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Cannabis: Updates, Neurobiology and Public Health

Cannabis: Updates, Neurobiology and Public Health. Garth Terry, MD, PhD garthterrymd@gmail.com Senior Fellow, Department of Psychiatry and Behavioral Sciences & Department of Radiology  University of Washington School of Medicine

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Cannabis: Updates, Neurobiology and Public Health

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  1. Cannabis: Updates, Neurobiology and Public Health Garth Terry, MD, PhD garthterrymd@gmail.com Senior Fellow, Department of Psychiatry and Behavioral Sciences& Department of Radiology University of Washington School of Medicine Advanced Fellow, Mental Illness Research, Education, and Clinical Center (MIRECC) VA Puget Sound November 9, 2018

  2. Disclosures • No financial disclosures • The content presented here might not represent those of the VA or University of Washington • Cannabis is not approved for any use by the FDA, and remains a Schedule I listed substance by the DEA • There are currently no FDA approved medications for treatment of cannabis use disorder

  3. Objectives • Learn the primary components and function of cannabis and the endocannabinoid system • Describe the biological and behavioral effects of cannabis in cannabis users • Understand the risks associated with cannabis on: • Mental health • Dependence • Withdrawal

  4. Cannabinoidstypically refer to certain compounds found in the cannabis plant D9-Tetrahydrocannabivarin D9-Tetrahydrocannabinol (THC) Cannabidiol (CBD) Cannabigerol Cannabivarin Cannabichromene Pacher, et al., Pharmacological Reviews, 2006 Howlett, et al., Pharmacological Reviews, 2002 Bonini et al., Journal of Ethnopharmacology, 2018 D8-Tetrahydrocannabinol Cannabidivarin

  5. SyntheticCannabinoidswere developed for research and medical purposes Agonists Inverse Agonists Rimonabant WIN 55,212-2 CP 55,940 AM281 Pacher, et al., 2006

  6. Endogenous Cannabinoidsare compounds found in the body and are involved in many regulatory processes Virodhamine Anandamide 2-Arachidonoylglycerol 2-Arachidonoyl glycerol ether (noladine ether) N-Arachidonoyl dopamine Pacher, et al., Pharmacological Reviews, 2006

  7. Where do cannabinoids go in the body? • Cannabinoid receptor, subtype 1 (CB1) • Primarily found in brain • Also found in peripheral neurons, adrenal gland, heart, liver, bone marrow, testis, spleen, immune cells • Cannabinoid receptor, subtype 2 (CB2) • Primarily found on immune cells • Also found in spleen, thymus, bone marrow • Transient receptor potential vanilloid 1 channels (TRPV1), 5-HT3,5-HT1a, GPR55, peroxisome proliferator-activated nuclear receptors, ligand gated ion channels, glycine transporter 1, fatty acid amide hydrolase, disrupted in schizophrenia protein (DISC1), … Pacher, et al., Pharmacological Reviews, 2006 Howlett, et al., Pharmacological Reviews, 2002 Pertwee, et al., Pharmacological Reviews, 2010

  8. CB1 Retrograde Neurotransmission to the CB1 Receptor Ca2+ Ca2+ Ca2+ NAPE-PLD Ca2+ Ca2+ Cell activation Anandamide Gi AC FAAH Arachidonic acid Ethanolamine Presynaptic neuron Post-synaptic neuron ■ = GABA, glutamate, or dopamine

  9. Estimation of CB1 receptor expression in human brain

  10. Objectives • Learn the primary components and function of cannabis and the endocannabinoid system • Describe the biological and behavioral effects of cannabis in cannabis users • Understand the risks associated with cannabis on: • Mental health • Dependence • Withdrawal

  11. D9-THC Anti-emetic (nausea) Increased appetite Anti-spasmodic Analgesic (pain relief) Anxiolytic (anti-anxiety) Bronchodilation Decrease intraocular pressure Therapeutic dose lower than psychoactive dose Heightened senses Cannabidiol (CBD) Anti-inflammatory Anti-convulsant Anti-anxiety Anti-psychotic Anti-oxidant Not intoxicating Potential Beneficial Effects of:

  12. Anxiogenic Short term memory impairment Cognitive impairment Impaired judgment Impaired senses Impaired motor skills Motor vehicle accidents Paranoia Increased risk for psychosis Talkativeness/ hyperactivity Increased heart rate Dry mouth Dry, red eyes Symptoms of chronic bronchitis Stroke Myocardial infarction Cancer Low birth weight Altered brain development (particularly in adolescents) Addiction/Dependence Withdrawal symptoms Potential Harmful Effects of Cannabis

  13. Cognitive impairment is greatest in persistent heavy cannabis users who started during adolescence, and is dose dependent Represents decline of 8 IQ points Meier, et al, PNAS, 2012

  14. Objectives • Learn the primary components and function of cannabis and the endocannabinoid system • Describe the biological and behavioral effects of cannabis in cannabis users • Understand the risks associated with cannabis on: • Mental health • Dependence • Withdrawal

  15. Psychiatric Illnesscan be potentially worsened with cannabis use • Psychosis and schizophrenia • Paranoia, hallucinations more likely to reoccur if experienced with early use • Increased risk of schizophrenia in adolescents • Increased risk for those with first degree relative with psychotic disorder • Heavier marijuana use, greater drug potency, and exposure at a younger age can all negatively affect the disease trajectory (e.g., by advancing the time of a first psychotic episode by 2 to 6 years) • Depression • Anxiety • May lower anxiety in some individuals, but at higher doses, appears to cause anxiety in most individuals • Post Traumatic Stress Disorder (PTSD) • ASSOCIATION, not causality, has been established

  16. Cannabis use in PTSD • Positive reinforcement: improves sleep, nightmares, night sweats, pain, and may enable avoidance • Negative reinforcement: cannabis withdrawal symptoms overlap with PTSD symptoms • Cannabis use (and cessation) has been associated with more severe PTSD symptoms • Less reduction of PTSD symptoms during treatment • Interference with fear extinction • Currently, quality evidence for cannabis as beneficial for PTSD treatment remains lacking Boden et al., Am J Addict 2013 Wilkinson et al., J Clin Psychiatry 2016

  17. Dependenceoccurs in some individuals who have difficulty stopping or experience withdrawal • 9% lifetime risk among those who try cannabis • 1 in 6 (~17%) risk among those who start in adolescence • ~50% risk among daily cannabis users Hall, Addiction, 2014

  18. Cannabis Withdrawal • Cessation of cannabis use that has been heavy and prolonged (i.e., usually daily or almost daily use over a period of at least a few months). • Three (or more) of the following signs and symptoms develop within approximately 1 week after Criterion A: • Irritability, anger, or aggression. • Nervousness or anxiety. • Sleep difficulty (e.g., insomnia, disturbing dreams). • 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, or headache. DSM-5

  19. Cannabis Withdrawal Lee et al, Am J Addict,2014

  20. Toxicology Assessment ~weekly user • Urine toxicology: • positive 2-8 days single or light use • Positive 30+ days for heavy, daily use • False positives possible with: • Dronabinol • NSAIDs • Pantoprazole (PPIs) • Hemp seed oil (in very large amounts) • Passive inhalation (yes, it’s possible) ~daily user ~daily user Ellis et al, ClinPharmacolTher, 1985; Anderson, Current Sports Medicine Reports, 2011

  21. Pharmacologic InterventionsCannabis Use Disorder • No FDA approved medications • Prior clinical trials either mixed or with limited results • Gabapentin: 1200mg/day for 12 weeks • N-acetylcysteine: 1200mg BID in adolescents • Zolpidem • Several compounds currently in clinical trials • Exercise helpful for initial period of abstinence

  22. Cannabis Hyperemesis Syndrome • Chronic cannabis users • Cyclic bouts of nausea & vomiting • Learned hot baths or showers to get relief • Stops with sustained cannabis cessation • Seen in context of ER visit for N/V with negative work-up • Potentially fatal 2o glucose & electrolyte imbalance • May be improved with capsaicin cream • Haloperidol/olanzapine effective in some cases Dezieck et al, Cllinical Toxicology, 2017 Lapoint et al, Western Journal of Emergency Medicine, 2018 Moon et al, ACG Case Reports, 2018 Richards et al, Clinical Toxicology, 2018 https://clinicaltrials.gov/ct2/show/NCT03223350

  23. Take Home Summary • Cannabis is a plant that contains chemicals (cannabinoids) that can interact with normal processes in the body. • Cannabinoids have several potential benefits and potential risks. • The risks of cannabis on cognition and psychosis are most profound on adolescents; in adults, cognitive impairment is likely reversible. • It is possible to become dependent on cannabis, and have withdrawal symptoms upon stopping it. • The effects of cannabis may change with the amount and duration it is used, in addition to many other factors. • There is no FDA approved treatments available. Medications may help during withdrawal. Education and psychotherapy may be effective interventions.

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