Cannabis In Cancer Care Donald I. Abrams, M.D. Chief, Hematology-Oncology Zuckerberg San Francisco General Professor of Clinical Medicine University of California San Francisco

Cannabinoid1 Receptor CB1 receptors identified throughout central and peripheral nervous system Density highest in cingulate gyrus, frontal cortex, hippocampus, cerebellum and basal ganglia CB1 receptors present in virtually all organs and tissues of the body

- Health Canada 2016 Pre-synaptic terminal Ca2+ K+ 4 4 2 2 3 3 6 6 Neurotransmitter vesicles Ca2+ K+ THC Dronabinol Nabilone 4 4 AA THC Dronabinol Nabilone - ETA Ca2+ 2 + CB1 receptor STOP STOP K+ CB1 receptor 2 MAGL 3 3 AEA 2-AG AEA 6 2-AG 2-AG 6 Post-synaptic terminal 5 PLD Neurotransmitter receptor 5 1 DAGL NAPE FAAH DAG 1 Neurotransmitter receptor AA Glycerol Health Canada 2016

Suppression of Neurotransmitter Release Serotonin (5-HT) Glutamate Acetylcholine GABA Noradrenaline Dopamine D-aspartate Cholecystokinin HEALTH CANADA

Endogenous Cannabinoid System Cellular uptake R Synthesis Metabolism Endocannabinoids CB2 Receptor CB1 Receptor CBx Receptor VR1 Receptor Signal Transduction Immune function Cell proliferation Inflammation Pain Appetite Cognition Immune function Emesis Muscle control Neuroexcitability Pain Reward IOP Thermoregulation Pain Vaso- dilation Pain Inflammation

Symptom Management Challenges Associated with Cancer and Its Treatments Despite therapeutic advancements, cancer and its treatments are associated with a number of difficult symptom management challenges, a few of which are shown here. For example, some demonstrable weight loss occurs in more than 50% of all cancer patients at some point during their illness.1 Cachexia is present in almost 50% of patients at the time of diagnosis.2 Early satiety is present in approximately 50% of all cancer patients.3 Anorexia is present in an estimated 15% to 40% of cancer patients at diagnosis and in as many as 80% of patients with advanced disease.3 In fact, the syndrome of anorexia and cancer cachexia is considered the most common paraneoplastic syndrome.1 Many factors contribute to the presence of anorexia in cancer patients, including nausea caused by the disease itself or by chemotherapy. Other common conditions include moderate to severe pain, which occurs in approximately one-third of all patients with cancer.4 In addition, anxiety or depression requiring psychological treatment is seen in about one-third of patients with cancer.5 Chemotherapy-induced nausea and vomiting remain two of the most feared effects of cancer treatment. Approximately 30% of patients taking a moderately or highly emetogenic chemotherapy regimen experience acute nausea and vomiting even after antiemetic prophylaxis.6 1. Arnold SM, et al. Paraneoplastic syndromes. In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:2511-2536. 2. Damsky D. Cachexia in patients with advanced cancer. Clin J Onc Nursing. 2002;6(4):235-238. 3. Body JJ. The syndrome of anorexia-cachexia. Curr Opin Oncol. 1999;11(4):255-260. 4. Foley KM. Management of cancer pain. In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:2977-3011. 5. Massie MJ, et al. Psychological issues. In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:3058-3065. 6. Carlson RH. Better antiemetic regimens still needed. Oncology Times. 2001;23(3):19-23. 1. Arnold SM, et al. In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 2001. 2. Damsky D. Clin J Onc Nursing. 2002;6(4):235-238. 3. Body JJ. Curr Opin Oncol. 1999;11:255-260. 4. Foley KM. In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 2001. 5. Massie MJ, et al. In: DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 2001. 6. Carlson RH. Oncology Times. 2001;23(3):19-23.

Oral Delta-9 THC: An Approved Drug Approved in 1986 for N&V from chemoRx; AIDS anorexia in 1992

Cannabinoids in Chemotherapy-Induced Peripheral Neuropathy Activation of CB1 and CB2 receptors suppresses development of vincristine-induced PN in rats Rahn et al, Br J Pharmacol 2007 In mice receiving daily cisplatin, anandamide plus a FAAH inhibitor attenuated CIPN Khasabova et al, J of Neuroscience 2012 In mice injected with paclitaxel, CBD pre-treatment aborts CIPN Ward et al, Br J Pharmacol 2014

Pain by Study Day n Day 1 Mean (95% CI) Day 5 Difference (95% CI)* Overall 21 39.6 (35.8, 43.3) 29.1 (25.4, 32.8) -10.7 (-14.4, -7.3) Morphine 10 34.8 (29.4, 40.1) 24.1 (18.8, 29.4) -11.2 (16.5, -6.0) Oxycodone 11 43.8 (38.6, 49.1) 33.6 (28.5, 38.6) -10.3 (14.8, -5.8) *p<0.001 Abrams et al, Clinical Pharmacology & Therapeutics 2011

New Indication for Medicinal Cannabis Lew et al HemOnc Today 2008

Cannabis Oil and Cancer

Gliomas Systematic Review 34 in vitro and/or in vivo experimental studies and one pilot human trial included All but one study showed that cannabinoids selectively kill tumor cells Antitumor activity Antiproliferative effects (cell cycle arrest) Decreased viability Cell death via toxicity, apoptosis, necrosis, autophagy Antiangiogenic effects Antimigratory effects Machado Rocha et al, J Neurooncology 2014

The Lone Human Trial 9 patients with recurrent GBM treated with 20-40 ug THC intra-tumorally per day x 15d Treatment was well tolerated Effect on survival no different from chemo In vitro, THC inhibited the proliferation and decreased viability of GBM cells from biopsies Guzman 2006 Later demonstrated that CBD enhanced the inhibitory effects of THC on GBM cell proliferation and survival Marcu 2010

Cannabis-Induced Euphoria Often described as a “side-effect” of Rx Is it really an “adverse experience”, particularly in the palliative care setting? Is a single treatment that increases appetite, decreases nausea and vomiting, relieves pain and improves mood and sleep a potentially useful tool in symptom management?