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7/6/2016

EARLY HISTORY

• 4000 BCE China: First reported use as foodstuff and cloth NNUAL EETING • 2737 BCE China: First reported medicinal use by Emperor Shen Neng 2016 A M • 430 BCE: Reported recreational use of the Scythians by Herodotus IS IT ALL JUST BLOWN SMOKE? • 100 BCE China: First reported use as paper • 70: Listed in Nero’s Pharmacopoeia by a physician in his army A REVIEW OF MEDICAL MARIJUANA • 1484: Became associated with witchcraft after Papal decree ANTHONY PAZANESE, PHARM.D. CLINICAL PHARMACY SPECIALIST, PAIN MANAGEMENT & PALLIATIVE CARE LAKELAND REGIONAL HEALTH

WGBH 2014 Lathrop 2015 2016 ANNUAL MEETING

DISCLOSURE MARIJUANA IN THE UNITED STATES

• Neither I nor any member of my immediate family has a vested interest in or • 1906: Pure Food and Drug Act passed; defined labeling requirements affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization • 1920s: Prohibition encourages as a substitute for alcohol whose philosophy could potentially bias my presentation. • 1937: Marihuana Tax Act criminalized the drug • Excise tax of $1 on anyone dealing in cannabis, for certain authorized uses • The “evil weed” causes “murder, insanity, death” • 1941: Cannabis removed from USP

http://www.tokeofthetown.com/2012/03/30/ Devils_harvest_poster_01.jpg

WGBH 2014 http://all-that-is-interesting.com/20th-century- Lathrop 2015 anti-marijuana-propaganda#12 2016 ANNUAL MEETING 2016 ANNUAL MEETING

OBJECTIVES MODERN MEDICAL MARIJUANA

• Describe the current legal status of medical marijuana with respect to indications • Early 1960s: Synthetic developed to discover therapeutic value for patients with pain or other palliative care symptoms • 1981: (Cesamet®) approved • Discuss the current evidence base for the use of medical marijuana for patients with pain or other palliative care symptoms • 1985: Dronabinol (Marinol ®) approved • 1996: California becomes the first state to legalize medical marijuana use • 2003: becomes the first country to approve medical marijuana • 2012: Colorado and Washington legalize recreational use • 2012: Washington DC decriminalizes use and possession

WGBH 2014 Lathrop 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING

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CURRENT LEGAL STATUS PHARMACOKINETICS OF THC

• 24 states and DC have enacted laws to legalize medical marijuana • Systemic bioavailability of 27% in heavy users, 14% in occasional users • 16 states have enacted laws to legalize • Systemic bioavailability of 10% taken orally; extensive hepatic metabolism • Legalization in Florida • Active metabolite: 11-OH-THC • SB 1030 signed on June 16, 2014 by Rick Scott • Highly lipophilic and protein bound; crosses blood brain barrier and placenta • Allows use of non-smoked cannabis oil less than 0.8% THC and more than 10% CBD • Peak plasma concentration within 10 minutes after inhaled, 1-2 hours orally • “Charlotte’s Web”

• “Qualified patient”: Patients with cancer, chronic seizures, or severe muscle spasms • t1/2 5-13 days in heavy users; 1.3 days in occasional users • Enrollment on the compassionate use registry • Urinary and fecal excretion • Physician Education • 8-hour CME course and subsequent examination by Florida Medical Association • Extreme interpatient variability in serum concentrations

ProCon.org 2015 Sharma P, Murthy P, Barath MS 2012

2016 ANNUAL MEETING 2016 ANNUAL MEETING

MAJOR CANNABINOIDS DRONABINOL (MARINOL®)

• ∆9-THC: Primary psychoactive constituent • Synthetic ∆9-THC • ∆8-THC: Less psychoactive than ∆9-THC • Schedule III • (CBN): Less powerful than ∆9-THC • Significant psychoactivity

9 • 11-OH-∆ -THC: Liable for psychological effects • Mostly affects CB1 receptors, though equal affinity for CB1 and CB2 • Cannabidiol (CBD): Anxiolytic and effects • Dose based on indication 2 • (-)∆8-THC-11-oic acid: activity • Chemotherapy Induced Nausea and Vomiting (CINV): 5-15 mg/m /dose • in AIDS or cancer: 2.5-10 mg before lunch and dinner • Duration of 4-6 hours (psychoactive effects); >24 hours (appetite stimulation)

http://stashpotshop.com/flower/

http://floridamarijuanainfo.org/wp-content/uploads/2014/06/marinol_211.gif

2016 ANNUAL MEETING 2016 ANNUAL MEETING

CANNABINOID PHARMACOLOGY NABILONE (CESAMET ®)

• Cannabinoids stimulate two primary G-protein coupled receptors • Similar to ∆9-THC • CB 1 • Schedule II • Cerebral cortex, hippocampus, basal ganglia, cerebellum • Linked to psychotropic effects of THC • Chemotherapy Induced Nausea and Vomiting: 1-2 mg BID • Regulates release of GABA • Frequent psychotomimetic reactions • tetrad symptoms • Hypothermia, analgesia, catalepsy, locomotor suppression • May persist for 48-72 hours following treatment cessation • Nabilone restricted to patients failing other treatments • CB2 • Located in immune and hematopoietic cells; low levels in CNS • Affects CB1 receptors • No psychotomimetic effects • Immunomodulatory, analgesic, anti-inflammatory, and antineoplastic effects http://www.nature.com/nrc/journal/v3/n1 0/box/nrc1188_BX1.html

http://www.cesamet.com/hcp-dosing-and-administration.asp

2016 ANNUAL MEETING 2016 ANNUAL MEETING

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NABIXIMOLS (SATIVEX®) ACUTE PAIN

• GW Pharmaceuticals • Few studies evaluating acute or postoperative pain • Cannabis-based oromucosal spray, containing ∆9-THC and CBD • Most available studies not well designed • Natural product via cold organic solvent • Measurement of tolerance and threshold only • Lack of positive control • Onset of 15-40 minutes allows titration • Naproxen shown to be more effective than placebo and cannabinoid in one study • Approved in Canada for MS-related spasticity and intractable cancer pain • Cannabinoid similar to placebo • Approved in the UK for MS-related spasticity • Surgical removal of impacted third molar • Consistent with most placebo-controlled studies using dronabinol and nabilone • Currently in US Phase III trials for cancer-related pain; no application for MS

http://thecompassionchronicles.com/2013/06/24/sativex-marijuana-yes-or-no/ Kalliomaki J, Segerdahl M, Webster L et al 2013

2016 ANNUAL MEETING 2016 ANNUAL MEETING

HERBAL CANNABIS

• Lacks standardization • Short term studies among smoked cannabis • Adulteration/contamination problems • Three patient-years of experience over four studies • Longer term studies (≥ 12 weeks) do exist among pharmacological products • Delivery mechanism • Reported efficacy is mixed, with adverse effects a limiting factor • Combustion and Vaporization • Tinctures and Oils • Smoked cannabis or placebo TID x 5 days for HIV sensory neuropathy • Edibles • Cannabis reduced pain by 34%, placebo 17% • Topical • Profile of Mood States did not significantly vary or favored placebo • Difficult to dose • NNT 3.6 for cannabis, 5.4 for , 3.4-4 for • Patients can self-titrate

Russo EB, Hohmann AG 2013 http://clubcannabisbarcelona.blogspot.com/2013/11/new-international-study-herbal-cannabis.html Chohan H, Greenfield AL, Yadav V et al 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING

ANALGESIC EFFICACY SPASTICITY

• Motor effects complicate animal models of pain • One study reviewing smoked cannabis among refractory MS patients • Neurophysical models • Crossover trial using smoked cannabis or placebo cigarette • Treatment reduced Ashworth Spasticity Scores by 2.7 points • Decreased response of pain neurons in spinal cord and thalamus • Treatment reduced pain VAS scores by 5.3 points • Primarily mediated through CB1 to inhibit neurotransmitter release • 17/30 subjects correctly and consistently guessed treatment phase • CB2 suppresses neuropathic pain through non-neuronal and neuronal mechanisms • Dizziness, fatigue more common in cannabis group • CBD (not THC) acts as a TRPV1 agonist • 2014 AAN systematic review of placebo-controlled studies • Pain sensitivity increased when CB1 antagonists given • Oral cannabis extracts with CBD and THC effective in reducing central pain in MS • Synergistic with • Oral cannabis extracts with only THC “probably effective” • “probably effective

Russo EB, Hohmann AG 2013 Russo EB, Hohmann AG 2013 Chohan H, Greenfield AL, Yadav V et al 2015 2016 ANNUAL MEETING 2016 ANNUAL MEETING

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APPETITE STIMULATION 2008 SYSTEMATIC REVIEW OF CINV

• Mediated by CB1 receptor • Cannabinoids viewed as modestly effective compared to gold-standard • Blockade in newborn mice halts milk ingestion • Primarily small, placebo-controlled trials; many not statistically significant • Levels of 2-Arachidionoylglycerol (2-AG) peak immediately after birth in mice • Possible Type-1 error • Stimulation of provokes overeating in satiated rats • Trends toward superiority against placebo • Wasting and common in end-stage disease • THC vs for cisplatin-induced N/V • 47% Metoclopramide, 13% THC completely controlled • Patients tend to prefer cannabis to other • Anecdotal reports of smoking more effective than oral

Grotenhermen 2004 Grant and Cahn 2005 Joy 1999 Williams CM, Kirkham TC 1999 Machado Rocha FC, Stefano SC, De Cassia Haiek R, et al 2008 2016 ANNUAL MEETING 2016 ANNUAL MEETING

APPETITE STIMULATION ADVERSE EFFECTS

• AIDS: weight loss of 5% decreases survival • Meta-analysis of 31 studies (23 RCTs) • Dronabinol shown to increase appetite and stable weight • ∆9-THC, ∆9-THC/CBD • Megestrol more effective in stimulating weight gain • 445 person years of exposure • Neither leads to increase in lean body mass • Serious adverse event rate similar to control • Decrease in HDL shown with chronic cannabis use • Relapse of MS, vomiting, UTI • No change in LDL , TG, FFA, or TC • Non-serious adverse events higher with cannabinoids • No change in glucose or insulin • Dizziness • Nervous system, psychiatric, GI disorders

Muniyappa R, Sable S, Ouwerkerk R, et al 2013 Wang T, Collet J, Shapiro S, et al 2008

2016 ANNUAL MEETING 2016 ANNUAL MEETING

CINV ENDOCRINOPATHY AND IMMUNOPATHY

• Central and peripheral mechanisms • Thyroid hormone axis • Immune Modulation

• Activation of Chemoreceptor Trigger Zone (CTZ) • Acute reduction in TSH and Thyroxine • CB2 receptor gene abundant in by as much as 90% for 6 hours in immune cells • Irritation and damage to GI mucosa rodents • B cells > NK >> monocytes > PMNs > • Highly dependent on chemotherapy agent • No change with chronic administration T8 > T4 • Not studied in humans • T and B cell proliferation inhibited • Current 5-HT3 antagonists highly effective • Unknown effect on viral replication • ~75% controlled when given cisplatin with and serotonin antagonists • Growth Hormone (GH)

• Gold standard + dexamethasone + 5-HT3 antagonist • Acute reduction in GH secretion due to stimulation of somatostatin release • Four day study; unknown long-term effects

Joy 1999 Brown TT, Dobs AS 2002 Machado Rocha FC, Stefano SC, De Cassia Haiek R, et al 2008 2016 ANNUAL MEETING 2016 ANNUAL MEETING

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ENDOCRINE EFFECTS IN MALES NEUROLOGICAL EFFECTS

• Testosterone levels • Motor • Acutely reduced testosterone in rhesus monkey by 65% for one hour • Low doses stimulate, high inhibit locomotion • No apparent change in heavy chronic users compared to casual users at baseline • Memory • Disrupted spermatogenesis • Disruption of short-term memory • Observed in rodents and primates • Cannabinoid agonists inhibit Ach, NE, Glu • Dose related oligospermia in chronic users by 58% • Driving Impairment • Reversible reductions seen after 5-6 weeks of chronic use • Conflicting reports of crash involvement related to drug use • Abnormal sperm morphology and decreased motility • No standardized method of measuring marijuana in practice • Studies show no increased rate of collisions secondary to marijuana use when controlling for demographics and alcohol use

Brown TT, Dobs AS 2002 Compton RP, Berning A 2015 Warner TD, Roussos-Ross D, Behnke M 2014 2016 ANNUAL MEETING 2016 ANNUAL MEETING

ENDOCRINE EFFECTS IN FEMALES PULMONARY EFFECTS

• Suppression of Luteinizing Hormone and Gonadotropin Releasing Hormone • Four times as much tar as cigarettes • Abolished ovulatory cycle in rats and rabbits • Rates of chronic bronchitis similar to tobacco • Normal menstrual cycles returned in treated monkeys after 3-4 months • Abnormalities in bronchial epithelium • Rhesus monkeys showed no difficulties with conception • Increased expression of proliferation markers • Decrease in prolactin • Increased epidermal growth factor receptor • Inconsistent in humans and monkeys • Not enough data on cancer rates • Only evident acutely; not with chronic use • Patients frequently use tobacco as well as marijuana • 40 year cohort study in Sweden showed two-fold risk of lung cancer in heavy use • Heavy use defined as 50 uses over a lifetime • Controlled for tobacco use

Brown TT, Dobs AS 2002 Mehra R, Moore B, Crothers K, et al 2006 Warner TD, Roussos-Ross D, Behnke M 2014 Callaghan RC, Allebeck P, Sidorchuk A 2012 2016 ANNUAL MEETING 2016 ANNUAL MEETING

PREGNANCY AND LACTATION CARDIOVASCULAR EFFECTS

• Inconsistent results regarding fetal teratogenicity • Increases HR by 80 to 100% acutely; decreases with chronic use nd rd • Reduced fetal growth in 2 and 3 trimesters • Orthostatic hypotension acutely • No association with mean birth weight, gestational age, or preterm delivery • 4.8 fold increase in risk of MI in the hour following use • Identification of effects in breastfeeding are inconsistent; no long-term studies • Case reports demonstrating possible increase in risk of stroke • Prolonged effects on cognition • Not associated with serious health problems for most young, healthy users • Decreased attentiveness and executive functioning between 6 and 16 years old • Conflicting reports of standardized testing scores • No precipitation or acceleration of atherosclerotic effects • Increased conduct disorders between 6 and 21 years old • Increased delinquency and externalizing behaviors • Greater risk for cigarette smoking and marijuana between 16 and 21

Warner TD, Roussos-Ross D, Behnke M 2014 Mittleman MA, Lewis RA, Maclure M, et al 2001 Thomas G, Kloner RA, Rezkalla S 2014 2016 ANNUAL MEETING 2016 ANNUAL MEETING

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CANNABINOID HYPEREMESIS SYNDROME GATEWAY THEORY

• Several proposed etiologies; not well understood • Alcohol/tobacco  soft drugs  hard drugs • Genetic variation leads to toxic accumulation • Association between regular cannabis use and later / use • Long-term use causes accumulation in cerebral fat, causing toxicity and emesis • Early initiation and regular use of cannabis predictive of use of other drugs • Enteric pro-emetic effects may override CNS-mediated antiemetic effects • Central effects of long term use on hypothalamic-pituitary-adrenal axis • Causal relationship is debated • Impairment of thermoregulation • Other substances supplied by same black market • Triad of symptoms • Cannabis does have physiologic effects on reward system • Long-term use (more than 1 year) • Cyclic vomiting with or without abdominal pain • Compulsive hot bathing

Sun S, Zimmermann AE 2013 http://www.geekalerts.com/u/Marijuana-Hey-At-Least-Its-Not-Crack.jpg

2016 ANNUAL MEETING 2016 ANNUAL MEETING

MOOD AND PSYCHIATRIC EFFECTS WITHDRAWAL

• 10-22 joints daily associated with social isolation and paranoid thinking • Not in DSM-IV. Acknowledged by ICD-10, and added to DSM-V • Heavy use can produce acute psychosis • Withdrawal generally mild • May precipitate schizophrenic episodes • Anxiety, depression, irritability, insomnia, vivid/unpleasant dreams • GI distress, decreased appetite, tremors, diaphoresis, thermodysregulation, headache • Schizophrenics prefer marijuana over alcohol and cocaine • 41% increase in risk of subsequent psychosis • Up to 85% of heavy THC users experience withdrawal upon cessation • Heavy marijuana use preceded depression among high school students • Onset 1-2 days after cessation, peak about 10 days after • Not suicidal ideation or attempt • Adolescents continuing daily use at 29 years old are 3 times more likely to develop anxiety disorders

Joy JE, Watson SJ, Benson JA 1999 Hadland SE, Harris SK 2014 Hadland SE, Harris SK 2014 2016 ANNUAL MEETING 2016 ANNUAL MEETING

DEPENDENCE TOXICITY

• DSM-V combined cannabis abuse and dependence into “” • Lethal dose in animals is 10,000 times effective dose • Use is most prevalent among ages 18-25 • Most reported deaths related to causes other than direct overdose • Earlier age at onset and psychiatric disorders associated with greater likelihood • Lab explosions, motor vehicle collisions, acute psychosis • First reported death after recreational use approved in Colorado occurred in 2014 • Accounts for second largest number of adolescent admissions to substance use treatment programs, second to alcohol • Cookie containing six servings of THC • One serving was eaten initially, with the other five 60 minutes later • 40% of high school students have used marijuana in their lifetime • Hostility noted with erratic speech about three hours after initial ingestion • Highest in males and black/Hispanic youth • Death caused by jumping off fourth floor balcony 3.5 hours after initial ingestion • 33% of boys and 25% girls by 9th grade • 9% use >20 days/month • Increase of exposure in children under 12 after legalization in Colorado • 0 of 790 patients from 2005-2009; 14 of 588 patients from 2009-2011 Hadland SE, Harris SK 2014 Hancock-Allen JB, Barker L, VanDyke M, et al 2014 Wang GS, Roosevelt G, Heard K 2013 2016 ANNUAL MEETING 2016 ANNUAL MEETING

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SUMMARY REFERENCES

• Cannabis is re-emerging as a therapeutic agent • Grotenhermen F. Pharmacology of cannabinoids. Neuroendocrinol Lett. 2004;25(1-2):14-23. • Grant I, Cahn BR. Cannabis and endocannabinioid modulators: Therapeutic promises and challenges. Clin Neurosci Res. 5(2-4):185-199. • Cannabidiol is currently approved for use in Florida, though not yet available • Williams CM, Kirkham TC. Anandamide induces overeating: Mediation by central cannabinoid (CB1) receptors. Psychopharmacology. 1999;143:315-317 • Cannabinoid receptors modulate analgesia, motor effects, emesis • Muniyappa R, Sable S, Ouwerkerk R, et al. Metabolic effects of chronic . Diabetes Care. 2013;36(8):2515-2422.

• Cannabinoids affect immune, endocrine, cardiovascular, pulmonary, and mental • Joy JE, Watson SJ, Benson JA. Marijuana and medicine: assessing the science base. Institute of Medicine. 1999. Available at health, including psychiatric disorders and cognition http://www.nap.edu/read/6376/chapter/5#105.

• Machado Rocha FC, Stefano SC, De Cassia Haiek R, et al. Therapeutic use of on chemotherapy-induced nausea and vomiting • Potential changes in abuse patterns if marijuana use becomes more widespread among cancer patients: systematic review and meta-analysis. Eur J Cancer Care. 2008;17(5):431-443. • Lack of standardization and quality control may limit use of herbal cannabis even • Wang T, Collet J, Shapiro S, et al. Adverse effects of medical cannabinoids: a systematic review. CMAJ. 2008;178(13): 1669-1678 if approved • Klein TW, Newton C, Larsen K, et al. The cannabinoid system and immune modulation. J Leuk Bio. 2003;74(4):486-496.

• Brown TT, Dobs AS. Endocrine effects of marijuana. J Clin Pharmcol. 2002; 42:90S-96S

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THANK YOU REFERENCES

• Warner TD, Roussos-Ross D, Behnke M. It’s not your mother’s marijuana: Effects on maternal-fetal health and the developing child. Clin Perinatol. Anthony Pazanese, Pharm.D. 2014;41(4): 877-894. Clinical Pharmacy Specialist, Pain Management and Palliative Care Lakeland Regional Health • Mehra R, Moore BA, Crothers K, et al. The association between marijuana smoking and lung cancer. Arch Intern Med. 2006;166:1359-1367. [email protected] • Callaghan RC, Allebeck P, Sidorchuk A. Marijuana use and risk of lung cancer: A 40-year cohort study. Cancer Causes Control. 2013;24:1811- 1820.

• Mittleman MA, Lewis RA, Maclure M, et al. Triggering myocardial infarction by marijuana. Circulation. 2001;103:2805-2809.

• Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: What cardiologists need to know. Am J Card. 2014; 113(1) 187-190.

• Compton RP, Berning A. Drug and Alcohol Crash Risk. National Highway Traffic Safety Administration. NHTSA’s Office of Behavioral Safety Research. February 2015. DOT HS 812 117

• Sun S, Zimmermann AE. Cannabinoid Hyperemesis Syndrome. Hosp Pharm. 2013; 48(8): 650-655.

• Hadland SE, Harris SK. Youth marijuana use: State of the science for the practicing clinician. Curr Opin Pediatr. 2014;26(4): 420-427.

• Wang GS, Roosevelt G, Heard K. Pediatric marijuana exposures in a medical marijuana state. JAMA Pediatr. 2013;167(7):630-633.

http://amobleyss6.blogspot.com/2013/03/medical-marijuana.html

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REFERENCES

• WGBH educational foundation. Frontline. Marijuana timeline. 2014.Available at http://www.pbs.org/wgbh/pages/frontline/shows/dope/etc/cron.html.

• Lathrop JR. Advanced Holistic Health Clinic. The 10,000 year world history of marijuana. 2015. Available at http://www.advancedholistichealth.org/history.html.

• ProCon.org. Medical Marijuana. 16 states with laws specifically about legal cannabidiol (CBD). 2016. Available at http://medicalmarijuana.procon.org/view.resource.php?resourceID=006473.

• Sharma P, Murthy P, Barath MS. Chemistry, metabolism, and toxicology of cannabis: Clinical implications. Iran J Psychiatry. 2012;7(4):149-156.

• Hancock-Allen JB, Barker L, VanDyke M, et al. Notes from the field: Death following ingestion of an edible marijuana product – Colorado – March 2014. MMWR. 2015;64(28):771-772.

• Russo EB, Hohmann AG. Role of cannabinoids in pain management. Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. Deer TR et al (eds.) American Academy of Pain Medicine 2013. Available at https://www.painsociety.com/files/6914/2230/0850/Russo-Hohmann_Role_of_cannabinoids_in_pain_management_from_Deer_2013.pdf.

• Kalliomaki J, Segerdahl M, Webster L, et al. Evaluation of the analgesic efficacy of AZD1940, a novel cannabinoid agonist, on post-operative pain after lower third molar surgical removal. Scandinavian Journal of Pain. 2013;4:17-22.

• Chohan H, Greenfield AL, Yadav V, et al. Use of cannabinoids for spasticity and pain management in MS. Curr Treat Options Neurol. 2016; 18(1).

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