Ray Bailey BPharm, R.Ph.

Medical Cannabis for Health Professionals

Educational Objectives� Explain the mechanisms of action and pharmacological properties

of Cannabis, including administration, dosing and formulations� Identify disease states where Cannabis has shown efficacy and

define particularly in Cancer patients � Discuss adverse drug reactions, drug interactions and required

monitoring� Outline the history of Medical Cannabis use� Discuss the Pharmacist role in counseling patients and caregivers

and legal implications� Discuss the Federal Prohibition and the impact on Clinical

Research and Pharmacist involvement

What is Cannabis (Marijuana)� The Cannabinoids – Some 113 identified to date

� Delta-9-THC (Tetrahydrocannabinol)� Cannabidol (CBD) Charlotte’s Web� Cannabigerol Acid – Chemical precursor to THC and CBD� Cannabinol (CBN) Most prevalent chemical compound� Cannabichomene (CBC)� Terpenoids – Produce Marijuana distinct aroma� Flavonoids – over 20 known

� Cannabis most common routes of administration� Smoked either rolled or in pipes� Ingested in many edible forms� Vaporized in a variety of marketed devices

The Endocannabinoid System� The Endocannabinoid System is the largest neural pathway in the human

body – responsible for total body homeostasis (Pain baseline theory)� Receptors first identified in 1992 – CB1 and CB2 and distributed

throughout the central nervous and immune systems� First naturally occurring endocannibinoids isolated

� Anandamide stimulates CB1 receptor site as does THC� 2-AG stimulates CB2 receptor site as does CBD

� Endocannabinoids serve as the primary messenger across the synapse and is thought to affect the release (modulation) of neurotransmitters. Their role in the synapse is more important and far more complex than previously thought. Much more research is needed.

� The proper endocannabinoid “tone” is associated with general well-being

A Biological System of Endocannabinoids Neurotransmitters and Receptors

Phytocannabinoids� More than 545 chemical constituents produced within the cannabis plant� Phytocannabinoids are cannabinoids produced by the cannabis plant in the form

of carboxylic acids:� THCA� CBDA

� Upon heating, or gradually warming up to room temperature over time, these cannabinoids are converted to their chemically neutral more widely known forms THC and CBD

� It is in this neutral form that THC become psychoactive to humans� Now thought that cannabinoids work in concert with each other, along with

terpenes to produce differences in medicinal and psychoactive effects

The Highly Studied Cannabinoids� THC

� Certain stains can produce up to 25% of the plants dry weight in THC� Primary psychoactive constituent of cannabis� Potent anti-inflammatory and analgesic� Is neuroprotective and reduces intraocular pressure, spasticity and muscle tension� No activity in the brain stem thusly impossible to lethally overdose. LD50 unknown

� CBD� Most common phytocannabinoid in fiber cannabis (hemp) and second most common in

drug cannabis varieties� Due to Project CBD, High-CBD cannabis varieties have reemerged. Some with a 20:1

CBDA to THCA concentration� Seems to be more neuroprotective with little or no psychoactive effects� GW Pharma has drug in clinical trials which is combination of THC and CBD called

Sativex (sublingual spray) Available in Europe and Canada� CBD compounds used in Israel for strokes patients in place of tPA� FDA has recently approved CBD based Epidiolex for 2 forms of severe childhood

epilepsies

The National Academics of Sciences -Engineering –Medicine (2017)

� Committee Report Health Effects of Marijuana

� Current State of Evidence� Recommendations for

Research� MARIE C. McCORMICK

(Chair), Sumner and Esther Feldberg Professor, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA

Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30: 515-527Article· Literature Review in Trends in Pharmacological Sciences 30(10):515-27 · October 2009 with 283 ReadsDOI: 10.1016/j.tips.2009.07.006 · Source: PubMed

Disease States Cannabis has Efficacy

� Migraine and Headaches� Multiple Sclerosis� Nausea and Vomiting (CINV)� Neuropathy� Pain� Parkinson’s Disease� PTSD� Schizophrenia� Seizure Disorders� Skin Conditions� Stress� Diabetes

References� “A. Shelef, Y. Barak, U. Berger, D. Paleacu, S. Tadger, I. Plopsky, Y. Baruch, “Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological

Symptoms of Dementia: An-Open Label, Add-On, Pilot Study,” Journal of Alzheimer’s Disease 2016;51:15–9.

� “E. M. Blessing, M. M. Steenkamp, J. Manzanares, C.R. Marmar, “Cannabidiol as a Potential Treatment For Anxiety Disorders,” Neurotherapeutics 2015;12: 825–36

� “D. R. Blake, et al., “Preliminary Assessment of the Efficacy, Tolerability and Safety of a Cannabis-Based Medicine (Sativex®) in the Treatment of Pain Caused by Rheumatoid Arthritis,” Rheumatology 45.1 (2006): 50–52.

� “S. J. Williams, J. P. Hartley, and J. D. Graham, “Bronchodilator Effect of Delta1-Tetrahydrocannabinol Administered by Aerosol of Asthmatic Patients,” Thorax 31, no. 6 (1976): 720–23; and J. P. Hartley, S. G. Nogrady, and A. Seaton, “Bronchodilator Effect of Delta1-Tetrahydrocannabinol,” British Journal of Clinical Pharmacology 5, no. 6 (1978): 523–25.

� “Ruth, Cooper, et al., “Cannabinoids in Attention-Deficit/Hyperactivity Disorder: A Randomised-Controlled Trial,” European Neuropsychopharmacology 26 (2016): S130.

� “C. H. Ashton, P. B. Moore, P. Gallagher, A. H. Young, “Cannabinoids in Bipolar Affective Disorder: A Review and Discussion of Their Therapeutic Potential,” Journal of Psychopharmacology2005;19:293–300.

� “Gil Bar-Sela, M. Vorobeichik, S. Drawsheh, A. Omer, V. Goldberg, E. Muller, “The Medical Necessity for Medicinal Cannabis: Prospective, Observational Study Evaluatingthe Treatment in Cancer Patients on Supportive or Palliative Care,” Evidence-Based Complementary and Alternative Medicine (2013).”

� “R. Noyes Jr., S. F. Brunk, D. A. Baram, A. Canter, “Analgesic Effect of Delta-9-Tetrahydrocannabinol,” The Journal of Clinical Pharmacology 1975;15:139–43.”

� “Sara Jane Ward, et al., “Cannabidiol Inhibits Paclitaxel-Induced Neuropathic Pain Through 5-Ht1a Receptors Without Diminishing Nervous System Function or Chemotherapy Efficacy,” British Journal of Pharmacology 171.3 (2014): 636–645.”

� “Mellar P. Davis, “Cannabinoids for Symptom Management and Cancer Therapy: the Evidence,” Journal of the National Comprehensive Cancer Network 14.7 (2016): 915–922.”

� “F. C. Rocha, J. G. Dos Santos Júnior, S. C. Stefano, D. X. da Silveira, “Systematic Review of the Literature on Clinical and Experimental Trials on the Antitumor Effects of Cannabinoids in Gliomas,” Journal of Neuro-Oncology 2014;116:11–24.”

� “Francesca Comelli, I. Bettoni, M. Colleoni, G. Giagnoni, and B. Costa, “Beneficial Effects of a Cannabis sativa Extract Treatment on Diabetes-Induced Neuropathy and Oxidative Stress,” Phytotherapy Research 23, no. 12 (2009): 1678–84.”

� “Joseph S. Alpert, “Marijuana for Diabetic Control,” American Journal of Medicine 126, no. 7 (2013): 557–”

� “Ethan B. Russo, “Clinical Endocannabinoid Deficiency (CECD): Can This Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and Other Treatment-Resistant Conditions?,” Neuroendocrinology Letters 25, nos. 1–2 (2004): 31.”

References� “Timna Naftali, et al., “Cannabis for Inflammatory Bowel Disease,” Digestive Diseases 32.4 (2014): 468-474.”

� “Robert S. Hepler and Ira R. Frank, “Marihuana Smoking and Intraocular Pressure,” JAMA: The Journal of the American Medical Association 217, no. 10 (1971): 1392.”

� “T. A. Mestre, J. J. Ferreira, “An Evidence-Based Approach in the Treatment of Huntington’s Disease,” Parkinsonism & Related Disorders 2012;18:316–20.”

� “Rosaria Greco and Cristina Tassorelli, “Endocannabinoids and Migraine,” Cannabinoids in Neurologic and Mental Disease (2015): 173.”

� “D. Centonze, F. Mori, G. Koch, F. Buttari, C. Codecà, S. Rossi, M. T. Cencioni, M. Bari, S. Fiore, G. Bernardi, L. Battistini, and M. Maccarrone, “Lack of Effect of Cannabis-Based Treatment on Clinical and Laboratory Measures in Multiple Sclerosis,” Neurological Sciences 30 (2009): 531–44; and David J. Rog, Turo J. Nurmikko, Tim Friede, and Carolyn A. Young, “Randomized, Controlled Trial of Cannabis- Based Medicine in Central Pain in Multiple Sclerosis,” Neurology 65 (2005): 812–19.”

� “Barbara Todaro, “Cannabinoids in the Treatment of Chemotherapy-Induced Nausea and Vomiting,” Journal of the National Comprehensive Cancer Network 10, no. 4 (2012): 487–92.”

� “Francisco C. Machado Rocha, S. C. Stéfano, R. De Cássia Haiek, L. M. Rosa Oliveira, and D. X. Da Silveira, “Therapeutic Use of Cannabis sativa on Chemotherapy-Induced Nausea and Vomiting among Cancer Patients: Systematic Review and Meta-Analysis,” European Journal of Cancer Care 17, no. 5 (2008): 431–43.”

� “B. Wilsey, T. Marcotte, Gouaux B. Deutsch, S. Sakai, H. Donaghe, “Low-Dose Vaporized Cannabis Significantly Improves Neuropathic Pain,” Journal of Pain 2013;14:136–48.”

� “Pablo Roitman, et al., “Preliminary, Open-Label, Pilot Study of Add-On Oral Δ9-Tetrahydrocannabinol in Chronic Post-Traumatic Stress Disorder,” Clinical Drug Investigation 34.8 (2014): 587–591.”

� “M. W. Manseau, D. C. Goff, “Cannabinoids and Schizophrenia: Risks and Therapeutic Potential,” Neurotherapeutics 2015;12:816–24.”

� “Attila Oláh, et al., “Differential Effectiveness of Selected Non-Psychotropic Phytocannabinoids on Human Sebocyte Functions Implicates Their Introduction in Dry/Seborrhoeic Skin and Acne Treatment,” Experimental Dermatology 25.9 (2016): 701–707.”

� “D. I. Abrams, C. A. Jay, S. B. Shade, H. Vizoso, H. Reda, S. Press, M. E. Kelly, M. C. Rowbotham, and K. L. Petersen, “Cannabis in Painful HIV-Associated Sensory Neuropathy: A Randomized Placebo- Controlled Trial,” Neurology 68, no. 7 (2007): 515–21.”

� “Tibor Harkany and Tamas L. Horvath. “(S) Pot on Mitochondria: Cannabinoids Disrupt Cellular Respiration to Limit Neuronal Activity,” Cell Metabolism 25.1 (2017): 8–10.”

� “J. H. Allen, et al., “Cannabinoid Hyperemesis: Cyclical Hyperemesis in Association with Chronic Cannabis Abuse,” Gut. 2004 ;53:1566–1570.”

� “I. Lotan, T. Treves, Y. Roditi, and R. Djaldetti, “Medical Marijuana (Cannabis) Treatment for Motor and Non-Motor Symptoms in Parkinson’s Disease: An Open-Label Observational Study,” Movement Disorders 28, supplement 1 (2013): 448.”

Cannabis and Cancer Pain� Pain was the primary symptom for which the evidence supporting the use of

cannabis medicines was rated as strong in the 2017 National Academies report.� Pain is the most common condition for which patients report using cannabis.� Finding the optimal dose for pain relief has been shown to be very important� A University of California San Diego study showed that low does provided little

relief while moderate doses produced good pain relief.� This same study showed that larger doses actually increased pain levels.� Perhaps confirming the results of the UC San Diego study a study of Sativex®

cannabinoid spray for intractable cancer pain showed that cannabis was most effective at lower and medium doses, which would seem to support the hypothesis that higher doses of cannabinoids do not necessarily provide increased pain relief.

� “Russell K. Portenoy, E. D. Ganae-Motan, S. Allende, R. Yanagihara, L. Shaiova, S. Weinstein, R. McQuade, S. Wright, and M. T. Fallon, “Nabiximols for Opioid-Treated Cancer Patients with Poorly- Controlled Chronic Pain: A Randomized, Placebo- Controlled, Graded-Dose Trial,” Journal of Pain 13, no. 5

(2012): 438–49.”

Cannabis and Cachexia� Cannabis medicines have shown effective in treating AIDS associated cachexia.

An early trial with oral THC using a dose or 2.5mg did show success in maintaining patients appetite over the 7 months of the study.

� Research studies looking at cancer-related cachexia has shown conflicting results

� The Cannabis in Cachexia Study Group was discontinued when cannabis showed little advantages over placebo.

� This study is often cited and was a randomized double-blind study of cancer patients

� It found that low doses of THC-CBD extract or THC were no better than placebo for appetite and produced more side effects.

� “Jeffrey E. Beal, et al., “Dronabinol as a Treatment for Anorexia Associated with Weight Loss in Patients with Aids,” Journal of Pain and Symptom Management 10.2 (1995): 89–97.”

� “Florian Strasser, D. Luftner, K. Possinger, G. Ernst, T. Ruhstaller, W. Meissner, Y. D. Ko, M. Schnelle, M. Reif, and T. Cerny, “Comparison of Orally Administered Cannabis Extract and Delta-9- Tetrahydrocannabinol in Treating Patients with Cancer- Related Anorexia-Cachexia Syndrome: A Multicenter, Phase III, Randomized, Double-Blind, Placebo- Controlled Clinical Trial from the Cannabis-In- Cachexia-Study-Group,” Journal of Clinical Oncology 24, no. 21 (2006): 3394–400.”

Cannabis Cancer Treatment

� Of many studies worldwide using cannabis as a treatment for GBM, I found this one most interesting

� A pilot study published in 2006 (referenced below) involved nine patients with glioblastoma multiforme that showed disease progression after all other conventional treatments were exhausted.

� A catheter was inserted in the tumor and a THC solution was injected daily in increasing doses for 10 days.

� The starting dose was small 20-40mg and was titrated up to 80-180mcg. � Three of the nine patients improved clinically and two lived

approximately one year.� “M. Guzmán, M. J. Duarte, C. Blázquez, J. Ravina, M. C. Rosa, I. Galve-

Roperh, C. Sánchez, G. Velasco, L. González-Feria, “A Pilot Clinical Study of Delta-9-Tetrahydrocannabinol in Patients With Recurrent Glioblastoma Multiforme,” British Journal of Cancer 2006;95:197–203.

Cannabis use in Cancer - Summary

� The treatment of the major symptoms of cancer by cannabis in various forms is not controversial. In fact a medical review of the uses of cannabis show strong scientific evidence to support use in pain, CINV, appetite stimulation and sleep

� There are randomized controlled clinical trials of good quality to support the treatment of pain, and controlled trials of weaker quality that support the treatment of CINV, insomnia, and appetite stimulation with weight loss. (one conflicting study cited and National Academies Report states insufficient evidence to support or refute.

� Medical cannabis is also effective for reducing, preventing, relieving, or distracting from both neuropathic and visceral pain.

References � “ R. Noyes Jr., S. F. Brunk, D. A. Baram, A. Canter, “Analgesic Effect of Delta-9-Tetrahydrocannabinol,” The Journal of Clinical Pharmacology

1975;15:139–43

� .D. I. Abrams, M. Guzman, “Cannabis in Cancer Care,” Clinical Pharmacology & Therapeutics 2015;97:575–86

� . Sara Jane Ward, et al., “Cannabidiol Inhibits Paclitaxel-Induced Neuropathic Pain Through 5-Ht1a Receptors Without Diminishing Nervous System Function or Chemotherapy Efficacy,” British Journal of Pharmacology 171.3 (2014): 636–645

� . Mary E. Lynch, Paula Cesar-Rittenberg, and Andrea G. Hohmann, “A Double-Blind, Placebo-Controlled, Crossover Pilot Trial with Extension Using an Oral Mucosal Cannabinoid Extract for Treatment of Chemotherapy-induced Neuropathic Pain,” Journal Of Pain And Symptom Management 47.1 (2014): 166–173.

� Sydney Tateo, “State of the Evidence: Cannabinoids and Cancer Pain—A Systematic Review,” Journal of the American Association of Nurse Practitioners (2016).

� Margherita Russo, et al., “Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis,” Pain Medicine 17.6 (2016): 1145–1154.

� P. F. Whiting, R. F. Wolff, S. Deshpande, M. Di Nisio, S. Duffy, A. V. Hernandez, J. C. Keurentjes, S. Lang, K. Misso, S. Ryder, S. Schmidlkofer, M Westwood, J. Kleijnen, “Cannabinoids For Medical Use: A Systematic Review and Meta-Analysis,” JAMA 2015;313:2456–73.138

� D. I. Abrams, M. Guzman, “Cannabis in Cancer Care,” Clinical Pharmacology & Therapeutics 2015;97:575–86.

� Tim Luckett, et al., “Clinical Trials of Medicinal Cannabis for Appetite-related Symptoms From Advanced Cancer: A Survey of Preferences, Attitudes and Beliefs Among Patients Willing to Consider Participation,” Internal Medicine Journal 46.11 (2016): 1269–1275.

� Mellar P. Davis, “Cannabinoids for Symptom Management and Cancer Therapy: the Evidence,” Journal of the National Comprehensive Cancer Network 14.7 (2016): 915–922.

� Erin M. Rock, et al., “Cannabinoid Regulation of Acute and Anticipatory Nausea,” Cannabis and Cannabinoid Research 1.1 (2016): 113–121.

� R. W. Gorter, “Cancer Cachexia And Cannabinoids,” Forschende Komplement-ärmedizin/Research in Complementary Medicine 6.Suppl. 3 (1999): 21–22

Pharmacy Implications� Smoked/Vaped Cannabis show peak concentrations in 10 minutes-decreased to 60% of

peak in 15 minutes and 20% in 20 minutes. Allows patient to titrate dose

� Ingested Cannabis- lower plasma levels due to first-pass effect and highly variable with peaks 1-6 hours later

� Sublingual admin levels similar to smoked/NO first pass

� 11-OH metabolite of ingested THC contribute greatly to psychotropic effects

� More than 55% of THC is excreted in the feces and ~20% in the urine

� Synthetic THC Marinol (Dronabinol) and Synthetic analog of THC Cesamet (Nabilone) Bioavailability 5-20%, Peak 1-6 hours, 10% of that achieved with smoking

� Side Effects of Medical Cannabis both inhaled and orally (THC)� Euphoria

� Dry mouth� Reddening of the eyes

� Increased appetite� Blurred vision� Dizziness and headache

� Sedation � Anxiety

Pharmacy Implications (Cont)� Currently very little data regarding potential drug interactions with

cannabis. We can make some predictions based on the known pharmacology of the compounds

� THC and CBD extensively metabolized by CYP3A4/5 and CYP2C9/19

� Patients who are poor metabolizers of CYP2C9 have been shown to have THC concentrations 3 times higher than extensive metabolizers

� Inhibitors of CYP2C9 could be expected to increase plasma concentration of THC

� Amiodarone, cimetidine, cotrimoxazole, metronidazole, fluconazole, voriconazole

� Ketoconazole is an inhibitor of CYP3A4 and has been reported to increase the AUC time curve of THC 1.2-1.8 fold

Pharmacy Implications (Cont)� Other CYP3A4 inhibitors could be expected to produce

similar increases � Rifampin is a CYP3A4 inducer and has been reported to

reduce THC levels by 20-40%. One study has shown a reduction CBD levels of 50-60%

� In vitro studies have shown THC and CBD to have limited ability to inhibit CPY450 enzymes

� Smoking itself (e.g. tobacco or cannabis) induces CYP1A2 which may increase clearance of some antipsychotics and antidepressants

History of Cannabis� 10,000 Years ago Cannabis found in

clay jars in Japan

� 4700 Years ago Cannabis was an important herbal remedy in China

� 1500- 200 BC Cannabis used as a medicine in India

� 500 BC Cannabis was the most important of all known medicinal plants in Persia

� 200 BC Cannabis used as a medicine in Egypt and Greece

� 1800’s Cannabis Indica brought to the US from India

� 1850-1941 Cannabis Tincture USP

The Federal ProhibitionCannabis remains a Schedule I drug on a Federal Level

The Federal Prohibition� Marijuana Tax Act of 1937� AMA and Pharmacist fought this act but succumb and Cannabis removed from USP in

1942 � Controlled Substance Act is a statute under the Comprehensive Drug Abuse Prevention and

Control Act of 1970 signed by President Nixon� Medical Cannabis is now legal in 33 States and D.C.� NIDA controls supply of Cannabis legal for Medical Research. University of Mississippi� DEA and NIDA have recently relaxed rules allowing researcher to obtain cannabis from

other sources for research� Until Rescheduled at a Federal level has no place in any licensed Pharmacy. Would be

putting DEA license at risk� If legal at a State level, Pharmacist should be able to counsel patients on potential SE and

drug interactions� In some States Medical Professional cannot obtain a Medical Cannabis Card� Why is most psychoactive component of Cannabis Schedule III and the raw plant Schedule

I?

Question?