Handout for the Neuroscience Education Institute (NEI) online activity: Marijuana: Drug of Abuse or Therapeutic Option? Learning Objectives • Explain how cannabinoids affect the body and the brain • Educate patients about: – Evidence of efficacy for mental health and other conditions – Potential risks of cannabis use Timeline 1989? 90?: Discovery of ~2000 BC: binding site 2015: Elimination of Chinese 1943: Marijuana for THC— 1992: US Public Health emperors removed from CB1 Endogenous Service oversight cannabinoid recommend listing as a 1963: 1964: THC receptor for obtaining anandamide marijuana as medication in US Cannabidiol isolated marijuana for discovered medicine Pharmacopeia isolated research purposes 1995: 1851: Marijuana 1961: United 1970: Marijuana is Endogenous Aug 11 2016: listed as a Nations Single labeled Schedule I cannabinoid 2-AG DEA declines to medication in US Convention on by the US discovered reschedule Pharmacopeia Narcotic Drugs: Substance Abuse marijuana marijuana said to Act; this restricts be dangerous with both personal use no medical value and access for research purposes THE INTERSECTION OF THE HEALTHCARE AND CANNABIS INDUSTRIES What is Cannabis? 500 chemicals 100 cannabinoids Best understood: THC and CBD Scheduling of Controlled Substances No medicinal value, high Moderate to Lower High potential Low potential potential for low potential potential for for abuse for abuse abuse for abuse abuse Schedule I Schedule II Schedule III Schedule IV Schedule V Marijuana Cocaine Tylenol w/ Tramadol Robitussin AC Heroin Methamphetamine codeine Alprazolam Lyrica LSD Dexedrine Ketamine Zolpidem Ecstasy Adderall Anabolic steroids Methaqualone Ritalin Testosterone (Quaalude) Vicodin Peyote Methadone Hydromorphone Meperidine Oxycodone Fentanyl https://www.dea.gov/druginfo/ds.shtml Legalization of Cannabis in the US legal Public Perception Do you think the use of marijuana should be made legal?1 70 58 58 60 50 50 44 51 46 48 40 34 34 36 31 28 % Yes 30 25 25 23 25 20 1516 12 10 0 1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009 2013 % who perceive great risk of harm from monthly use2: 28.5% 1. http://www.gallup.com/poll/186260/back-legal-marijuana.aspx. 2. http://www.samhsa.gov/data/sites/default/files/report_2404/ShortReport-2404.html. Concerns for Healthcare Professionals Cannabis is marketed as a therapeutic, medicinal product— but not developed or dispensed by health professionals Concerns for Healthcare Professionals Remember when cigarettes, alcohol, and heroin were marketed as therapeutic products to treat specific conditions? Concerns for Healthcare Professionals: Increasing Potency DEA-seized materials. ElSohly MA et al. Biol Psychiatry 2016; http://dx.doi.org/10.1016/j.biopsych.2016.01.004. WHAT DOES CANNABIS DO? The Endocannabinoid System The Endocannabinoid System Regulates: Neurodevelopment Coordination Stress Appetite CB1 in Brain: Memory Intraocular Cortex Emetic reflex Cognition pressure Nucleus accumbens Reward Basal ganglia Heart rate Hypothalamus Immune function Cerebellum Hippocampus GI motility Female Amygdala reproductive Spinal cord function Brainstem CB2 in Brain: Glial cells Brainstem http://www.fundacion-canna.es/en/endocannabinoid-system; Lu et al. Biol Psychiatry 2016;79:516-25. The Endocannabinoid System: Retrograde Neurotransmission CB receptor 1. EC precursors in lipid membranes The Endocannabinoid System: Retrograde Neurotransmission 3. Released EC CB receptor binds to presynaptic CB1 or CB2 4. Inhibits release of receptors inhibitory and excitatory NTs 2. NT binding (or depolarization) triggers 1. EC precursors in enzymatic reaction to lipid membranes form and release EC The Endocannabinoid System: Receptors and Ligands central and peripheral neuron terminals immune cells CB1 CB1 CB2 CB2 anandamide: 2-AG: high- low-efficacy efficacy agonist agonist 2-AG: high- anandamide: efficacy agonist very low- efficacy agonist Pre- (and Post-)Natal Neurodevelopment: Role of Endocannabinoid System immature neurons cue direct involved in migration axonal neural stem eliminated growth cell survival stem cell promote neurite outgrowth eliminated neurogenesis selection migration differentiation synaptogenesis position cortical involved in interneurons proliferation Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed. 2008; Zhou Y et al. Int J Biochem Cell Biol 2014;47:104-8; Maccarrone M et al. Nat Rev Neurosci 2014;15(12):786-801. Brain Changes During Adolescent Development Competitive elimination of synapses ECS regulates (loss of dendritic arborization) drop off in glutamate, GABA, adulthood synaptic pruning, Prefrontal and white matter excitatory development synapses Anandamide Prefrontal DA CB1 receptors innervation Prefrontal inhibitory synapses age 5 ages 6–19 adulthood CB1: increase in striatum, PFC, and hippocampus. Abundant in white matter during neural development. Present in oligodendrocytes. Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Insel TR. Nature 2010;468(7321):187-93; Viveros MP et al. J Psychopharmacol 2012;26(1):164-76; Lubman DI et al. Pharmacol Ther 2015;148:1-16. WHAT DOES CANNABIS DO? Effects on Cognition, Motivation, Psychosis, and the Developing Brain Potential Effects of Cannabis Neurodevelopment Coordination Stress Appetite Pain Intraocular Memory Emetic reflex pressure Cognition Reward Heart rate Immune function GI motility Female reproductive function Potential Effects of Cannabis Risk of neuro- Impaired Neurodevelopment Coordination development d/o? coordination TreatStress wasting Impaired short- Appetitesyndrome? term memory, Treat chronicPain pain? concentration, Intraocular Memory EmeticAnti-emetic? reflex Treat glaucoma? alertness, pressure Cognition judgment, time Tachycardia Reward Heart rate perception, CV risk Treat cancer? Immune function reaction time Treat autoimmune d/o? Amotivation TreatGI motility IBS? Female Impaired reproductive fertility? function Effects of Chronic, Heavy Cannabis Use on Endocannabinoid System • Reduced anandamide in cerebrospinal fluid1 – Correlated with persistent psychotic symptoms • Reduced cannabinoid 1 receptor2 • Abnormalities in brain regions high in CB1 receptors (hippocampus, PFC)3 – Associated with higher levels of cannabis use (dose, age of onset, duration) 1. Morgan CJA et al. Br J Psychiatry 2013;202:381-2. 2. Rotter A et al. Eur Addict Res 2013;19:13-20. 3. Lorenzetti V et al. Biol Psychiatry 2016;79:e17-31. Does Cannabis Use Affect Cognitive Capacity? • Short-term: YES • Long-term: mixed data – Meta-analysis: non-intoxicated users do worse than non-users, BUT – In studies with at least 1 month abstinence, difference not seen • Neuroimaging data: inconsistent, don't seem to correlate with neuropsychological test performance • Genetic factors that increase risk of impairment (COMT, AKT1)? • Magnitude and persistence of impairment may depend on: – Frequency and duration of use – Age of onset of use – Length of abstinence Volkow ND et al. JAMA Psychiatry 2016;73(3):292-7. Meta-analysis: Schreiner AM et al. Psychopharmacology 2012;20(5):420-9. Does Cannabis Use Reduce Motivation? High School Completion 16 8 4 2 1 Adjusted odds ratio <Monthly Monthly Weekly Daily or more or more Degree Attainment 16 8 4 2 1 Adjusted odds ratio <Monthly Monthly Weekly Daily or more or more Silins E et al. Lancet Psychiatry 2014;1(4):286-93. Cannabis Use Blunts Nucleus Accumbens Response to Reward Anticipation Time 1 to Time 2 Results Time 2 to Time 3 Results Activation, Age 22 y Age 22 y Residuals Activation, Age 24 y Residuals Activation, Marijuana Use, Age 20 y Residuals Marijuana Use, Age 22 y Residuals NAcc NAcc Left: Past marijuana use at age 20 (time 1) and NAcc activation during reward anticipation at age 22 (time 2). Right: Past marijuana use at age 22 (time 2) and NAcc activation during reward anticipation at age 24 (time 3). Martz ME et al. JAMA Psychiatry 2016; doi:10.1001/jamapsychiatry.2016.1161. Cannabis Users Show Reduced Striatal DA Synthesis Capacity p=0.016 Data are from Bloomfield MA et al. Biol Psychiatry 2014;75(6):470-8. Additional studies: Bloomfield MAP et al. Psychopharmacology 2014;231(11):2251-9; van de Giessen E et al. Mol Psychiatry 2016; doi:10.1038/mp.2016.21. Does Cannabis Use Increase Risk of Acute Psychosis? Healthy Human Participants: Transient Induction of Psychosis THC data: D'Souza DC et al. Neuropharmacology 2004;29(8):1558-72. Ketamine and amphetamine data: Krystal et al. Arch Gen Psychiatry 2005;62:985-94. Salvinorin A data: Ranganathan et al. Biol Psychiatry 2012;72:871-9. Sherif M et al. Biol Psychiatry 2016;79:526-38. Does Cannabis Use Increase Risk of a Psychotic Disorder? Lifetime risk of schizophrenia in: general population cannabis users1,2 1% 2% Are there subgroups at higher risk? 13.7% of US population uses cannabis at least once per year3 1. Gage SH et al. Biol Psychiatry 2016;79:549-56; 2. Volkow N et al. JAMA Psychiatry 2016;73(3):292-7; 3. UNODC. World Drug Report 2011 (United Nations Publication, Sales No. E.11.XI.10); http://www.unodc.org/documents/data-and- analysis/WDR2011/World_Drug_Report_2011_ebook.pdf. Risk of a Psychotic Disorder in Subgroups of Cannabis Patients Lifetime risk of schizophrenia in: frequent and/or users w/ cannabis users1 high-potency users2 first-degree relative1,2 20% 6% 2% DRD2 (Rs1076560 T allele)3 COMT (Val-158 allele)4 AKT1 (Rs2494732 C/C 1. Gage SH et al. Biol Psychiatry 2016;79:549-56. genotype)5-6 2. Volkow N et al. JAMA Psychiatry 2016;73(3):292-7. 3. Colizzi M et al. Schizophr Bull 2015;41(5):1171-82. 4. Henquet C et