clinical applications for cannabis and cannabinoids
TRANSCRIPT
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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