Medical Cannabis. Kari L. Franson, PharmD, PhD, BCPP Associate Dean for Professional Education

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1 Medical Cannabis Kari L. Franson, PharmD, PhD, BCPP Associate Dean for Professional Education

2 At the end of this activity, participants should be able to: 1) Identify the contents in cannabis that effect physiologic processes 2) Describe the pharmacology of cannabis to explain: a. Uses b. Effect on the reward pathway c. Acute toxicity and long term risks 3) Outline the pharmacokinetic differences between different cannabis dosage forms

3 Disclosure Statement Dr. Franson has nothing to disclose and no conflicts of interest or funding sources Dr. Franson will be discussing unapproved drugs and unapproved uses for drugs This presentation is based on Borgelt LM, Franson KL, Nussbaum Am, Wang GS. The Pharmacologic and Clinical Effects of Medical Cannabis Pharmacotherapy 2013;33(2):

4 Cannabis

Cannabis Contains over 400 compounds Over 100 cannabinoids Non-cannabinoid compounds are similar to those found in tobacco (except nicotine) Terpenes are variable, contribute to aroma (limonene,

5 Cannabis Contains over 400 compounds Over 100 cannabinoids Non-cannabinoid compounds are similar to those found in tobacco (except nicotine) Terpenes are variable, contribute to aroma (limonene, pinene) and serve as a precursor to cannabinoids Cannabinoids & terpenes are found in flowering tops > buds > top leaves > lower leaves > stems stalks Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacotherapy. 2013

6 Cannabis (indica, sativa, ruderalis) What is in the different species? 9 -tetrahydrocannabinol THC: most psychoactive & has most medical claims Cannabidiol CBD: little psychoactive & most medical promise Cannabigerol - CBG Tetrahydrocannabivarin THC-V Cannabichromene CBC Tetrahydrocannabinolic acid THC-A Cannabinol - CBN Pertwee RG. Br J Pharmacology. 2006

7 Other common cannabinoids Anandamide, 2-AG (endocannabinoids) Dronabinol, nabilone (THC molecule Pharma products) Epidiolex (CBD extract Pharma product) Sativex (THC & CBD extract Pharma product) Rimonabant (CB1 receptor inverse agonist Pharma product) HU-210 ( Spice, synthetic cannabinoid on street) Most interact with the endocannabinoid system via G-proteincoupled receptors in the body, but not CBD Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacotherapy. 2013

8 Regulatory effect of cannabinoids at the CB1 receptor 1. Inhibition of adenylyl cyclase activity 2. Alter second messenger systems such that CA++ influx is inhibited Neuromodulation by anandamide particularly relevant to modulation of GLU (shown), Ach, GABA, DA, NE There is a known tolerance to THC via down regulation of CB1 receptors High probability of tolerance with chronic use, and low with intermittent Pertwee RG. Br J Pharmacology. 2008

Cannabis activity at CB1 receptors Structure THC effect CBD effect Neocortex Altered thinking, judgement Delayed onset time to intoxication with THC Basal ganglia Slowed reaction time Reduced

9 Cannabis activity at CB1 receptors Structure THC effect CBD effect Neocortex Altered thinking, judgement Delayed onset time to intoxication with THC Basal ganglia Slowed reaction time Reduced psychomotor abnormalities from THC Hypothalamus appetite No to little effect on appetite Amygdala Panic, paranoia Decrease THC induced anxiety Nucleus accumbens Euphoria Attenuated THC induced euphoria Hippocampus Impaired memory Attenuated THC induced memory effects Cerebellum Impaired coordination Reduced coordination abnormalities from THC Brain stem Anti-nausea effects Hippocampus, forebrain Anti-epileptic effects? Anti-epileptic effects for certain populations 1996 Spinal cord Altered pain sensitivity TRPV reduction in pain

10 Non-cannabinoid targets linked to cannabis Other G-protein receptors: GPR55, GPR55940, etc. G-protein-coupled receptors: noncompetitive inhibitor at µ- and d-opioid receptors, NE, DA, 5-HT Ligand-gated ion channels: allosteric antagonism at 5-HT3, nicotinic, and enhance activation of glycine receptors Transient receptor potential channels (TRPVs): bind and activate TRPV1 similar to capsaicin, also CB1 receptors are located near TRPV1 Ion channels: inhibition of Ca, K, Na channels by noncompetitive antagonism Peroxisome Proliferator-Activated Receptors: PPARa and PPARg are activated Pertwee, RG. British Journal of Pharmacology. 2006

11 Evidence for the use of medical cannabis in medical conditions

12 Number of states with various approved medical conditions Alzheimer s disease (8) Epilepsy/seizures (24) Nausea (22) ALS (11) Glaucoma (22) Pain (22) Arthritis (4) Hepatitis C (10) Parkinson s disease (7) Cachexia (22) HIV/AIDS (23) PTSD (9) Cancer (25) Multiple sclerosis (22) Terminal condition (4) Crohn s/gi disorders (16) Muscle spasticity (22) accessed 5/17/2016

13 Meta-analysis of chemotherapy induced nausea and vomiting 15 randomized trials, most compared cannabis (dronabinol, nabilone, levonantradol) to prochlorperazine, 1 each for hydroxyzine, metoclopramide, ondansetron Dronabinol showed anti-emetic efficacy over neuroleptics Depression (13%), hallucinations (6%), paranoid delusions (5%), occurred, but patients preferred cannabis over control (RR 0.33; 95% CI ) Potter BE, Epilepsy & Behavior 2013 Eur J Cancer Care 2008;17:431-43

14 Review of cannabis and appetite stimulation 8 controlled studies, mostly in patients with cachexia related to AIDS or cancer 3 of these are with smoked marijuana (largest with 67 patients) Generally seems to promote weight gain/retard weight loss, although this was not statistically significant in all studies Always performs poorer than oral megestrol acetate

15 2015 cannabis treatment meta-analysis and review 79 trials (28 pain) 7 of 28 trials used MMJ Evaluated trials with >30% reduction in pain à 8 trials 2 cancer pain trials 6 neuropathic pain trials Concluded moderate quality of evidence to support the use in pain Recommendations Treat debilitating medical conditions Patients have failed trials of 1 st & 2 nd line agents Failed trial of FDA approved dronabinol or nabilone Avoid in patients with active substance abuse or psychotic disorder Know states MMJ laws and advise patients accordingly Whiting PF, Wolff RF, Deshpande S, et al. JAMA 2015 Hill KP. JAMA 2015

16 University of California Center for Medicinal Cannabis Research Grant I. Report to the State of California 2010

17 EBM guideline CAM for MS Yadav V, Bever C, Bowen J, Bowling A, et. Al. Neurology 2014

18 Seizures Most data in pediatric refractory epilepsies CBD 0.5 to 28 mg/kg/day, in 2 or 3 divided doses THC never greater than 0.8 mg/kg/day 84% parents reported reduction in seizure frequency > 50% of these were decreased by 80% Most weaned patient from another AED after starting CBD Adults case reports and patient surveys àseizure exacerbation with discontinuation àgerman study no effect Friedman D, Devinsky D, NEJM 2015

19 Glaucoma Systemic administration of cannabis IOP by 30% Pilot study of 6 patients IOP for 2 hours Uncontrolled study open-angle glaucoma THC qid IOP Patients appear to develop tolerance, but there may be neuroprotective effects Flach AJ. Trans-American Ophthalmological Society 202

20 Sleep disorders Administration of anandamide induces sleep but inhibits REM sleep, daytime drowsiness Multiple studies for other indications (particularly fibromyalgia) have evaluated sleep as an outcome and show cannabinoids may improve sleep Withdrawal from cannabis leads to sleep, longer sleep onset, less slow wave sleep Abramovici H. Controlled Substances and Tobacco Directorate at Health Canada, 2013

21 The reward pathway NIDA (

22 THC and the reward pathway

Lifetime dependency risk with use 100 75 % 50 25

23 Lifetime dependency risk with use % % 23% 17% 15% 9% 0 Hall and Degenhardt, Lancet 2009

24 The THC addiction profile Substance Abuse and Mental Health Services Administration reports more than 360,000 admitted for treatment for addiction (2010) Cannabis listed as primary drug Teens have 1 in 6 chance of becoming addicted 16% teen risk vs 9% adult risk Long-term users report withdrawal symptoms: Irritability, sleeplessness, decreased appetite, anxiety, drug craving Available at: Marijuana AdmissionsAged18to30EarlyVsAdult.htm. Accessed February 19, 2015.

25 Brain development in adolescence Limbic region Immediate rewards Impulsive behavior Cortex Long term gain Thoughtful behavior accessed 5/28/2013

26 Long term exposure causes reduced cerebral blood flow and enhanced dopaminergic neurotransmission Implicated in psychosis Can disrupt long-term memory Can lead to cognitive decline Kulhalli V, et al. Indian J Psychiatry Meier MH, et al. Proc Natl Acad Sci. 2012

27 Chronic cognitive effects (A) Relation between amount of marijuana smoked 2 and Repetition of Numbers Task, number correct for the high Shipley IQ group (squares) and the low Shipley IQ group (circles). (B) Relation between amount of marijuana smoked 2 and performance on the Stroop task for the high Shipley IQ group (squares) and the low Shipley IQ group (circles). Bolla KI, et al. Neurology, 2002

28 Concentration vs CNS effects VAS feeling high (U) THC (ng/ml) Time (hrs) Time (hr) feeling high alertness L Zuurman, et al. Br J Clin Pharmacol 2008

29 Acute CNS symptoms euphoria feeling high sedation impaired judgment panic and anxiety attacks acute psychosis, disorientation, delusions, hostility, depersonalization, hallucinations, paranoia, psychomotor agitation Crippa JA, Derenusson GN, Chagas MH, et al. Harm Reduct J. 2012

30 Management of intoxication Supportive (fluids, quiet room) Tachycardia (propranolol) Arrhythmia (flecainide, propafenone, digoxin) Acute psychotic state (Olanzapine, haloperidol) Acute panic anxiety state (lorazepam, alprazolam) Acute manic & depressive syndromes (benzodiazepines, antipsychotics)

31 CNS changes THC vs CBD Bhattacharyya S, et al. Neuropsychopharmacology

32 Concentration vs heart rate effect THC (ng/ml) heart rate (bpm) Time (hr) Time (hr) L Zuurman, et al. Br J Clinical Pharmacology. 2008

33 Heart rate variability The physiological phenomenon of variation in the time interval between heartbeats (RR-interval) Measured as the standard deviation of the successive differences (SDSD) HRV is a predictor of mortality after MI

34 Acute cardiovascular effects Heart rate HRV L Zuurman, et al. Br J Clinical Pharmacology. 2008

35 Cannabis use and long-term mortality among survivors of AMI Kaplan-Meier estimates of post-mi survival among 87 cannabis users and 174 propensity-matched nonusers. Jouanjus E, J Am Heart Assoc. 2014

36 Relative risk of myocardial infarction onset after smoking cannabis 3882 patients with acute MI average 4 days after MI 124 (3.2%) reported smoking cannabis in prior year, 37 within 24 hours, and 9 within 1 hour of MI symptoms. A rare trigger of MI The working group on cannabis complications. J Am Heart Assoc Mittleman M et al. Circulation 2001 Copyright American Heart Association, Inc. All rights reserved.

37 Pharmacokinetics

38 THC highly lipophilic & most psychoactive Typical effective dosing of THC Low dose < 7 mg Medium dose = 7 18 mg High dose > 18 mg There is a known tolerance to THC down regulation of CB1 receptors, and G-protein activation High probability of tolerance with chronic use, and low with intermittent L Zuurman, et al. Br J Clinical Pharmacology. 2008

39 PK profile of inhaled THC Vaporizing cannabis turns ~50% of the THC content into vapor Up to 50% of inhaled vapor is exhaled again, and some undergoes localized metabolism in the lung Bioavailability of a inhaled dose of THC is between 10-25% Effects are perceptible within seconds and fully apparent in a few minutes Strougo A, et al. J Psychopharmacology. 2008

40 PK profile of oral THC Bioavailability of THC after oral ingestion ranges from 5-20% in the controlled environment of clinical studies Onset of effect is delayed: 1-3 hours Duration is prolonged due to continued slow absorption from the gut Agurell S, Halldin M, Lindgren JE, et al. Pharmacological reviews. 1986

41 Comparison of THC administration INHALED C max : 3-10 min F: 10-25% Duration: 1-4 hrs t 1/2 : ~19 hrs ORAL C max : 1-3 hrs F: 5-20% Duration: 4-10 hrs t 1/2 : ~7 days TOPICAL (in guinea pigs) C max : 1.4 hrs F:? Duration: 48 hrs t 1/2 :? days

Oral formulations (edibles) increase risk of toxicity The slow onset, extended duration & variable absorption lead to toxicity JAMA study: Too much product variability à 23% under-labeled, 60%

42 Oral formulations (edibles) increase risk of toxicity The slow onset, extended duration & variable absorption lead to toxicity JAMA study: Too much product variability à 23% under-labeled, 60% over-labeled Overdosing on oral cannabis is significantly increased if one is already high from smoked cannabis or drunk on alcohol Vandrey R, et al. JAMA, 2015 Erowid E, Erowid F. Erowid Extracts. 2011

43 Oral Cannabis Dosing: The L.E.S.S. method Start Low: Begin with a small piece ( 1/3 of inhaled) Establish Potency: Measure or weigh the piece you try and make note of it Slow: Then wait a minimum of 90 minutes on an empty stomach, or minutes otherwise Supplement as Needed: Evaluate whether or not to consume another small piece. Erowid E, Erowid F. "The L.E.S.S. Method: A Measured Approach to Oral Cannabis." Erowid Extracts. Nov 2011;21:6-9.

44 Further dosing considerations THC substrate of CYP3A4 & 2C9 CBD substrate of CYP3A4 & 2C19 Possible drug interactions sedation, ataxia: CNS depressants, anticholinergics heart rate: sympathomimetics effects of: hexobarbital, hydrocortisone, clozapine, phenytoin, warfarin effects of: propofol, indinavir, theophylline Horn JR, Pharmacy Times 2014

45 Questions? or What else do you want to know?

46 References 1) Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005;65: ) Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: A randomized placebocontrolled trial. Neurology 2007;68: ) Abrams DI, Vizoso HP, Shade SB, et al. Vaporization as a smokeless cannabis delivery system: A pilot study. Clin Pharmacol Ther. 2007;82: ) Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 2007;107: ) Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. Journal of Pain 2008;9: ) Martin-Sanchez E, Furukawa TA, Taylor J, Martin JLR. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Medicine 2009;10; ) Ellis R, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: A randomized, crossover clinical trial. Neuropsychopharmacology 2009:34; ) Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010;182:E ) Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011;72: ) Abrams DI, Couey P, Shade SB, et al. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011:90; ) Wilsey B, Marcotte T, Deutsch R, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. Journal of Pain 2012;14:

Medical Cannabis. Kari L. Franson, PharmD, PhD, BCPP Associate Dean and Associate Professor Department of Clinical Pharmacy

Medical Cannabis. Kari L. Franson, PharmD, PhD, BCPP Associate Dean and Associate Professor Department of Clinical Pharmacy Medical Cannabis Kari L. Franson, PharmD, PhD, BCPP Associate Dean and Associate Professor Department of Clinical Pharmacy Objectives Identify the main constituents of cannabis Review the endocannabinoid