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Cannabis(CannabissativaL.)anditsrole inthetreatmentofterminallyillpatients SouthAfricanlegalandmedicalreform

The National Drug Master Plan 2013/2017 (NDMP) mandates an indepth investigation of the dynamic nature of cannabis in South Africa. The inclusion of as many relevant parties as possible is requiredto discuss the decriminalisation andregulation ofcannabiseffectively. That can only be achievedby putting moral differences aside and collectively following anevidencebased approach. Themostmoral policyis themosteffectiveonethatdoestheleastharm.

The political implications of the introduction of the Medical Innovation Bill have yet to be fully established. Offtopic arguments are frequently usedtodivertattention from importantmedical issues.It is important to distinguish between arguments grounded in evidence and political bravado. These arguments are only useful for politicians to frame the issue in their favour and upon closer inspection rarelystanduptoscrutiny.

There are many South Africans affected by lifethreatening illnesses, some of whom are faced with the ineffectiveness of conventional treatments. Cannabis is known to be utilised as palliative treatment for cancer, lupus, multiple sclerosisand a varietyofother ailments. Many cancer patientscannotaffordthe necessary treatment and need to rely on financial and communal aid. This document will focus mostly on the challenges faced by South Africans living with cancer and their pursuit of cannabis as an alternativetreatmentoption.

The medical profession has traditionally been reluctant to accept alternative medicine as a course of treatment for pain, spasticity, nausea, rest and other cancer related symptoms. It isoftenclaimed that alternative medicine lacks the evidence necessary to back up its claims. This stance dismisses experienceasavalidsourceofevidenceandleadstoavarietyofproblemsandmisconceptions.1

People who insist that there is neither evidence nor sufficient data to back up a hypothesis are often the same who prevent research funds from being made availabletogeneratejustthat data.2
We are faced with a catch22 situation. On the one hand the scarcity of data is blamed for the weakness of alternative medicine hypotheses. On the other hand this lack of data is not remedied because of the tendencytodenyresearch funding.Many alternative treatmentscannotbe patentedand as a result do not attract as much funding. In other cases, however, pharmaceutical corporations have beenclamouringforthosepatentsthatareavailable.

TheFontaineCenter.Thefallaciousnessofproposedargumentsagainstalternativemedicine.Retrievedfrom http://www.thefitcenter.com/site/Health_News_files/alternative%20medicine.pdf 2 Ibid.

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CannabisandCancer
New evidence indicates that the lethal effects of the sun's rays may have exerted powerful selection pressureonearlyhumansbetween1.2and1.8millionyearsago.3 Despite black skin being an evolutionary development and an advantage to protect against carcinoma and the effects of the suns UV radiation, cancer affects many. Cancer SAestimates one in fourSouth Africansareaffected bycancerinsomemanner. Cancer affects notjusttheafflictedbuttheir family,and consequentlytheNationalHealthSystem.CANSAaccuratelydescribesthesituationwearefacedwith:

The communicable disease spectrum in subSaharan Africa is dominated by the HIV/TB coepidemic, with other sexually transmitted diseases also prevalent. HIV has also had a profound impact on the incidence of HIVassociated malignancies, such as Kaposi sarcoma, lymphoma, and cervical cancer. The major noncommunicable diseases (NCD) in South Africa are cardiovascular diseases, diabetes, cancers, chronic respiratory diseases and mental illness. Theseillnesses are prevalent in both urban and rural communities but are most prominent in poor peoplelivinginurbansettings. The latest census data for South Africa (2011) shows a 13 percent increase in population size since 2001, to nearly 52 million people. The latest government statistics (2010) reveal that cancer is on the increase, and the disease now ranks sixth among the main causes of death. Cancer remains one of the major killers threateningthesocioeconomicdevelopmentofSouthAfricaandAfricaatlarge. National Cancer Registry data also reveals that cancers of the prostate, cervix, breast, colorectum and esophagus remain highly prevalent, but prevention efforts linked to early detection and diagnosis may offer improved prognosis and better outcomes.4
While the implementation and success of the HPV vaccines being rolled out this yearhaveyet to reach its goals, the existing population still is affected by glioma, breast, lung, cervical, uteri, prostate, testicularorotherformsofcancer. Research has shown that cannabis has the potential to treat certain forms of cancer. There are documented cases of cannabis being used as an alternative palliative treatment for patients with endstage cancer. In lieu of this many jurisdictions permit cannabis to be used medicinally under prescription. The therapeutic application of cannabis is not limited to palliative care. There is a growing body of knowledge that indicates cannabis may play a role the treatment of cancer and helpus understand the disease. It is important to do further research on this topic and to mitigate its effect on South African society.

BelfastTelegraphTue11/03/2014Cancer'droveblackskinevolution' http://www.belfasttelegraph.co.uk/news/localnational/uk/cancerdroveblackskinevolution30042167.html 4 CANSAhttp://www.cansa.org.za/makingstridesagainstcancerinsouthafrica/

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Tableofcontents
CannabisandCancer OncologyandPalliativeCare OpioidsversusCannabinoids Laboratory,AnimalandPreclinicalStudies Cancer Deliverymethods 1.BrainGliomas 2.Oral 3.Breast 4.Lung 5.Skin 6.Blood 7.BiliaryTractCholangiocarcinoma 8.Liver 9.Pancreatic 10.Uterine 11.Ovarian 12.Prostate 13.Bladder 14.ColorectalCRC 15.GeneralCancer

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OncologyandPalliativeCare
Cannabis provides pain relief and palliative care whereother medicationsproduceundesiredsideeffects from conventional chemo and radiation therapy. As palliative medicine practitioners, our specialty should embracethescientificprocess,which continuestodocumentthetherapeutic effects of cannabis. As is often the case in hospice, we must bewilling to advocateforourpatients who want to legitimately access a medicine that could potentially be very beneficialfor them andis safer than otheroptionssuch as opioids. The medicinal cannabis user should not be consideredacriminal... our legalsystemshould beusingscienceandlogicasthebasisofpolicymakingratherthanpoliticalorsocietalbias.5

Properpalliativecarewillmitigatemostpeoplesdesiretodie
DrNatalyaDinat6 Most research conducted to date has beenperformed with synthetic cannabinoids.Cannabinoid refers to a group of closely related compounds that are found in the cannabis plant. It includes the main psychoactive component of cannabis, namely 9tetrahydrocannabinol, or THC for short. Patients have reported a greater therapeutic effect from consuming cannabis in itsnaturalformwhencomparedto the effectofindividualcannabinoids.

Both the state and private sectors [of palliative care] are vastly under resourced and neglected. Few medical aids actually provideaccesstothisformofcare.
DrBrentTipping7 The consumption of cannabis is effective intreating symptoms associatedwithcancerand conventional anticancer therapies, such as nausea, weight loss, pain, and fatigue, according toobservational study datapublishedinthejournalEvidenceBasedComplementaryandAlternativeMedicine.8 All cancer or anticancer treatmentrelated symptoms, including nausea, vomiting, mood disorders, fatigue, weight loss, anorexia, constipation, sexual function, sleep disorders, itching, and pain had significant improvement," authors reported. "No significant differencewasfound in the level of infections, mouth dryness, cough, shortness of breath, diarrhea, and leukocyte count or albumin level during the timebetweenthetwointerviews.9 The population of the prolonged users in the current study reported significant improvement in all aspects of supportive and palliative oncology care. The improvement in symptoms should push the use ofcannabisinthepracticeofoncologypalliativetreatment.10

AmericanJournalofHospiceandPalliativeMedicine.CannabisinPalliativeMedicine:ImprovingCareandReducing OpioidRelatedMorbidity.Retreivedfrom: http://cannabinergy.com/wpcontent/uploads/2011/10/CannabisinPalliativeCare1.pdf 6 FormerheadofthecentreforpalliativecareattheUniversityoftheWitwatersrand 7 SpecialistgeriatricianandphysicianattheUniversityoftheWitwatersrandDonaldGordonMedicalCentre 8 Study: Cannabis use associated with significant improvement in palliative oncology care. Retrieved March 1, 2014, from http://norml.org/news/2013/08/29/studycannabisuseassociatedwithsignificantimprovementinpalliativeoncologycare 9 Barsela,G.,Vorobeichik,M.,Drawsheh,S.,Omer,A.,Goldberg,V.,Muller,E(2013).Themedicalnecessityformedicinal cannabis:Prospective,observationalstudyevaluatingthetreatmentincancerpatientsonsupportiveorpalliativecare.
5

doi:10.1155/2013/510392. 10 Ibid.

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OpioidsversusCannabinoids
Opioids and cannabinoids have many things in common.They are bothamong the worldsoldest known classes of drugs, with documentation of usage dating back millennia. They both produce their 12 pharmacological effect via actions at specific receptors, found throughout the body.11, Both of these classes of compounds are also made endogenously in the human body and are part of the normal regulatory, homeostatic processes necessary for life. Without endorphins (opioids) and endocannabinoids(cannabinoids),ourbodieswouldnotfunctionproperly.13 In reviewing the possibleacuteand longtermadverse effects of cannabinoidsastherapeuticagents one needs also to be mindful that other agents that are used for treatment of pain or spasticity also have adverse effects. Opioids produce sedation,nausea, constipationand dependence, withdrawalfromwhich results in serious abstinence syndrome with much more severe effects e.g. severe autonomic, gastrointestinal,andpsychiatricthantherathermildcannabiswithdrawalphenomena. Tricyclic antidepressants and antiepileptic drugs commonly prescribed for chronic pain have psychotropic (e.g. sedation), anticholinergic (e.g. constipation, dizziness, palpitations, visual disturbance, urinary retention), and neuromuscular effects. Drugs for spasticity produce sedation (e.g. baclofen), hypotension (e.g. tizanidine) and serious interactions with antibiotics (e.g. tizanidine and ciprofloxacin). Benzodiazepines that are sometimes prescribed for spasticity can produce sedation, psychomotor incoordination, memory lapses, and paradoxical reactions, as well as dependence and withdrawal syndromes. Opioids and sedativehypnotics are also drugs of abuse, and their ability to induce physiological dependence and serious withdrawal states exceed those of cannabis. Therefore, judgements on relative benefits and risks of cannabinoids as medicines need to be viewed within the broadercontextofriskbenefitofotheragentsaswell. 14

Laboratory,AnimalandPreclinicalStudies
Cannabinoids are a group of compounds produced exclusively by the cannabis plant. These plantderived compounds may be referred to as phytocannabinoids. Although 9tetrahydrocannabinol (THC) is the primary psychoactive ingredient, other known compounds with biologic activity are cannabinol, cannabidiol (CBD), cannabichromene, cannabigerol, tetrahydrocannabivarin, and 8THC. CBD, in particular, is thought to have significant analgesic and antiinflammatory activity without the psychoactiveeffect(high)of9THC. One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors. During this 2year study, groups of mice and rats were given various doses of THC by gavage. A doserelated decrease in the incidence of hepatic adenomatumors and hepatocellular carcinoma (HCC) was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were also noted in the rats. In another study, 9THC, 8THC, and cannabinol were found to inhibit the

11

ViganoA.,BrueraE.,SuarezAlmazorM.E.(2000).Age,painintensityandopioiddoseinpatientswithadvancedcancer. doi:10.1002/(SICI)1097 12 AggarwalS.K.,CarterG.T.,SullivanMD,MorrillR,ZumBrunnenC,MayerJD.,MedicinaluseofcannabisintheUnited States:historicalperspectives,currenttrends,andfuturedirections.JOpioidManag.20095(3):153168PMID:19662925 13 Carter,G.T.,Flanagan,AM,Earleywine,M.,Abrams,D.I.,Aggarwa,lS.K.,Grinspoon,L.CannabisinPalliative Medicine:ImprovingCareandReducingOpioidRelatedMorbidity.AmericanJournalofHospice&PalliativeMedicine.PMID: 2144324 14 Carter,G.T.,Flanagan,A.M.,EarleywineM.,AbramsD.I.,AggarwalS.K.,GrinspoonL.MedicalMarijuana:Clearing AwaytheSmoke.PMC3358713

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growth of Lewis lung adenocarcinoma cells in vitro and in vivo. In addition, other tumors have been showntobesensitivetocannabinoidinducedgrowthinhibition. Cannabinoids may cause antitumor effects by various mechanisms, including induction of cell death, inhibitionofcellgrowth,andinhibitionoftumorangiogenesisinvasionandmetastasis. One review summarises the molecular mechanisms of action of cannabinoids as antitumor agents. Cannabinoids appear to kill tumor cells but do not affect their nontransformed counterparts and may even protect them from cell death. These compounds have been shown to induce apoptosis in glioma cells in culture and induce regression of glioma tumors in mice and rats. Cannabinoids protect normal glialcellsofastroglialandoligodendrogliallineagesfromapoptosismediatedbytheCB1receptor.15

Cancer
Delivery methods
A drug is any substance, synthetic or natural, legal or illegal, that is consumed with the intention of bringing about change in a person's behaviour, emotions and thoughts. Substances not usually considered as drugs may function asdrugs under certain circumstances, for example foods,beverages, solventsandaerosols. Cannabiscanbeadministeredinanumberofways: Orally,asaliquidorsolid,thatisabsorbedthroughthestomach. Topically,asaliquidorsolid,thatisabsorbedthroughtheskin. Sublingually,diffusingintothebloodthroughtissuesunderthetongue. Inhaled,vaporbreathedintothelungs. Smoked,smokebreathedintolungs. Intratumoralinjection. 16 Rectally. Gavage.

9Tetrahydrocannabinol (THC) is the primary cannabinoid of [cannabis] and has been shown to either potentiateorinhibittumorgrowth,dependingonthetypeofcanceranditspathogenesis.17

15

NationalCancerInstitute21/11/2013Cancer.govCancerandcannaibnoids http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page4 16 Guzman,Duarteetc.,ApilotclinicalstudyofDelta9tetrahydrocannabinolinpatientswithrecurrentglioblastoma multiforme,BritishJournalofCancer,2006Jul1795(2):197203.,PMCID:PMC2360617. 17 Preet,A.,Ganju,R.K.,Groopman,J.E.(2007).9Tetrahydrocannabinolinhibitsepithelialgrowthfactorinducedlung cancercellmigrationinvitroaswellasitsgrowthandmetastasisinvivo.doi10.1038/sj.onc.1210641

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1.BrainGliomas
Gliomas (tumors in the brain) are especially aggressivemalignant formsofcancer, often resulting in the death of affected patients within one to two years following diagnosis. There is no cure for glioma and most available treatments provide only minor symptomatic relief. A review ofmodernscientificliterature reveals numerous preclinical studies and one pilot clinical study demonstrating cannabinoids ability to act as antineoplastic agents, particularly on glioma cell lines. Antineoplastic agentsaim to preventand inhibitthegrowthandspreadoftumors. Writing in theSeptember 1998 issue of the journal FEBS Letters,investigatorsat MadridsComplutense University, School of Biology, first reported that 9THC induced apoptosis (programmed cell death) in glioma cells in culture.18 Investigators followed up their initial findings in 2000, reporting that the administration ofboth THCand the syntheticcannabinoidagonistWIN 55,2122 induceda considerable regressionofmalignantgliomasinanimals.19 Researchers again confirmed cannabinoids ability to inhibit tumor growth in animals in 2003.20 That same year, Italian investigators at the University of Milan, DepartmentofPharmacology, Chemotherapy and Toxicology, reported that thenonpsychoactivecannabinoid, cannabidiol (CBD), inhibited the growth of various human glioma cell lines in vivo and in vitro in a dose dependent manner. Writing in the November 2003 issue of the Journal of Pharmacology and Experimental Therapeutics Fast Forward, researchers concluded, Nonpsychoactive CBD ... produce[s] a significant antitumor activity both in vitroandinvivo,thussuggestingapossibleapplicationofCBDasanantineoplasticagent.21 In 2004, Guzman and colleagues reported that cannabinoids inhibited glioma tumor growth in animals and in human glioblastoma multiforme (GBM) tumor samples byaltering blood vessel morphology (e.g., VEGF pathways). Writing in the August 2004 issueof Cancer Research,investigatorsconcluded, [t]he present laboratory and clinical findings provide a novel pharmacological target for cannabinoidbased therapies. 22 Investigators at the California Pacific Medical Center Research Institute reported thattheadministration of THC on human glioblastoma multiforme cell lines decreased the proliferation of malignant cells and induced cell death more rapidly than did the administration of WIN 55,2122. Researchers also noted that THC selectively targeted malignant cells while ignoring healthy ones in a more profound manner than the synthetic alternative.23 A separate preclinical trial reported that the combined administrationof THC and the pharmaceutical agent temozolomide (TMZ) enhanced autophagy (breakdown of cellular components to ensure it survival during times of starvation) in brain tumors resistant to conventional anticancertreatments.24 Guzman and colleagues have also reported that THC administration decreases recurrent glioblastoma multiforme tumor growth in patients diagnosed with recurrent GBM. In the first ever pilot clinical trial assessing the use of cannabinoids and GBM, investigators found that the intratumoral administration of THC was associated with reduced tumor cell proliferation in two ofnine subjects.The fair safetyprofile of THC, together with its possible antiproliferative action on tumor cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of
Guzmanetal.(1998).Delta9tetrahydrocannabinolinducesapoptosisinC6gliomacells.PMID:9771884 Guzmanetal.(2000).Antitumoralactionofcannabinoids:involvementofsustainedceramideaccumulationand extracellularsignalregulatedkinaseactivation.doi:10.1038/73171 20 Guzmanetal.(2003).Inhibitionoftumorangiogenesisbycannabinoids.TheFASEBJournal17:529531. 21 Massietal.(2004).Antitumoreffectsofcannabidiol,anonpsychotropiccannabinoid,onhumangliomacelllines. doi:10.1124/jpet.103.061002 22 Guzmanetal.2004.Cannabinoidsinhibitthevascularendothelialgrowthfactorpathwaysingliomas(PDF).Cancer Research64:56175623. 23 Allisteretal.2005.Cannabinoidsselectivelyinhibitproliferationandinducedeathofculturedhumanglioblastomamultiforme cells.JournalofNeurooncology74:3140. 24 Torresetal.2011.AcombinedpreclinicaltherapyofcannabinoidsandTemozolomideagainstglioma.MolecularCannabis Therapeutics10:90.
18 19

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cannabinoids, investigators concluded.25 Several additional investigators have also recently called for 27 28 further exploration of cannabisbased therapies for the treatment of glioma.26, , A separatecase report, published in 2011 in the journal of the International Society for PediatricNeurosurgery, alsodocuments the spontaneous regression of residual brain tumors in two children coinciding with the subjectsuseof cannabis.29 A study published in The Journal of Neuroscience examined the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. They conducted a magnetic resonance imaging study that looked at THC (the main active compound in [cannabis])and found thatit reduced neuronal injury in rats. The results of this study provide evidence that the cannabinoid system canservetoprotectthebrainagainstneurodegeneration.30 Consequently, many experts now believe that cannabinoids may represent a new class of anticancer 32 drugs that retard cancer growth, inhibit angiogenesis and the metastatic spreading of cancer cells.31, Angiogenesisreferstotheformationofnewbloodvesselsfromexistingones. A 1997 inquiry by the British Medical Association found cannabis more effective than Marinol, and a 1998 review by the House of Lords Science & Technology Select Committee concluded that "Cannabinoids are undoubtedly effective asantiemetic agents invomiting induced by anticancer drugs. Someusersofbothfindcannabisitselfmoreeffective." The 1999 Institutes of Medicine report suggested: "In patients already experiencing severe nausea or vomiting, pills are generally ineffective, because of the difficulty in swallowing orkeeping a pill down, and slow onset of the drug effect. Thus an inhalation (but, preferablynot smoking)cannabinoiddrugdelivery systemwouldbeadvantageousfortreatingchemotherapyinducednausea."

2.Oral
The primary cannabinoids, 9THC and 8THC are known to disturb the mitochondrial function and possess antitumor activities. These observations prompted the investigation into their effects on the mitochondrial O(2) consumption in human oral cancer cells (Tu183). This epithelial cell line over expressesbcl2andishighlyresistanttoanticancerdrugs. Cannabinoidsarepotentinhibitorsofcellularrespirationandaretoxictohighlymalignantoraltumors.33

Guzmanetal.2006.Apilotclinicalstudyofdelta9tetrahydrocannabinolinpatientswithrecurrentglioblastomamultiforme. BritishJournalofCancer(2006)95,197203.doi:10.1038/sj.bjc.6603236 26 ParolaroandMassi.2008.Cannabinoidsasapotentialnewdrugtherapyforthetreatmentofgliomas.ExpertReviewsof Neurotherapeutics8:3749 27 Galantietal.2007.Delta9TetrahydrocannabinolinhibitscellcycleprogressionbydownregulationofE2F1inhuman glioblastomamultiformecells.ActaOncologica12:19PMID:17934890 28 Calatozzoloetal.2007.Expressionofcannabinoidreceptorsandneurotrophinsinhumangliomas.NeurologicalSciences 28:304310.PMID:18175076 29 Citednorml.org:Foroughietal.2011.Spontaneousregressionofseptumpellucidum/fornicealpilocyticastrocytomas possibleroleofcannabisinhalation.ChildsNervousSystem27:671679. 30 Neuroprotectionby9Tetrahydrocannabinol,theMainActiveCompoundinMarijuana,againstOuabainInducedinvivo Excitotoxicity.TheJournalofNeuroscience,1September2001,21(17):64756479 31 NatalyaKogan.2005.Cannabinoidsandcancer.MiniReviewsinMedicinalChemistry5:941952. 32 Sarafarazetal.2008.Cannabinoidsforcancertreatment:progressandpromise.CancerResearch68:339 33 Cannabinoidsinhibitcellularrespirationofhumanoralcancercells.Pharmacology.201085(6):32835.doi: 10.1159/000312686.Epub2010Jun2.
25

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3.Breast
Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. A study published in the US National Library of Medicine, conducted by the California Pacific Medical Centre determined that cannabidiol (CBD) inhibits human breast cancer cell proliferationandinvasion.TheyalsodemonstratedthatCBDsignificantlyreducestumormass.34 9THC exhibits antitumor effects on various cancer cell types, but its use in chemotherapy is limited by its psychotropic activity. THCacid was assessed whether there is any advantage in using Cannabis extracts (enriched in either cannabidiol or THC) over pure cannabinoids. Results obtained in a panel of tumor celllines clearly indicatethat, ofthe five natural compounds tested, cannabidiol is the mostpotent inhibitorofcancercellgrowth.35 A study published in the journal Molecular Cancer showed that THC reduced tumor growth and tumor numbers. They determined that cannabinoids inhibit cancer cell proliferation, induce cancer cell apoptosis and impair tumor angiogenesis. The studyprovidesstrongevidencefor the use of cannabinoid basedtherapiesforthemanagementofbreastcancer.36 A further study published in the Proceedings of the National Academy of SciencesoftheUnited States ofAmerica(PNAS)determinedthatcannabinoidsinhibithumanbreastcancercellproliferation. 37 A study published by the American Association for Cancer Research, investigated how Cannabidiol induces programmed cell death in breast cancer cells by coordinating the crosstalk between apoptosis and autophagy. The study revealed an intricate interplay between apoptosis and autophagy in CBDtreated breast cancer cells and highlighted the value of continued investigation into the potential useofCBDasanantineoplasticagent.38

4.Lung
Little is known about the activity of cannabinoids like THC on epidermal growth factor receptoroverexpressinglungcancers,whichareoftenhighlyaggressiveandresistanttochemotherapy. The study published in the journal Oncogene, by Harvard Medical School's Experimental Medicine Department determined that THC inhibits epithelial growth factor induced lung cancer cell migration. Additionally, in in vivo studies in severe combined immunodeficientmice,there wassignificant inhibition of the subcutaneous tumor growth and lung metastasis of A549 cells in THCtreated animals as compared to vehicletreated controls. They go on to state that THC should be explored as novel therapeuticmoleculesincontrollingthegrowthandmetastasisofcertainlungcancers.39 A study published by the US National Library of Medicine by the Institute of Toxicology and Pharmacology,fromtheDepartmentof GeneralSurgery in Germanydeterminedthatcannabinoids inhibit cancer cell invasion. Effects were confirmed in primary tumor cells from a lung cancer patient. Overall, dataindicatedthatcannabinoidsdecreasecancercellinvasiveness.40

34

Pathwaysmediatingtheeffectsofcannabidiolonthereductionofbreastcancercellproliferation,invasion,and metastasis.BreastCancerResTreat.2012May133(1):4014.PMID:20859676 35 Antitumoractivityofplantcannabinoidswithemphasisontheeffectofcannabidiolonhumanbreastcarcinoma.Published onlinebeforeprintMay25,2006,doi:10.1124/jpet.106.105247JPETMay25,2006 36 CannabinoidsreduceErbB2drivenbreastcancerprogressionthroughAktinhibition.MolecularCancer2010,9:196 doi:10.1186/147645989196 37 Theendogenouscannabinoidanandamideinhibitshumanbreastcancercellproliferation.PNASJuly7,1998vol.95no.14 83758380 38 Cannabidiolinducesprogrammedcelldeathinbreastcancercellsbycoordinatingthecrosstalkbetweenapoptosisand autophagy.MolCancerTher.2011Jul10(7):116172.doi:10.1158/15357163.MCT101100.Epub2011May12.PMID: 21566064http://www.ncbi.nlm.nih.gov/pubmed/21566064?dopt=Abstract 39 9Tetrahydrocannabinolinhibitsepithelialgrowthfactorinducedlungcancercellmigrationinvitroaswellasitsgrowth andmetastasisinvivo.Oncogene(2008)27,339346publishedonline9July2007 40 Cannabidiolinhibitslungcancercellinvasionandmetastasisviaintercellularadhesionmolecule1.2012

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A further study published by the US National Library of Medicine,conductedby HarvardMedical School investigated the role ofcannabinoid receptors in lungcancercells.They determined its effectiveness and suggestedthatitshouldbeusedfortreatmentagainstlungcancercells.41

5.Skin
Nonmelanomaskincancerisoneofthemostcommonmalignanciesinhumans.Differenttherapeutic strategies for the treatment of these tumors are currently being investigated. Given the growth inhibiting effects of cannabinoids on gliomas and the wide tissue distribution of the two subtypes of cannabinoid receptors (CB1 and CB2)[.]42 The CB1 receptor mostly found in the central and peripheral nervous system and is activated by endocannabinoids (cannabinoids naturally produced in the body) and plant cannabinoids (also known as phytocannabinoids). The CB2 receptor is related to theCB1 receptorand helpedtoexplaintheeffectsofcannabinoidsontheimmunesystem. In vivo studies in humans and nude mice have shown an anticancer effect on the development ofskin tumors. Cannabinoid treatment has been shown to induce apoptosis in tumor cells. This phenomenon is accompanied by reduced tumor vascularisation and decreased expression in proangiogenic factors. Thesestudiesjustifyfurtherresearchintotreatmentofskintumors.43

6.Blood
Plantderived cannabinoids, including 9tetrahydrocannabinol, induce apoptosis in leukemic cells, although the precise mechanism remains unclear. It was investigated that the effect of THC on the upstream and downstream events modulates the extracellular signalregulated kinase (ERK) module of mitogenactivatedproteinkinasepathwaysprimarilyinhumanJurkatleukemiaTcells.44 A study published in the journal Molecular Pharmacology recently showed that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma. The study was supported by grants from the SwedishCancerSociety,TheSwedishResearchCouncilandtheCancerSocietyinStockholm.45 A further study published in the International Journal of Cancer also determined and illustrated that cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer andinmantlecell lymphoma. 46

7.BiliaryTractCholangiocarcinoma
Currently, only gemcitabine plus platinum demonstrates the considerable activity for cholangiocarcinoma. The anticancer effect of 9tetrahydrocannabinol (THC), the principal active component of cannabinoidshasbeendemonstrated in various kinds of cancers.47A studyevaluated the antitumor effects of THC on cholangiocarcinoma cells.48 It found that THC induces apoptosis in tumor cellsandinhibitedthemigrationandspreadofcancercells.49

Apr26(4):153548.PMID:22198381 41 Cannabinoidreceptors,CB1andCB2,asnoveltargetsforinhibitionofnonsmallcelllungcancergrowthandmetastasis. CancerPrevRes(Phila).2011Jan4(1):6575PMID:21097714 42 Inhibitionofskintumorgrowthandangiogenesisinvivobyactivationofcannabinoidreceptors.JClinInvest.2003Jan PMID:12511587http://www.ncbi.nlm.nih.gov/pubmed/12511587 43 Inhibitionofskintumorgrowthandangiogenesisinvivobyactivationofcannabinoidreceptors.JClinInvest.2003Jan PMID:12511587http://www.ncbi.nlm.nih.gov/pubmed/12511587 44 Delta9tetrahydrocannabinolinducedapoptosisinJurkatleukemiaTcellsisregulatedbytranslocationofBadto mitochondria.MolCancerRes.2006Aug4(8):54962.PMID:16908594 45 CannabinoidReceptorMediatedApoptosisInducedbyR(+)MethanandamideandWin55,2122IsAssociatedwith CeramideAccumulationandp38ActivationinMantleCellLymphomaAugust25,2006,doi:10.1124/mol.106.02598 46 Gustafsson,K.,Wang,X.,Severa,D.,Eriksson,M.,Kimby,E.,Merup,M.,Christensson,B.,Flygare,J.andSander,B. (2008),Expressionofcannabinoidreceptorstype1andtype2innonHodgkinlymphoma:Growthinhibitionbyreceptor activation.Int.J.Cancer,123:10251033.doi:10.1002/ijc.23584 47 Thedualeffectsofdelta(9)tetrahydrocannabinoloncholangiocarcinomacells:antiinvasionactivityatlowconcentration andapoptosisinductionathighconcentration.CancerInvest.2010May28(4):35763.doi:10.3109/07357900903405934. PMID:19916793http://www.ncbi.nlm.nih.gov/pubmed/19916793 48 Ibid. 49 Ibid.

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8.Liver
Hepatocellular carcinoma (HCC) is the third cause of cancerrelated death worldwide. When these tumors are in advanced stages, few therapeutic options are available. Therefore, it isessential to search fornewtreatmentstofightthisdisease. It was observed that 9THC and JWH015 (acannabinoid receptor2CB2 cannabinoid receptorselective agonist) reduced the viability of the human HCC cell lines HepG2 (human hepatocellular liver carcinoma cell line) and HuH7 (hepatocellular carcinoma cells), an effect that relied on the stimulation of CB2 receptor. It was also found that 9THC and JWH015induced autophagy relies on tribbles homolog 3 (TRB3) upregulation, and subsequent inhibition of the serinethreonine kinase Akt/mammalian target of rapamycinC1axisandadenosinemonophosphateactivatedkinase(AMPK)stimulation. Pharmacological and genetic inhibition of AMPK upstream kinases supported that calmodulinactivated kinase kinase was responsible for cannabinoidinduced AMPK activation and autophagy. In vivo studies revealed that 9THC and JWH015 reduced the growth of HCC subcutaneous xenografts, an effect that was not evident when autophagy was genetically or pharmacologically inhibited in those tumors. Moreover, cannabinoids were also ableto inhibit tumorgrowthand ascitesin an orthotopicmodel ofHCC xenograft. The findings may contributeto the designofnew therapeuticstrategies for the management of HCC.50

9.Pancreatic
Pancreatic adenocarcinomas are among the most malignant forms of cancer. A published study inThe American Journal of Cancer undertook toinvestigate the actionofcannabinoids,a new familyofpotential antitumoralagents,inpancreaticcancer. Cannabinoid receptors are expressed in human pancreatic tumor cell lines and tumor biopsiesatmuch higherlevelsthaninnormalpancreatictissue. Cannabinoids also reduced the growth of tumor cells in two animal models of pancreatic cancer. In addition, cannabinoid treatment inhibited the spreading ofpancreatic tumorcells. Moreover,cannabinoid administration selectively increased apoptosis and TRB3 expression inpancreatictumor cells but not in normal tissue. In conclusion, results presented show that cannabinoids lead to apoptosis of pancreatic tumor cells via a CB2 receptor and de novosynthesised ceramidedependent upregulation of p8and the endoplasmicreticulumstressrelatedgenesATF4andTRB3. These findings may contribute to set the basis for a new therapeutic approach for the treatment of pancreaticcancer.51

10.Uterine
One study in mice and rats suggested that cannabinoids may have a protective effect against the development of certain types of tumors. During this 2year study, groups of mice and rats were given various doses of THC by gavage. A doserelated decrease in the incidence of hepatic adenomatumors and hepatocellular carcinoma (HCC) was observed in the mice. Decreased incidences of benign tumors (polyps and adenomas) in other organs (mammary gland, uterus, pituitary, testis, and pancreas) were alsonotedintherats.52

50

Antitumoralactionofcannabinoidsonhepatocellularcarcinoma:roleofAMPKdependentactivationofautophagy. CellDeathDiffer.2011Jul18(7):1099111.doi:10.1038/cdd.2011.32.Epub2011Apr8. 51 CannabinoidsInduceApoptosisofPancreaticTumorCellsviaEndoplasmicReticulumStressRelatedGenesdoi: 10.1158/00085472.CAN060169CancerResJuly1,2006 52 NationalCancerInstituteCannabisandCannabinoids21/11/2013 http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page4

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11.Ovarian
Cannabinoid receptors as a target for therapy of ovarian cancer. Ovarian cancer represents one of the leading cause of cancerrelated deaths for women and isthemostcommongynecologic malignancy.In spite of relative low morbidity, ovarian cancer has a high fatality ratio, with overall 5year survival of less than 30%. At present, there are inadequate treatment options for the management of advanced ovarian cancer, and therefore development of novel approaches for treatment of this disease are needed. Cannabinoids, the active components of Cannabis sativa L. and their derivatives have received considerable attention in recent yearsdue to their diverse pharmacological activitiessuch as cell growth inhibitionandtumorregression. To date, two different cannabinoid receptors have been characterized and cloned from mammalian tissues: the "central" CB1receptor and the "peripheral" CB2 receptor.The study foundthat compared to normal Chinese hamster ovarian (CHO) cells, the expression levels of both cannabinoid receptors CB1 andCB2weresignificantlyhigherinhumanovariancancercellsOVCAR3andSKOV3. The study found that treatment of both OVCAR3 and SKOV3 cells with WIN55,2122 resulted in downregulation of the expression of PCNA and VEGF. These results support a new therapeutic approach for the treatment of ovarian cancer. It is also conceivable that with available cannabinoids as leadcompounds,nonhabitformingagentsthathavehigherbiologicaleffectscouldbedeveloped.53

12.Prostate
Prostate cancer is a global public health problem, and it is the most common cancer in men and the second cause for cancerrelated death.54 Experimental evidence shows that prostate tissue possesses cannabinoidreceptorsandtheirstimulationresultsinantiandrogeniceffects. Prostate cancer cells possess increased expression of both cannabinoid 1 and 2 receptors, and stimulation of these results ina decrease incell viability, increasedapoptosis,anddecreased androgen receptor expression and prostatespecific antigen excretion. It would be of interest to conduct clinical studies utilising cannabinoids for patients with metastatic prostate cancer, taking advantage not only of its beneficial effects on prostate cancer but also of theiranalgesicproperties forbone metastaticcancer pain. The US National Library of Medicine outlined multiple studies proving the effectiveness ofcannabis onprostatecancer.55 The potent antiproliferative and cytotoxic effects of ANA on metastatic prostatic cancer cells might provide basis for the design of new therapeutic agents for effective treatment of recurrent and invasive prostatic cancers. A study published in the US National Library of Medicine illustrates a decrease in prostaticcancercellsbyactingthroughcannabinoidreceptors.56 Another study published by the US National Library of Medicine determined that clinical testing of CBD against prostate carcinoma is important and that cannabinoid receptor activation induces prostate carcinomacellapoptosis.Itwasdeterminedthatcannabidiolsignificantlyinhibitedcellviability.57

53

CannabinoidreceptorsasatargetfortherapyofovariancancerProcAmerAssocCancerRes,Volume47,2006 http://www.aacrmeetingabstracts.org/cgi/content/abstract/2006/1/1084 54 Health24CANSASouthAfricanCancerStatistics 55 The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications. Indian J Urol. 2012JanMar28(1):914.PMCID:PMC3339795 56 Antiproliferativeandapoptoticeffectsofanandamideinhumanprostaticcancercelllines:implicationofepidermalgrowth factorreceptordownregulationandceramideproduction.Prostate.2003Jun1556(1):112.PMID:12746841 57 NonTHCcannabinoidsinhibitprostatecarcinomagrowthinvitroandinvivo:proapoptoticeffectsandunderlying mechanisms.BrJPharmacol.2013Jan168(1):79102.PMID:22594963

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13.Bladder
A study where researchers compared the risk of bladder cancer in morethan 83,000men who smoked cigarettes only, (cannabis) only, or both substances. Investigators found that men who only smoked cannabisweretheleastlikelytodevelopbladdercanceroverthecourseof11years. Thevalueofthestudymaybetospurotherresearchintonewtreatmentsforbladdercancer.58

14.ColorectalCRC
Colon cancer is a major public health problem and affects many South African citizens. Those living in impoverished conditions tend to be more at risk due to the lack of adequate medical treatment. Cannabisbased medicines have shown promise as adjunctive treatments for colon cancer. A study investigated the effect of a cannabis extract consisting mostly of cannabidiol (CBD). Cannabidiol is a cannabinoidandisamajorconstituentofthecannabisplant. The study concludedthat CBD BDSattenuatescoloncarcinogenesis and inhibits colorectal cancer cell proliferation via CB1 and CB2 receptor activation. The results may have some clinical relevance for the useofcannabisbasedmedicinesincancerpatients.59 Emerging evidence suggests that cannabinoids may exert beneficial effects in intestinal inflammation and cancer. Adaptive changes of theendocannabinoid system have been observedinintestinal biopsies from patients with inflammatory bowel disease and colon cancer. Studies on epithelial cells have shown that cannabinoids exert antiproliferative, antimetastatic and apoptotic effects as well as reducing cytokine release and promoting wound healing. In vivo, cannabinoids via direct or indirect activationof CB(1) and/or CB(2) receptors exert protective effects in wellestablished models of intestinal inflammation and colon cancer. Pharmacological elevation of endocannabinoid levels may be a promisingstrategytocounteractintestinalinflammationandcoloncancer.60 Colon cancer affects millions of individuals in Western countries. Cannabidiol, a safe and nonpsychotropic ingredient of cannabis sativa, exerts pharmacological actions (antioxidant and intestinal antiinflammatory) and mechanisms (inhibition of endocannabinoid enzymatic degradation) potentiallybeneficialforcoloncarcinogenesis.61 In colorectal carcinoma cell lines, cannabidiol protected DNA from oxidative damage, increased endocannabinoid levels and reduced cell proliferation in a CB(1), TRPV1 and PPARantagonists sensitive manner. It is concluded that cannabidiol exerts chemopreventive effectinvivo andreducescell proliferationthroughmultiplemechanisms.62,63

58

USATodayMay11,2013Studyclaimsmarijuanatiedtolowerbladdercancerrisk www.usatoday.com/story/news/nation/2013/05/11/studyclaimsmarijuanatiedtolowerbladdercancerrisk/2153019/ 59 InhibitionofcoloncarcinogenesisbyastandardizedCannabissativaextractwithhighcontentofcannabidiol. Phytomedicine.2013Dec24PMID:24373545http://www.ncbi.nlm.nih.gov/pubmed/24373545 60 Cannabinoidsinintestinalinflammationandcancer.PharmacolRes.2009AugPMID:19442536 https://www.ncbi.nlm.nih.gov/pubmed/19442536 61 Theendogenouscannabinoid,anandamide,inducescelldeathincolorectalcarcinomacells:apossiblerolefor cyclooxygenase2GutBMJ2005http://gut.bmj.com/content/54/12/1741.abstract 62 Ibid. 63 Chemopreventiveeffectofthenonpsychotropicphytocannabinoidcannabidiolonexperimentalcoloncancer.JMolMed (Berl).2012AugPMID:22231745http://www.ncbi.nlm.nih.gov/pubmed/22231745

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15.GeneralCancer
Cannabinoids, the active components of cannabis and their derivatives, induce tumor regression in rodents. However, the mechanism of cannabinoid antitumoral action in vivo is as yet unknown. Here it was shown that local administration of a non psychoactivecannabinoid tomice inhibitsangiogenesis of malignant gliomas as determined by immunohistochemical analyses andvascular permeability assays. In vitro and in vivo experiments show that at least two mechanismsmay beinvolved in thiscannabinoid action: the direct inhibition of vascular endothelial cell migration and survival as well as the decreaseof the expression of proangiogenic factors (vascular endothelial growth factor and angiopoietin2) and matrix metalloproteinase2 in the tumors. Inhibition of tumor angiogenesis may allow newstrategies for thedesignofcannabinoidbasedantitumoraltherapies. 64 Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumorangiogenesis,hereitwasstudiedwhethercannabinoidsaffectit. The study found among other things, that changes in theVEGF pathway wereparalleled bychangesin tumor size. Moreover, intratumoral administration of the cannabinoid 9tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR2 activation in the tumors. Because blockade oftheVEGF pathwayconstitutesoneof the mostpromising antitumoral approaches currently available, the present findings provide a novel pharmacological target forcannabinoidbasedtherapies.65

64 65

Inhibitionoftumorangiogenesisbycannabinoids.FASEBJ.2003Mar17(3):52931.Epub2003Jan2PMID:12514108 Cannabinoidsinhibitthevascularendothelialgrowthfactorpathwayingliomas.CancerRes.2004Aug1564(16):561723. PMID:15313899

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