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

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

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

Cannabinoids typically refer to certain compounds found in the cannabis plant Cannabichromene D9-Tetrahydrocannabivarin D9-Tetrahydrocannabinol (THC) Cannabidiol (CBD) Cannabivarin Cannabigerol As of 2018, 538 naturally occurring compounds in cannabis sativa, and >100 identified as cannabinoids Cannabinol is a product of non-enzymatic oxidative breakdown of THC, and therefore can become a marker of prior THC content and age of cannabis product. Cannabidivarin D8-Tetrahydrocannabinol Pacher, et al., Pharmacological Reviews, 2006 Howlett, et al., Pharmacological Reviews, 2002 Bonini et al., Journal of Ethnopharmacology, 2018

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

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

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

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

Estimation of CB1 receptor expression in human brain

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

Potential Beneficial Effects of: 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 Cannabis use is associated with decreased risk of metabolic syndrome and diabetes, however is associated with increased risk of pre-diabetes.

Potential Harmful Effects of Cannabis 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 Cancer: moderate evidence of no association between lung or head & neck cancers and cannabis smoking; there are some reports of increased risk of bladder cancer and cannabis smoking; there is limited evidence of statistical association between non-seminoma-type testicular germ cell tumors and cannabis smoking. Most other cancers have insufficient evidence to support or refute an association with cannabis use.

Cognitive impairment is greatest in persistent heavy cannabis users who started during adolescence, and is dose dependent Adolescent vulnerability. Shown is change in full-scale IQ (in SD units) from childhood to adulthood among study members with 1, 2, or 3+ diagnoses of cannabis dependence as a function of age of onset of cannabis dependence. Individuals with adolescent-onset cannabis dependence (black bars) experienced greater IQ decline than individuals with adult-onset cannabis dependence (gray bars). IQ decline of approximately −0.55 SD units among individuals with adolescent-onset cannabis dependence in the 3+ group represents a decline of 8 IQ points. Error bars = SEs. Represents decline of 8 IQ points Meier, et al, PNAS, 2012

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

Psychiatric Illness can 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 Depression is a risk factor for the development of problem cannabis use. Bipolar disorder, anxiety disorders, ADHD, and personality disorders (with exception of oppositional behaviors in youth) are not risk factors for problem cannabis use. Marijuana use also worsens the course of illness in patients with schizophrenia and can produce a brief psychotic reaction in some users that fades as the drug wears off. The amount of drug used, the age at first use, and genetic vulnerability can all influence this relationship. One example is a study  that found an increased risk of psychosis among adults who had used marijuana in adolescence and who also carried a specific variant of the gene for catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine and norepinephrine. Notes courtesy of Jodi Gilman

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 Since cannabis use and PTSD symptoms has been shown as association, its presently unclear if cannabis is used by those with more severe PTSD, or if cannabis is ineffective in reducing (or perhaps worsens over the long term) PTSD symptoms. An association has been made between cannabis use and increased incidence in violence of individuals with PTSD who use cannabis. Boden et al., Am J Addict 2013 Wilkinson et al., J Clin Psychiatry 2016

Dependence occurs 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 Lifetime risk for dependence of other substances: tobacco 32%, heroin 23%, cocaine 17%, alcohol 15% Stimulant treatment of attention deficit hyperactivity disorder (ADHD) during adolescence is not  a risk factor for the development of problem cannabis use. Being male and smoking cigarettes are risk factors for the progression of cannabis use to problem cannabis use. Initiating cannabis use at an earlier age is a risk factor for the development of problem cannabis use. No difference between males and females in the recurrence of problem cannabis use. Hall, Addiction, 2014

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

Cannabis Withdrawal Chronic cannabis users, last use ~48 hours prior, average use ~9 joints/day; cohort population decreased over time Lee et al, Am J Addict, 2014

Toxicology Assessment 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) ~weekly user ~daily user ~daily user Ellis et al, Clin Pharmacol Ther, 1985; Anderson, Current Sports Medicine Reports, 2011

Pharmacologic Interventions Cannabis 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

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 Typically males with cannabis use, generally daily, >2 years Diagnostic Criteria: 1 At least one discrete episode in the prior year and two episodes in the past 6 months, occurring at least 1 week apart 2 Presentation after prolonged excessive cannabis use (3–5 times daily for at least 2 years) 3 Relief of vomiting episodes by sustained cessation of cannabis use The diagnosis is supported by pathologic bathing behavior (prolonged hot baths or showers), age below 50 years, weight loss of more than 5 kg, morning predominance of symptoms and unaffected bowel habits during attacks of nausea and vomiting, morning predominance of symptoms. Capsaicin cream 0.075% applied TID – q4h in periumbilical region may improve symptoms, due to continued blacking of peripheral TRPV1 receptors, which is dephosphorylated and causes desensitization, leading to vagal afferent communicating with vagal efferents via area postrema, a brain region with high TRPV1 density 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

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.