Medical Cannabis Resource Guide

1

Contents

2 About Tilray

3 About Medical Cannabis

8 Why Tilray?

Selection

Supply

Research

Support

9 An Introduction to THC and CBD

11 Medical cannabis legislation

12 Delivery Methods

13 Current Applications

Arthritis

Cancer

16 Chronic pain

17 Crohn’s disease and ulcerative colitis

18 Epilepsy

19 Glaucoma

20 HIV/AIDS

21 Multiple Sclerosis

2

About TilrayTilray is a Licensed Producer (LP) of medical cannabis in Canada. In April of 2014, we opened a 60,000 square foot cultivation, research and distribution center on Vancouver Island, British Columbia. This makes Tilray one of the world’s largest facilities dedicated to the production of medical cannabis.

Tilray’s mission is to become Canada’s leading producer of medical cannabis. Our staff includes PhDs, botanists and master horticulturists, all fully dedicated to providing healthcare practitioners and their patients with only the best products and services.

We are actively engaged in research—internally and in partnership with other academic institutions and laboratories worldwide—to advance the body of knowledge concerning cannabis and its use as medicine. We acknowledge that a significant amount of evidence supporting medical cannabis is anecdotal. However, combined with a growing body of clinically viable evidence confirming medical cannabis’ efficacy, the great magnitude of such evidence strongly supports continued, robust research.

It is important to note that, while hundreds of thousands of patients have reported obtaining relief from the use of cannabis, no evidence has come forth indicating significant toxicity. This fact has led to more and more healthcare practitioners recommending medical cannabis to their patients. Medical use of cannabis is legal in Canada, as well as Austria, the Czech Republic, Finland, Germany, Israel, Italy, the Netherlands, Portugal and Spain. As of this writing, medical use has been regulated in over 25 states in the United States.

For more information:

1-844-TILRAY1 (845-7291) doctors@tilray.ca www.tilray.ca

1100 Maughan Road Nanaimo, BC V9X 1J2

3

About Medical CannabisMedical cannabis is receiving increasing consideration as an effective therapy in the treatment of some diseases and alleviation of symptoms. While synthesized cannabinoids have been legally available for many years, use of the whole cannabis flower and cannabis extracts is only recently gaining greater acceptance, largely due to increasing evidence that such use can be a safe and effective adjunct or alternative to traditional pharmaceuticals.

Some members of the medical community have been tentative regarding the authorization of cannabis. However, research is being advanced in nations such as Canada, the US and Israel, and hundreds of thousands of patients worldwide have experimented with medical cannabis with a remarkably large percentage reporting positive effects. Increasingly, this anecdotal evidence is being corroborated by results of clinical research. At this stage, medical use of cannabis has shown potential efficacy in treating the following conditions or symptoms:

Alcohol and opioid withdrawal symptoms (drug withdrawal symptoms) 1

Alzheimer’s disease, dementia 2

Arthritis and musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, fibromyalgia, osteoporosis 3

Cachexia (wasting syndrome) and loss of appetite in AIDS and cancer patients and anorexia nervosa 4

Cancer 5

Chronic pain 6

Diseases of the pancreas (diabetes, pancreatitis) 7

Epilepsy 8

Gastrointestinal system disorders (Crohn’s disease, irritable bowel syndrome, inflammatory bowel disease, pancreatitis, metabolic syndrome/obesity, ulcerative colitis) 9

Glaucoma 10

Headache and migraine11

Hepatitis C and diseases of the liver (fibrosis, steatosis, ischemia-reperfusion injury, hepatic encephalopathy) 12

HIV/AIDS 13

4

Hypertension 14

Inflammation 15

Inflammatory skin diseases (dermatitis, psoriasis, pruritus) 16

Metabolic syndrome 17

Movement disorders (dystonia, Huntington’s disease, Parkinson’s disease, Tourette syndrome) 18

Multiple sclerosis 19

Nausea and vomiting 20

Obesity 21

Palliative care (relief from pain and other distressing symptoms, and the enhancement of quality of life) 22

Post-operative pain 23

Psychiatric disorders (anxiety and depression, sleep disorder, post-traumatic stress disorder (PTSD)) 24

1. Bachhuber et al. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern. Med. 2014, Aug 25 doi:10.1001/jamainternmed. 2014. 4005.

Lucas et al. Cannabis as a substitute for alcohol and other drugs: A dispensary-based survey of substitution effect in Canadian medical cannabis patients. Addict. Res. Theory 2013 21(5):435-442.

2. Cao et al. The potential therapeutic effects of THC on Alzheimer’s Disease. Int. J. Alzheimers Dis. 2014 (42): 973-984.

Marchalant, Y., Baranger, K., Wenk, G.L., Khrestchatisky, M. & Rivera, S. Can the benefits of cannabinoid receptor stimulation on neuroinflammation, neurogenesis and memory during normal aging be useful in AD prevention? J. Neuroinflammation 2012 (9):10-13.

Bardou, I. DiPatrizio, N., Brothers, H.M., Kaercher, R.M., Baranger, K., Mitchem, M.R., Hopp, S.C., Wenk, G.L. & Marchalant, Y. Pharmacological manipulation of cannabinoid neurotransmission reduces neuroinflammation associated with normal aging. Health 2012 (4):679-684.

3. Idris AI, et al. Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab. 2009 10(2):139-147.

Huang, Q.Y., et al. Multiple osteoporosis susceptibility genes on chromosome. Bone 2009 44(5):984-988.

Eubanks et al. A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol. Pharm. 2006 3(6):773–777.

Karsak M, et al. Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum. Mol. Genet. 2005 14(22):3389-3396.

5

4. Machado. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur. J. cancer Care 2008. (5):431-43.

Vinciguerra, V., Moore, T., & Brennan, E. Inhalation marijuana as an antiemetic for cancer chemotherapy. N Y State J. Med. 1988 (10):525–527.

Abrahamov, A., & Mechoulam, R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sciences 1995 56(23-24):2097–2102.

Chang, A. E., Shiling, D. J., Stillman, R. C., Goldberg, N. H., Seipp, C. A., Barofsky, I., & Rosenberg, S. A. A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy. Cancer 1981 47(7):1746–1751.

Chang, A. E., Shiling, D. J., Stillman, R. C., Goldberg, N. H., Seipp, C. A., Barofsky, I., et al. Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Ann. Intern. Med. 1979 91(6):819–824.

Strasser, F. 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. J. Clin. Oncol. 2006 24(21):3394–3400.

5. Alexander A et al. Cannabinoids in the treatment of cancer. Cancer Lett. 2009 18:285(1):6-12. 

Guzman, M., Duarte, M. J., Blázquez, C., Ravina, J., Rosa, M. C., Galve-Roperh, I., et al. A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br. J. Cancer 2006 95(2):197–203.

6. Lucas, P. Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain. J. Psychoactive Drugs 2012 44(2):125-133.

Martin-Sanchez E, Toshiaki A., et al. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Medicine 2009 10(8):1353-1368.

Russo, E.B. Cannabinoids in the management of difficult to treat pain. Therap. and Clincial Risk Manag. 2008 4(1):245-259.

7. Li et al. Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice. Pancreas 2013 42(1): 123-9.

Selvarajah et al. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy. Diabetes Care 2010 33(1):128-30.

Michalski et al. Cannabinoids ameliorate pain and reduce disease pathology in cerulein-induced acute pancreatitis. Gastroenterology 2007 132(5):1968-78.

DiMarzo, V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia 2008 51(8):1356-1367.

8. Devinsky et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014 55(6):791-802.

Maa & Paige. The case for medical marijuana in epilepsy. Epilepsia 2014 55(6):783-786.

9. Naftali et al. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin. Gastroenterol Hepatol. 2013 11:1276-1280.

Lal et al. Cannabis use among patients with inflammatory bowel disease. Eur. J. Gastroenterol Hepatol. 2011 23:891-896.

DiCarlo & Izzo. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin. Investig. Drugs 2003 12:39-49.

Baron et al. Ulcerative colitis and marijuana. Ann Intern. Med. 1990 112:471.

Pertwe, R. Cannabinoids and the gastrointestinal tract. Gut. 2001 48:859-867.

10. Tomida et al. Cannabinoids and glaucoma. Br. J. Ophthalmol. 2004 88(5):708–713.

11. Greco R, Mangione AS, Sandrini G. Effects of anandamide in migraine: data from an animal model. J. Headache Pain 2011 12:177-83.

Greco R, Gasperi V, Maccarrone M, Tassorelli C. The endocannabinoid system and migraine. Experimental Neurology. 2010 2010224(1):85-91.

El-Mallakh, R. Marijuana and migraine. Headache 1987 27:442-443.

6

12. Bruent, L. et al. Marijuana smoking does not accelerate progression of liver disease in HIV-hepatitis C coinfection: a longitudinal cohort analysis. Clin. Infect Dis. 2013 57(5):663-70.

Teixeira-Clerc et al. CB1 cannabinoid receptor antagonism: a new strategy for treatment of liver fibrosis. Nature Med. 2006 12(6):671-6.

Sylvestre et al. Cannabis use improves retention and virological outcomes in patients treated for hepatitis C. Eur. J. Gastroenterol Hepatol 2006 18(10):1057-63.

13. Abrams, D. I., Jay, C. A., Shade, S. B., Vizoso, H. et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007 68:515-521.

14. Steffens, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005 434:782-786.

Batkai et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 2004 110:1996-220.

15. Cost et al. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch. Pharmacol. 2004 369(3):294-299.

Sugiara et al. New perspectives in the studies on endocannabinoid and cannabis: 2-arachidonoylglycerol as a possible novel mediator of inflammation. JPS 2004 96(4):367-375.

16. Neff et al. Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease. Am. J. H. Gastroenterol. 2002 97:2117-2119.

Dvorak et al. Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflammation Research 2003 25-238-245.

Dvorak et al. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain 2003 102:283-288.

Szepietowski et al. Efficacy and tolerance of the cream containing structured physiological lipid endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerologic Croatica 2005 13:97-103.

Paus et al. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J. Clin. Invest. 2006 116:1174-1185.

17. Vemuri et al. Pharmacotherapeutic targeting of the endocannabinoid signalling system: Drugs for obesity and the metabolic syndrome. Physiol. Behav. 2008 93:671–686.

Pacher et al. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006 58(3):389–462.

18. Sagredo et al. Cannabinoids: novel medicines for the treatment of Huntington’s disease. Recent Patents on CNS Drug Discovery 2012 7:41-48.

Sagredo et al. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease. J. Neurosci. Res. 2011 89:1509-1518.

Luvone et al. Cannabidiol: a promising drug for neurodegenerative disorders? CNS Neurosci. Ther. 2009 15:65-75.

Bilsland et al. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. The FASEB Jrnl. 2006 20:1003-1005.

Weydt et al. Cannabinol delays symptom onset in SOD1 transgenic mice without affecting survival. Amyotroph. Lateral Scler. Other Motor Neuron. Discord. 2005 6:182-184.

Amtmann et al. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am. J. Hosp. Palliat. Care 2004 21:95-104.

Raman et al. Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. Amyotroph. Lateral Scler. Other Motor Neuron. Disord. 2004 5:33-39.

Consroe et al. Controlled clinical trial of cannabidiol in Huntington’s Disease. Pharmacol. Biochem BE 1991 40:701-708.

7

19. Corey-Bloom et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ 2012 10:1143-1150.

de Lago et al. Cannabinoids ameliorate disease progression in a model of multiple sclerosis in mice, acting preferentially through CB(1) receptor-mediated anti-inflammatory effects. Neuropharmacology 2012 62(7):2299-308.

Wade et al. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms of multiple sclerosis. MS. 2006 12:639-645.

20. Machado. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur. J. Cancer Care 2008 17(5):431-43.

Vinciguerra, V., Moore, T., & Brennan, E. Inhalation marijuana as an antiemetic for cancer chemotherapy. N Y State J. Med. 1988 88(10):525-527.

Abrahamov, A., Abrahamov, A., & Mechoulam, R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sciences 1995 56(23-24):2097-2102.

Chang, A. E., Shiling, D. J., Stillman, R. C., Goldberg, N. H., Seipp, C. A., Barofsky, I., & Rosenberg, S. A. A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy. Cancer 1981 47(7):1746-1751.

Chang, A. E., Shiling, D. J., Stillman, R. C., Goldberg, N. H., Seipp, C. A., Barofsky, I., et al. Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Ann. Intern. Med. 1979 91(6):819-824.

21. Le Strat & Le Foll. Obesity and Cannabis Use: Results From 2 Representative National Surveys. Am. J. Epidemiol. 2001 174(8):929-933.

Hayatbakhsh et al. Cannabis use and obesity and young adults. A.m J. Drug Alcohol Abuse 2010 36: 350-35.

22. Green & De-Vries. Cannabis use in palliative care – an examination of the evidence and the implications for nurses. J. Clin. Nurs. 2010 19:2454-2462.

Carter, G. T. Cannabis in Palliative Medicine: Improving Care and Reducing Opioid-Related Morbidity. Am. J. Hosp. Palliat. Care 2011 28(5):297-303.

23. Holcroft et al. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiolog. 2006 104:1040-6.

24. Greer et al. PTSD symptom reports of patients evaluated for the New Mexico medical cannabis program. J. Psychoactive Drugs 2014 46(1):73-77.

Bonn-Miller et al. Cannabis Use Among Military Veterans After Residential Treatment for Posttraumatic Stress Disorder. Psychol. Addict. Behav. 2011 25(3):485-491.

Leweke & Koethe Cannabis and psychiatric disorders: it is not only addiction. Addiction Biology 2008 13:264-275.

Denson & Earleywine. Decreased depression in marijuana users. Addict. Behav. 2005 31(4):738-42.

8

Why Tilray?

SelectionTilray lets healthcare practitioners and patients choose from one the widest and varied strain selections in the industry. This ensures that patients will find the strains that best address their symptoms.

SupplyHealthcare practitioners and patients expect and deserve only the best service and products. Accordingly, we provide expedited delivery, prompt follow-up and consistent quality of each product we offer.

ResearchWe actively partner with leading scientists, academic institutions, healthcare practitioners, botanists and master horticulturists to build the body of knowledge about medical cannabis.

e-PortalTilray’s secure online e-portal allows physicians to easily and quickly manage patient records, receive patient feedback and issue authorizations. It facilitates the verification process so patients can place an order within minutes of their medical document being verified. In addition, the portal keeps the physician updated on events and educational information.

We’ve also introduced faxed medical documents to expedite the patient approval process. The new fax form is available on our website. The healthcare practitioner will be responsible for retaining a copy of the medical document in their records.

Tilray Assurance ProgramPart of our ongoing commitment to improving the patient experience, the Tilray Assurance Program was created specifically for patients who do not have insurance coverage for medical cannabis. It offers patient credits for new registrations and renewals, along with senior and compassionate pricing programs.

SupportSupport is available to physicians and patients 24 hours a day, 7 days a week. Tilray is the sole LP offering round-the-clock support. Our support team can be reached at 1-844-TILRAY1 (845-7291) or by email at tilray@tilray.ca.

9

An Introduction to THC and CBDMedical cannabis contains hundreds of different chemical and pharmacological components.

Cannabinoids, the primary therapeutic chemical components in cannabis, are found in leaves and flowering tops of plants. There are over 100 cannabinoids identified in the cannabis plant, of which at least five are psychoactive. The two most studied and best understood cannabinoids are:

1. Delta-9-tetrahydrocannabinol (THC)

2. Cannabidiol (CBD)

The ratio of THC to CBD appears to play a large role in determining the therapeutic effects of cannabis. The concentration of each of these two cannabinoids depends on the plant strain and the conditions in which the plant was grown.

THC is the component in cannabis responsible for the psychoactive effects or “high” felt from cannabis. It has also been shown to be responsible for the immunosuppressive, anti-inflammatory1 and analgesic properties2, 3, 4 of cannabis.

CBD is the second most prevalent cannabinoid after THC. Research has shown that CBD produces a physical effect without the psychoactive effects associated with THC. CBD is thought to be responsible for anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptic effects of cannabis.1, 5

Since the concentration of THC and CBD determines some of the potential health benefits and possible side effects of medical cannabis, a consistent THC-to-CBD ratio ensures that patients receive the cannabinoid concentration that has been shown to be beneficial for them. Furthermore, there is evidence CBD and THC work together to produce a synergy of effects and regulate each other. For instance, CBD may block anxiety provoked by THC.6

“Cannabidiol (CBD), one major non-psychotomimetic compound of the Cannabis sativa plant, has shown anxiolytic effects in both humans and in animals.”7

-M. M. Bergamaschi et al.

“Cannabinoid drugs can modulate the production of cytokines, which are central to inflammatory processes in the body.”8

-Janet E. Joy et al.

10

1 to 1.25 grams per day is the average use rate by Canadian patients as reported by Health Canada at the 2014 Canadian Consortium for the Investigation of Cannabinoids (CCIC) conference in Toronto.

0.5 to 1.5 grams is the average daily dried flower cannabis use rate reported from medical cannabis programs in the Netherlands and Israel.3

For healthcare practitioners comfortable with the dosing of medical cannabis, our registration process gives you greater control over your patient’s course of treatment. In other cases, our team can work with you and your patients to determine the best strain and dose for optimal symptom management.

1. Joy, J. E., Watson, S. J., and Benson, J. A. Cannabis and medicine: Assessing the science base. Washington, DC: National Academy Press 1999.

2. De Petrocellis, L., Ligresti, A., Moriello, A. S., Allara, M. et al. Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 2011 163:1479-1494.

3. Izzo, A. A., Borrelli, F., Capasso, R., Di, Marzo, V et al. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 2009 30:515-527.

4. Musty, R. E., Guy, G. W., Whittle, B. A., and Robson, P. J. Natural cannabinoids: interactions and effects. The medicinal uses of cannabis and cannabinoids. London: Pharmaceutical Press 2004.

5. Pertwee, R. G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol. 2008 153: 199-215.

6. Zuardi, A. W., Shirakawa, I., Finkelfarb, E., and Karniol, I. G. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl.) 1982 76:245-250.

7. Bergamaschi, M. M., Queiroz, R. H., Chagas, M. H., de Oliveira, D. C. and others. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment naive social phobia patients. Neuropsychopharmacology 2011 36:1219-1226.

8. Joy, J. E., Watson, S. J., and Benson, J. A. Cannabinoids and animal physiology. Cannabis and medicine: Assessing the science base. Washington, DC: National Academy Press 1999. 67p.

11

Medical cannabis legislationHealth Canada’s new regulations, the Marihuana for Medical Purposes Regulations (MMPR), came into effect on April 1, 2014. The new system allows the production and distribution of medical cannabis products (including whole flowers, oils, and capsules) by licensed producers overseen by Health Canada.

Health care practitioners (i.e. physicians and certain nurse practitioners) are able to authorize use of medical cannabis without any special training or licenses. Patients who apply to Tilray for medical cannabis must submit an application form and medical document signed by their health care practitioner. This application process can be completed by mail or through Tilray’s e-portal service.

All licensed producers under the MMPR must produce, process, and package medical cannabis in secure facilities like the one Tilray operates in Nanaimo, British Columbia. These facilities are regularly audited for compliance with applicable regulations.

Storefront distribution is not permitted under the MMPR. Instead, medical cannabis shipments are sent by secure courier. Patients have the option to receive their cannabis at their personal residence or at their healthcare practitioner’s office, with the healthcare practitioner’s consent.

The MMPR can be viewed in full at: http://www.laws-lois.justice. gc.ca/eng/regulations/SOR- 2013-119/

12

Delivery MethodsThere are three primary methods for administering cannabis: smoking, vaporization and ingestion. Physicians may want to consult with their patients to determine the preferred mode of delivery.

Cannabis must be heated to a temperature of 160-185° C in order for a process called decarboxylation to occur to the cannabinoids in the cannabis plant. Specifically, decarboxylation converts the tetrahydrocannabinolic acid (THCA) contained in dried cannabis into tetrahydrocannabinol (THC), and the cannabidiolic acid (CBDA) into cannibidiol (CBD).

• Smoking and vaporization offer the benefits of rapid onset of effect and ease of dose titration, which may be important for patients seeking fast symptom relief. Whereas smoking requires the burning of cannabis (typically using a pipe or cigarette), vaporization utilizes a device (vaporizer or nebulizer) that heats the cannabis to a temperature high enough to trigger decarboxylation and release cannabinoids as vapour, but too low to ignite or burn the cannabis. The vapour is then inhaled. Vaporization may be preferred by those concerned with the potential risks and irritation associated with smoking.1, 2 Relative to smoking, vaporization is practically odourless.

• Oral consumption offers patients an application method that bypasses the pulmonary system entirely. While the effects of inhalation of cannabis smoke or vapour are nearly immediate and typically last two to four hours, the onset of effects from orally ingested cannabis (e.g., drops, sprays, capsules) is 60 to 90 minutes, and effects can last from eight to twelve hours.3 To achieve a comparable concentration of THC in the bloodstream, the dosage for orally ingested cannabis needs to be increased approximately 2.5 times4, 5 relative to smoking or vaporization.

“[A]n oral dose of 20 mg Delta9-THC would be approximately equivalent to a “smoked dose” of 8 mg of Delta9-THC.”3

1. Hazekamp, A., Ruhaak, R., Zuurman, L., van, Gerven J. et al. Evaluation of a vaporizing device (Volcano) for the pulmonary administration of tetrahydrocannabinol. J. Pharm. Sci. 2006 95:1308-1317.

2. Pomahacova, B., Van der Kooy, F., Verpoorte, R. Cannabis smoke condensate III: the cannabinoid content of vaporised Cannabis sativa. Inhal. Toxicol. 2009 21:1108-1112.

3. For further details, see the Health Canada publication Information for Health Care Professionals: Cannabis and the cannabinoids (February 2013) at http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/infoprof-eng.php, which discusses cannabis intake via oral ingestion, vaporization, smoking, and topical application. Note that Tilray does not currently offer edible forms of cannabis or endorse their use, since the sale and possession of cannabis derivatives is currently prohibited under Canadian law. Although courts have found that patients are entitled to possess and consume cannabis derivatives in certain cases (see R. v. Smith, 2012 BCSC 544 and 2014 BCCA 322), this case is being considered by the Supreme Court of Canada. Physicians, patients, and caregivers are advised to check the judicial status and legal risks associated with creating and possessing cannabis derivatives (including edibles) before proceeding.

4. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003 42:327-60.

5. Zuurman, L., Ippel, A. E., Moin, E., and van Gerven, J. M. Biomarkers for the effects of cannabis and THC in healthy volunteers. Br. J. Clin. Pharmacol. 2009 67:5-21.

13

Current ApplicationsContemporary research suggests cannabis may alleviate symptoms of a wide range of medical conditions. The following is a list of the most prominent current applications:

ArthritisIn the first-ever controlled trial of a cannabis-based medicine (Sativex) in the treatment of pain due to rheumatoid arthritis, a significant analgesic effect was observed. Compared to a placebo, the patients administered cannabis reported significant improvements in pain and quality of sleep.1

“The spinal cord is loaded with cannabinoid receptors. These cannabinoid compounds [from marijuana] apparently reduce swelling from inflammation [a major symptom of arthritis]. But more than that, they kill the pain from inflammation specifically. They work on the peripheral nerves that carry pain from your joint into the spinal cord.”2

- J. Michael Walker, PhD

“Studies from chronic cannabis smokers have provided much of the evidence for immunomodulatory [modifying or regulating the immune system] effects of cannabis in humans...Cannabinoids can modulate both the function and secretion of cytokines [regulatory proteins] from immune cells. Therefore, cannabinoids may be considered for treatment of inflammatory disease.”3

- J. Ludovic Croxford

1. Blake D.R., Robson P., Ho M., Jubb R.W., McCabe C.S. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford) 2006 Jan;45(1):50-2.

2. J. Michael Walker. Arthritis Today Dec. 2000.

3. J. Ludovic Croxford, Takashi Yamamura. Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases? Department of Immunology, National Institute of Neuroscience. Tokyo 187-8502p Published online: July 14, 2005.

14

CancerLack of appetite and attendant weight loss are symptoms commonly experienced by those diagnosed with cancer.1, 2 Cannabis has long been associated with stimulating appetite,3 and pre-clinical studies show a correspondence between cannabis application and improvements in appetite, along with modest weight gain in some cancer patients.4, 5, 6

Cannabis has been shown to be an effective analgesic and its use can be combined with opioids without significantly altering plasma opioid levels.7, 8

Perhaps most interesting, a body of evidence is building indicating a correlation between application of cannabis and the inhibition of tumour growth.9, 10, 11 One study has indicated THC and CBD work together to slow tumour growth more effectively than when they are applied individually.12

“Those treated with both irradiation and the cannabinoids saw the most beneficial results and a drastic reduction in size. In some cases, the tumours effectively disappeared in the animals.”11

–Dr. Wai Liu et al.

“Delta(9)-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities.”12

- J. P. Marcu et al.

“Delta(9)-tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients.”13

- M. Guzmán et al.

15

1. Tchekmedyian, N. S., Zahyna, D., Halpert, C., and Heber, D. Clinical aspects of nutrition in advanced cancer. Oncology 1992 49 Suppl 2:3-7.

2. Walsh, D., Donnelly, S., and Rybicki, L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 2000 8:175-179.

3. Mattes, R. D., Engelman, K., Shaw, L. M., and Elsohly, M. A. Cannabinoids and appetite stimulation. Pharmacol. Biochem. Behav. 1994 49:187-195.

4. Foltin, R. W., Fischman, M. W., Byrne, M. F. Effects of smoked cannabis on food intake and body weight of humans living in a residential laboratory. Appetite 1988 11:1-14.

5. Plasse, T. F., Gorter, R. W., Krasnow, S. H., Lane, M. et al. Recent clinical experience with dronabinol. Pharmacol. Biochem. Behav. 1991 40:695-700.

6. Nelson, K., Walsh, D., Deeter, P., and Sheehan, F. A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. J. Palliat. Care 1994 10:14-18.

7. Abrams, D. I., Couey, P., Shade, S. B., Kelly, M. E. et al. Cannabinoid-opioid interaction in chronic pain. Clin. Pharmacol. Ther. 2011 90:844-851.

8. Ware, M. A., Wang, T., Shapiro, S., Robinson, A. et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010 182:E694-E701.

9. Malfitano, A. M., Ciaglia, E., Gangemi, G., Gazzerro, P. et al. Update on the endocannabinoid system as an anticancer target. Expert. Opin. Ther. Targets 2011 15:297- 308.

10. Grimaldi, C. and Capasso, A. The endocannabinoid system in the cancer therapy: an overview. Curr. Med. Chem. 2011 18:1575-1583.

11. Katherine A. Scott, Angus G. Dalgleish, and Wai M. Liu. The combination of cannabidiol and delta9-Tetrahydrocannabinol. Mol. Cancer Ther. 2014 1-13

12. Marcu, J. P., Christian, R. T., Lau, D., Zielinski, A. J. et al Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol. Cancer Ther. 2010 9:180-189.

13. Guzman, M., Duarte, M. J., Blazquez, C., Ravina, J. et al. A pilot clinical study of delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br. J. Cancer 2006 95:197-203.

16

Chronic painA large and growing body of clinical and anecdotal evidence supports the efficacy of cannabis as an analgesic.1, 2, 3, 4 Unlike other common pharmaceutical analgesics, there appears to be no risk of overdose.5

Cannabis has been shown to interact with endocannabinoid receptors, unique from those activated by opioids. Accordingly, cannabis can supplement the use of opioids5, 6, 7 and studies show an improvement in pain relief with patients taking morphine and oxycodone when their treatment was supplemented with vaporized cannabis.8

Reports indicate that cannabis reduced pain and improved sleep patterns of patients suffering from post-traumatic or postsurgical pain.1

Reported side effects of cannabis include but are not limited to: sedation, confusion, dizziness, anxiety, dry eyes and dry mouth. The degree of side effects may be dependent on quantity of dose and strain of cannabis.9

“[I]t is difficult to compare studies of interventions for chronic pain with studies of experimentally-induced pain because of fundamental differences in the physiological state of the subjects, differences in the stimulus conditions and experimental protocols employed in the studies, and differences in the outcomes which are measured.”6

- Health Canada

“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%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis.”8

- D. I. Abrams et al.

1. Ware, M. A., Wang, T., Shapiro, S., Robinson, A. et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010 182:E694-E701.

2. Wilsey, B., Marcotte, T., Deutsch, R., Gouaux, B. et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J. Pain 2012 14:136-148.

3. Ellis, R. J., Toperoff, W., Vaida, F., van den Brande, G. et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009 34:672-680.

4. Wallace, M., Schulteis, G., Atkinson, J. H., Wolfson, T. et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 2007 107:785-796.

5. Porcella, A., Casellas, P., Gessa, G. L., and Pani, L. Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana. Mol. Brain Res. 1998 58:240-245.

6. Straiker, A. J., Maguire, G., Mackie, K., and Lindsey, J. Localization of cannabinoid CB1 receptors in the human anterior eye and retina. Invest Ophthalmol. Vis. Sci. 1999 40:2442-2448.

7. Porcella, A., Maxia, C., Gessa, G. L., and Pani, L. The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein. Eur.J.Neurosci. 2000 12: 1123-1127.

8. Abrams, D. I., Couey, P., Shade, S. B., Kelly, M. E. et al. Cannabinoid-opioid interaction in chronic pain. Clin. Pharmacol. Ther. 2011 90:844-851.

9. Wilsey, B., Marcotte, T., Tsodikov, A., Millman, J. et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J. Pain. 2008 9:506- 521.

17

Crohn’s disease and ulcerative colitisEvidence from pre-clinical trials and clinical studies indicates cannabis may have some effectiveness in treating inflammatory bowel disease (IBD) symptoms such as abdominal pain, diarrhea and inflammation.1 Again, correlation with the body’s endocannabinoid system is proposed as a factor.2,3 Animal testing has shown a slowing of weight loss, reduction of colon inflammation4 and a significant decrease in macroscopic damage.5

Studies on human subjects have compelled researchers to urge further investigation of the efficacy of cannabis in the treatment of colitis and Crohn’s disease.6 Significantly, subjects report improvements in quality of life, relating to their ability to perform daily activities and maintain a social life.6

“THC was the most effective drug. The effects of these phytocannabinoids were additive, and CBD increased some effects of an ineffective THC dose to the level of an effective one. THC alone and in combination with CBD protected cholinergic nerves whereas sulphasalazine did not.”5

- J. M. Jamontt

“The results indicate that cannabis may have a positive effect on disease activity, as reflected by reduction in disease activity index and in the need for other drugs and surgery. Prospective placebo-controlled studies are warranted to fully evaluate the efficacy and side effects of cannabis in CD.”6

- T. Naftali et al.

“Three months’ treatment with inhaled cannabis improves quality of life measurements, disease activity index, and causes weight gain and rise in BMI in long-standing IBD patients.”7

- A. Lahat et al.

1. Information for Health Care Professionals: Cannabis (marihuana, cannabis) and the cannabinoids. May 2013. http://www.hc-sc.gc.ca/dhp-mps/marihuana/ med/infoprof-eng.php#chp70.

2. Di Sabatino, A., Battista, N., Biancheri, P., Rapino, C. et al. The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease. Mucosal. Immunol 2011 4:574-583.

3. Izzo, A. A. and Sharkey, K. A. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol. Ther. 2010 126:21-38.

4. Borrelli, F., Aviello, G., Romano, B., Orlando, P. et al. Cannabidiol, a safe and non-psychotropic ingredient of the cannabis plant Cannabis sativa, is protective in a murine model of colitis. J. Mol. Med. Berl. 2009 87:1111-1121.

5. Jamontt, J. M., Molleman, A., Pertwee, R. G., and Parsons, M. E. The effects of delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis. Br. J. Pharmacol. 2010 160:712-723.

6. Naftali, T., Lev, L. B., Yablecovitch, D., Half, E. et al. Treatment of Crohn’s disease with cannabis: an observational study. Isr. Med. Assoc. J. 2011 13: 455-458.

7. Lahat, A., Lang, A., and Ben-Horin, S. Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study. Digestion 2012 85:1-8.A.

18

EpilepsyThe causes of epilepsy remain unknown in about half of all cases. However, recent discoveries have revealed an intercellular signalling system involving the brain’s cannabinoid receptors. Activation of these receptors has been implicated in helping to explain the anticonvulsant properties of cannabinoids.1, 2, 3, 4, 5

Cannabidiol (CBD), which along with THC is the cannabinoid currently receiving the most attention for medical applications, has shown particular promise in reducing the frequency and severity of seizures.6 CBD has the added advantage of having minimal psychoactive effects, which may facilitate treatment for children.

“Preliminary, uncontrolled clinical studies suggest that cannabidiol may have antiepileptic effects in humans.”7

- E. Gordon

“The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.”6

- B. Lutz

1. Romigi, A., Bari, M., Placidi, F., Marciani, M. G. et al. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy. Epilepsia 2010 51:768-772.

2. Wallace, M. J., Martin, B. R., and DeLorenzo, R. J. Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur. J. Pharma 2010 452:295-301.

3. Wallace, M. J., Blair, R. E., Falenski, K. W., Martin, B. R. et al. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 2003 307:129-137.

4. Shafaroodi, H., Samini, M., Moezi, L., Homayoun, H. et al. The interaction of cannabinoids and opioids on pentylenetetrazole-induced seizure threshold in mice. Neuropharmacology 2004 47:390-400.

5. Alger BE. Endocannabinoids and Their Implications for Epilepsy. Epilepsy Currents 2004 4(5):169-173.

6. Lutz, B. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem. Pharmacol. 2004 68:1691-1698.

7. Gordon, E. and Devinsky, O. Alcohol and cannabis: effects on epilepsy and use by patients with epilepsy. Epilepsia 2001 42:1266-1272.

19

GlaucomaEvidence supporting the application of cannabis in treating glaucoma goes back to 1971, when Hepler and Frank reported a 25% to 30% reduction in intraocular pressure (IOP) among a small group that had smoked cannabis.1 It has been proposed that cannabis may activate receptors in the endocannabinoid system of the eye. (Decreased levels of endocannabinoids have been observed in glaucoma patients post-mortem.2) Subsequent clinical testing has confirmed that application of cannabinoids reduces IOP, but that effects are relatively short in duration.3

While the exact mechanism causing the pressure reduction has not yet been confirmed,4 it has been proposed that a reduction of capillary pressure, decreased aqueous humour production and improved aqueous humour uveoscleral outflow may be involved.5, 6, 7, 8

“Aside from lowering IOP, cannabinoids such as Δ-THC and CBD may also have neuroprotective effects which could also be useful in the management of glaucoma.”3

- Health Canada

1. Hepler RS, Frank IR. Marihuana smoking and intraocular pressure (letter). JAMA 1971 217:1392.

2. Chen, J., Matias, I., Dinh, T., Lu, T. et al. Finding of endocannabinoids in human eye tissues: implications for glaucoma. Biochem. Biophys. Res. Commun. 2005 330:1062-1067.

3. Information for Health Care Professionals: Cannabis (marihuana, cannabis) and the cannabinoids. (May 2013). Retrieved from http://www.hc-sc.gc.ca/dhp-mps/marihuana/ med/infoprof-eng.php#chp70.

4. Tomida, I., Pertwee, R. G., and zuara-Blanco, A. Cannabinoids and glaucoma. Br. J. Ophthalmol. 2004 88:708-713.

5. Porcella, A., Casellas, P., Gessa, G. L., and Pani, L. Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana. Mol. Brain Res. 1998 58:240-245.

6. Straiker, A. J., Maguire, G., Mackie, K., and Lindsey, J. Localization of cannabinoid CB1 receptors in the human anterior eye and retina. Invest Ophthalmol. Vis. Sci. 1999 40:2442-2448.

7. Porcella, A., Maxia, C., Gessa, G. L., and Pani, L. The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein. Eur. J. Neurosci. 2000 12: 1123-1127.

8. Song, Z. H. and Slowey, C. A. Involvement of cannabinoid receptors in the intra-ocular pressure-lowering effects of WIN55212-2. J. Pharmacol. Exp. Ther. 292:136-139.

20

HIV/AIDSApplication of cannabis has been found to increase daily caloric intake and body weight in patients with AIDS, while improving mood and sleep.1, 2 It has also been shown to relieve nausea and vomiting,3 and provide a significant decrease in pain.4, 5 Patients have also reported a reduction in anxiety and relief from depression.6

“Patients who smoked marijuana experienced 70-100% relief from nausea and vomiting, while those who used the THC capsule experienced 76-88% relief.”3

–Richard E. Musty et al.

“As compared with placebo, cannabis and dronabinol dose dependently increased daily caloric intake and body weight in HIV-positive cannabis smokers... Effects of cannabis and dronabinol were comparable, except that only cannabis (3.9% THC) improved ratings of sleep.”1

–M. Haney

1. Haney, M., Gunderson, E. W., Rabkin, J., Hart, C. L. et al. Dronabinol and cannabis in HIV-positive cannabis smokers. Caloric intake, mood, and sleep. J. Acquir. Immune. Defic. Syndr. 2007 45:545-554.

2. Haney, M., Rabkin, J., Gunderson, E., and Foltin, R. W. Dronabinol and marijuana in HIV(+) cannabis smokers: acute effects on caloric intake and mood. Psychopharmacology (Berl.) 2005 181:170-178.

3. Musty, R and Rossi, R. Effects of smoked cannabis and oral delta-9-tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: A review of state clinical trials. J. Cannabis Ther. 2001 1:29-42.

4. Abrams, D. I., Jay, C. A., Shade, S. B., Vizoso, H. et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007 68:515-521.

5. Ellis, R. J., Toperoff, W., Vaida, F., van den Brande, G. et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009 34: 672-680.

6. Woolridge, E., Barton, S., Samuel, J., Osorio, J. et al. Cannabis use in HIV for pain and other medical symptoms. J. Pain Symptom Manage. 2005 29: 358-367.

21

Multiple SclerosisStudies support the effectiveness of cannabis in treating a number of symptoms associated with MS, including pain and muscle spasticity1. In addition, patients have reported improvement in quality of life when treated with the cannabinoid derivative, dronabinol.2

Animal studies reveal, “THC has been shown to inhibit both clinical and histologic experimental autoimmune encephalomyelitis (EAE), it may prove to be a new and relatively innocuous agent for the treatment of immune-mediated diseases.”3

“Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity.1

- J. Corey-Bloom et al.

“Oral dronabinol reduced central pain in patients with multiple sclerosis. Spontaneous pain intensity was reduced and pain relief was higher during dronabinol treatment than during placebo treatment, pressure evoked pain tended to decrease, and the patients tended to score better in the bodily pain domain of the health related quality of life questionnaire.”2

- K. B. Svendsen et al.

1. Corey-Bloom, J., Wolfson, T., Gamst, A., Jin, S. et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ 2012 184:1143-1150.

2. Svendsen, K. B., Jensen, T. S., and Bach, F. W. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 2004 329:253-260.

3. Lyman, W. D., Sonett, J. R., Brosnan, C. F., Elkin, R. and others. Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J. Neuroimmunol. 1989 23:73-

22

Health Canada’s Information for Health Care Professionals: Cannabis (marihuana, marijuana, cannabis) and the cannabinoids reviews existing academic research into the application of cannabinoids for different conditions. For the complete Health Canada document, please visit:

http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/infoprof-eng.php

For more information:

1-844-TILRAY1 (845-7291)

doctors@tilray.ca

www.tilray.ca

1100 Maughan Road

Nanaimo, BC

V9X 1J2