Handout for the Neuroscience Education Institute (NEI) online activity:

Marijuana: Drug of Abuse or Therapeutic Option? Learning Objectives

• Explain how affect the body and the brain • Educate patients about: – Evidence of efficacy for mental health and other conditions – Potential risks of 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 recommend listing as a 1963: 1964: THC for obtaining marijuana as medication in US 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/ Robitussin AC Heroin Methamphetamine codeine Alprazolam Lyrica LSD Dexedrine 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 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

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

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. 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 al. Neuropsychopharmacol 2006;31(12):2748-57. 5. van Winkel R et al. Neuropyschopharmacol 2011;36(12)2529-37. 6. Di Forti M et al. Biol Psychiatry 2012;72(10):811-6. Does Cannabis Use Affect the Course of a Psychotic Disorder?

Greater risk of psychosis relapse Greater risk of psychosis relapse in non-user in continued cannabis user

Schoeler T et al. Lancet Psychiatry 2016;3(3):215-25. Does Cannabis Use Affect the Developing Brain?

immature neurons cue direct involved in migration axonal neural stem eliminated growth cell survival stem cell promote altered cortical cell neurite development death outgrowth of major NT systems

eliminated

neurogenesis selection migration differentiation synaptogenesis position cortical involved in interneurons proliferation ECS effects Cannabis effects (animal data, acute pre/neonatal exposure) Lubman DI et al. Pharmacol Ther 2016;148:1-16. Does Cannabis Use Affect the Developing Brain? Cannabis use: downregulated CB1 receptors Competitive elimination of synapsesin white matter (loss of dendritic arborization) drop off in ECS regulates adulthood glutamate, GABA, synaptic pruning, Prefrontal and white matter excitatory development synapses

Anandamide Prefrontal DA CB1 receptors innervation

Prefrontal Cannabis use: inhibitory disrupted synapses glutamate NT

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. Heavy Cannabis Use Prior to Brain Maturation: Animal Studies

• Greater and more persistent cognitive deficits – Learning, working memory, object recognition • Disruption in social behavior • More depressive-like behaviors – Reduced consumption of palatable food, passive response to acute stress • Impaired prepulse inhibition • Increased locomotor activity

Lubman DI et al. Pharmacol Ther 2015;148:1-16. Does Cannabis Use Affect the Developing Brain?

1 2 3+ Diagnosis Diagnose Diagnoses n=12s n=21 n=17 n=57 n=23 n=14 Scale IQ (in SD Units) Units) SD (in IQ - Scale From Age 13 to Age 38 Change in Full

Cannabis-dependent before age 18 Not cannabis-dependent before age 18 Meier MH et al. PNAS 2012;109(40):E2657-64. Answers Needed

• Adolescent Brain Cognitive Development Study – Funded by NIH – Prospectively following children for 10 years beginning at ages 9–10 – Began recruiting September 2016 – http://abcdstudy.org/ HOW MIGHT CANNABIDIOL ATTENUATE THE NEGATIVE EFFECTS OF CANNABIS? THC vs.vs. CannabidiolCannabidiol

isomer of THC

psychoactive NOT psychoactive anxiogenic anxiolytic anticonvulsant under investigation by NIDA and NIH for therapeutic uses

Greydanus DE et al. Disease Month 2015;61:118-75; Iseger TA, Bossong MG. Schizophr Res 2015;162:153-61. THC vs. Cannabidiol: Different Binding Properties central and peripheral neuron terminals immune cells

CB1 CB1

CB2 CB2

THC: CBD: does not bind CB receptors; THC: partial agonist may interact with 5HT receptors (low affinity?) THC vs. CBD: Psychiatric Effects

Cannabis w/ Cannabis w/ CBD alone Low CBD Content High CBD Content Psychosis Higher risk of Lower risk of Possible symptoms hallucinations and hallucinations and antipsychotic effects delusions delusions Psychotic disorder Earlier age of onset Later age of onset

Cognition Higher risk of acute Lower risk of acute memory impairment memory impairment Anxiety Anxiogenic Anxiolytic Increased Reduced amygdalar amygdalar activity activity

Iseger TA, Bossong MG. Schizophr Res 2016;162:153-61. Shifting Ratio of THC: Cannabidiol

DEA-seized materials. ElSohly MA et al. Biol Psychiatry 2016; http://dx.doi.org/10.1016/j.biopsych.2016.01.004. CannabisCannabis vs.vs. “The“The Synthetics” Synthetics”

CB1 CB1 CB1 CB1

THC: partial agonist Synthetics: full agonist CBD 800X greater affinity for CB1

No CBD

Cameron K et al. Psychopharmacology 2013;227(3):493-9; Loeffler G et al. Milit Med 2012;177(9):1041-8. CANNABIS AND CANNABINOIDS AS THERAPEUTIC TOOLS The State of the Evidence Approved

Active Formulation Approval(s) Schedule ingredient

Dronabinol Synthetic Oral capsule Chemo-induced nausea and III THC or solution vomiting (US)

Appetite boost in AIDS wasting syndrome (US) Synthetic Oral capsule Chemo-induced nausea and II (due to THC vomiting (US) its potency) analog Purified Spray Spasticity caused by MS (UK, N/A ~1:1 THC Canada, Europe, Australia, and CBD New Zealand, Israel)

Pain in MS and in cancer (Canada, Israel) Cannabinoids for Medical Use: Meta-analysis MODERATE-QUALITY LOW-QUALITY EVIDENCE VERY LOW-QUALITY EVIDENCE EVIDENCE Spasticity in MS Nausea/vomiting from chemo Anxiety (public 4 trials/2280 participants 28 trials/1772 participants speaking) (nabiximols, nabilone, (nabiximols, ) 1 trial/24 participants dronabinol, THC/CBD Weight gain in HIV (cannabidiol) capsule) 4 trials/255 participants Depression Chronic neuropathic or (dronabinol) No direct study; cancer pain Tourette syndrome documented as a result in 28 trials/2454 participants 5 studies (smoked THC, 2 trials/36 participants (nabiximols) nabiximols) (THC capsule) Sleep 2 trials/54 participants POSITIVE EFFECT (nabilone) NO EFFECT Psychosis Whiting PF et al. JAMA 2 trials/71 participants 2015;313(24):2456-73. (cannabidiol) RCTs from 1975–2014. Cannabinoids for Medical Use: American Academy of Neurology Review "A" (strong) "B" (moderate) "C" (weak) "U" (insufficient) Spasticity (MS) Spasticity (MS) Tremor (MS) Spasticity (MS) OCE THC, nabiximols nabiximols smoked cannabis Pain (MS) Pain (MS) Pain (MS) OCE THC, nabiximols smoked cannabis Urinary dysfunction Huntington's (MS) disease nabiximols nabilone, CBD POSITIVE EFFECT capsule NO EFFECT Urinary dysfunction (MS) Tourette OCE: oral cannabis syndrome extract (THC or OCE, THC THC/CBD) Tremor (MS) THC Koppel BS et al. OCE, THC Cervical dystonia Neurology dronabinol 2014;82:1556-63. Levodopa-induced RCTs from 1948–2013. dyskinesia Epilepsy OCE CBD ECS-Based Medicines No Longer Under Investigation

• Peripherally restricted CB1 agonists – Studied in pain; failed due to metabolic and cardiovascular effects • Synthetic CB1 agonists – Damaged kidneys in young children; serious cardiovascular adverse effects • Global CB1 antagonists – Efficacy in diabetes and obesity, but failed due to CNS side effects – Negative study for cessation • Fatty acid amide hydrolase (FAAH) inhibitors – Promote cardiovascular inflammation, metabolic side effects – Phase I study of French formulation in healthy volunteers halted due to death and serious brain injury • US FDA: "BIA 10-2474 exhibits a unique toxicity that does not extend to other drugs in the class" Under Investigation: Cannabidiol

Preclinical Phase I Phase II Phase III

Dravet syndrome (GW Pharma; epidiolex*)

Lennox-Gastaut syndrome (GW Pharma; epidiolex*) tuberous sclerosis (GW Pharma; epidiolex) severe pediatric epilepsies (INSYS) glioma (GW Pharma; GWP42003*) schizophrenia (GW Pharma; GWP42003)

neonatal hypoxic- ischemic encephalopathy (GW Pharma; GWP42003*)

*Orphan drug designation Under Investigation: Other

Preclinical Phase I Phase II Phase III cancer pain (GW Pharma; nabiximols spray)

MS spasticity (GW Pharma; nabiximols spray) type 2 diabetes (GW Pharma; delta-9- tetrahydrocannabivarin) epilepsy (GW Pharma; )

*Orphan drug designation Why Is Medical Marijuana Not a Viable Prescription Option?

Drug approval standards Medical marijuana status • Consistent, pure, well-defined • Unprocessed plant containing chemical formulation 500 chemicals with 100+ • Consistent, well-defined cannabinoids pharmacokinetic profile • Compounds may vary from • Safety data in healthy plant to plant population and in specific • Residual impurities (pesticides, medical disorder (double-blind, fungal contaminants) placebo-controlled RCT) • Dosing is not well regulated • Efficacy data in specific medical disorder (double-blind, placebo-controlled RCT) • Warnings regarding all potential side effects Cannabis Is Like a Box of Chocolates…

Benbadis SR et al. Expert Rev Neurother 2014;14(12):1453-65. "…future medicinal uses will most likely lie in drugs based on cannabinoid chemicals or extracts with defined concentrations that can be reliably produced."

—Nora Volkow Questions for Future Research

• What factors contribute to negative effects and risks of cannabis exposure? – Age at initiation? – Quantity used? – Frequency of use? – Potency? – Duration of use? • What are the long-term consequences of heavy cannabis use prior to brain maturation? WHAT'S A HEALTHCARE PROFESSIONAL TO DO? American Society of Addiction Medicine (ASAM) Recommendations

• Cannabis-related products should not be distributed unless/until they have FDA approval • Smoking is not an appropriate drug delivery mechanism • Need for federal regulatory standards for approval and distribution • State should not enact regulatory standards more permissive than federal ones • Clinicians who choose to discuss medical use of cannabis must: – Adhere to established professional tenets of proper patient care – Have a preexisting and ongoing relationship with the patient – Not recommend cannabis as a disproportionately large portion of practice – Not issue recommendation without adequate information regarding composition and dose – Have adequate training in identifying substance abuse and addiction

ASAM Medical Marijuana Task Force White Paper. 2012. Learnaboutsam.org/wp- content/uploads/2013/02/American-Society-of-Addiction-Medicine-2011-Medical- Marijuana-Task-Force-White-Paper.pdf. College of Family Physicians of Canada (CFPC) Recommendations

• Pain: only for patients with neuropathic pain that has failed to respond to standard treatment (including adequate trial of pharmaceutical cannabinoids) • Anxiety: not appropriate therapy • Insomnia: not appropriate therapy • Not appropriate for: – <25 years of age – Personal/family history of psychosis – Current or past cannabis use disorder – Cardiovascular or respiratory disease – Pregnant, planning pregnancy, or breastfeeding

College of Family Physicians of Canada. Authorizing Dried Cannabis for Chronic Pain or Anxiety: Preliminary Guidance from the College of Family Physicians of Canada. Mississauga, ON: College of Family Physicians of Canada; 2014. Screening for Cannabis Use Disorder

• NIDA Quick Screen—NIDA-modified ASSIST • NM-ASSIST full • CAGE-AID • Risk factors – Current mood or anxiety disorder – History of substance use Cautions About Cannabis Use: Time to Peak Concentration

Inhalation Oral • Fast brain uptake • Delayed brain uptake • Higher risk of addiction • Lower risk of addiction • Risk of impairment • Risk of impairment greatest immediately and delayed and may be within first 2 hours greatest between 2–6 hours after consumption Summary

• Wide-ranging role of endocannabinoid system suggests potential therapeutic uses of cannabis, but also potential adverse effects, especially during neurodevelopment • Scant evidence beyond pain in cancer, nausea/vomiting, and spasticity in MS • Hope for use in severe pediatric epilepsy (Phase III) • Media hype but no actual evidence for use in psychiatric conditions (PTSD, anxiety, depression) • Variations in potencies, cannabinoid constituents, dosing, and route of administration make medical marijuana difficult to recommend • Potential for use in numerous therapeutic indications, but Schedule I status severely limits ability to research Posttest Question 1

Your patient, a 33-year-old woman whom you have been treating for 3 years for major depressive disorder, discloses to you that 6 weeks ago, she visited a cannabis clinic and was certified for the use of medical marijuana to treat chronic back pain resulting from a car accident and subsequent surgery 2 years ago. As part of your discussion regarding the risk/benefit assessment of cannabis use for chronic pain, you tell her that: 1. Randomized controlled trials provide moderate to strong evidence for efficacy in chronic back pain 2. Randomized controlled trials provide moderate to strong evidence for efficacy in some other types of chronic pain 3. Randomized controlled trials provide moderate to strong evidence for lack of efficacy in chronic pain 4. There are not enough data to help determine if there is efficacy for chronic pain Posttest Question 2

Your patient, a 26-year-old man whom you have been treating for 3 years for posttraumatic stress disorder (PTSD), discloses to you that 6 weeks ago, he visited a cannabis clinic and was certified for the use of medical marijuana to treat his PTSD symptoms. As part of your discussion regarding the risk/benefit assessment of cannabis use for PTSD, you tell him that: 1. Randomized controlled trials provide moderate to strong evidence for efficacy in multiple symptom domains of PTSD 2. Randomized controlled trials provide moderate to strong evidence for efficacy only in sleep/nightmares associated with PTSD 3. Randomized controlled trials provide moderate to strong evidence for lack of efficacy in PTSD 4. There are not enough data to help determine if there is efficacy for PTSD Posttest Question 3

Synthetic THC is approved for: 1. Nothing 2. Chemo-induced nausea 3. Appetite boost in AIDS wasting syndrome 4. Dravet syndrome (pediatric epilepsy) 5. 2 and 3 6. 2, 3, and 4