sleep & appetite; ↓ relapse
• Cons: ↑ mood, not ↑ abstinence initiation
• Clinical trial ongoing
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Detox & Withdrawal: Agonist - 3
• 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
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Detox & Withdrawal: Non-agonist
• 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
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Detox & Withdrawal: Non-agonist - 2
• 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
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Rehabilitation/Relapse Prevention
• 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
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Rehabilitation: Antagonist
• Cannabidiol (CBD) - CB antagonist
• In cannabis; 5HT partial agonist, FAAH inhibitor
• Antidepressant, anxiolytic, antipsychotic
• Preclinical studies: ↓ THC effects
• Human studies just begun
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Rehabilitation: Antagonist - 2
• 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
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Rehabilitation: Non-antagonist
• Rimonabant (Accomplia)
• CB1 inverse agonist; “reverses” CB1 activity
• Obesity Rx (Europe)
• Pros: ↓ rapid HR, ↓ “high”
• Cons: withdrawn from market (safety concerns)
• Inhibit transmission at CB1 → serious side effects
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Rehabilitation: Non-antagonist - 2
• 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
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Promising Results
• Target: Detox (achieve initial abstinence)
• Gabapentin (Neurontin)
• NAC
• Target: Rehabilitation (↓ relapse)
• CB agonists (agonist replacement)
• Nabilone (Cesamet)
• Dronabinol (Marinol)
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Future Directions
• Large RCTs to test efficacy
• Safety trials for FDA approval
• Consider novel approaches
– CB1 antagonist without serious side effects
– Rx that ↑ CB signaling
– Drug combinations
• ↑ Understanding of endocannabinoid system
• Rx of co-morbid disorders
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Summary
• 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
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