Cannabis and Cannabinoids: Review of Existing and Potential Therapeutic Applications in Oncology

Cannabis and Cannabinoids: Review of Existing and Potential Therapeutic Applications in Oncology

2 Pamela C. Cartright, MAE, RT (R)(T) Assistant Professor and Program Director Radiation Therapy Program Armstrong State University Savannah GA 31406 pam.cartright@armstrong.edu

3 Objectives: Upon completion of this presentation, the audience will be able to: Trace the historical use of marijuana both commercially and recreationally Describe what is meant by cannabinoid receptors and cannabinoids List the pharmaceutical and non-pharmaceutical forms of cannabinoids Explain the legal and regulatory policies faced by healthcare professionals and by patients regarding the therapeutic use of both pharmaceutical and non-pharmaceutical cannabinoid and cannabis products. Review the evidence for medical uses of marijuana and cannabinoids Review the data that points to the potential for harm vs. general benefits to the body through the use of marijuana. Relate the medical use of marijuana and cannabinoids to effective therapeutic applications in cancer patients

4 10,000-year History of Marijuana Use Hemp has been used for centuries (beginning as early as 8000+ BC) as rope, in the making of textiles in China and Turkestan, and paper Psychotropic properties mentioned in 0-100 BC

5 10,000-year History of Marijuana Use 1378 1533 1621 1800 1842 1850 1850-1915 1906

6 10,000-year History of Marijuana Use 1910 1914 1915-1927 1937 1941 1942

7 10,000-year History of Marijuana Use 1960 1970 1971 1972 1976 1977-1981

8 10,000-year History of Marijuana Use 1985 1988 1992 1996

9 10,000-year History of Marijuana Use 1997 1999 2000 2001 Canada even has a commercial https://cannagrowers.ca/

10 10,000-year History of Marijuana Use 2009: President Obama made steps toward ending the very unsuccessful 20-year "war on drugs" initiated during the Regan administration by stating that individual drug use is really a public health issue, and should be treated as such. The U.S. Justice Department announced that federal prosecutors will no longer pursue medical marijuana users and distributors who comply with state laws.

11 10,000-year History of Marijuana Use Oct 2010 Nov 2010 Nov 2012 July 7, 2014 Nov 2014 July 24, 2015

12 What is the difference in cannabis and a cannabinoid? Cannabis is can be tall or short The female plant is short, branchier and has a more abundant source of the psychoactive substance tetrahydrocannabinol (THC) Has over 500 natural compounds and cannabinoids make up about 85 of those. Some are psychoactive and some are not

13 There is Sativa and There is Indica

14 Genetic Production Plants that produce high levels of THC express genes that code for the enzyme THCA synthase. This enzyme converts CBG into THCA, which becomes THC when heated. These plants are typically considered indica. Some plants express genes that code for the enzyme CBDA synthase. This enzyme converts CBG into CBDA, the precursor of CBD, instead. These plants are typically considered sativa.

15 What is the difference in cannabis and a cannabinoid? Out of the 85 cannabinoids, two stand out: tetrahydrocannabinol (THC) and cannabidiol (CBD). THC, known for its psychoactive properties, is the reason you feel buzzed after ingesting marijuana. Too much THC can trigger anxiety and paranoia

16 What is the difference in cannabis and a cannabinoid? CBD is a non-psychoactive cannabinoid and actually works to calm the high. CBD has numerous medicinal benefits, such as antiinflammatory properties and the ability to protect the neurons from injury or degeneration.

17 A little terminology THC: best known cannabinoid; the primary psychoactive compound. CBN: non-psychoactive and is generally attributed with a sedative effect. THCV: commonly believed to be an appetite suppressant.

18 A little terminology CBC: Least understood, believed to stimulate bone growth CBVD: May offer an option for the treatment of epilepsy CBD: Most of the medical benefits come from this compound; not psychoactive THCA: Most prominent compound in fresh undried cannabis CBG: Non-psychoactive cannabinoid CBDA: Non-psychoactive cannabinoid believed to have anti-inflammatory properties

19 Cannabinoid Receptors Endocannabinoid System (ECS) Cannabinoid receptors are active sites that are found within different parts of the body, each with a unique function that contributes to the balance of an internal environment. Scientific research has indicated there are two types of receptors in this system, the CB1 and the CB2 receptors.

20 The Endocannabinoid System

21 Pharmaceutical and Non-pharmaceutical forms of cannabinoids

22 A little terminology: Drug Classifications An updated and complete list of the schedules is published annually in Title 21 Code of Federal Regulations (C.F.R.) 1308.11 through 1308.15. Schedule 1 drug Schedule 2 drug Schedule 3 drug Schedule 4 drug Schedule 5 drug

23 Pharmaceutical Cannabinoids The first two cannabinoid pharmaceuticals are legal in the US Dronabinal (Marinol) Nabilone (Cesamet) Nabiximols (Sativex)

24 Dronabinal or delta-9-thc 1985: The FDA approves dronabinol, a synthetic THC, for cancer patients. Used to treat nausea and vomiting caused by chemotherapy in people who have already taken other medications to treat this type of nausea and vomiting without good results. May be habit forming

25 Nabilone (Cesamet) Schedule I drug available through RX in the form of a capsule Chemical structure similar to THC Approved for marketing by the FDA in1985 Used for treatment of nausea and vomiting associated with chemotherapy

26 Nabiximols (Sativex) Sativex (nabiximols) is a cannabis-based oral spray. It is the first drug made with ingredients extracted from the cannabis plant. Sativex contains an equal 1:1 ratio of THC and CBD. The active ingredients are absorbed through the inner linings of the mouth. As a result, it enters the bloodstream quicker than other oral cannabinoid preparations.

27 Non-pharmaceutical Cannabis

28 Legalities Both Federal and State Federal law prohibits the possession, selling, or harvesting of marijuana

29 Many Supporters of Legalization Cite Health Benefits The most frequently cited reasons for supporting the legalization of marijuana are its medicinal benefits (41%) and the belief that marijuana is no worse than other drugs (36%) with many explicitly mentioning that they think it is no more dangerous than alcohol or cigarettes.

30 Recreational Usage Should be Illegal, Medicinal Use OK About one-in-five opponents of legalization (19%) say marijuana is illegal and needs to be policed 11% say it is a gateway to harder drugs and 8% say it is especially harmful to young people. A small share of opponents (7%) say that while the recreational use of marijuana should be illegal, they do not object to legalizing medical marijuana.

31 Marijuana Laws on 50 States 4 states- Colorado, Washington, Oregon - and the District of Columbia have passed measures to legalize marijuana use 14 states have decriminalized certain amounts of marijuana 23 states plus the District of Columbia, allow medical marijuana According to this map, Mississippi has decriminalization laws, still prohibited in Alabama and Louisiana

32 Insurance In the United States, health insurance companies may not pay for a medical marijuana prescription All expenses incurred fulfilling a medical marijuana prescription will possibly be incurred as out-of-pocket. However, the New Mexico Court of Appeals has ruled that workers' compensation insurance must pay for marijuana prescribed as part of the state's Medical Cannabis Program.

33 Where federal and state law clash, federal law always trumps.

34 The American Medical Association, the Institute of Medicine, and the American College of Physicians contend that the patchwork of state laws do little to establish clinical standards for marijuana use Have called for reclassification of cannabis as a Schedule II controlled substance

35 Comparing the potential for harm vs. general benefits to the body through the use of marijuana Medical use Typically, adverse effects of medical cannabis use are not serious. The amount of cannabis normally used for medicinal purposes is not believed to cause any permanent cognitive impairment in adults Long-term treatment in adolescents should be weighed carefully as they are more susceptible

36 Harm vs. Benefit Recreational use Acute effects: Anxiety and panic Impaired attention and memory (while intoxicated) Increased risk of psychotic symptoms Possible increased risk of accidents if driving while intoxicated

37 Harm vs. Benefit Recreational use Chronic Decline in IQ Lung Cancer Addiction Psychosis

38 The term medical marijuana is ambiguous in that it can refer to 2 of the 3 forms in which cannabinoids occur. These include: Endocannabinoids: (naturally synthesized in the body) Phytocannabinoids (Botanical cannabis) Synthetic cannabinoids (Pharmaceutical)

39 Review the evidence for medical uses of Cannabis sativa (botanical cannabis) and cannabinoids: beginning with the 19 th century and Dr. O Shaughnessy

40 Traditional Eastern medicine met Western medicine when W. B. O Shaughnessy, an Irish physician working in Calcutta in the 1830s, wrote a paper extolling Indian hemp. Dr. O Shaughnessy s report included an analysis of the known history of medicinal cannabis uses by physicians in India and the Middle East.

41 The Institute of Medicine issued a report based on a summary of the peer-reviewed literature addressing the efficacy of therapeutic marijuana use. The 1999 study found at least some benefit for smoked marijuana in : stimulating appetite particularly in AIDS-related wasting syndrome combating chemotherapy-induced nausea and vomiting, severe pain, and some forms of spasticity

42 2015: Update of Cannabis and Its Medical Use, World Health Organization Neuropathic Pain Nausea and Vomiting Appetite Multiple Sclerosis Glaucoma Post-traumatic stress disorder (PTSD) Epilepsy

43 AIDS Wasting, Cachexia and Appetite Enhancement Studies have shown that smoked or ingested cannabis, either as a botanical or a synthetic THC (dronabinol), improves appetite, increases weight, and improves quality of life in HIV/AIDS patients. Seven Randomized Clinical Trials with smoked cannabis or individual cannabinoids of short duration (21-84 days) were identified for the treatment of AIDS in a small number of patients

44 Multiple Sclerosis Multiple sclerosis (MS) is an inflammatory, autoimmune, degenerative disease of the central nervous system. It is among the most common causes of non-traumatic neurological disability in young adults of northern European descent. Three Randomized Clinical Trials were identified which used inhaled or vaporized cannabis to treat MS symptoms.

45 Multiple Sclerosis A double-blind randomized placebo-controlled study of inhaled cannabis smoke on postural responses was performed in 10 adult patients (five female, five male) with spastic MS and 10 normal volunteers matched for age, sex, and weight. Tracking errors were higher for patients than controls and response speed of the patients was lower, with eyes closed. The conclusion of the study investigators was that cannabis smoking worsens posture and balance in MS patients

46 Multiple Sclerosis Placebo-controlled, crossover trial of 37 adults, with 30 completing the trial Authors concluded that smoked cannabis was superior to placebo in spasticity and pain reduction in participants.

47 Glaucoma Cannabis lowers blood pressure and may also reduce aqueous humor production via cannabinoid receptor activation, pharmacological actions that temporarily reduce IOP In 2009, the American Glaucoma Society recommended against the use of cannabis because of "its side effects and short duration of action, coupled with a lack of evidence that its use alters the course of glaucoma"

48 Post-traumatic stress disorder (PTSD) There are no large scale Randomized Clinical Trials with cannabis to alleviate PTSD symptoms.

49 Epilepsy As of 2012, there have been few studies of the anticonvulsive properties of CBD and epileptic disorders. In 2014-15, Epidiolex, a cannabis-based product developed for experimental treatment of epilepsy, underwent stage 2 trials in the US in 2014.

50 Cannabis and the Cancer Patient The U.S. Food and Drug Administration has not approved Cannabis as a treatment for cancer or any other medical condition.

51 Relevance of Use for Cancer Patients Neuropathic Pain Nausea and Vomiting Anxiety and Depression Possible Induction of Apoptosis in Tumor Cells

52 Possible Induction of Apoptosis in Tumor Cells At present, data show contradictory results. The promise of cannabinoids as anti-tumor agent stems from preclinical research, using either cultured cells derived from human or rodent tumors, or mouse tumor models.

53 National Cancer Institute/CAM The National Cancer Institute (NC) under the umbrella of the National Institute of Health, has a section called the Complementary and Alternative Medicine (CAM) Under this section cannabis and cannabinoids are listed.

54 National Cancer Institute/CAM Laboratory/Animal/Preclinical studies Neuropathic Pain Nausea and Vomiting Anxiety and Depression Possible Induction of Apoptosis in Tumor Cells

55 National Cancer Institute/CAM Laboratory/Animal/Preclinical studies Antitumor Effects In 1996, the National Toxicology Program did a study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors. In 2006, another study, delta-9-thc, delta-8-thc, and cannabinol were found to inhibit the growth of Lewis lung adenocarcinoma cells in vitro and in vivo

56 National Cancer Institute/CAM Laboratory/Animal/Preclinical studies Antitumor Effects Investigations from 2011 have confirmed that CB1 and CB2 receptors may be potential targets in non-small cell lung carcinoma and breast cancer. Both plant-derived and endogenous cannabinoids have been studied for anti-inflammatory effects.

57 National Cancer Institute/CAM Laboratory/Animal/Preclinical studies Antitumor Effects In 2010 and 2011, studies have been done that show the antitumor effect of cannabinoids (i.e., CBD and THC) in preclinical models of breast cancer. A 2012 investigation into the antitumor effects of CBD examined the role of intercellular adhesion molecule-1 (ICAM-1). In 2013: A combined preclinical therapy of cannabinoids and temozolomide against glioma.

58 National Cancer Institute/CAM Human/Clinical Studies Cancer Treatment Antiemetic Effect Appetite Stimulation Analgesia Anxiety and Sleep

59 National Cancer Institute/CAM Human/Clinical Studies Cannabinoids Cannabis

60 National Cancer Institute/CAM Human/Clinical Studies Appetite Stimulation Anorexia, early satiety, weight loss, and cachexia are problems experienced by cancer patients. Such patients are faced not only with the disfigurement associated with wasting but also with an inability to engage in the social interaction of meals.

61 National Cancer Institute/CAM Human/Clinical Studies Pain Cancer pain results from inflammation, invasion of bone or other pain-sensitive structures, or nerve injury. When cancer pain is severe and persistent, it is often resistant to treatment with opioids.

62 National Cancer Institute/CAM Human/Clinical Studies Anxiety and Sleep No studies specifically addressing these issues

63 Where is the Current Research? Reviewing the list of NCI-supported cancer clinical trials for cancer CAM clinical trials, the finding were: Dronabinol: no results Marijuana: no results Nabiximols: no results Nabilone: no results Cannabidiol: no results

64 If Cannabis Were Reclassified as a Schedule 2 Drug The Schedule II classification of these pharmaceuticals countenances not only a healthy respect for their addictive potential but also a robust appreciation for their medicinal value

65 The Habitual User vs. the Naive User Medical and recreational users differ in how they use the drug. The amount used and goals of ingestion diverge. The fundamental motivation (symptom relief) of the former does not match the goal (getting high) of the latter

66 Smoked Cannabis vs. Oral Cannabinoids Some patients prefer smoked cannabis over oral cannabinoids, with rationales that include: Ability to self-titrate smoked cannabis The swallowing of pills is difficult while experiencing emesis Onset of relief is faster with smoking The whole plant ( entourage ) is more effective

67 Smoked Cannabis vs. Oral Cannabinoids A significant proportion of older cancer patients with no previous cannabis experience have refused to continue its use because they found the psychoactive effects too unpleasant.

68 Summary

69 Thank you Pamela C. Cartright, MAE, RT (R)(T) Assistant Professor and Program Director Radiation Therapy Program Armstrong State University Savannah GA 31406 pam.cartright@armstrong.edu

70 References Advanced Holistic Health http://www.advancedholistichealth.org/history.html CannLabs http://cannlabs.com/cannabinoids/ MedlinePlus https://www.nlm.nih.gov/medlineplus/druginfo/meds/a607054.html Study: Patients find cannabis more effective than cannabis pharmaceuticals http://www.leafscience.com/2013/11/04/patients-find-cannabis-effectivecannabis-pharmaceuticals/ Thomas AA, Wallner LP, Quinn VP, et al.: Association between cannabis use and the risk of bladder cancer: results from the California Men's Health Study. Urology 85 (2): 388-92, 2015.

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72 References Volkow ND, Baler RD, Compton WM, Weiss SR (2014). "Adverse health effects of marijuana use". N. Engl. J. Med. 370 (23): 2219 27.doi:10.1056/NEJMra1402309. PMID 24897085. http://www.cancer.gov/aboutcancer/treatment/cam/hp/cannabispdq#cit/section_5.44 Agurell S, Halldin M, Lindgren JE, et al.: Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38 (1): 21-43, 1986. Mehra R, Moore BA, Crothers K, et al.: The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med 166 (13): 1359-67, 2006.

73 References Sutton IR, Daeninck P: Cannabinoids in the management of intractable chemotherapy-induced nausea and vomiting and cancer-related pain. J Support Oncol 4 (10): 531-5, 2006 Nov-Dec. Duran M, Pérez E, Abanades S, et al.: Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol 70 (5): 656-63, 2010. Johnson JR, Burnell-Nugent M, Lossignol D, et al.: Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 39 (2): 167-79, 2010. Lynch ME, Cesar-Rittenberg P, Hohmann AG: A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 47 (1): 166-73, 2014.