Clinical Applications for Cannabis and Cannabinoids

8/10/2019 Clinical Applications for Cannabis and Cannabinoids

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Working to Reform Marijuana Laws

The National Organization for the Reform of Marijuana Laws (www.norml.org)

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TableofContents

Introduction ..........................................................................................................................................2Foreword...............................................................................................................................................7 IntroductiontotheEndocannabinoidSystem...............................................................................11 WhyIRecommendMedicalCannabis............................................................................................17 AlzheimersDisease...........................................................................................................................19 AmyotrophicLateralSclerosis(ALS)..............................................................................................22 ChronicPain .......................................................................................................................................24

Diabetes

Mellitus................................................................................................................................27

Dystonia...............................................................................................................................................31 Epilepsy...............................................................................................................................................33 Fibromyalgia.......................................................................................................................................34 GastrointestinalDisorders................................................................................................................37 Gliomas/Cancer..................................................................................................................................40 HepatitisC ..........................................................................................................................................46HumanImmunodeficiencyVirus(HIV).........................................................................................48 HuntingtonsDisease.........................................................................................................................51 Hypertension ......................................................................................................................................52

Incontinence........................................................................................................................................54 MethicillinresistantStaphyloccusaureus(MRSA) .........................................................................56MultipleSclerosis...............................................................................................................................57 Osteoporosis .......................................................................................................................................61Pruritus................................................................................................................................................63 RheumatoidArthritis ........................................................................................................................65SleepApnea ........................................................................................................................................67TourettesSyndrome..........................................................................................................................68


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Introduction

Humanshavecultivatedandconsumedthefloweringtopsofthefemalecannabisplant,colloquiallyknownasmarijuana,sincevirtuallythebeginningofrecordedhistory.Cannabisbasedtextilesdatingto7,000B.C.EhavebeenrecoveredinnorthernChina,andtheplantsuseasamedicinalandmoodalteringagentdatebacknearlyasfar.In2008,archeologistsinCentralAsiadiscoveredovertwopoundsofcannabisinthe2,700yearoldgraveofanancientshaman.Afterscientistsconductedextensivetestingonthematerialspotency,theyaffirmed, [T]hemostprobableconclusion...isthat[ancient]culture[s]cultivatedcannabisforpharmaceutical,psychoactive,anddivinatorypurposes.

Modernculturescontinuetoindulgeintheconsumptionofcannabisforthesesamepurposes,despiteapresentday,virtualworldwidebanontheplantscultivationanduse.IntheUnitedStates,federalprohibitionsoutlawingcannabis recreational,industrial,andtherapeuticusewerefirstimposedbyCongressundertheMarihuanaTaxActof1937andthenlaterreaffirmedbyfederallawmakers decisiontoclassifymarijuana aswellasalloftheplantsorganiccompounds(knownascannabinoids) asaScheduleIsubstanceundertheControlledSubstancesActof1970.Thisclassification,whichassertsbystatutethatcannabisisequallyasdangeroustothepublicasisheroin,definescannabisanditsdozensofdistinctcannabinoidsaspossessing ahighpotentialforabuse,...nocurrentlyacceptedmedicaluse,...[and]alackofacceptedsafetyfortheuseofthedrug...undermedicalsupervision. (Bycontrast,cocaineandmethamphetamine whichremainillicitforrecreationalusebutmaybeconsumedunderadoctorssupervision areclassifiedasScheduleIIdrugs;examplesofScheduleIIIandIVsubstancesincludeanabolicsteroidsandValiumrespectively,whilecodeinecontaininganalgesicsaredefinedbyalawasScheduleVdrugs,thefederalgovernmentsmostlenientclassification.)InJuly2011,theObamaAdministrationrebuffedanadministrativeinquiryseekingtoreassesscannabis ScheduleIstatus,andfederallawmakerscontinuetocitethedrugsdubiouscategorizationastheprimaryrationaleforthegovernmentsongoingcriminalizationoftheplantandthosewhouseit.AthreejudgepanelfortheUSCourtofAppealsfortheDistrictofColumbiaaffirmed

theAdministrationspositionin2013,arguingthatajudicialreviewofcannabis federallyprohibitedstatuswasnotwarrantedatthistime.

Nevertheless,thereexistslittleifanyscientificbasistojustifythefederalgovernmentspresentprohibitivestanceandthereisamplescientificandempiricalevidencetorebutit.DespitetheUSgovernment snearlycenturylongprohibitionoftheplant,cannabisis


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nonethelessoneofthemostinvestigatedtherapeuticallyactivesubstancesinhistory.Todate,thereareover20,000publishedstudiesorreviewsinthescientificliteraturereferencingthecannabisplantanditscannabinoids,nearlyhalfofwhichwerepublishedwithinthelastfiveyearsaccordingtoakeywordsearchonthesearchenginePubMedCentral,theUSgovernmentrepositoryforpeerreviewedscientificresearch.Whilemuchoftherenewedinterestincannabinoidtherapeuticsisaresultofthediscoveryoftheendocannabinoidregulatorysystem(whichisdescribedindetaillaterinthisbooklet),someofthisincreasedattentionisalsoduetothegrowingbodyoftestimonialsfrommedicalcannabispatientsandtheirphysicians.

Thescientificconclusionsoftheoverwhelminglymajorityofmodernresearchdirectlyconflictswiththefederalgovernmentsstancethatcannabisisahighlydangeroussubstance

worthyofabsolutecriminalization.

Forexample,inFebruary2010investigatorsattheUniversityofCaliforniaCenterforMedicinalCannabisResearchpubliclyannouncedthefindingsofaseriesofrandomized,placebocontrolledclinicaltrialsonthemedicalutilityofinhaledcannabis.Thestudies,whichutilizedthesocalled goldstandard FDAclinicaltrialdesign,concludedthatmarijuanaoughttobea firstlinetreatment forpatientswithneuropathyandotherseriousillnesses.

SeveralofstudiesconductedbytheCenterassessedsmokedmarijuanasabilitytoalleviate

neuropathicpain,anotoriouslydifficulttotreattypeofnervepainassociatedwithcancer,diabetes,HIV/AIDS,spinalcordinjuryandmanyotherdebilitatingconditions.Eachofthetrialsfoundthatcannabisconsistentlyreducedpatients painlevelstoadegreethatwasasgoodorbetterthancurrentlyavailablemedications.

AnotherstudyconductedbytheCentersinvestigatorsassessedtheuseofmarijuanaasatreatmentforpatientssufferingfrommultiplesclerosis.ThatstudydeterminedthatsmokedcannabiswassuperiortoplaceboinreducingspasticityandpaininpatientswithMS,andprovidedsomebenefitbeyondcurrentlyprescribedtreatments.

AsummaryoftheCentersclinicaltrials,publishedin2012intheOpenNeurologyJournal,concluded: Evidenceisaccumulatingthatcannabinoidsmaybeusefulmedicineforcertainindications....TheclassificationofmarijuanaasaScheduleIdrugaswellasthecontinuingcontroversyastowhetherornotcannabisisofmedicalvalueareobstaclestomedicalprogressinthisarea.BasedonevidencecurrentlyavailabletheScheduleIclassificationis


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nottenable;itisnotaccuratethatcannabishasnomedicalvalue,orthatinformationonsafetyislacking.

Aroundtheglobe,similarlycontrolledtrialsarealsotakingplace.A2010reviewbyresearchersinGermanyreportsthatsince2005therehavebeen37controlledstudiesassessingthesafetyandefficacyofmarijuanaanditsnaturallyoccurringcompoundsinatotalof2,563subjects.Bycontrast,manyFDAapproveddrugsgothroughfarfewertrialsinvolvingfarfewersubjects.

Asclinicalresearchintothetherapeuticvalueofcannabinoidshasproliferatedsotoohasinvestigators understandingofcannabis remarkablecapabilitytocombatdisease.Whereasresearchersinthe1970s,80s,and90sprimarilyassessedcannabis abilitytotemporarily

alleviatevariousdiseasesymptoms suchasthenauseaassociatedwithcancerchemotherapy scientiststodayareexploringthepotentialroleofcannabinoidstomodifydisease.

Ofparticularinterest,scientistsareinvestigatingcannabinoids capacitytomoderateautoimmunedisorderssuchasmultiplesclerosis,rheumatoidarthritis,andinflammatory

boweldisease,aswellastheirroleinthetreatmentofneurologicaldisorderssuchasAlzheimersdiseaseandamyotrophiclateralsclerosis(a.k.a.LouGehrigsdisease.)In2009,theAmericanMedicalAssociation(AMA)resolvedforthefirsttimeintheorganizationshistory thatmarijuanasstatusasafederalScheduleIcontrolledsubstancebereviewed

withthegoaloffacilitatingtheconductofclinicalresearchanddevelopmentofcannabinoidbasedmedicines.

Investigatorsarealsostudyingtheanticanceractivitiesofcannabis,asagrowingbodyofpreclinicalandclinicaldataconcludesthatcannabinoidscanreducethespreadofspecificcancercellsviaapoptosis(programmedcelldeath)andbytheinhibitionofangiogenesis(theformationofnewbloodvessels).Arguably,theselatterfindingsrepresentfarbroaderandmoresignificantapplicationsforcannabinoidtherapeuticsthanresearcherscouldhaveimaginedsomethirtyoreventwentyyearsago.

THESAFETYPROFILEOFMEDICALCANNABIS

Cannabinoidshavearemarkablesafetyrecord,particularlywhencomparedtoothertherapeuticallyactivesubstances.Mostsignificantly,theconsumptionofmarijuana regardlessofquantityorpotency cannotinduceafataloverdose.Accordingtoa1995


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reviewpreparedfortheWorldHealthOrganization, Therearenorecordedcasesofoverdosefatalitiesattributedtocannabis,andtheestimatedlethaldoseforhumansextrapolatedfromanimalstudiesissohighthatitcannotbeachievedby...users.

In2008,investigatorsatMcGillUniversityHealthCentreandMcGillUniversityinMontrealandtheUniversityofBritishColumbiainVancouverreviewed23clinicalinvestigationsofmedicalcannabinoiddrugs(typicallyoralTHCorliquidcannabisextracts)andeightobservationalstudiesconductedbetween1966and2007.Investigators didnotfindahigherincidencerateofseriousadverseeventsassociatedwithmedicalcannabinoidusecomparedtononusingcontrolsoverthesefourdecades.

Thatsaid,cannabisshouldnotnecessarilybeviewedasa harmless substance.Itsactive

constituentsmayproduceavarietyofphysiologicalandeuphoriceffects.Asaresult,theremaybesomepopulationsthataresusceptibletoincreasedrisksfromtheuseofcannabis,suchasadolescents,pregnantornursingmothers,andpatientswhohaveafamilyhistoryofmentalillness.Patientswithdecreasedlungfunction(suchaschronicobstructivepulmonarydisease)orthosewhohaveahistoryofheartdiseaseorstrokemayalsobeatagreaterriskofexperiencingadversesideeffectsfrommarijuana.Aswithanymedication,patientsshouldconsultthoroughlywiththeirphysicianbeforedecidingwhetherthemedicaluseofcannabisissafeandappropriate.

HOWTOUSETHISREPORT

Asstatescontinuetoapprovelegislationenablingthephysiciansuperviseduseofmedicalmarijuana,morepatientswithvaryingdiseasetypesareexploringtheuseoftherapeuticcannabis.Manyofthesepatientsandtheirphysiciansarenowdiscussingthisissueforthefirsttimeandareseekingguidanceonwhetherthetherapeuticuseofcannabismayormaynotbeadvisable.Thisreportseekstoprovidethisguidancebysummarizingthemostrecentlypublishedscientificresearch(20002013)onthetherapeuticuseofcannabisandcannabinoidsfor20clinicalindications.

Insomeofthesecases,modernscienceisnowaffirminglongtimeanecdotalreportsofmedicalcannabisusers(e.g.,theuseofcannabistoalleviateGIdisorders).Inothercases,thisresearchishighlightingentirelynewpotentialclinicalutilitiesforcannabinoids(e.g.,theuseofcannabinoidstomodifytheprogressionofdiabetes.)


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Theconditionsprofiledinthisreportwerechosenbecausepatientsfrequentlyinquireaboutthetherapeuticuseofcannabistotreatthesedisorders.Inaddition,manyoftheindicationsincludedinthisreportmaybemoderatedbycannabistherapy.Inseveralcases,preclinicaldataandclinicaldataindicatethatcannabinoidsmayhalttheadvancementofthesediseasesinamoreefficaciousmannerthanavailablepharmaceuticals.

Forpatientsandtheirphysicians,thisreportcanserveasaprimerforthosewhoareconsideringusingorrecommendingmedicalcannabis.Forothers,thisreportcanserveasanintroductiontothebroadrangeofemergingclinicalapplicationsforcannabisanditsvariouscompounds.

PaulArmentano

DeputyDirectorNORML|NORMLFoundationWashington,DC

January7,2014

*TheauthorwouldliketoacknowledgeDrs.DaleGieringer,EstelleGoldstein,DustinSulak,GregoryCarter,StevenKarch,andMitchEarleywine,aswellasBernardEllis,MPH,formerNORMLinternsJohnLucy,ChristopherRasmussen,andRitaBowles,forprovidingresearchassistanceforthisreport.TheNORMLFoundationwouldalsoliketoacknowledgeDaleGieringer,PaulKuhn,andRichardWolfefortheirfinancialcontributionstowardthe

publicationofthisreport.

**ImportantandtimelypublicationssuchasthisareonlymadepossiblewhenconcernedcitizensbecomeinvolvedwithNORML.FormoreinformationonjoiningNORMLormakingadonation,pleasevisit:http://www.norml.org/join.TaxdeductibledonationsinsupportofNORMLspubliceducationcampaignsshouldbemadepayabletotheNORMLFoundation.


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Foreword

GregoryT.

Carter,

MD

DepartmentofRehabilitationMedicineUniversityofWashingtonSchoolofMedicine

MarijuanaisacolloquialtermusedtorefertothedriedflowersofthefemaleCannabisSativaandCannabisIndicaplants.Marijuana,orcannabis,asitismoreappropriatelycalled,hasbeenpartofhumanitysmedicinechestforalmostaslongashistoryhasbeenrecorded.

Allformsofcannabisplantsarequitecomplex,containingover400chemicals.Approximately60ofthesechemicalsareclassifiedascannabinoids.Amongthemost

psychoactiveofthecannabinoidsisdelta9tetrahydrocannabinol(THC),theactiveingredientintheprescriptionmedicationsdronabinol(Marinol)andnaboline(Cesamet).Othermajorcannabinoidsincludecannabidiol(CBD)andcannabinol(CBN),bothofwhicharenonpsychoactivebutpossessdistinctpharmacologicaleffects.

CannabiswasformallyintroducedtotheUnitedStatesPharmacopoeia(USP)in1854,thoughwrittenreferencesregardingtheplantstherapeuticusedatebackasfaras2800B.C.By1900,cannabiswasthethirdleadingactiveingredient,behindalcoholandopiates,inpatentmedicinesforsaleinAmerica.However,followingtheMexicanRevolutionof1910,

MexicanimmigrantsfloodedintotheUnitedStates,introducingtoAmericanculturetherecreationaluseofmarijuana.Antidrugcampaignerswarnedagainsttheencroaching,socalled MarijuanaMenace, andallegedthatthedrugsusewasresponsibleforawaveofserious,violentcriminalactivity.In1937,aftertestimonyfromHarryAnslinger astrongopponentofmarijuanaandheadoftheFederalBureauofNarcoticsinthe1930s andagainsttheadviceoftheAmericanMedicalAssociation,theMarijuanaTaxActwaspushedthroughCongress,effectivelyoutlawingallpossessionanduseofthedrug.

Atthetimeofthelawspassage,therewerenofewerthan28patentedmedicinescontainingcannabisavailableinAmericandrugstoreswithaphysiciansprescription.

ThesecannabisbasedmedicineswereproducedbyreputabledrugcompanieslikeSquibb,Merck,andEliLily,andwereusedsafelybytensofthousandsofAmericancitizens.TheenactmentoftheMarijuanaTaxActabruptlyendedtheproductionanduseofmedical


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cannabisintheUnitedStates,andby1942cannabiswasofficiallyremovedfromthePhysiciansDeskReference.

Fortunately,overthepastfewdecadestherehasbeenasignificantrebirthofinterestintheviablemedicalusesofcannabis.Muchoftherenewedinterestincannabisasamedicineliesnotonlyinthedrugseffectiveness,butalsoinitsremarkablylowtoxicity.Lethaldosesinhumanshavenotbeendescribed.Thisdegreeofsafetyisveryrareamongmodernmedicines,includingmostoverthecountermedications.Asaresult,theNationalInstitutesofHealth(NIH),theNationalAcademyofSciencesInstituteofMedicine,andeventheUSFoodandDrugAdministrationhaveallissuedstatementscallingforfurtherinvestigationintothetherapeuticuseofcannabisandcannabinoids.

Thediscoveryofanendogenouscannabinoidsystem,withspecificreceptorsandligands,hasprogressedourunderstandingofthetherapeuticactionsofcannabisfromfolkloretovalidscience.Itnowappearsthatthecannabinoidsystemevolvedwithourspeciesandisintricatelyinvolvedinnormalhumanphysiology specificallyinthecontrolofmovement,pain,reproduction,memory,andappetite,amongotherbiologicalfunctions.Inaddition,theprevalenceofcannabinoidreceptorsinthebrainandperipheraltissuessuggeststhatthecannabinoidsystemrepresentsapreviouslyunrecognizedubiquitousnetworkinthenervoussystem.

Cannabinoid

receptor

sites

are

now

known

to

exist

in

the

nervous

systems

of

all

animals

moreadvancedthanhydraandmollusks.Thisisaresultofatleast500millionyearsofevolution.Thehumanbodysneurological,circulatory,endocrine,digestive,andmusculoskeletalsystemshavenowallbeenshowntopossesscannabinoidreceptorsites.Indeed,evencartilagetissuehascannabinoidreceptors,whichmakescannabisaprimetherapeuticagenttotreatosteoarthritis.Cannabinoidshavebeenshowntoproduceanantiinflammatoryeffectbyinhibitingtheproductionandactionoftumornecrosisfactor(TNF)andotheracutephasecytokines,whichalsomakesthemidealcompoundstotreattheautoimmuneformsofarthritis.Itisnowsuggestedbysomeresearchersthatthesewidelyspreadcannabinoidreceptorsystemsarethemechanismsbywhichthebodymaintains

homeostasis(theregulationofcellfunction),allowingthebodystissuestocommunicatewithoneanotherinthisintricatecellulardancewecall life. Withthisknowledgeofthewidespreadactionofcannabinoidswithinallthesebodilysystems,itbecomesmucheasiertoconceptualizehowthevariousformsofcannabinoidsmighthaveapotentiallytherapeuticeffectondiseasesrangingfromosteoarthritistoamyotrophiclateralsclerosis(ALS).


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Anotheroneoftheexcitingtherapeuticareasthatcannabismayimpactischronicpain.Cannabinoidsproduceanalgesiabymodulatingrostralventromedialmedullaneuronalactivityinamannersimilarto,butpharmacologicallydistinctfrom,thatofmorphine.Thisanalgesiceffectisalsoexertedbysomeendogenouscannabinoids(anandamide)andsyntheticcannabinoids(methanandamide).Ideally,cannabinoidscouldbeusedaloneorinconjunctionwithopioidstotreatpeoplewithchronicpain,improvetheirqualityoflifeandallowthemtoreturntobeingaproductivecitizen.

Whendiscussingthetherapeuticuseofcannabisandcannabinoids,opponentsinevitablyrespondthatpatientsshouldnotsmoketheirmedicine.Patientsnolongerhaveto.Medicalcannabispatientswhodesiretherapidonsetofactionassociatedwithinhalation,butwho

areconcernedaboutthepotentialharmsofnoxioussmokeeliminatetheirintakeofcarcinogeniccompoundsbyengaginginvaporizationratherthansmoking.Cannabisvaporizationlimitsrespiratorytoxinsbyheatingcannabistoatemperaturewherecannabinoidvaporsform(typicallyaround180190degreesCelsius),butbelowthepointofcombustionwherenoxioussmokeandassociatedtoxins(e.g.,carcinogenichydrocarbons)areproduced(near230degreesCelsius).Thiseliminatestheinhalationofanyparticulatematterandremovesthehealthhazardsofsmoking.Inclinicaltrials,vaporizationhasbeenshowntosafelyandeffectivelydeliverpharmacologicallyactive,aerosolizedcannabinoidsdeeplyintothelungs,wheretherichvascularbedwillrapidlydeliverthemtotissues

throughout

the

body.

Thefollowingreportsummarizesthemostrecentlypublishedscientificresearchonthetherapeuticuseofcannabisandcannabinoidsformorethanadozendiseases,includingAlzheimers,amyotrophiclateralsclerosis,diabetes,hepatitisC,multiplesclerosis,rheumatoidarthritis,andTourettessyndrome.Itismyhopethatreadersofthisreportwillcomeawaywithafairandbalancedviewofcannabis aviewthatissubstantiatedbyscientificstudiesandnotbyanecdotalopinionorparanoia.Cannabisisneitheramiraclecompoundnortheanswertoeveryonesills.However,itdoesappeartohaveremarkabletherapeuticbenefitsthatarethereforthetakingifthegovernmentalbarriersformore

intensivescientificstudyareremoved.

Thecannabisplantdoesnotwarrantthetremendouslegalandsocietalcommotionthathasoccurredoverit.Overthepast30years,theUnitedStateshasspentbillionsinanefforttostemtheuseofillicitdrugs,particularlymarijuana,withlimitedsuccess.Manyveryillpeoplehavehadtofightlongcourtbattlestodefendthemselvesfortheuseofacompound


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thathashelpedthem.Rationalmindsneedtotakeoverthewarondrugs,separatingmyth

fromfact,rightfromwrong,andresponsiblemedicalusefromotherlesscompelling

behavior.

Themedicalmarijuanausershouldnotbeconsideredacriminalinanystate.Mostmajor

medicalgroups,includingtheInstituteofMedicine,agreethatcannabisisacompoundwith

significanttherapeuticpotentialwhose adverseeffects...arewithintherangeofeffects

toleratedforothermedications. Overadecadeago,theDrugEnforcementAdministration

(DEA)studiedthemedicalpropertiesofcannabis.Afterconsiderablestudy,DEA

AdministrativeLawJudgeFrancisL.Youngconcluded: Theevidenceclearlyshowsthat

marijuanaiscapableofrelievingthedistressofgreatnumbersofveryillpeople,anddoing

sowithsafetyundermedicalsupervision....Itwouldbeunreasonable,arbitraryand

capriciousfortheDEAtocontinuetostandbetweenthosesufferersandthebenefitsofthis

substance.

Despitethisconclusion,overadecadelatertheDEAandtherestofthefederalgovernment

persistintheirpolicyoftotalprohibition.Nevertheless,thescientificprocesscontinuesto

evaluatethetherapeuticeffectsofcannabisthroughongoingresearchandassessmentof

availabledata.Withregardtothemedicaluseofcannabis,ourlegalsystemshouldtakeasimilarapproach,usingscienceandlogicasthebasisofpolicymakingratherthanrelying

onpoliticalrhetoricandfalseperceptionsregardingtheallegedharmfuleffectsof

recreationalmarijuanause.


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IntroductiontotheEndocannabinoidSystem

DustinSulak,

DO

MaineIntegrativeHealthcare

Asyoureadthisreviewofthescientificliteratureregardingthetherapeuticeffectsofcannabisandcannabinoids,onethingwillbecomequicklyevident:cannabishasaprofoundinfluenceonthehumanbody.Thisoneherbanditsvarietyoftherapeuticcompoundsseemtoaffecteveryaspectofourbodiesandminds.Howisthispossible?

InmyintegrativemedicineclinicincentralMaine,wetreatoverathousandpatientswithahugediversityofdiseasesandsymptoms.InonedayImightseecancer,Crohnsdisease,

epilepsy,chronicpain,multiplesclerosis,insomnia,Tourettessyndromeandeczema,justtonameafew.Alloftheseconditionshavedifferentcauses,differentphysiologicstates,andvastlydifferentsymptoms.Thepatientsareoldandyoung.Someareundergoingconventionaltherapy.Othersareonadecidedlyalternativepath.Yetdespitetheirdifferences,almostallofmypatientswouldagreeononepoint:cannabishelpstheircondition.

Asaphysician,Iamnaturallywaryofanymedicinethatpurportstocureall.Panaceas,snakeoilremedies,andexpensivefadsoftencomeandgo,withbigclaimsbutlittle

scientificorclinicalevidencetosupporttheirefficacy.AsIexplorethetherapeuticpotentialofcannabis,however,Ifindnolackofevidence.Infact,Ifindanexplosionofscientificresearchonthetherapeuticpotentialofcannabis,moreevidencethanonecanfindonsomeofthemostwidelyusedtherapiesofconventionalmedicine.

Atthetimeofwriting,aPubMedsearchforscientificjournalarticlespublishedinthelast20yearscontainingtheword cannabis revealed7,704results.Addtheword cannabinoid,andtheresultsincreaseto15,899articles.Thatsanaverageofmorethantwoscientificpublicationsperdayoverthelast20years!Thesenumbersnotonlyillustratethepresentscientificinterestandfinancialinvestmentinunderstandingmoreaboutcannabisanditscomponents,buttheyalsoemphasizetheneedforhighqualityreviewsandsummariessuchasthedocumentyouareabouttoread.

Howcanoneherbhelpsomanydifferentconditions?Howcanitprovidebothpalliativeandcurativeactions?Howcanitbesosafewhileofferingsuchpowerfuleffects?Thesearch


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toanswerthesequestionshasledscientiststothediscoveryofapreviouslyunknownphysiologicsystem,acentralcomponentofthehealthandhealingofeveryhumanandalmosteveryanimal:theendocannabinoidsystem.

WhatIsTheEndocannabinoidSystem?

Theendogenouscannabinoidsystem,namedaftertheplantthatledtoitsdiscovery,isperhapsthemostimportantphysiologicsysteminvolvedinestablishingandmaintaininghumanhealth.Endocannabinoidsandtheirreceptorsarefoundthroughoutthebody:inthe

brain,organs,connectivetissues,glands,andimmunecells.Ineachtissue,thecannabinoidsystemperformsdifferenttasks,butthegoalisalwaysthesame:homeostasis,themaintenanceofastableinternalenvironmentdespitefluctuationsintheexternal

environment.

Cannabinoidspromotehomeostasisateverylevelofbiologicallife,fromthesubcellular,totheorganism,andperhapstothecommunityandbeyond.Heresoneexample:autophagy,aprocessinwhichacellsequesterspartofitscontentstobeselfdigestedandrecycled,ismediatedbythecannabinoidsystem.Whilethisprocesskeepsnormalcellsalive,allowingthemtomaintainabalancebetweenthesynthesis,degradation,andsubsequentrecyclingofcellularproducts,ithasadeadlyeffectonmalignanttumorcells,causingthemtoconsumethemselvesinaprogrammedcellularsuicide.Thedeathofcancercells,ofcourse,promotes

homeostasis

and

survival

at

the

level

of

the

entire

organism.

Endocannabinoidsandcannabinoidsarealsofoundattheintersectionofthebodysvarioussystems,allowingcommunicationandcoordinationbetweendifferentcelltypes.Atthesiteofaninjury,forexample,cannabinoidscanbefounddecreasingthereleaseofactivatorsandsensitizersfromtheinjuredtissue,stabilizingthenervecelltopreventexcessivefiring,andcalmingnearbyimmunecellstopreventreleaseofproinflammatorysubstances.Threedifferentmechanismsofactiononthreedifferentcelltypesforasinglepurpose:minimizethepainanddamagecausedbytheinjury.

Theendocannabinoidsystem,withitscomplexactionsinourimmunesystem,nervoussystem,andallofthebodysorgans,isliterallyabridgebetweenbodyandmind.Byunderstandingthissystemwebegintoseeamechanismthatexplainshowstatesofconsciousnesscanpromotehealthordisease.


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Inadditiontoregulatingourinternalandcellularhomeostasis,cannabinoidsinfluenceapersonsrelationshipwiththeexternalenvironment.Socially,theadministrationofcannabinoidsclearlyaltershumanbehavior,oftenpromotingsharing,humor,andcreativity.Bymediatingneurogenesis,neuronalplasticity,andlearning,cannabinoidsmaydirectlyinfluenceapersonsopenmindednessandabilitytomovebeyondlimitingpatternsofthoughtandbehaviorfrompastsituations.Reformattingtheseoldpatternsisanessentialpartofhealthinourquicklychangingenvironment.

WhatAreCannabinoidReceptors?

Seasquirts,tinynematodes,andallvertebratespeciessharetheendocannabinoidsystemasanessentialpartoflifeandadaptationtoenvironmentalchanges.Bycomparingthe

geneticsofcannabinoidreceptorsindifferentspecies,scientistsestimatethattheendocannabinoidsystemevolvedinprimitiveanimalsover600millionyearsago.

Whileitmayseemweknowalotaboutcannabinoids,theestimatedtwentythousandscientificarticleshavejustbeguntoshedlightonthesubject.Largegapslikelyexistinourcurrentunderstanding,andthecomplexityofinteractionsbetweenvariouscannabinoids,celltypes,systemsandindividualorganismschallengesscientiststothinkaboutphysiologyandhealthinnewways.Thefollowingbriefoverviewsummarizeswhatwedoknow.

Cannabinoid

receptors

are

present

throughout

the

body,

embedded

in

cell

membranes,

and

arebelievedtobemorenumerousthananyotherreceptorsystem.Whencannabinoidreceptorsarestimulated,avarietyofphysiologicprocessesensue.Researchershaveidentifiedtwocannabinoidreceptors:CB1,predominantlypresentinthenervoussystem,connectivetissues,gonads,glands,andorgans;andCB2,predominantlyfoundintheimmunesystemanditsassociatedstructures.ManytissuescontainbothCB1andCB2receptors,eachlinkedtoadifferentaction.Researchersspeculatetheremaybeathirdcannabinoidreceptorwaitingtobediscovered.

Endocannabinoidsarethesubstancesourbodiesnaturallymaketostimulatethese

receptors.Thetwomostwellunderstoodofthesemoleculesarecalledanandamideand2arachidonoylglycerol(2AG).Theyaresynthesizedondemandfromcellmembranearachidonicacidderivatives,havealocaleffectandshorthalflifebeforebeingdegradedbytheenzymesfattyacidamidehydrolase(FAAH)andmonoacylglycerollipase(MAGL).


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Phytocannabinoidsareplantsubstancesthatstimulatecannabinoidreceptors.Delta9tetrahydrocannabinol,orTHC,isthemostpsychoactiveandcertainlythemostfamousofthesesubstances,butothercannabinoidssuchascannabidiol(CBD)andcannabinol(CBN)aregainingtheinterestofresearchersduetoavarietyofhealingproperties.Mostphytocannabinoidshavebeenisolatedfromcannabissativa,butothermedicalherbs,suchasechinaceapurpura,havebeenfoundtocontainnonpsychoactivecannabinoidsaswell.

Interestingly,themarijuanaplantalsousesTHCandothercannabinoidstopromoteitsownhealthandpreventdisease.Cannabinoidshaveantioxidantpropertiesthatprotecttheleavesandfloweringstructuresfromultravioletradiation cannabinoidsneutralizetheharmfulfreeradicalsgeneratedbyUVrays,protectingthecells.Inhumans,freeradicalscauseaging,cancer,andimpairedhealing.Antioxidantsfoundinplantshavelongbeen

promotedasnaturalsupplementstopreventfreeradicalharm.

Laboratoriescanalsoproducecannabinoids.SyntheticTHC,marketedasdronabinol(Marinol),andnabilone(Cesamet),aTHCanalog,arebothFDAapproveddrugsforthetreatmentofseverenauseaandwastingsyndrome.Someclinicianshavefoundthemhelpfulintheofflabeltreatmentofchronicpain,migraine,andotherseriousconditions.Manyothersyntheticcannabinoidsareusedinanimalresearch,andsomehavepotencyupto600timesthatofTHC.

Cannabis,

The

Endocannabinoid

System,

And

Good

Health

Aswecontinuetosortthroughtheemergingscienceofcannabisandcannabinoids,onethingremainsclear:afunctionalcannabinoidsystemisessentialforhealth.Fromembryonicimplantationonthewallofourmothersuterus,tonursingandgrowth,torespondingtoinjuries,endocannabinoidshelpussurviveinaquicklychangingandincreasinglyhostileenvironment.AsIrealizedthis,Ibegantowonder:cananindividualenhancehis/hercannabinoidsystembytakingsupplementalcannabis?Beyondtreatingsymptoms,beyondevencuringdisease,cancannabishelpuspreventdiseaseandpromotehealthbystimulatinganancientsystemthatishardwiredintoallofus?

Inowbelievetheanswerisyes.Researchhasshownthatsmalldosesofcannabinoidsfrommarijuanacansignalthebodytomakemoreendocannabinoidsandbuildmorecannabinoidreceptors.Thisiswhymanyfirsttimemarijuanausersdontfeelaneffect,but

bytheirsecondorthirdtimeusingtheherbtheyhavebuiltmorecannabinoidreceptorsandarereadytorespond.Morereceptorsincreaseapersonssensitivitytocannabinoids;smaller


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doseshavelargereffects,andtheindividualhasanenhancedbaselineofendocannabinoidactivity.Ibelievethatsmall,regulardosesofmarijuanamightactasatonictoourmostcentralphysiologichealingsystem.

Manyphysicianscringeatthethoughtofrecommendingabotanicalsubstance,andareoutrightmortifiedbytheideaofsmokingamedicine.Ourmedicalsystemismorecomfortablewithsingle,isolatedsubstancesthatcanbeswallowedorinjected.Unfortunately,thismodelsignificantlylimitsthetherapeuticpotentialofcannabinoids.

Unlikesyntheticderivatives,herbalmarijuanamaycontainoveronehundreddifferentcannabinoids,includingTHC,whichallworksynergisticallytoproducebettermedicaleffectsandlesssideeffectsthanTHCalone.Whilemarijuanaissafeandworkswellwhen

smoked,manypatientsprefertouseavaporizerorcannabistincture.Scientificinquiryandpatienttestimonialsbothindicatethatherbalmarijuanahassuperiormedicalqualitiestosyntheticcannabinoids.

In1902ThomasEdisonsaid, Therewereneversomanyable,activemindsatworkontheproblemsofdiseaseasnow,andalltheirdiscoveriesaretendingtowardthesimpletruththatyoucantimproveonnature. Cannabinoidresearchhasproventhisstatementisstillvalid.

So,

is

it

possible

that

medical

marijuana

could

be

the

most

useful

remedy

to

treat

the

widest

varietyofhumandiseasesandconditions,acomponentofpreventativehealthcare,andanadaptivesupportinourincreasinglytoxic,carcinogenicenvironment?Yes.ThiswaswellknowntotheindigenousmedicalsystemsofancientIndia,China,andTibet,andasyouwillfindinthisreport,isbecomingincreasinglywellknownbyWesternscience.Ofcourse,weneedmorehumanbasedresearchstudyingtheeffectivenessofmarijuana,buttheevidencebaseisalreadylargeandgrowingconstantly,despitetheDEAsbesteffortstodiscouragecannabisrelatedresearch.

Doesyourdoctorunderstandthebenefitofmedicalcannabis?Canheorsheadviseyouin

theproperindications,dosage,androuteofadministration?Likelynot.Despitethetwolargestphysicianassociations(AmericanMedicalAssociationandAmericanCollegeofPhysicians)callingformoreresearch,theObamaadministrationpromisingnottoarrestpatientsprotectedunderstatemedicalcannabislaws,a5,000yearhistoryofsafetherapeuticuse,andahugeamountofpublishedresearch,mostdoctorsknowlittleornothingaboutmedicalcannabis.


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Thisischanging,inpartbecausethepublicisdemandingit.Peoplewantsafe,naturalandinexpensivetreatmentsthatstimulateourbodies abilitytoselfhealandhelpourpopulationimproveitsqualityoflife.Medicalcannabisisonesuchsolution.Thissummaryisanexcellenttoolforspreadingtheknowledgeandhelpingtoeducatepatientsandhealthcareprovidersonthescientificevidencebehindthemedicaluseofcannabisandcannabinoids.


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WhyIRecommendMedicalCannabis

EstelleTobyGoldstein,MD

NapaCounty,California

December2013

WhywouldahighlycredentialedMDpsychopharmacologist,boardcertifiedpsychiatristandformerFDAclinicaltrialsprimaryinvestigatorbecomeachampionofmedicinalcannabis?

EspeciallyconsideringIhaveneverusedit.

I

ll

tell

you

why.

Forthepasttwoyears,Ihavebeenworkingtobringhonest,scientificandmedicalinformationtothosewhoreallyneedmedicalcannabis.Iblogregularlyathttp://betterbrainsonline.comandhavedonesoforseveralyears.Iconsidermyselfnotonlyaneducator,butawatchdogandpublicguardian,awhistleblowerandanactivistforpublichealthandconsumerprotection.

Somehavequestionedmymotivationforswimmingoutsidethemainstreamofthemedicalestablishment.MymotivesareselfishIwanttobetruetomyself,sleepwellatnight,and

beabletolookatmyselfinthemirroreachmorning.

Ioriginallywantedtobeabrainsurgeonanddidmyinternshipandresidenciesinthatfield,alsopickingupafellowshipinneurology.AfterastintintheUSArmy,Ichangedspecialtiestopsychiatrywithafellowshipinpsychopharmacology.

Immediatelyfollowingmyeducation,IbecameajuniorprofessorattheUniversityofKansasandlatertheUniversityofOklahoma.Inthoseinstitutions,IperformedmanyclinicaltrialsduringthedevelopmentphasesofsuchfamiliardrugsasProzacandZyprexa.

Ipickedupthe RenegadeDoctor sobriquetwhenIbrokewithacademia notonlydisillusionedbythebackstabbingpoliticsofpublishorperish,butalsowiththerestrictionsonresearchimposedbyBigPharma.Ihadalwaysbeenawareofthepervasiveinfluenceofthedrugcompaniesfrommydaysinmedicalschoolandinprivatepractice.Thegovernmentpharmaconnectionshavegraduallybecomepublicknowledge(although


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nottothefullextentpossible,asthepublicwontbelieveitall),butmypersonalbreakwithtraditionalmedicinecameafteracatastrophicillness.

In1999,Ifoundmyselfdyingofacongenitalconditionthattraditionalmedicinemisdiagnosedandmistreated.Ihadtocuremyselftosurvive.Iwroteabookaboutthisstruggle,butforthesakeofbrevity,letsjustsayIhadtobroadenmyhorizonsbeyondthemedicalestablishmentifIwantedtolive.

Ibasicallycuredmyself,intheprocesslosingaround200lbswithoutdrugs,diet,exerciseorsurgery.ThenIlaunchedanalternativemedicinepracticespecializinginnotonlyvitaminsandmineralsupplements,butaminoacidsandotherexotic butentirelynontoxicandtotallysafe treatments.

Butdespitemyownpastexperiencewithnontraditionaltherapies,IwasstillskepticalaboutmedicinalcannabiswhenitbecamelegalinCalifornia.IwaspracticinginSanDiegoatthetime.Mypracticehadtobecashonlyasinsurancewouldonlypayforprescriptiontreatments.Asmypracticedwindledandpeoplebecamemoreandmoredependentupongovernmentpaidprogramsfortheirhealthcare,Istarteddoingsomemoreresearch(inthemostliteralandtechnicalsense).

Iopenedmymindtocannabis.Ireadliteraturefromallovertheworld.Iexaminedresearchprotocolstofindflawsintheirdesigns.Itriedtodeconstructtheresultstoseeiftheywere

warrantedbythedata.Intheend,IwasconvincedthatmarijuanawasavaluableadditiontothePharmacopoeiaofmedicinalproductsandpharmaceuticalsubstances.

In2012,IbecameaCannabisdoctor.MarijuanaisthesafestdrugIhaveeverrecommendedtoapatient.Ipreferittoanyantianxietydrug,moodstabilizer,sleepmedicineorpainremedycurrentlyonthemarketintheUSA.

Myfieldisstillachallenge,duetotherefusalofthefederalgovernmenttorecognizethemedicaluseofcannabis.Butasmorestatesallowmedicaluseandassomemorestatesmakemarijuanalegalforalladultscannabiscanbetakenseriouslyasauseful,safeandsuperiorremedytoahugevarietyofproblemsplaguingmedicalconsumerstoday.

IproudlyholdmyheadhighwhenItellpeople, Iamamedicalmarijuanadoctor.


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AlzheimersDisease

Alzheimer

s

disease

(AD)

is

a

neurological

disorder

of

unknown

origin

that

is

characterized

byaprogressivelossofmemoryandlearnedbehavior.PatientswithAlzheimersarealsolikelytoexperiencedepression,agitationandappetiteloss,amongothersymptoms.Over4.5millionAmericansareestimatedtobeafflictedwiththedisease.NoapprovedtreatmentsormedicationsareavailabletostoptheprogressionofAD,andfewpharmaceuticalshavebeenFDAapprovedtotreatsymptomsofthedisease.

AreviewoftherecentscientificliteratureindicatesthatcannabinoidtherapymayprovidesymptomaticrelieftopatientsafflictedwithADwhilealsomoderatingtheprogressionofthedisease.

WritingintheFebruary2005issueoftheJournalofNeuroscience,investigatorsatMadridsComplutenseUniversityandtheCajalInstituteinSpainreportedthattheintracerebroventricularadministrationofthesyntheticcannabinoidWIN55,2122preventedcognitiveimpairmentanddecreasedneurotoxicityinratsinjectedwithamyloid

betapeptide(aproteinbelievedtoinduceAlzheimers).AdditionalsyntheticcannabinoidswerealsofoundtoreducetheinflammationassociatedwithAlzheimersdiseaseinhuman

braintissueinculture. Ourresultsindicatethat...cannabinoidssucceedinpreventingtheneurodegenerativeprocessoccurringinthedisease, investigatorsconcluded.[1]Followup

studiesbyinvestigatorsdemonstratedthattheadministrationofthenonpsychotropicplantcannabinoidcannabidiol(CBD)alsomitigatedmemorylossinamousemodelofthedisease.[2]

InvestigatorsatTheScrippsResearchInstituteinCaliforniain2006reportedthatTHCinhibitstheenzymeresponsiblefortheaggregationofamyloidplaquetheprimarymarkerforAlzheimersdiseaseinamanner considerablysuperior toapprovedAlzheimersdrugssuchasdonepezilandtacrine. OurresultsprovideamechanismwherebytheTHCmoleculecandirectlyimpactAlzheimersdiseasepathology, researchersconcluded. THCanditsanaloguesmayprovideanimprovedtherapeutic[option]forAlzheimersdisease[by]...simultaneously treatingboththesymptomsandtheprogressionof[the]disease.[3]

Morerecently,investigatorsatOhioStateUniversity,DepartmentofPsychologyandNeuroscience,reportedthatolderratsadministereddailydosesofWIN55,2122fora


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periodofthreeweeksperformedsignificantlybetterthannontreatedcontrolsonawatermazememorytest.WritinginthejournalNeurosciencein2007,researchersreportedthatratstreatedwiththecompoundexperienceda50percentimprovementinmemoryanda40to50percentreductionininflammationcomparedtocontrols.[4]

Previouspreclinicalstudieshavedemonstratedthatcannabinoidscanpreventcelldeathbyantioxidation.[5]Someexpertsbelievethatcannabinoids neuroprotectivepropertiescouldalsoplayaroleinmoderatingAD.[6]WritingintheSeptember2007issueoftheBritishJournalofPharmacology,investigatorsatIrelandsTrinityCollegeInstituteofNeuroscienceconcluded, [C]annabinoidsofferamultifacetedapproachforthetreatmentofAlzheimersdiseasebyprovidingneuroprotectionandreducingneuroinflammation,whilstsimultaneouslysupportingthebrainsintrinsicrepairmechanismsbyaugmenting

neurotrophinexpressionandenhancingneurogenesis....ManipulationofthecannabinoidpathwayoffersapharmacologicalapproachforthetreatmentofADthatmaybeefficaciousthancurrenttreatmentregimens.[7]

InadditiontopotentiallymodifyingtheprogressionofAD,clinicaltrialsalsoindicatethatcannabinoidtherapycanreduceagitationandstimulateweightgaininpatientswiththedisease.Mostrecently,investigatorsatBerlinGermanysChariteUniversitatmedizin,DepartmentofPsychiatryandPsychotherapy,reportedthatthedailyadministrationof2.5mgofsyntheticTHCoveratwoweekperiodreducednocturnalmotoractivityand

agitation

in

AD

patients

in

an

open

label

pilot

study.[8]

Clinicaldatapresentedatthe2003annualmeetingoftheInternationalPsychogeriatricAssociationpreviouslyreportedthattheoraladministrationofupto10mgofsyntheticTHCreducedagitationandstimulatedweightgaininlatestageAlzheimerspatientsinanopenlabelclinicaltrial.[9]ImprovedweightgainandadecreaseinnegativefeelingsamongADpatientsadministeredcannabinoidswerepreviouslyreportedbyinvestigatorsintheInternationalJournalofGeriatricPsychiatryin1997.[10]

AdditionalstudyassessingtheuseofcannabinoidsforAlzheimerswouldappeartobe

warranted.

REFERENCES

[1]Ramirezetal.2005.PreventionofAlzheimersdiseasepathologybycannabinoids.TheJournalofNeuroscience25:19041913.


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[2]IsraelNationalNews.December16,2010. IsraeliresearchshowscannabidiolmayslowAlzheimersdisease.

[3]Eubanksetal.2006.AmolecularlinkbetweentheactivecomponentofmarijuanaandAlzheimersdiseasepathology.MolecularPharmaceutics3:773777.

[4]Marchalantetal.2007.AntiinflammatorypropertyofthecannabinoidagonistWIN552122inarodentmodelofchronicbraininflammation.Neuroscience144:15161522.

[5]Hampsonetal.1998.Cannabidiolanddelta9tetrahydrocannabinolareneuroprotectiveantioxidants.ProceedingsoftheNationalAcademyofSciences95:82688273.

[6]ScienceNews.June11,1998. Marijuanachemicaltappedtofightstrokes.

[7]CampbellandGowran.2007.Alzheimersdisease;takingtheedgeoffwithcannabinoids?BritishJournalofPharmacology152:655662.

[8]Waltheretal.2006.Delta9tetrahydrocannabinolfornighttimeagitationinseveredementia.Physcopharmacology185:524528.

[9]BBCNews.August21,2003. CannabisliftsAlzheimersappetite.

[10]Voliceretal.1997.EffectsofdronabinolonanorexiaanddisturbedbehaviorinpatientswithAlzheimersdisease.InternationalJournalofGeriatricPsychiatry12:913919.


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AmyotrophicLateralSclerosis(ALS)

Amyotrophic

lateral

sclerosis

(ALS),

also

known

as

Lou

Gehrig

s

disease,

is

a

fatal

neurodegenerativedisorderthatischaracterizedbytheselectivelossofmotorneuronsinthespinalcord,brainstem,andmotorcortex.Anestimated30,000AmericansarelivingwithALS,whichoftenarisesspontaneouslyandafflictsotherwisehealthyadults.MorethanhalfofALSpatientsdiewithin2.5yearsfollowingtheonsetofsymptoms.

AreviewofthescientificliteraturerevealsanabsenceofclinicaltrialsinvestigatingtheuseofcannabinoidsforALStreatment.However,recentpreclinicalfindingsindicatethatcannabinoidscandelayALSprogression,lendingsupporttoanecdotalreportsbypatientsthatcannabinoidsmaybeefficaciousinmoderatingthediseasesdevelopmentandin

alleviatingcertainALSrelatedsymptomssuchaspain,appetiteloss,depressionanddrooling.[1]

WritingintheMarch2004issueofthejournalAmyotrophicLateralSclerosis&OtherMotorNeuronDisorders,investigatorsattheCaliforniaPacificMedicalCenterinSanFranciscoreportedthattheadministrationofTHCbothbeforeandaftertheonsetofALSsymptomsstaveddiseaseprogressionandprolongedsurvivalinanimalscomparedtountreatedcontrols.[2]

AdditionaltrialsinanimalmodelsofALShaveshownthattheadministrationofothernaturallyoccurringandsyntheticcannabinoidscanalsomoderateALSprogressionbutnotnecessarilyimpactsurvival.[34]OnerecentstudydemonstratedthatblockingtheCB1cannabinoidreceptordidextendlifespaninanALSmousemodel,suggestingthatcannabinoidsbeneficialeffectsonALSmaybemediatedbynonCB1receptormechanisms.[5]

Asaresult,expertsarecallingforclinicaltrialstoassesscannabinoidsforthetreatmentofALS.WritingintheAmericanJournalofHospice&PalliativeMedicinein2010,ateamofinvestigatorsreported, Basedonthecurrentlyavailablescientificdata,itisreasonabletothinkthatcannabismightsignificantlyslowtheprogressionofALS,potentiallyextendinglifeexpectancyandsubstantiallyreducingtheoverallburdenofthedisease. Theyconcluded, Thereisanoverwhelmingamountofpreclinicalandclinicalevidencetowarrantinitiatingamulticenterrandomized,doubleblind,placebocontrolledtrialofcannabisasadiseasemodifyingcompoundinALS.[6]


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REFERENCES

[1]Amtmannetal.2004.Surveyofcannabisuseinpatientswithamyotrophiclateralsclerosis.TheAmericanJournalofHospiceandPalliativeCare21:95104.

[2]Ramanetal.2004.Amyotrophiclateralsclerosis:delayeddiseaseprogressioninmicebytreatmentwithacannabinoid.AmyotrophicLateralSclerosis&OtherMotorNeuronDisorders5:3339.

[3]Weydtetal.2005.CannabinoldelayssymptomonsetinSOD1transgenicmicewithoutaffectingsurvival.AmyotrophicLateralSclerosis&OtherMotorNeuronDisorders6:182184.

[4]Bilslandetal.2006.IncreasingcannabinoidlevelsbypharmacologicalandgeneticmanipulationdelaydiseaseprogressioninSOD1mice.TheFASEBJournal20:10031005.

[5]Ibid.

[6]Carteretal.2010.Cannabisandamyotrophiclateralsclerosis:hypotheticalandpracticalapplications,andacallforclinicaltrials.AmericanJournalofHospice&PalliativeMedicine27:347356.


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ChronicPain

AsmanyasoneinfiveAmericansliveswithchronicpain.[1]Manyofthesepeoplesufferfromneuropathicpain(nerverelatedpain) aconditionthatisassociatedwithnumerousdiseases,includingdiabetes,cancer,multiplesclerosis,andHIV.Inmostcases,theuseofstandardanalgesicmedicationssuchasopiatesandNSAIDS(nonsteroidalantiinflammatorydrugs)isineffectiveatrelievingneuropathicpain.Further,longtermuseofmostconventionalpainrelievers,includingacetaminophen,opioids,andNSAIDs,isassociatedwithahostofpotentialadversesideeffects,includingstroke,erectiledysfunction,heartattack,hepatoxicity,andaccidentaloverdosedeath.

Surveydataindicatesthattheuseofcannabisiscommoninchronicpainpopulations[2]andseveralrecentFDAdesignedclinicaltrialsindicatethatinhaledmarijuanacansignificantlyalleviateneuropathicpain.Theseincludeapairofrandomized,placebocontrolledclinicaltrialsdemonstratingthatsmokingcannabisreducesneuropathyinpatientswithHIVbymorethan30percentcomparedtoplacebo.[34](AdditionaldetailsonthesestudiesappearintheHIVsectionofthisbook.)Inaddition,a2007UniversityofCaliforniaatSanDiegodoubleblind,placebocontrolledtrialreportedthatinhaledcannabissignificantlyreducedcapsaicininducedpaininhealthyvolunteers.[5]A2008UniversityofCaliforniaatDavisdoubleblind,randomizedclinicaltrialreportedbothhighandlowdosesofinhaledcannabisreducedneuropathicpainofdiversecausesinsubjectsunresponsivetostandardpaintherapies.[6]A2010McGillUniversitystudyreportedthatsmokedcannabissignificantlyimprovedmeasuresofpain,sleepqualityandanxietyinparticipantswithrefractorypainforwhichconventionaltherapieshadfailed.[7]A2013clinicaltrialreportedthatbothinhaledcannabisandoralTHCsignificantlydecreasedpainsensitivityandincreasedpaintoleranceinhealthysubjectsexposedtoexperimentalpainfulstimuli.[8]

Areviewoftheseandothertrialsin2011intheBritishJournalofClinicalPharmacologyconcluded, [I]tisreasonabletoconsidercannabinoidsasatreatmentoptionforthemanagementofchronicneuropathicpainwithevidenceofefficacyinothertypesofchronic

painsuchasfibromyalgiaandrheumatoidarthritisaswell.[9]Aseparatereviewpublishedin2012inTheClinicalJournalofPainfurtherconcluded, Overall,basedontheexistingclinicaltrialsdatabase,cannabinergicpainmedicineshavebeenshowntobemodestlyeffectiveandsafetreatmentsinpatientswithavarietyofchronicpainconditions....Incorporatingcannabinergicmedicinetopicsintopainmedicineeducationseemswarrantedandcontinuingclinicalresearchandempirictreatmenttrialsareappropriate.[10]


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Preclinicaldataindicatesthatcannabinoids,whenadministeredinconcertwithoneanother,aremoreeffectiveatamelioratingneuropathicpainthantheuseofasingleagent.InvestigatorsattheUniversityofMilanreportedin2008thattheadministrationofsinglecannabinoidssuchasTHCorCBDproducelimitedreliefcomparedtotheadministrationofplantextractscontainingmultiplecannabinoids,terpenes(oils),andflavonoids(pigments).

Researchersconcluded: [T]heuseofastandardizedextractofCannabissativa...evokedatotalreliefofthermalhyperalgesia,inanexperimentalmodelofneuropathicpain,...amelioratingtheeffectofsinglecannabinoids, investigatorsconcluded.... Collectively,thesefindingsstronglysupporttheideathatthecombinationofcannabinoidandnoncannabinoidcompounds,aspresentin[plantderived]extracts,providesignificantadvantagesinthereliefofneuropathicpaincomparedwithpurecannabinoidsalone.[11]

In2009,aninternationalteamofinvestigatorsfromtheUnitedKingdom,BelgiumandRomaniaaffirmedthesepreclinicalfindingsinaclinicalstudyofintractablecancerpainpatients.Theyconcluded: [I]nthisstudy,theTHC/CBDextractshowedamorepromisingefficacyprofilethantheTHCextractalone.ThisfindingissupportedbyevidenceofadditionalsynergybetweenTHCandCBD.CBDmayenhancetheanalgesicpotentialofTHCbymeansofpotentinverseagonismatCB2receptors,whichmayproduceantiinflammatoryeffects,alongwithitsabilitytoinhibitimmunecellmigration....Theseresultsareveryencouragingandmeritfurtherstudy.[12]

A2011clinicaltrialassessingtheadministrationofvaporizedplantcannabisinchronicpainpatientsonadailyregimenofmorphineoroxycodonereportedthatinhaled cannabisaugmentstheanalgesiceffectofopioids. Authorsconcluded, Thecombination(ofopioidsandcannabinoids)mayallowforopioidtreatmentatlowerdoseswithfewersideeffects.[13]Aseparate2013FDAapprovedtrialassessingtheimpactofvaporizedcannabisonneuropathicpainreportedthatevenlowdosesofTHC(1.29percent) providedstatisticallysignificant30%reductionsinpainintensitywhencomparedtoplacebo.[14]

Basedonthesefindings,somepainexpertsarenowadvisingthatphysiciansrecommend

cannabis

therapy

in

addition

to

or

in

lieu

of

opiate

medications

to

reduce

the

morbidity

andmortalityratesassociatedwithprescriptionpainmedications. [15]

REFERENCES

[1]NewYorkTimes.October21,1994. Studysays1in5Americanssuffersfromchronicpain.


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[2]Coneetal.2008.Urinedrugtestingofchronicpainpatients:licitandillicitdrugpatterns.JournalofAnalyticalToxicology32:532543.

[3]Abramsetal.2007.CannabisinpainfulHIVassociatedsensoryneuropathy:arandomizedplacebocontrolledtrial.Neurology68:515521.

[4]Ellisetal.2008.SmokedmedicinalcannabisforneuropathicpaininHIV:arandomized,crossoverclinicaltrial.Neuropsychopharmacology34:67280.

[5]Wallaceetal.2007.DosedependenteffectsofsmokedcannabisonCapsaicininducedpainandhyperalgesiainhealthyvolunteersAnesthesiology107:785796.

[6]Wilseyetal.2008.Arandomized,placebocontrolled,crossovertrialofcannabiscigarettesinneuropathicpain.JournalofPain9:506521.

[7]Wareetal.2010.Smokedcannabisforchronicneuropathicpain:arandomizedcontrolledtrial.CMAJ182:694701.

[8]Cooperetal.2013.Comparisonoftheanalgesiceffectsofdronabinolandsmokedmarijuanaindailymarijuanasmokers.Neuropsychopharmacology38:19841992.

[9]LynchandCampbell.2011.Cannabinoidsfortreatmentofchronicnoncancerpain;asystematicreviewofrandomizedtrials.BritishJournalofClinicalPharmacology72:735744.

[10]SunilAggerwal.2012.Cannabinergicpainmedicine:aconciseclinicalprimerandsurveyofrandomizedcontrolledtrialresults.TheClinicalJournalofPain[Epubaheadofprint].

[11]Comellietal.2008.AntihyperalgesiceffectofaCannabissativaextractinaratmodelofneuropathicpain.PhytotherapyResearch22:10171024.

[12]Johnsonetal.2009.Multicenter,doubleblind,randomized,placebocontrolled,parallelgroupstudyoftheefficacy,safetyandtolerabilityofTHC:CBDextractinpatientswithintractablecancerrelatedpain.JournalofSymptomManagement39:167179.

[13]Abramsetal.2011.Cannabiniodopioidinteractioninchronicpain.ClinicalPharmacology&Therapeutics90:844851.

[14]Wilseyetal.2013.Lowdosevaporizedcannabissignificantlyimprovesneuropathicpain.TheJournalofPain14:136148.

[15]MarkCollen.2012.Prescribingcannabisforharmreduction.HarmReductionJournal9:1.


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DiabetesMellitus

Diabetesmellitusisagroupofautoimmunediseasescharacterizedbydefectsininsulinsecretionresultinginhyperglycemia(anabnormallyhighconcentrationofglucoseinthe

blood).Therearetwoprimarytypesofdiabetes.Individualsdiagnosedwithtype1diabetes(alsoknownasjuvenilediabetes)areincapableofproducingpancreaticinsulinandmustrelyoninsulinmedicationforsurvival.Individualsdiagnosedwithtype2diabetes(alsoknownasadultonsetdiabetes)produceinadequateamountsofinsulin.Type2diabetesisalessseriousconditionthattypicallyiscontrolledbydiet.Overtime,diabetescanleadto

blindness,kidneyfailure,nervedamage,hardeningofthearteriesanddeath.ThediseaseisthethirdleadingcauseofdeathintheUnitedStatesafterheartdiseaseandcancer.

Preclinicalstudiesindicatethatcannabinoidsmaymodifydiabetesprogressionandthattheyalsomayprovidesymptomaticrelieftothosesufferingfromit.[12]A2006studypublishedinthejournalAutoimmunityreportedthatinjectionsof5mgperdayofthenonpsychoactivecannabinoidCBDsignificantlyreducedtheincidenceofdiabetesinmice.Investigatorsreportedthat86%ofuntreatedcontrolmiceinthestudydevelopeddiabetes.Bycontrast,only30%ofCBDtreatedmicedevelopedthedisease.[3]Inaseparateexperiment,investigatorsreportedthatcontrolmicealldevelopeddiabetesatamedianof17weeks(range1520weeks),whileamajority(60percent)ofCBDtreatedmiceremaineddiabetesfreeat26weeks.[4]A2013studyassessingtheeffectofTHCV(tetrahydrocannabivarin)ingeneticallymodifiedobesemicereportedthatthecannabinoidsadministrationproducedseveralmetabolicallybeneficialeffectsrelativetodiabetes,includingreducedglucoseintolerance,improvedglucosetolerance,improvedlivertriglyceridelevels,andincreasedinsulinsensitivity.Authorsconcluded, Basedonthesedata,itcanbesuggestedthatTHCVmaybeusefulforthetreatmentofthemetabolicsyndromeand/ortype2diabetes(adultonsetdiabetes),eitheraloneorincombinationwithexistingtreatments.[5]

Otherpreclinicaltrialsreportthatcannabinoidsmaymitigatevarioussymptomsofthe

disease.WritingintheMarch2006issueoftheAmericanJournalofPathology,researchersattheMedicalCollegeofVirginiareportedthatratstreatedwithCBDforperiodsofonetofourweeksexperiencedsignificantprotectionfromdiabeticretinopathy[6] onetheleadingcauseofblindnessinworkingageadults.


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Cannabinoidshavealsobeenshowntoalleviateneuropathicpainassociatedwiththediseaseinanimalmodels.ApairofstudiespublishedinthejournalNeuroscienceLettersin2004reportedthatmiceadministeredacannabisreceptoragonistexperiencedareductionindiabeticrelatedtactileallodynia(painresultingfromnoninjuriousstimulustotheskin)comparedtonontreatedcontrols.[78]Thefindingssuggestthat cannabinoidshaveapotentialbeneficialeffectonexperimentaldiabeticneuropathicpain. Morerecently,researchersfromtheUnitedStates,SwitzerlandandIsraelreportedintheJournaloftheAmericanCollegeofCardiologythattheadministrationofCBDreducesvarioussymptomsofdiabeticcardiomyopathy(weakeningoftheheartmuscle)inamousemodeloftype1diabetes.Authorsconcluded, [T]heseresultscoupledwiththeexcellentsafetyandtolerabilityprofileofCBDinhumans,stronglysuggestthatitmayhavegreattherapeuticpotentialinthetreatmentofdiabeticcomplications. [9]

Inrecentyears,observationaltrialshavereportedthatthosewhoconsumecannabispossessalowerriskofcontractingtype2diabetesthandononusers.ResearchersattheUniversityofCalifornia,LosAngelesassessedtheassociationbetweendiabetesmellitusandmarijuanauseamongadultsaged20to59inanationallyrepresentativesampleoftheUSpopulationof10,896adults.Theyreportedthatpastandpresentcannabisconsumerspossessedalowerprevalenceofadultonsetdiabetes,evenafterauthorsadjustedforsocialvariables(ethnicity,levelofphysicalactivity,etc.),despiteallgroupspossessingasimilarfamilyhistoryofdiabetes.Researchersdidnotfindanassociationbetweencannabisuseandotherchronicdiseases,includinghypertension,stroke,myocradialinfarction,orheartfailurecomparedtononusers.Authorsconcluded, Ouranalysis...showedthatparticipantswhousedmarijuanahadalowerprevalenceofDMandloweroddsofDMrelativetononmarijuanausers.[10]

AseparateobservationaltrialpublishedintheAmericanJournalofMedicinein2013reportedthatcannabisconsumingsubjectspossessfavorableindicesrelatedtodiabeticcontrolcomparedtothosewithoutahistoryofmarijuanause.ResearchersatHarvardMedicalSchoolandtheBethIsraelDeaconessMedicalCenterinBostonassessedtherelationship

betweenmarijuanauseandfastinginsulin,glucose,andinsulinresistanceinasampleof

4,657malesubjects.Theyconcluded, [S]ubjectswhoreportedusingmarijuanainthepastmonthhadlowerlevelsoffastinginsulinandHOMAIR[insulinresistance],aswellassmallerwaistcircumferenceandhigherlevelsofHDLC[highdensitylipoproteinor goodcholesterol].Theseassociationswereattenuatedamongthosewhoreportedusingmarijuanaatleastonce,butnotinthepast30days,suggestingthattheimpactofmarijuanauseoninsulinandinsulinresistanceexistsduringperiodsofrecentuse.[1112]


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Commentingonthe2013AmericanJournalofMedicinestudy,thejournalsEditorinChiefwroteinanaccompanyingcommentary: Theseareindeedremarkableobservationsthataresupported,astheauthorsnote,bybasicscienceexperimentsthatcametosimilarconclusions....Wedesperatelyneedagreatdealmorebasicandclinicalresearchintotheshort andlongtermeffectsofmarijuanainavarietyofclinicalsettingssuchascancer,diabetes,andfrailtyoftheelderly.IwouldliketocallontheNIHandtheDEAtocollaborateindevelopingpoliciestoimplementsolidscientificinvestigationsthatwouldleadtoinformationassistingphysiciansintheproperuseandprescriptionofTHCinitssyntheticorherbalform.[13]

REFERENCES

[1]CroxfordandYamamura.2005.Cannabinoidsandtheimmunesystem:Potentialforthetreatmentofinflammatorydiseases.JournalofNeuroimmunology166:318.

[2]Luetal.2006.Thecannabinergicsystemasatargetforantiinflammatorytherapies.CurrentTopicsinMedicinalChemistry13:14011426.

[3]Weissetal.2006.Cannabidiollowersincidenceofdiabetesinnonobesediabeticmice.Autoimmunity39:143151.

[4]Ibid

[5]Wargentetal.2013.Thecannabinoid9tetrahydrocannabivarin(THCV)amelioratesinsulinsensitivityin

twomousemodelsofobesity.Nutrition&Diabetes3[onlineaheadofprint]

[6]ElRemessyetal.2006.Neuroprotectiveandbloodretinalbarrierpreservingeffectsofcannabidiolinexperimentaldiabetes.AmericanJournalofPathology168:235244.

[7]Dogruletal.2004.Cannabinoidsblocktactileallodyniaindiabeticmicewithoutattenuationofitsantinociceptiveeffect.NeuroscienceLetters368:8286.

[8]Ulugoletal.2004.TheeffectofWIN55,2122,acannabinoidagonist,ontactileallodyniaindiabeticrats.NeuroscienceLetters71:167170.

[9]Rajeshetal.2010.Cannabidiolattenuatescardiacdysfunction,oxidativestress,fibrosis,andinflammatoryandcelldeathsignalingpathwaysindiabeticcardiomyopathy.JournaloftheAmericanCollegeofCardiology56:21152125.

[10]Rajavashisthetal.2012.Decreasedprevalenceofdiabetesinmarijuanausers.BMJOpen2


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[11]Penneretal.2013.Marijuanauseonglucose,insulin,andinsulinresistanceamongUSadults.AmericanJournalofMedicine126:583589.Previousobservationaldatahassimilarlyreportedthattheprevalenceofobesityinthegeneralpopulationissharplyloweramongmarijuanaconsumersthanitisamongnonusers.

[12]StratandFoll.2011.AmericanJournalofEpidemiology174:929933.

[13]ScienceDaily.May15,2013 Marijuanausershavebetterbloodsugarcontrol.


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Dystonia

Dystonia

is

a

neurological

movement

disorder

characterized

by

abnormal

muscle

tension

andinvoluntary,painfulmusclecontractions.ItisthethirdmostcommonmovementdisorderafterParkinsonsdiseaseandtremor,affectingmorethan300,000peopleinNorthAmerica.

Asmallnumberofcasereportsandpreclinicalstudiesinvestigatingtheuseofcannabisandcannabinoidsforsymptomsofdystoniaarereferencedintherecentscientificliterature.A2002casestudypublishedintheJulyissueofTheJournalofPainandSymptomManagementreportedimprovedsymptomsofdystoniaaftersmokingcannabisina42yearoldchronicpainpatient.Investigatorsreportedthatsubjectssubjectivepainscorefellfrom9tozero

(onazeroto10visualanalogscale)followingcannabisinhalation,andthatthesubjectdidnotrequireanyadditionalanalgesicmedicationforthefollowing48hours. Noothertreatmentinterventiontodatehadresultedinsuchdramaticoverallimprovementin[thepatients]condition, investigatorsconcluded.[1]

Asecondcasestudyreportingsignificantclinicalimprovementfollowingcannabisinhalationinasingle25yearoldpatientwithgeneralizeddystoniaduetoWilsonsdiseasewasdocumentedbyanArgentinianresearchteamintheAugust2004issueofthejournalMovementDisorders.[2]

Alsoin2004,aGermanresearchteamattheHannoverMedicalSchoolreportedsuccessfultreatmentofmusiciansdystoniaina38yearoldprofessionalpianistfollowingadministrationof5mgofTHCinaplacebocontrolledsingledosetrial.[3]Investigatorsreportedclearimprovementofmotorcontrolinthesubjectsaffectedhand,andnoted,[Two]hoursafterTHCintake,thepatientwasabletoplaytechnicallydemandingliterature,whichhadnotbeenpossiblebeforetreatment.Priortocannabinoidtreatment,thesubjecthadbeenunresponsivetostandardmedicationsandwasnolongerperformingpublicly.TheresultsprovideevidencethatTHCintakesignificantlyimproves[symptomsof]focaldystonia,investigatorsconcluded.

Bycontrast,a2002randomized,placebocontrolledstudyinvestigatingtheuseofthesyntheticoralcannabinoidnaboline(Cesamet)in15patientsafflictedwithgeneralizedandsegmentalprimarydystoniadidnotshowasignificantreductionindystonicsymptoms.[4]


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Investigatorsspeculatedthatthisresultmayhavebeendoserelated,andthatadministrationofahigherdosagemayhaveyieldedadifferentoutcome.

Atleastonerecentpreclinicaltrialindicatesthatbothsyntheticcannabinoidsaswellashighdosesofthenaturalnonpsychoactivecannabinoidcannabidiol(CBD)couldmoderatethediseaseprogressionofdystoniainanimals.[5]Limitedreferencesregardingtheuseofcannabinoidsfordystoniainhumans[6]andanimals[7]inthe1980sandthe1990salsoappearinthescientificliterature.Itwouldappearthatadditional,largerclinicaltrialsarewarrantedtoinvestigatetheuseofcannabisandcannabinoidsforthisindication.

REFERENCES

[1]Chatterjeeetal.2002.Adramaticresponsetoinhaledcannabisinawomanwithcentralthalamicpainanddystonia.TheJournalofPainandSymptomManagement24:46.

[2]Rocaetal.2004.CannabissativaanddystoniasecondarytoWilsonsdisease.MovementDisorders20:113115.

[3]Jabuschetal.2004.Delta9tetrahydrocannabinolimprovesmotorcontrolinapatientwithmusiciansdystonia(PDF).MovementDisorders19:990991.

[4]Foxetal.2002.Randomised,doubleblind,placebocontrolledtrialtoassessthepotentialofcannabinoidreceptorstimulationinthetreatmentofdystonia.MovementDisorders17:145149.

[5]Richteretal.2002.Effectsofpharmacologicalmanipulationsofcannabinoidreceptorsonseveredystoniainageneticmodelofparoxysmaldyskinesia.EuropeanJournalofPharmacology454:145151.

[6]Consroeetal.1986.Openlabelevaluationofcannabidiolindystonicmovementdisorders.InternationalJournalofNeuroscience30:277282.

[7]Richteretal.1994.(+)WIN552122,anovelcannabinoidagonist,exertsantidystoniceffectsinmutantdystonichamsters.EuropeanJournalofPharmacology264:371377.


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Epilepsy

Epilepsyisacentralnervoussystemdisordercharacterizedbyuncontrollabletwitchingofthearmsorlegsand/orseizures.Onein26Americanswilldevelopepilepsyduringtheirlifetime,accordingtostatisticspublishedbyTheEpilepsyFoundation.Conventionaltreatmenttomitigatesymptomsofthisdisorderincludesmedicationsorsometimessurgery.

Despiteanecdotalreportsofcannabisalleviatingepilepticsymptoms,clinicaldataestablishingcannabinoidsefficacyforthisconditioninadultsisnotatthistimewelldocumented.[1]However,inrecentyears,clinicianshavebegantofocusspecificallyontheabilityofcannabidioltopotentiallymitigatesymptomsassociatedwithintractablepediatric

epilepsyafterseveralcasereportsattractedprominentmainstreammediaattention.[2]Parentsofchildrenwithsevereepilepsyalsoreportinonlinesurveyssuccessfulexperienceswithcannabidiolenrichedcannabis.[3]

Inthefallof2013,theUnitedStatesFoodandDrugAdministrationgrantedorphandrugstatustoimported,pharmaceuticallystandardizedCBDextractsforuseinexperimentalpediatrictreatment.Clinicaltrialsassessingthesafetyandefficacyofthetreatmentinchildrenwithsevereformsofthedisease,suchasDravetsyndrome,areslatedtobeginin2014.[4]

REFERENCES

[1]Editorial.2012.Marijuanaforepilepsy:windsofchange.Epilepsy&Behavior29:435436

[2]SaundraYoung,CNN.com.August7,2013. Marijuanastopschildssevereseizures.

[3]PorterandJacobson.2013.Reportofaparnetsurveyofcannabidiolenrichedcannabisuseinpediatrictreatmentresistantepilepsy.Epilepsy&Behavior29:574577.

[4]SusanLivio,NewJerseyStarLedger.December6,2013.FDAapprovedmedicalmarijuanaclinicaltrialgetsunderwaynextmonthforkidswithepilepsy.


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Fibromyalgia

Fibromyalgia

(FM)

is

a

chronic

pain

syndrome

of

unknown

etiology.

The

disease

is

characterizedbywidespreadmusculoskeletalpain,fatigueandmultipletenderpointsintheneck,spine,shouldersandhips.Anestimated3to6millionAmericansareafflictedbyfibromyalgia,whichisoftenpoorlycontrolledbystandardpainmedications.

Fibromyalgiapatientsfrequentlyselfreportusingcannabistherapeuticallytotreatsymptomsofthedisease,[12]andphysiciansininstanceswhereitislegalforthemdosooftenrecommendtheuseofcannabistotreatmusculoskeletaldisorders.[34]Todatehowever,therearefewclinicaltrialsassessingtheuseofcannabinoidstotreatthedisease.

WritingintheJuly2006issueofthejournalCurrentMedicalResearchandOpinion,investigatorsatGermanysUniversityofHeidelbergevaluatedtheanalgesiceffectsoforalTHCinninepatientswithfibromyalgiaovera3monthperiod.Subjectsinthetrialwereadministereddailydosesof2.5to15mgofTHCandreceivednootherpainmedicationduringthetrial.Amongthoseparticipantswhocompletedthetrial,allreportedasignificantreductionindailyrecordedpainandelectronicallyinducedpain.[5]

A2008studypublishedinTheJournalofPainreportedthattheadministrationofthesyntheticcannabinoidnabilonesignificantlydecreasedpainin40subjectswithfibromylagia

inarandomized,doubleblind,placebocontrolledtrial. Asnabiloneimprovedsymptomsandwaswelltolerated,itmaybeausefuladjunctforpainmanagementinfibromyalgia,investigatorsconcluded.[6]Aseparate2010trialperformedatMcGillUniversityinMontrealreportedthatlowdosesofnabilonesignificantlyimprovedsleepqualityinpatientsdiagnosedwiththedisease.[7]

Mostrecently,a2011observational,casecontroltrialreportedthattheuseofcannabisisassociatedwithbeneficialeffectsonvarioussymptomsoffibromyalgia,includingthereliefofpainandmusclestiffness.InvestigatorsattheInstitutdeRecercaHospitaldelMarinBarcelona,Spain,assessedtheassociatedbenefitsofcannabisinpatientswithfibromyalgiacomparedwithFMpatientswhodidnotusethesubstance.Twentyeightusersandnonusersparticipatedinthestudy.

Authorsreported: PatientsusedcannabisnotonlytoalleviatepainbutforalmostallsymptomsassociatedtoFM,andnoonereportedworseningofsymptomsfollowing


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cannabisuse....Significantreliefofpain,stiffness,relaxation,somnolence,andperceptionofwellbeing,evaluatedbyVAS(visualanaloguescales)beforeandtwohoursaftercannabisselfadministrationwasobserved. Cannabisusersinthestudyalsoreportedhigheroverallmentalhealthsummaryscoresthandidnonusers.Investigatorsconcluded:ThepresentresultstogetherwithpreviousevidenceseemtoconfirmthebeneficialeffectsofcannabinoidsonFMsymptoms.[8]

Previousclinicalandpreclinicaltrialshaveshownthatbothnaturallyoccurringandendogenouscannabinoidsholdanalgesicqualities,[912]particularlyinthetreatmentofpainresistanttoconventionalpaintherapies.(Pleaseseethe ChronicPain sectionofthisbookforfurtherdetails.)Asaresult,someexpertshavesuggestedthatcannabinoidsarepotentiallyapplicableforthetreatmentofchronicpainconditionssuchasfibromyalgia,[13]

andhavetheorizedthatthediseasemaybeassociatedwithanunderlyingclinicaldeficiencyoftheendocannabinoidsystem.[14]

REFERENCES

[1]Swiftetal.2005.SurveyofAustraliansusingcannabisformedicalpurposes.HarmReductionJournal4:218.

[2]Wareetal.2005.ThemedicinaluseofcannabisintheUK:resultsofanationwidesurvey.InternationalJournalofClinicalPractice59:291295.

[3]DaleGieringer.2001.Medicaluseofcannabis:experienceinCalifornia.In:GrotenhermenandRusso(Eds).CannabisandCannabinoids:Pharmacology,Toxicology,andTherapeuticPotential.NewYork:HaworthPress:153170.

[4]Gorteretal.2005.MedicaluseofcannabisintheNetherlands.Neurology64:917919.

[5]Schleyetal.2006.Delta9THCbasedmonotherapyinfibromyalgiapatientsonexperimentallyinducedpain,axonreflexflare,andpainrelief.CurrentMedicalResearchandOpinion22:12691276.

[6]Skrabeketal.2008.Nabiloneforthetreatmentofpaininfibromyalgia.TheJournalofPain9:164173.

[7]Wareetal.2010.Theeffectsofnabiloneonsleepinfibromyalgia:resultsofarandomizedcontrolledtrial.

Anesthesiaand

Analgesia110:604610.

[8]Fizetal.2011.Cannabisuseinpatientswithfibromyalgia:Effectonsymptomsreliefandhealthrelatedqualityoflife.PLoSOne6.

[9]BurnsandIneck.2006.Cannabinoidanalgesiaasapotentialnewtherapeuticoptioninthetreatmentofchronicpain.TheAnnalsofPharmacotherapy40:251260.


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[10]DavidSecko.2005.Analgesiathroughendogenouscannabinoids.CMAJ173.

[11]Wallaceetal.2007.Dosedependenteffectsofsmokedcannabisoncapsaicininducedpainandhyperalgesiainhealthyvolunteers.Anesthesiology107:78596.

[12]Coxetal.2007.Synergybetweendelta9tetrahydrocannabinolandmorphineinthearthriticrat.EuropeanJournalofPharmacology567:125130.

[13]LynchandCampbell.2011.op.cit.

[14]EthanRusso.2004.Clinicalendocannabinoiddeficiency(CECD):Canthisconceptexplaintherapeuticbenefitsofcannabisinmigraine,fibromyalgia,irritablebowelsyndromeandothertreatmentresistantconditions?NeuroendocrinologyLetters25:3139.


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GastrointestinalDisorders

Gastrointestinal(GI)disorders,includingfunctionalboweldiseasessuchasirritablebowelsyndrome(IBS)andinflammatoryboweldiseasessuchasCrohnsdisease(CD)andcolitis,afflictmorethanoneinfiveAmericans,particularlywomen.WhilesomeGIdisordersmay

becontrolledbydietandpharmaceuticalmedications,othersarepoorlymoderatedbyconventionaltreatments.SymptomsofGIdisordersoftenincludecramping,abdominalpain,inflammationoftheliningofthelargeand/orsmallintestine,chronicdiarrhea,rectal

bleedingandweightloss.

Patientswiththesedisordersfrequentlyreportusingcannabistherapeutically.Accordingto

surveydatapublishedin2011intheEuropeanJournalofGastroenterology&Hepatology,CannabisuseiscommonamongstpatientswithIBDforsymptomrelief,particularlyamongstthosewithahistoryofabdominalsurgery,chronicabdominalpainand/oralowqualityoflifeindex.[1]Severalanecdotalreports[23]andahandfulofcasereports[45]alsoexistinthescientificliterature.

PreclinicalstudiesdemonstratethatactivationoftheCB1andCB2cannabinoidreceptorsexertbiologicalfunctionsonthegastrointestinaltract.[6]Effectsoftheiractivationinanimalsincludesuppressionofgastrointestinalmotility,[7]inhibitionofintestinalsecretion,[8]reducedacidreflux,[9]andprotectionfrominflammation,[10]aswellasthepromotionofepithelialwoundhealinginhumantissue.[11]

ObservationaltrialdatareportsthatcannabistherapyuseisassociatedwithareductioninCrohnsdiseaseactivityanddiseaserelatedhospitalizations.InvestigatorsattheMeirMedicalCenter,InstituteofGastroenterologyandHepatologyassessed diseaseactivity,useofmedication,needforsurgery,andhospitalizationbeforeandaftercannabisusein30patientswithCD.Authorsreported, Allpatientsstatedthatconsumingcannabishadapositiveeffectontheirdiseaseactivity anddocumented significantimprovement in21subjects.

Specifically,researchersfoundthatsubjectswhoconsumedcannabis significantlyreducedtheirneedforothermedications.Participantsinthetrialalsoreportedrequiringfewersurgeriesfollowingtheiruseofcannabis. Fifteenofthepatientshad19surgeriesduringanaverageperiodofnineyearsbeforecannabisuse,butonlytworequiredsurgeryduringanaverageperiodofthreeyearsofcannabisuse, authorsreported.Theyconcluded: The


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resultsindicatethatcannabismayhavea positiveeffectondiseaseactivity,asreflectedbyareductionindisease activityindexandintheneedforotherdrugsandsurgery.[12]

Inafollowup,placebocontrolledtrial,inhaledcannabiswasreportedtodecreaseCrohnsdiseasesymptomsinsubjectswithatreatmentresistantformofthedisease.Nearlyhalfofthepatientsinthetrialachieveddiseaseremission.[13]

Today,manyexpertsbelievethatcannabinoidsand/ormodulationoftheendogenouscannabinoidsystemrepresentsanoveltherapeuticapproachforthetreatmentofnumerousGIdisordersincludinginflammatoryboweldiseases,functionalboweldiseases,gastrooesophagaelrefluxconditions,secretorydiarrhea,gastriculcersandcoloncancer.[1416]

REFERENCES

[1]Laletal.2011.Cannabisuseamongpatientswithinflammatoryboweldisease.EuropeanJournalofGastroenterology&Hepatology23:891896.

[2]Gahlinger,PaulM.1984.GastrointestinalillnessandcannabisuseinaruralCanadiancommunity.JournalofPsychoactiveDrugs16:263265.

[3]Swiftetal.2005.SurveyofAustraliansusingcannabisformedicalpurposes.HarmReductionJournal4:218.

[4]Baronetal.1990.Ulcerativecolitisandmarijuana.AnnalsofInternalMedicine112:471.

[5]JeffHergenrather.2005.CannabisalleviatessymptomsofCrohnsDisease.OShaughnessys2:3.

[6]MassaandMonory.2006.Endocannabinoidsandthegastrointestinaltract.JournalofEndocrinologicalInvestigation29(Suppl):4757.

[7]RogerPertwee.2001.Cannabinoidsandthegastrointestinaltract.Gut48:859867.

[8]DiCarloandIzzo.2003.Cannabinoidsforgastrointestinaldiseases:potentialtherapeuticapplications.ExpertOpiniononInvestigationalDrugs12:3949.

[9]Lehmannetal.2002.Cannabinoidreceptoragonisminhibitstransientloweresophagealsphincter

relaxationsandrefluxindogs.Gastroenterology123:11291134.

[10]Massaetal.2005.Theendocannabinoidsysteminthephysiologyandpathophysiologyofthegastrointestinaltract.JournalofMolecularMedicine12:944954.

[11]Wrightetal.2005.Differentialexpressionofcannabinoidreceptorsinthehumancolon:cannabinoidspromoteepithelialwoundhealing.Gastroenterology129:437453.


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[12]Naftalietal.2011.TreatmentofCrohnsdiseasewithcannabis:anobservationalstudy.JournaloftheIsraeliMedicalAssociation13:455458.

[13]Naftalietal.2013.CannabisinducesaclinicalresponseinpatientswithCrohnsdisease:aprospectiveplacebocontrolledstudy.ClinicalGastroenterologyandHepatology11:12761280.

[14]MassaandMonory.2006.op.cit.

[15]IzzoandCoutts.2005.Cannabinoidsandthedigestivetract.HandbookofExperimentalPharmacology168:573598.

[16]Izzoetal.2009.Nonpsychotropicplantcannabinoids:newtherapeuticopportunitiesfromanancientherb.TrendsinPharmacologicalSciences30:515527.


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Gliomas/Cancer

Gliomas(tumorsinthebrain)areespeciallyaggressivemalignantformsofcancer,oftenresultinginthedeathofaffectedpatientswithinonetotwoyearsfollowingdiagnosis.Thereisnocureforgliomasandmostavailabletreatmentsprovideonlyminorsymptomaticrelief.

Areviewofthemodernscientificliteraturerevealsnumerouspreclinicalstudiesandonepilotclinicalstudydemonstratingcannabinoids abilitytoactasantineoplasticagents,particularlyongliomacelllines.

WritingintheSeptember1998issueofthejournalFEBSLetters,investigatorsatMadridsComplutenseUniversity,SchoolofBiology,firstreportedthatdelta9THCinduced

apoptosis(programmedcelldeath)ingliomacellsinculture.[1]Investigatorsfolloweduptheirinitialfindingsin2000,reportingthattheadministrationofbothTHCandthesyntheticcannabinoidagonistWIN55,2122 inducedaconsiderableregressionofmalignantgliomas inanimals.[2]Researchersagainconfirmedcannabinoids abilitytoinhibittumorgrowthinanimalsin2003.[3]

Thatsameyear,ItalianinvestigatorsattheUniversityofMilan,DepartmentofPharmacology,ChemotherapyandToxicology,reportedthatthenonpsychoactive

cannabinoid,cannabidiol(CBD),inhibitedthegrowthofvarioushumangliomacelllinesinvivoandinvitroinadosedependentmanner.WritingintheNovember2003issueoftheJournalofPharmacologyandExperimentalTherapeuticsFastForward,researchersconcluded,NonpsychoactiveCBD...produce[s]asignificantantitumoractivitybothinvitroandinvivo,thussuggestingapossibleapplicationofCBDasanantineoplasticagent.[4]

In2004,Guzmanandcolleaguesreportedthatcannabinoidsinhibitedgliomatumorgrowthinanimalsandinhumanglioblastomamultiforme(GBM)tumorsamplesbyalteringbloodvesselmorphology(e.g.,VEGFpathways).WritingintheAugust2004issueofCancer

Research,

investigators

concluded,

The

present

laboratory

and

clinical

findings

provide

a

novelpharmacologicaltargetforcannabinoidbasedtherapies.[5]

InvestigatorsattheCaliforniaPacificMedicalCenterResearchInstitutereportedthattheadministrationofTHConhumanglioblastomamultiformecelllinesdecreasedtheproliferationofmalignantcellsandinducedcelldeathmorerapidlythandidthe


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administrationofWIN55,2122.ResearchersalsonotedthatTHCselectivelytargetedmalignantcellswhileignoringhealthyonesinamoreprofoundmannerthanthesyntheticalternative.[6]AseparatepreclinicaltrialreportedthatthecombinedadministrationofTHCandthepharmaceuticalagenttemozolomide(TMZ) enhancedautophagy (programmedcelldeath)inbraintumorsresistanttoconventionalanticancertreatments.[7]

GuzmanandcolleagueshavealsoreportedthatTHCadministrationdecreasesrecurrentglioblastomamultiformetumorgrowthinpatientsdiagnosedwithrecurrentGBM.InthefirsteverpilotclinicaltrialassessingtheuseofcannabinoidsandGBM,investigatorsfoundthattheintratumoraladministrationofTHCwasassociatedwithreducedtumorcellproliferationintwoofninesubjects. ThefairsafetyprofileofTHC,togetherwithitspossibleantiproliferativeactionontumorcellsreportedhereandinotherstudies,mayset

thebasisforfuturetrialsaimedatevaluatingthepotentialantitumoralactivityofcannabinoids, investigatorsconcluded.[8]Severaladditionalinvestigatorshavealsorecentlycalledforfurtherexplorationofcannabisbasedtherapiesforthetreatmentofglioma.[911]Aseparatecasereport,publishedin2011inthejournaloftheInternationalSocietyforPediatricNeurosurgery,alsodocumentsthespontaneousregressionofresidual

braintumorsintwochildrencoincidingwiththesubjectsuseofcannabis.[12]

Inadditiontocannabinoids abilitytomoderategliomacells,separatestudiesdemonstratethatcannabinoidsandendocannabinoidscanalsoinhibittheproliferationofothervariouscancercelllines,includingbreastcarcinoma,[1317]prostatecarcinoma,[1822]colorectalcarcinoma,[2324]gastricadenocarcinoma,[25]skincarcinoma,[26]leukemiacells,[2730]neuroblastoma,[3132]lungcarcinoma,[3334]uteruscarcinoma,[35]thyroidepithelioma,[36]pancreaticadenocarcinoma,[3738]cervicalcarcinoma,[39]oralcancer,[40]biliarytractcancer(cholangiocarcinoma)[41]andlymphoma.[4243]

Consequently,someexpertsnowbelievethatcannabinoids mayrepresentanewclassofanticancerdrugsthatretardcancergrowth,inhibitangiogenesisandthemetastaticspreadingofcancercells.[4445]... [T]hesecompoundsareinexpensivetoproduceandmakingbetteruseoftheiruniquepropertiescouldresultinmuchmorecosteffectiveanti

cancerdrugsinfuture.[46]Israelicliniciansarepresentlyrecommendingthatcannabinoidtreatment beofferedto...patientsintheearlierstagesofcancer.[47]

REFERENCES

[1]Guzmanetal.1998.Delta9tetrahydrocannabinolinducesapoptosisinC6gliomacells.FEBSLetters436:610.


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[2]Guzmanet

Documents

Clinical Applications for Cannabis and Cannabinoids