MEDICAL CANNABIS: Symptom Management

MEDICAL CANNABIS: Symptom Management Diana Martins Welch, MD Division of Geriatrics and Palliative Medicine Northwell Health June 9, 2017 May 25, 2017 1 DISCLOSURES None May 25, 2017 2 1

OBJECTIVES Understand the history of medicinal cannabis Learn the basics of the human endocannabinoid system Review the major phytocannabinoids and learn their medicinal properties Review the evidence, and lack thereof, for cannabis therapeutic effects Learn about the NY State Medical Marijuana Program May 25, 2017 3 As of November 2016 May 25, 2017 4 2

May 25, 2017 5 BIOLOGICAL COMPONENTS OF CANNABIS Cannabinoids THC, CBD Minor Cannabinoids CBC, CBG, CBN, THC V, CBD V, CBC V Terpenes trans caryophyllene, α caryophyllene, α pinene, β pinene, terpinolene, myrcene, limonene, linalool, phytol, squalene Carotenoids β carotene Fatty Acids Linoleic acid, palmitoleic acid, linolenic acid, palmitic acid, oleic acid, stearic acid, myristic acid, arachidonic acid Sterols β sitosterol, campesterol, stigmasterol Vitamin E Triglycerides May 25, 2017 6 3

PHYTOCANNABINOIDS Gaoni Y, Mechoulam R. J Am Chem Soc 1964;86:1646 7. May 25, 2017 7 PHYTOCANNABINOIDS Phytocannabinoids have pharmacological activity due to their receptor based effects on the endocannabinoid system Additional pharmacological effects, such as antiinflammatory mechanisms may be non receptor mediated. May 25, 2017 8 4

May 25, 2017 9 RISK OF DEPENDENCE DRUG LIFETIME RISK OF DEPENDENCE Nicotine 32% Heroin 23% Cocaine 17% Alcohol 15% Marijuana 9% Bostwick, 2012 May 25, 2017 10 5

May 25, 2017 11 MEDICAL CANNABIS LEGALITY LINKED TO FEWER OPIOID OVERDOSE DEATHS JAMA, 2014 A time series analysis was conducted of medical cannabis laws and state level death certificate data in the United States from 1999 to 2010; all 50 states were included. Examination of the association between medical cannabis laws and opioid analgesic overdose mortality in each year after implementation of the law showed that such laws were associated with a lower rate of overdose mortality that generally strengthened over me: year 1 ( 19.9%), year 2 ( 25.2%), year 3 ( 23.6%), year 4 ( 20.2%), year 5 ( 33.7%), and year 6 ( 33.3%). In secondary analyses, the findings remained similar. May 25, 2017 12 6

SCIENTIFIC LITERATURE INDEXED BY PubMed Sommers, C. The Future of Clinical Cannabis: Part 1. 2016 May 25, 2017 13 History of Cannabis May 25, 2017 14 7

HISTORY OF CANNABIS 2900 BC Chinese emperor Fu Hsi references Ma (cannabis) as a popular medicine 2700 BC Father of Chinese medicine Emperor Shen Nung discovers healing properties of cannabis 1213 BC Egyptians use cannabis for glaucoma, inflammation 1000 BC Bhang (mix of cannabis and milk) used as medicine in India 200 BC Medical cannabis used in ancient Greece May 25, 2017 15 HISTORY OF CANNABIS 1500s The Spanish brought cannabis to the Americas 1839 Sir William O Shaughnessy researched cannabis in India 1850 United States Pharmacopeia classifies marijuana as a legitimate medical compound 1936 The American propaganda film Reefer Madness was made to scare American youth away from using cannabis. 1937 Marijuana Tax Act banned cannabis use and sales 1970 Controlled Substances Act Schedule I May 25, 2017 16 8

CANNABIS PROHIBITION IN THE U.S. Harry Anslinger First director of the Federal Bureau of Narcotics in 1930 Launched a vigilant campaign against cannabis over the 3 decades he remained in office. The term marihuana (Spanish in origin) was used in anti cannabis propaganda to make it sound more foreign. There are 100,000 total marijuana smokers in the US, and most are Negroes, Hispanics, Filipinos and entertainers. Their Satanic music, jazz and swing, result from marijuana usage. This marijuana causes white women to seek sexual relations with Negroes, entertainers and any others. Harry Anslinger, testifying before Congress in 1937 May 25, 2017 17 FEDERAL CANNABIS The U.S. federal government currently grows and provides cannabis for a small number of patients. In 1976 the federal government created the Investigational New Drug (IND) compassionate access research program to allow patients to receive up to nine pounds of cannabis from the government each year. Today, five surviving patients still receive medical cannabis from the federal government, paid for by federal tax dollars. Americans for Safe Access May 25, 2017 18 9

Back to the science May 25, 2017 19 ENDOCANNABINOID SYSTEM Ubiquitous network in the nervous system that regulates synaptic neurotransmission in both excitatory and inhibitory circuits Humans naturally produce cannabinoids endocannabinoids Endocannabinoids interact with specific receptors found on neurons and immune cells Act to reduce excess nerve activity and suppress inflammation Functions in parallel and in conjunction with adrenergic, cholinergic, and dopaminergic systems in both the central and autonomic nervous systems May 25, 2017 20 10

ENDOCANNABINOID SYSTEM Three main components: Endocannabinoids (endogenous lipid ligands) Anandamide & 2 AG Receptors CB 1 & CB 2 (G protein coupled), TRPV1 Regulatory Enzymes Synthesis and hydrolysis of endocannabinoids (ex: fatty acid amidohydrolase, FAAH; monoacylglycerol lipase, MAGL) May 25, 2017 21 ENDOCANNABINOIDS Anandamide (AEA) Partial agonist of CB1 receptors, low affinity to CB2 (1992) 2 AG Fully efficacious agonist of both CB1 and CB2 receptors (1995) May 25, 2017 22 11

CANNABINOID RECEPTORS CB1 receptor G protein receptor that serves as a target for both endocannabinoids and phytocannabinoids. 10 times more prevalent in the CNS as compared to the μ opioid receptor. Found in high densities in the neuron terminals of the basal ganglia (affecting motor activity), cerebellum (motor coordination), hippocampus (short term memory), neocortex (thinking), and hypothalamus and limbic cortex (appetite and sedation). To a lesser extent, the CB1 receptors are found in periaqueductal gray dorsal horn (pain), immune cells, liver, thyroid, uterus, bones and testicular tissue May 25, 2017 23 May 25, 2017 24 12

6/2/2017 CANNABINOID RECEPTORS CB2 receptor (CB2r) Found on immune cells and tissues, is primarily immunomodulatory and anti inflammatory Expressed on the cell membranes of B and T cells, macrophages and spleen. When signaled, CB2r are generally inhibitory to immune cell activation. CB2r expression is inducible, their number is increased by inflammation. Reduced CB2r signaling results in increased severity of inflammation as found in studies in mice. May 25, 2017 25 May 25, 2017 26 13

Medicinal effects of Cannabis May 25, 2017 27 Modulating endocannabinoid activity may have therapeutic potential in almost all diseases affecting humans, including obesity/metabolic syndrome, diabetes and diabetic complications, neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal, skin diseases, pain, psychiatric disorders, cachexia, cancer, chemotherapy induced nausea and vomiting, among many others. Pacher and Kunos FEBS J. 2013 May; 280(9): 1918 1943 May 25, 2017 28 14

REASONS FOR MEDICAL CANNABIS USE REASON FOR USE % REPORTING REASON Pain Relief 82.6% To Sleep 70.6% To Relax 55.6% Muscle Spasms 41.3% Anxiety 38.1% To Stimulate Appetite 38.0% Nausea 27.7% Depression 26.1% Reinarman et al., 2011 May 25, 2017 29 POTENTIAL THERAPEUTIC BENEFITS OF CANNABIS Nausea and Vomiting Anorexia and Cachexia Spasticity Movement Disorders Pain Glaucoma Epilepsy Asthma Autoimmune Diseases and Inflammation Psychiatric Symptoms Miscellaneous, Mixed Syndromes: Pruritus, Chronic Fatigue Syndrome, Attention Deficit Disorder, Restless Leg Syndrome, Hiccups May 25, 2017 30 15

PHARMACOLOGIC EFFECTS OF THC Psychotropic Initial euphoria and relaxation followed by depressant period Alterations in memory and cognitive perceptual abilities Immunosuppressive/immunomodulatory Cardiovascular Tachycardia, orthostatic hypotension, peripheral vasodilation Analgesic Anti emetic Appetite stimulation May 25, 2017 31 PHARMACOLOGIC ACTIONS OF CBD Anticonvulsive Analgesic Anti anxiety Anti depressant Anti psychotic Anti inflammatory Immunosuppressive Inhibits FAAH enzyme Potential benefit in Parkinson s, Alzheimer s disease, Diabetes mellitus, Cancer May 25, 2017 32 16

CANNABINOID MEDICINES Dronabinol (Schedule III) Chemo induced nausea/vomiting (1985) Anorexia associated with weight loss from AIDS (1992) Nabilone (Schedule II) Chemo induced nausea/vomiting (1985) Nabiximols (not FDA approved) Cannabis derived liquid extract formulated from 2 strains of Cannabis sativa into an oromucosal spray. Approved in 10 countries for: Spasticity from MS Neuropathic pain in MS patients Intractable cancer pain Rimonabant (CB1 antagonist) Anorectic antiobesity drug Taken off market due to serious psychiatric effects May 25, 2017 33 2015 Dronabinol, nabiximols, nabilone, CBD. Only 2 studies evaluated cannabis 79 trials included (6462 participants) Most trials showed improvement in symptoms (not all statistically significant) Compared with placebo, cannabinoids were associated with a greater average number of patients showing: a complete nausea and vomiting response; 3 trials, reduction in pain; 8 trials, a greater average reduction in numerical rating scale pain assessment; 6 trials, average reduction in the Ashworth spasticity scale; 5 trials, There was an increased risk of short term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. May 25, 2017 34 17

2011 Included neuropathic pain, fibromyalgia, RA and mixed chronic pain 18 RCTs (2003 2010), 766 total participants Overall quality of trials was excellent 15 or the 18 trials that met inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared to placebo, several reported significant improvements in sleep. There were no serious adverse side effects. This systematic review of 18 recent good quality randomized trials demonstrates that cannabinoids are a modestly effective and safe treatment option for chronic non cancer (predominantly neuropathic) pain. Given the prevalence of chronic pain, its impact on function and the paucity of effective therapeutic interventions, additional treatment options are urgently needed. More large scale trials of longer duration reporting on pain and level of function are required. May 25, 2017 35 SYNERGY WITH OPIOIDS Abrams et al (2011) studied 21 individuals with chronic pain, on a regimen of twice daily doses of sustained release Morphine or Oxycodone Admitted participants for 5 day inpatient stay Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2 4, and in the morning of day 5. Blood sampling was performed at 12 h intervals on days 1 and 5. Extent of chronic pain was assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%) after the addition of vaporized cannabis. Concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects May 25, 2017 36 18

NEUROPATHIC PAIN FIVE RCTs Wilsey et al: A Randomized, Placebo Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. J Pain. 2008 June ; 9(6): 506 521. Ellis et al: Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. 2009 February ; 34(3): 672 680. Wallace et al: Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. J Pain. 2015 July ; 16(7): 616 627. Ware et al: Smoked Cannabis for Chronic Neuropathic Pain: A randomized controlled trial. CMAJ. 2010 Oct 5;182(14):E694 701. Abrams et al: Cannabis in Painful HIV Associated Sensory Neuropathy: a randomized placebo controlled trial. Neurology. 2007 Feb 13;68(7):515 21. May 25, 2017 37 CANNABIS FOR NAUSEA AND VOMITING Central regulation of emesis occurs via the: Dorsal Vagal Complex (DVC) Area Postrema located outside BBB, provides communication between blood borne signals Nucleus of the solitary tract Dorsal motor nucleus of the vagus } Contain CB1 receptors Meta analysis of 3 RCTs (Machado, et al, 2008) showed statistically significant benefit of Dronabinol on CINV. Scarcity of data comparing cannabis to first line anti emetics May 25, 2017 38 19

CANNABIS FOR CANCER ASSOCIATED PAIN The CB1r is found in the CNS and in peripheral nerve terminals. Elevated levels of the CB1r (like opioid receptors) are found in areas of the brain that modulate nociceptive processing. Cannabinoids may contribute to pain modulation through an anti inflammatory mechanism a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents such as histamine and serotonin and on keratinocytes to enhance the release of analgesic opioids. May 25, 2017 39 CANNABIS FOR CANCER ASSOCIATED PAIN Johnson, et al (2010) performed a placebo controlled RCT comparing THC:CBD extract to THC only extract to placebo. 2x as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain numerical rating scale (NRS) score when compared with placebo The number of THC only group responders was similar to placebo and did not reach statistical significance. No change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids May 25, 2017 40 20

CANNABIS FOR ANOREXIA/CACHEXIA SYNDROME Numerous nuclei in the medulla are involved in the regulation of appetite and nausea coordinate sensory input from the brainstem, vagal complex, vestibular organs, and peripheral organs. CB1r are present in the hypothalamus (controls food intake) and in mesolimbic reward system which may be involved in the motivational/reward aspects of eating. Endocannabinoids and CB1 agonists inhibit vagal fibers to promote eating and CB1 antagonists to decrease or inhibit food intake. Trials conducted in the 1970s in healthy controls found that smoked cannabis (especially when used in a social/communal setting) led to an increase in caloric intake, predominantly in the form of between meal snacks, (mainly fatty and sweet foods). Lack of clinical studies showing benefit in cancer patients May 25, 2017 41 CANNABIS FOR MUSCLE SPASTICITY Meta analysis by Whiting et al (2015): Fourteen studies (33 reports; 2280 participants) assessed spasticity due to MS or paraplegia Studies generally suggested that cannabinoids were associated with improvements in spasticity, but this failed to reach statistical significance in most studies Cannabinoids (nabiximols, dronabinol, and THC/CBD) were associated with a greater average improvement on the Ashworth scale for spasticity compared with placebo, although this did not reach statistical significance. The average number of patients who reported an improvement on a global impression of change score was also greater with nabiximols than placebo. May 25, 2017 42 21

CANNABIS FOR SEIZURE DISORDERS Strong evidence indicates the anticonvulsant activity of CBD compounds (Wallace et al., 2001; Blair et al., 2015) Activation of CB1 receptor has proven to dampen neurotransmission and produce an overall reduction in neuronal excitability. In many clinical trials cannabis was administered in tandem with the patient s previously prescribed medications. Some of the patients were able to lower the dosage of the medications, and in some cases completely stop them, with no increase in seizures during the trial period. Reddy and Golub, J Pharmacol Exp Ther 357:45 55, April 2016 May 25, 2017 43 CANNABIS AS AN ANTI NEOPLASTIC AGENT Antiproliferative effects were originally reported in 1975 by Munson et al. who demonstrated that delta 9 THC, delta 8 THC, and cannabinol inhibited Lewis lung adenocarcinoma cell growth in vitro as well as in mice. Cannabinoids may exert their antitumor effects by a number of different mechanisms, including: direct induction of transformed cell death, direct inhibition of transformed cell growth, inhibition of tumor angiogenesis and metastasis Research on cannabis as an anti neoplastic medication in humans is lacking May 25, 2017 44 22

THE ENTOURAGE EFFECT The enhancement of cannabinoid effects by non cannabinoid components. May 25, 2017 45 FACTORS INFLUENCING CANNABIS EFFECTS Dose of cannabis consumed Ratio of the various cannabinoids in the cannabis product Route of administration Time since consumption Health status of the patient Age of the patient Co administration of other drugs/medicines Whether or not the patient has been using cannabis recreationally (or receiving cannabis therapy) long term or if the patient is cannabis naïve May 25, 2017 46 23

Cart3726 May 25, 2017 47 CONTRAINDICATIONS Absolute Contraindications Acute psychosis and other unstable psychiatric conditions Relative Contraindications Severe cardiovascular, immunological, liver or kidney disease Cannabis may exacerbate arrhythmia or a history of arrhythmias May 25, 2017 48 24

SIDE EFFECTS/ADVERSE EFFECTS OF CANNABIS USE Distorted perception Loss of motor coordination Difficulty with concentration/problem solving Dry mouth Tachycardia Psychosis and Schizophrenia (increased risk with personal/family hx) Infertility In vivo and in vitro studies have shown that cannabis may disrupt the hypothalamus pituitary gonadal axis, spermatogenesis, and sperm function Cannabinoid hyperemesis syndrome Impaired driving May 25, 2017 49 CANNABIS USE DISORDER A problematic pattern of cannabis use leading to clinically significant impairment or distress. Manifested by at least 2 of the following within a 12 month period (DSM V): Cannabis is often taken in larger amounts or over a longer period than was intended. Persistent desire or unsuccessful efforts to cut down or control cannabis use. Great deal of time spent obtaining, using or recovering from effects of cannabis. Craving, or a strong desire or urge to use cannabis. Recurrent cannabis use resulting in a failure to fulfill major obligations. Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis. Important activities are given up or reduced because of cannabis use. Recurrent cannabis use in situations in which it is physically hazardous. Continued use despite knowledge of problems caused or exacerbated by cannabis. Tolerance Withdrawal symptoms May 25, 2017 50 25

CANNABIS WITHDRAWAL SYNDROME Includes restlessness, irritability, mild agitation, insomnia, strange dreams, appetite loss, nausea, and cramping. Regular cannabis intake is related to a desensitization and downregulation CB1 receptors. Starts to reverse within the first 2 days of abstinence; receptors return to normal functioning within 4 weeks of abstinence. CWS severity is dependent on the amount of cannabis used precessation, gender, and heritable and several environmental factors. Bonnet U, et al. 2017 May 25, 2017 51 New York State Medical Marijuana Program May 25, 2017 52 26

COMPASSIONATE CARE ACT Governor Cuomo passed bill (Compassionate Care Act) on June 19, 2014 Program launched on January 7, 2016 Five registered organizations, 4 dispensaries each Bloomfield Industries Inc. Columbia Care NY LLC Etain, LLC PharmaCann LLC Vireo Health of New York LLC May 25, 2017 53 PRACTITIONER QUALIFICATIONS Be qualified to treat patients with one or more of the serious conditions. Be licensed, in good standing as a physician/np/pa and practicing medicine Have completed a four hour course approved by the Commissioner Have registered with the New York State Department of Health (NYSDOH). May 25, 2017 54 27

ELIGIBILITY CRITERIA Serious Medical Condition Clinically Associated Condition Cancer HIV +/ AIDS ALS Parkinson s MS Spinal cord injury with spasticity Epilepsy IBD Neuropathy Huntington s Disease Chronic Pain Seizures Severe nausea Severe or persistent muscle spasms Severe or chronic pain resulting in substantial limitation of function Cachexia or wasting syndrome May 25, 2017 55 APPROVED MODES OF ADMINISTRATION 1. Liquid or oil preparations for metered oromucosal or sublingual administration (Onset: 30 min; duration 4 6 hours) 2. Metered liquid or oil preparations for vaporization (Onset: Immediate to 5 min; duration 2 4 hours) 3. Capsules for oral administration (Onset: 1 2 hours; duration 6 8 hours) Smoking medical cannabis is expressively prohibited and edible cannabis containing products are not approved in NY State May 25, 2017 56 28

DOSES AVAILABLE IN NYS 1:20 THC:CBD 1:1 THC:CBD 20:1 THC:CBD Maximum of 10mg THC/dose May 25, 2017 57 CERTIFICATION PROCESS 1. Practitioner makes recommendation via HCS website 2. Prints and signs Certificate for patient Certification expires 1 year after date of issuance unless patient is terminally ill 3. Patient registers on NY.gov website $50 fee (waived for financial hardship) 4. If application is approved, DOH issues a registry card to patient May 25, 2017 58 29

May 25, 2017 59 NYS NUMBERS TO DATE.. As of May 30, 2017: 1,040 practitioners have registered with the NYS Medical Marijuana Program, and 20,494 patients have been certified. May 25, 2017 60 30

LEGAL CONSIDERATIONS FOR PRACTITIONERS ACP statement, 2008: ACP strongly supports exemption from federal criminal prosecution, civil liability, or professional sanctioning, such as loss of licensure or credentialing, for physicians who prescribe or dispense medical marijuana in accordance with state law. US Attorney General Eric Holder in 2009 announced that legally pursuing people who were using medical marijuana was not a priority, differentiating between illicit drug users and patients/caregivers who are abiding by state laws. The Justice Department in 2013 declared US Attorneys would no longer pursue actions against physicians for recommending medical marijuana in states where it has been made legal. May 25, 2017 61 LEGAL CONSIDERATIONS Federal employees barred from medical cannabis use Driving under the influence May 25, 2017 62 31

MORE TO COME NY Commissioner of Health reviewing scientific evidence for medical marijuana for: PTSD Alzheimer s Disease Muscular Dystrophy Dystonia Rheumatoid Arthritis May 25, 2017 63 OBSTACLES Lack of validated studies on the various benefits of medical cannabis Cannabis remains classified as a Schedule I drug Schedule I drugs, substances, or chemicals are defined as drugs with no currently accepted medical use and a high potential for abuse. FDA requires Phase 3 studies to be done with the same drug that the sponsor is seeking to market As long as the DEA/NIDA monopoly on cannabis research exists it will not be possible to develop an FDA approved prescription medicine with NIDA cannabis. May 25, 2017 64 32

THE FUTURE OF CANNABIS RESEARCH Identification of compounds that retain therapeutic effects without the side effects Alternative methods of delivery Manipulation of the endocannabinoidsystem A selective transporter for the re uptake of anandamide may exist (evidence mixed at present, controversial) May 25, 2017 65 MRS. B May 25, 2017 66 33

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Thank You By forcing marijuana to languish as a Schedule I drug with a high potential for abuse, no accepted medical use, and no accepted safety for use in medically supervised treatment, the federal government thumbs an illogical nose at contemporary public sentiment, recent scientific discoveries, and potentially head to toe therapeutic breakthroughs. This reclassification would be a first step toward reconciling federal and state law and permitting long stifled research into a potential trove of therapeutic applications to commence. Bostwick JM, Mayo Clin Proc 2012 May 25, 2017 69 35