ÿWPC‰ ßhÅ ›sÏñÁ} 6²&r¨ÚHÁ)õ\2##‚É$;k ¡¹–üC•_µéG©Çq¨,†$Y‘—8¨¹Nå½ÒV«5˜·xZÙQ3¾[X ž`¶Ö$R_KéŠ ­ ,¢)°’Âp™Ks¯„Feô ÏXꩦ<[sÓð*'NŠ‚¬«Þ‘©C©$r‡ôUbvòˆ”ç·Ê!g8ßâX¹Dº1ßKa»%Ê?µÊ³èž' ö’‹ˆq'4Çu"à g™øÝœH¨óþÖupåèB$ÞM­CIü>‚¬N,(«á:äÞr®ÿïZ=6Îò?–gœX6<.›mIUhê°¦‰pe˜üÉ‹d ÛX°YwPL~³àœ§‘t_8 3ˆÃìažŒ—¼ésSn«¾ºÀ€cD'z4Öô™,:ÔFsvE—Qýï¡ø""‡XÊA˜‚ëÎoöÝl·\Îù‹­÷£)eÂQ&‰L M·vŠù¤À·Â1ÏÓòJž*8NËžôˆtõ¼Ÿ–`Ú¦î0X\‘^‰‡ÏÌDx 0\Áj8ý·ù |Ü#•­xííÅ9MÉдDÐr0X>L„j¬~t>ã$„,÷™e¡·@aG# âUkNí %; 0(Aw@i4©½Ì mÎÆå 0e« 0e } UN… ÆÓ UeD™ ‘Ý 0Dn E² 01ø´ 0Lø¬ ½¤ 0`a 0DÁ 0@EMU]UNe A©³ 0D\ 0¤ D D+Z 0K…Ð(ØURRZ 0Db B¦ÃË 0DÓ 0D[cks{ƃ 0eI 0@® 0eî 0@S“›UN£ñññ 0Dùùùùù 0L=˜HP LaserJet IIIHPPCL5MSØ,,,,,Ø,0nLÒxÈhH  Z6Times New Roman RegularX($¡¡ ÛÇÜDÝÞ{ßàDáâãÓ€ä}ý"x3|xä,ÿU‹ÿÀÀÀ1, 2, 3,Level 1Level 2Level 3Level 4Level 54#(þ2Quick 1)Úƒ ÚÚ  Ú)à0 àÛ€ Û 4#)N2Quick 1.Úƒ ÚÚ  Ú.à0 àÛ€ Û (ÖÃ9 Z ‹6Times New Roman RegularLevel 1Level 2Level 3Level 4Level 5u„š Z‹,Korinna BT Regular ‡Ý ƒ¯)ÝÝ  Ý›ßA€,)¬LdE°LAßà€Ä"Ä"Ä"(#àÚ  Ú1Ú  Ú(3¯$©©Ý ƒ!ÝÝ  ÝdAA „þ4MedMarTitmedical marijuana titleÔ€Xõ‹XXXÔÔ€î$% îXXõ‹Ôò òà@ìì*ìàÔ€Xõ‹XXXÔÔ€î$% îXXõ‹Ôó óvAA Õ4MedMar2hdmedical marijuana 2nd level headÔ€Š¹s ‹îîÔÔ€Š¹s ‹ ‹Š¹sÔò òÔ€Š¹s ‹îîÔÔ€Š¹s ‹ ‹Š¹sÔó ó ³›Ô‡&ëò &XXÔÓ*°,X°‚,` ˜X°œX*ÓÝ ƒ‘tÿÝòòÚ  Ú*Ú  ÚóóÝ  Ý€¢Dronabinol£€is€currently€marketed€in€the€United€States€for€the€stimulation€of€appetite€in€AIDS€patients.€€Ô#ccddÔTheÐ ° Ðeffects€of€smoked€marijuana€on€cachexia€associated€with€AIDS€or€cancer€would€need€to€be€determined.Ô#ddccíÔÔ#†Xò:X &&ëò#Ô(2‘t$¤¤Ý ƒ!ÝÝ  ÝòòÚ  Ú0Ú  Úóó(#Ã$òòÚ  Ú0Ú  Úóó2c0Quick "ð"ðà0 à  xÖÃ9 Z‹6Times New Roman Regular!%$›&OLE 2.0 Box <=8ÿÿÿÿÿÿÿÿÿÿCÿÿ HKKKK(3¯$££Ý ƒ!ÝÝ  Ýf 94MedMar3hdmeducal marijuana head 3Ô€(Xõ%!XXXÔÔ€(Xõ%!XXXÔ Ñ ´ Ñ'ÈÈÈÈdxd( ±þ$’’ò òFigure€Ú  Ú1Ú  Úó ó ›Ý ƒ‘tÿÝòòÚ  Ú**Ú  ÚóóÝ  ÝÓ*°,X°‚,` ˜X°œX*ÓÔ‡&ëò &XXÔ€Ô#ccddÔ¢Dronabinol£€is€currently€marketed€in€the€United€States€for€the€control€of€nausea€and€vomiting€associatedÔ#ddccƒÔÐ ° Ðwith€cancer€chemotherapy€in€patients€who€have€failed€to€respond€adequately€to€conventional€¢antiemetic£Ïtreatments.€€The€effects€of€smoked€marijuana€for€this€indication€merit€consideration€for€further€research.Ô#†Xò:X &&ëòc#Ô„@FÐ Z‹:Korinna BT Kursiv Regular (3¯$ªªÝ ƒ!ÝÝ  Ý d (3¯$§§Ý ƒ!ÝÝ  Ý(3¯$¦¦Ý ƒ!ÝÝ  Ý   A, B,Level 1Level 2Level 3Level 4Level 54#)Ž2Quick A)Úƒ6ÚÚ  Ú)à0 àÛ€6Û2âb0Quick ððà0 à4#)Þ2Quick A.Úƒ6ÚÚ  Ú.à0 àÛ€6Û2c0Quick 2ð2ðà0 à (ÈhH  Z 6Times New Roman Regular 6ûb$Triangleððà0 à>c$"Small Circleð"ðà0 àÝ ƒ!ÝÝ  ݛ݂„þÿÝÔ€Xò:XXXÔÔ€î5zîXXò:Ôò òÝ  ÝÑX°ÑÑ  ÑÖ€ÿÿÖÑœÈÑòòÝ‚„þÝà@dd"ìàÝ  ÝExecutive€Summaryóó݃„þ¸ÝŒˆÐ ° ЌԀî5zîîî5zÔÔ€Xò:Xîî5zÔó óÝ  ÝÌÓ/€d/ÓââOâââ  âver€the€past€18€months€there€has€been€wide„ranging€public€discussion€on€the€potentialÐ ¼  Ðâ d(#d(#°(#°(#âmedical€uses€of€marijuana,€particularly€smoked€marijuana.€€To€contribute€to€the€resolution€ofÏâ °(#°(#d(#d(#âthe€debate,€the€National€Institutes€of€Health€(NIH)€held€a€2„day€scientific€meeting€on€February€19„¼20,€1997,€to€review€the€scientific€data€concerning€the€potential€therapeutic€uses€for€marijuana€andÏthe€need€for€and€feasibility€of€additional€research.ÌÌCentral€to€the€current€debate€about€the€therapeutic€uses€of€marijuana€is€the€claim€that€smokedÏñÙñÔ#aaddÔñÙñmarijuana€offers€therapeutic€advantages€over€the€currently€available€oral€form€(¢dronabinol£€capsulesñÙñÔ#ddaa/ÔñÙñ)€ofÐ 0 €  Ðits€most€active€ingredient,€delta„9„tetrahydrocannabinol€(ð¬ðòò9óó„THC),€for€a€wide€variety€ofÐ l  Ðconditions.€€As€the€therapeutic€claims€surrounding€marijuana€are€wide„ranging,€10€separate€NIHÏñÚñÔ#aaddÔñÚñInstitutes€(with€interest€in€the€relevant€areas)€selected€a€group€of€eight€experts€with€broad€experienceñÚñÔ#ddaa¾ÔñÚñ€ñÛñÔ#aaddÔñÛñinÐ ôD  Ðclinical€studies€and€therapeutics€(and€none€of€whom€had€a€predetermined€position€on€the€medicalñÛñÔ#ddaacÔñÛñ€utilityÐ à0  Ðof€marijuana)€to€examine€the€data€from€the€published€scientific€literature€Ô#ccddÔpresented€by€speakers€inÐ Ì  Ðthe€various€therapeutic€fields.€€The€Ad€Hoc€Group€of€Experts€also€consideredÔ#ddccxÔ€public€commentsÐ ¸ Ðincluding€those€of€patients€and€advocacy€groups€as€well€as€written€material€Ô#ccddÔsubmitted€to€theÐ ¤ô ÐGroup€after€the€meeting.€The€Expert€Group€was€asked€to€focus€on€four€questions:Ô#ddccŠÔÐ à ÐÌòòQuestion€1€„€óóWhat€research€has€been€done€previously€and€what€is€currently€known€about€theÐ h¸ Ðpossible€medical€uses€of€marijuana?ÌÌòòQuestion€2€„€óóWhat€are€the€major€unanswered€scientific€questions?Ð ,| ÐÌòòQuestion€3€„€óóWhat€are€the€diseases€or€conditions€for€which€marijuana€might€have€potential€as€aÐ T Ðtreatment€and€that€merit€further€study?ÌÌòòQuestion€4€„€óóWhat€special€issues€have€to€be€considered€in€conducting€clinical€trials€of€theÐ È Ðtherapeutic€uses€of€marijuana?ÌÌEach€presentation€of€data€by€a€speaker€was€followed€by€a€question„and„answer€session€by€theÏExpert€Group.€€There€was€no€requirement€that€individuals€on€the€Group€agree€or€express€aÏconsensus€view,€although€they€were€free€to€do€so€if€they€so€desired.€€A€second€day€was€providedÏfor€public€comment€and€further€discussion€by€the€Expert€Group.ÌÌÔ#ccddÔThis€report€is€a€compilation€of€the€opinions€of€the€Expert€Group.€€Speakers€reviewed€the€literatureÔ#ddcc¾ ÔÐ (%x # Ðon€the€potential€efficacy€of€cannabinoids,€including€smoked€marijuana,€in€the€areas€of€analgesia,ÏÔ#ccddÔneurological€and€movement€disorders,€nausea€and€vomiting€associated€with€cancer€chemotherapyÔ#ddccÀ Ô,Ð 'P"% Ðglaucoma,€and€appetite€stimulation/cachexia.€€A€review€of€selected€aspects€of€the€general€clinicalÏpharmacology€of€marijuana€precedes€the€disorder„specific€commentary.ÌÌThe€discovery€of€receptors€in€the€central€nervous€system€(CNS)€for€cannabinoid€compounds,€andÏÔ#ccddÔthe€presence€of€an€endogenous€ligand€for€these€receptors,€is€of€importance€to€the€debateÐ œ+ì&* ÐconcerningÔ#ddccaÔ€the€potential€therapeutic€uses€of€marijuana.€€This€discovery€supports€aÐ ˆ,Ø'+ Ðâ ârecommendation€for€more€basic€research€to€discover€the€functional€roles€of€the€cannabinoidÐ t-Ä(, Ðreceptors€as€a€key€underpinning€for€possible€therapeutic€applications.€€Such€an€approach€allowsÏthe€bridging€of€knowledge€from€molecular€neurobiology€to€animal€studies€to€human€clinical€trials.Ìâ âÌThe€scientific€process€should€be€allowed€to€evaluate€the€potential€therapeutic€effects€of€marijuanaÏfor€certain€disorders,€dissociated€from€the€societal€debate€over€the€potential€harmful€effects€ofÏnonmedical€marijuana€use.€€All€decisions€on€the€ultimate€usefulness€of€a€medical€intervention€areÏbased€on€a€benefit/risk€calculation,€and€marijuana€should€be€no€exception€to€this€generallyÏaccepted€principle.ÌÌThe€availability€of€THC€in€capsule€form€does€not€fully€satisfy€the€need€to€evaluate€the€potentialÏÔ#ccddÔmedical€utility€of€marijuana.€€The€Expert€Group€noted€that,€although€delta„9„¢tetrahydrocannabinol£Ô#ddccžÔÐ è 8  Ð(Ô#ccddÔTHC,€dronabinol,€Marinolòòððóó,€or€ð¬ðòò9óó„THC)€is€the€principal€psychoactive€component€of€the€cannabisÔ#ddcc?ÔÐ Ô$  ÐÔ#aaddÔleaf,€there€may€be€other€compounds€in€the€leaf€that€have€useful€therapeutic€properties.€€FurthermoreÔ#ddaaëÔ,Ð À  ÐÔ#ccddÔthe€bioavailability€and€pharmacokinetics€of€THC€from€smoked€marijuana€are€substantially€differentÔ#ddccÔÐ ¬ü  Ðthan€those€of€the€oral€dosage€form.€€These€are€the€rationales€for€studying€the€pharmacologicalÏactions€of€other€constituents€of€the€cannabis€leaf,€as€well€as€determining€whether€a€differentialÏbenefit€occurs€with€smoked€marijuana€rather€than€oral€dronabinol.ÌÌÔ#ccddÔThe€Expert€Group€noted€that€even€for€conditions€where€good€therapies€are€available,€someÐ H˜ Ðpatients€develop€adverse€reactions€or€are€nonresponders.€€The€needs€of€this€subset€ofÏ¢nonresponders£Ô#ddcc/Ô€must€be€considered€in€the€deliberations€on€testing€marijuana€as€a€possibleÐ  p Ðtherapeutic€agent.ÌÌThe€Expert€Group€also€noted€that€risks€associated€with€marijuana,€especially€smoked€marijuana,Ïmust€be€considered€not€only€in€terms€of€immediate€adverse€effects€on€the€lung;€e.g.,€bronchi€andÏalveoli,€but€also€long„term€effects€in€patients€with€chronic€diseases.€€Additionally,€age,€immuneÏstatus,€the€development€of€intercurrent€illnesses,€and€concomitant€diseases€should€be€considered€Ô#ccddÔinÐ ¨ø Ðthe€determination€of€the€risk€calculation.€€The€possibility€that€frequent€and€prolonged€marijuanaÔ#ddcc ÔÐ ”ä Ðuse€might€lead€to€clinically€significant€impairments€of€immune€system€function€is€great€enough€Ô#ccddÔthatÐ €Ð Ðrelevant€studies€should€be€part€of€any€marijuana€medication€development€research,€particularlyÔ#ddcc4ÔÐ l¼ Ðwhen€marijuana€will€be€used€by€patients€with€compromised€immune€systems.€€Concerns€wereÏexpressed€by€members€of€the€Expert€Group€on€the€use€of€smoked€marijuana€because€of€theÏcombustion€byproducts,€particularly€when€marijuana€would€be€used€for€conditions€requiringÏÔ#aaddÔchronic€therapy.€€Hence,€a€recommendation€was€made€for€the€development€of€insufflation/inhalationÔ#ddaañÔÐ #l! Ðdevices€or€dosage€forms€capable€of€delivering€purer€THC€or€cannabinoids€to€the€lungs€free€ofÏdangerous€combustion€byproducts.ÌÌThe€major€conclusions€in€each€therapeutic€area€are€summarized€below.ÌÌÝ‚ÕÿÝÔ€ŠŒ ŠXXò:ÔÔ€ŠŒ Š ŠŠŒÔò òÝ  ÝÑ€#‘ÑÝ‚ÕTÝÝ  ÝAnalgesia݃ÕTÁ݌Р¤(ô#' ЌԀXò:X ŠŠŒÔÔ€Xò:XXXò:Ôó óÝ  ÝÌNo€clinical€trials€involving€smoked€marijuana€have€been€performed€in€patients€with€naturallyÏoccurring€pain.€€Two€adequate€and€well„controlled€studies€in€cancer€pain€compared€graded€dosesÏof€Ô‡Xò:XXXò:Ôoral€ðˆðòò9óó„THCÔ#†Xò:XXXò:" #Ô€to€placebo,€and€one€of€these€included€graded€doses€of€codeine€as€a€control.€Ð h,¸'+ Ðâ âAlthough€there€was€evidence€of€analgesic€efficacy,€the€studies€indicate€there€is€a€narrowÐ T-¤(, Ðtherapeutic€margin€between€the€doses€that€produce€useful€analgesia€and€those€producingÏunacceptable€adverse€CNS€effects.Ìâ âò òÌó óÝ‚ÕÿÝÔ€ŠŒ ŠXXò:ÔÔ€ŠŒ Š ŠŠŒÔò òÝ  ÝÝ‚ÕÜ!ÝÝ  ÝNeurological€and€Movement€Disorders݃ÕÜ!8"݌РtÄ ÐŒÔ€Xò:X ŠŠŒÔÔ€Xò:XXXò:Ôó óÝ  ÝÌÔ#ccddÔNumerous€preclinical€and€clinical€studies€of€the€use€of€cannabinoids€in€neurological€and€movementÔ#ddccô"ÔÐ ` ° Ðdisorders€have€been€reported€as€accounts€of€animal€experiments,€clinical€anecdotes,€surveys,€andÏclinical€studies.ÌÌEvidence€that€marijuana€relieves€spasticity€produced€by€multiple€sclerosis€(MS)€and€partial€spinalÏcord€injury€is€largely€anecdotal.€€Large„scale€trials€or€controlled€studies€to€compare€marijuana€orÏTHC€with€currently€available€therapies€have€not€been€performed.€€There€is€no€published€evidenceÏthat€cannabinoids€are€superior€or€equivalent€to€available€therapies.ÌÌPreclinical€evidence€suggests€a€possible€role€for€cannabinoids€in€the€treatment€of€the€epilepsies,Ïparticularly€generalized€and€partial€tonic„clonic€seizures.€€There€is€scant€information€on€the€use€ofÏmarijuana€or€other€cannabinoids€for€the€actual€treatment€of€epilepsy.ÌÌIndividual€case€studies€have€reported€some€benefit€of€smoked€marijuana€in€treatment€of€dystonicÏstates.€€Smoked€marijuana€or€oral€THC€administrations€for€Parkinsonððs€disease€or€œHuntingñãñdñãññäñtñäñonððs›Ïchorea€have€not€been€effective.ÌÌCannabinoids€have€shown€efficacy€as€immune€modulators€in€animal€models€of€neurologicalÏconditions€such€as€experimental€allergic€encephalomyelitis€(EAE)€and€neuritis.€€These€dataÏsuggest€that€cannabinoids€might€modify€the€presumed€autoimmune€cause€of€a€disease€such€as€MS.€ÏHowever,€long„term€risks€of€smoked€marijuana€need€to€be€quantified€when€considering€chronicÏtherapy€for€neurological€conditions.ÌÌÝ‚ÕÿÝÔ€ŠŒ ŠXXò:ÔÔ€ŠŒ Š ŠŠŒÔò òÝ  ÝÝ‚Õ)ÝÝ  ÝNausea€and€Vomiting€Associated€With€Cancer€Chemotherapy݃Õ)c)݌Р”ä ЌԀXò:X ŠŠŒÔÔ€Xò:XXXò:Ôó óÝ  ÝÌThere€is€a€large€body€of€literature€on€the€effects€of€cannabinoids€on€chemotherapy„induced€nauseaÏand€vomiting.€€Most€of€the€clinical€trials€used€oral€dronabinol€rather€than€smoked€marijuana.€€TheÏoral€THC€studies€showed€this€dosage€form€to€be€superior€to€placebo€and€generally€equivalent€orÏsuperior€to€prochlorperazine,€but€inferior€to€metoclopramide.€€Only€one€study€compared€smokedÏmarijuana€and€dronabinol€in€a€crossover€design.€€Of€the€20€patients€studied,€9€had€no€preference,Ï7€preferred€dronabinol,€and€4€preferred€smoked€marijuana.ÌÌÔ#ccddÔSince€the€approval€of€dronabinol€in€the€mid€1980s€for€the€relief€of€nausea€and€vomiting€associatedÔ#ddccR,ÔÐ ô&D"% Ðwith€cancer€chemotherapy,€more€effective€antiemetics€have€been€developed,€such€as€ondansetron,Ïgranisetron,€and€dolasetron,€each€combined€with€dexamethasone.€€The€relative€efficacy€ofÏcannabinoids€versus€these€newer€antiemetics€has€not€been€evaluated.€€Smoked€marijuana€wasÏtested€in€one€trial€in€patients€who€previously€had€no€benefit€from€older€antiemetic€agents.€€NearlyÏÔ#ccddÔone„quarter€of€patients€who€initially€agreed€to€participate€later€declined€citing€bias€againstÐ +à&* ÐsmokingÔ#ddccg.Ô,€the€harshness€of€smoke,€and€preference€for€dronabinol.€€Among€the€remaining€56Ð |,Ì'+ Ðâ âpatients,€78percent€rated€smoked€marijuana€very€effective€or€moderately€effective.€€Sedation€wasÐ h-¸(, ÐÑ#‘ÑÑ´ÈÑÑ  ÑñãñÑ#‘ÑÑ´ÈÑÑ  Ññãñseen€in€88€percent€and€dry€mouth€in€77€percent.€€It€is€not€known€whether€smoked€marijuanaÏñãñÑ#‘ÑÑ´ÈÑÑ  Ññãñwould€benefit€patients€refractory€to€the€current€generation€of€antiemetic€therapy.Ìâ ââ âÌÝ‚ÕÿÝÔ€ŠŒ ŠXXò:ÔÔ€ŠŒ Š ŠŠŒÔò òÝ  ÝÝ‚ÕÃ0ÝÝ  ÝGlaucoma݃ÕÃ01݌РtÄ ÐŒÔ€Xò:X ŠŠŒÔÔ€Xò:XXXò:Ôó óÝ  ÝÌSmoked€marijuana€has€been€shown€to€lower€intraocular€pressure€(IOP)€in€subjects€with€normalÏIOP€and€patients€with€glaucoma.€€The€duration€of€the€pressure„lowering€effect€is€3€to€4€hours.€ÏSingle„administration€studies€have€reported€blood€pressure€falls€concurrently€with€the€IOPÏlowering,€raising€concern€that€blood€flow€to€the€optic€nerve€could€be€compromised.€€MitigatingÏthis€concern€are€data€suggesting€that€tolerance€may€develop€to€cardiovascular€effects.€€Efforts€toÏavoid€or€reduce€side€effects€led€to€the€development€of€a€topical€dosage€form€of€THC.€€TopicallyÏapplied€THC€did€not€lower€IOP.ÌÌThe€mechanism€of€all€IOP„lowering€drugs€currently€used€to€treat€glaucoma€is€known€with€theÏÔ#ccddÔexception€of€marijuana.€€The€interactive€effect€of€marijuana€with€currently€available€¢IOP£„loweringÔ#ddcct4ÔÐ ¬ü  Ðagents€is€not€known€but€is€evaluable.€€Elucidation€of€the€mechanism€of€action€of€marijuanaððs€IOP„¼lowering€effect€is€crucial€to€its€potential€utilization€for€treatment€of€glaucoma;€a€uniqueÏmechanism€of€action€might€provide€additive€benefit€whereas€a€mechanism€identical€to€an€availableÏmedication€would€suggest€an€unfavorable€benefit/risk€ratio.ÌÌÝ‚ÕÿÝÔ€ŠŒ ŠXXò:ÔÔ€ŠŒ Š ŠŠŒÔò òÝ  ÝÝ‚Õt6ÝÝ  ÝAppetite€Stimulation/Cachexia݃Õt6Ð6݌Р4„ ЌԀXò:X ŠŠŒÔÔ€Xò:XXXò:Ôó óÝ  ÝÌClinical€studies€and€survey€data€in€healthy€populations€have€shown€a€strong€relationship€betweenÏmarijuana€use€and€increased€eating.€€Marijuana€is€reported€to€increase€food€enjoyment€and€theÏnumber€of€times€individuals€eat€per€day.€€Mechanistic€studies€of€marijuana€on€taste€and€satietyÏhave€shown€that€it€does€not€affect€taste€or€produce€a€collapse€of€normal€satiety€mechanisms.€ÏFood€intake€associated€with€marijuana€use€is€influenced€by€the€social€setting.ÌÌÔ#ccddÔThere€are€no€controlled€studies€of€marijuana€in€the€AIDS„wasting€syndrome,€nor€have€there€beenÐ ¨ø Ðany€systematic€studies€of€the€effects€of€smoked€marijuana€on€immunological€status€in€HIV„¼infectedÔ#ddccS9Ô€patients.€€Smoking€(tobacco,€marijuana,€or€crack€cocaine)€has€been€shown€to€increase€theÐ € Ð Ðrisk€of€developing€bacterial€pneumonia€in€HIV„positive€immune„compromised€patients.€ÏDronabinol€has€been€shown€to€increase€appetite€and€produce€weight€gain€in€AIDS€and€cancerÏpatients,€although€the€weight€gain€is€not€in€lean€body€mass.€€Dronabinol€is€approved€for€theÏtreatment€of€anorexia€in€patients€with€AIDS„associated€weight€loss.ÌÌÝ‚ÕÿÝÔ€ŠŒ ŠXXò:ÔÔ€ŠŒ Š ŠŠŒÔò òÝ  ÝÝ‚Õ<ÝÝ  ÝQuestion€3:€€Which€Diseases€œñßñorñßññàñandñàñ›€Conditions€Merit€Further€Study?݃Õ<k<݌Р&X!$ ЌԀXò:X ŠŠŒÔÔ€Xò:XXXò:Ôó óÝ  ÝÌConcerning€Question€3,€there€were€varying€degrees€of€enthusiasm€to€pursue€smoked€marijuana€forÏseveral€indications.€€This€enthusiasm€was€tempered€by€the€fact€that,€for€many€of€these€disorders,Ïeffective€alternative€treatments€are€already€available.€€Given€the€general€consensus€among€theÏexperts€that€the€number,€design€and€documentation€of€studies€performed€to€date€with€smokedÏmarijuana€did€not€provide€definitive€answers,€it€was€difficult€to€compare€marijuana€with€productsÏthat€had€received€regulatory€approval€under€more€rigorous€experimental€conditions.€€This€doesÏnot€mean,€however,€that€the€issue€should€be€foreclosed.€€It€simply€means€that€in€order€to€evaluateÏvarious€hypotheses€concerning€the€potential€utility€of€marijuana€in€various€therapeutic€areas,€moreÐ h.¸)- Ðand€better€studies€would€be€needed.€€In€the€words€of€Dr.€William€Beaver,€Professor€ofÏPharmacology€and€Anesthesia,€Georgetown€University€School€of€Medicine,€who€chaired€theÏworkshop,€ð ðFor€at€least€some€potential€indications,€marijuana€looks€promising€enough€toÏrecommend€that€there€be€new€controlled€studies€done.ðð€€The€indications€in€which€varying€levels€ofÏinterest€was€expressed€are€the€following:ÌÌÓ*°,X°‚,` ˜X°œX*ÓÝ‚AûbÿÝÝ  ÝÝ‚Aûb3BÝððà0 Ü àÝ  ÝAppetite€stimulation/cachexiaÙ*ƒ!٢׃×Ý ƒ#ÃÝòòÚ  Ú*Ú  ÚóóÝ  Ý×  ף݃Aûb3BNBÝŒÐ8 ˆÜ(#Ü(# ÐŒÝ  ÝÝ‚AûbÿÝÝ  ÝÝ‚AûbOCÝððà0 Ü àÝ  ÝNausea€and€vomiting€following€¢anticancer£€therapy¢×ƒ'@×Ý ƒ#ÃÝòòÚ  Ú**Ú  ÚóóÝ  Ý×  ף݃AûbOCjCÝŒÐ$ tÜ(#Ü(# ÐŒÝ  ÝÝ‚AûbÿÝÝ  ÝÝ‚AûbcDÝððà0 Ü àÝ  ÝNeurological€and€movement€disorders݃AûbcD~D݌Р`Ü(#Ü(# ÐŒÝ  ÝÝ‚AûbÿÝÝ  ÝÝ‚AûbEÝððà0 Ü àÝ  ÝAnalgesia݃AûbE-EÝŒÐü L Ü(#Ü(# ÐŒÝ  ÝÝ‚AûbÿÝÝ  ÝÝ‚Aûb§EÝððà0 Ü àÝ  ÝGlaucoma݃Aûb§EÂEÝŒÐè 8 Ü(#Ü(# ÐŒÝ  ÝÌAccordingly,€the€NIH€should€consider€relevant€administrative€mechanisms€to€facilitate€grantÏapplications€in€each€of€these€areas.€€Whether€or€not€the€NIH€is€the€primary€source€of€grantÏsupport€for€a€proposed€bona€fide€clinical€research€study,€if€that€study€meets€U.S.€regulatoryÏstandards€(U.S.€Food€and€Drug€Administration€(FDA)€protocol€approval€and€Drug€EnforcementÏAdministration€(¢DEA£)€controlled€substances€registration)€the€study€should€receive€marijuanaÏand/or€matching€placebo€supplied€by€the€National€Institute€on€Drug€Abuse€(¢NIDA£).€€In€this€way,Ïa€new€body€of€studies€may€emerge€to€test€the€various€hypotheses€concerning€marijuana.ÌÌThe€last€question,€Question€4,€concerning€the€special€issues€involved€in€conducting€clinical€trialsÏwith€marijuana,€was€particularly€difficult.€€There€was€considerable€discussion€and€debate€as€toÏÔ#ccddÔwhether€smoked€marijuana€(with€the€inherent€health€risks€of€smoking)€would€need€to€demonstrateÔ#ddcc†IÔÐ øH Ðclear€superiority€or€some€unique€benefit€compared€with€other€medications€currently€available€forÏÔ#ccddÔthese€conditions.€€Ô‡Xò:XXXò:ÔThe€Expert€Group€concluded€that€smoked€marijuana€should€be€held€toÐ Ð  ÐstandardsÔ#ddcc‚JÔ€equivalent€to€other€medications€for€efficacy€and€safety€considerations.€€Moreover,€thereÐ ¼  Ðmight€besome€patient€populations;€e.g.,€cancer€patients€experiencing€nausea€and€vomiting€duringÏchemotherapyò ò,€ó ófor€whom€the€inhalation€route€might€offer€advantages€over€the€currently€availableÐ ”ä ÐÔ#aaddÔcapsule€formulation.€€This€raises€many€issues€concerning€the€best€mode€of€administration.€€GenerallyÔ#ddaa…LÔÐ „Ô Ðaccepted€pharmacotherapy€development€schema€would€favor€finding€routes€of€administrationÏunder€which€dosing€could€be€more€tightly€controlled€and€easily€titrated.€€Smoking€plant€materialÏÔ#ccddÔposes€difficulties€in€standardizing€testing€paradigms,€and€components€of€the€smoke€are€hazardousÔ#ddccàMÔ,Ð H!˜ Ðespecially€in€the€immunocompromised€patient.€€Additionally,€practical€problems€exist.€€Given€theÏno„smoking€policy€of€hospitals€and€public€facilities,€it€would€be€difficult€to€imagine€the€utility€ofÏsmoked€marijuana€in€these€settings.€€Therefore,€the€experts€generally€favored€the€development€ofÏalternative€dosage€forms,€including€an€inhaler€dosage€form€into€which€a€controlled€unit€dose€ofÏTHC€could€be€placed€and€volatilized.€€Other€problems€noted€were€the€difficulty€in€attempting€toÏâ âmatch€placebo€control€against€Ô#†Xò:XXXò:§J#Ôsmoked€Ô‡Xò:XXXò:Ômarijuana€(especially€for€those€with€previous€marijuanaÐ Ð& "% Ðexperience),€and€the€fact€that€under€U.S.€law,€researchers€will€need€to€obtain€DEA€registration€toÏhandle€marijuana,€which€is€currently€a€Schedule€I€controlled€substance€(see€Appendix).Ìâ âÌÔ#†Xò:XXXò:¸P#ÔIn€summary,€the€testing€of€smoked€marijuana€to€evaluate€its€therapeutic€effects€is€a€difficult,€butÐ tÄ Ðnot€impossible,€task.€€Until€studies€are€done€using€scientifically€acceptable€clinical€trial€design€andÏsubjected€to€appropriate€statistical€analysis,€the€questions€concerning€the€therapeutic€utility€ofÏmarijuana€will€likely€remain€much€as€they€have€to€dateð"ðlargely€unanswered.€€To€the€extent€thatÏthe€NIH€can€facilitate€the€development€of€a€scientifically€rigorous€and€relevant€database,€the€NIHÏshould€do€so.Ð   ` ÐòòÝ‚„þÿÝÔ€Xò:XàXò:ÔÔ€î5zîàXò:Ôò òÝ  ÝÝ‚„þ8TÝà@ÖÖ$ìàÝ  ÝIntroductionóó݃„þ8T”TÝŒˆÐ ° ЌԀî5zîîî5zÔÔ€Xò:Xîî5zÔó óÝ  ÝÌÓ/€d/ÓââOâââ  ân€February€19€and€20,€1997,€the€National€Institutes€of€Health€(NIH)€held€a€meetingÐ ¼  Ðâ d(#d(#°(#°(#âconcerning€the€potential€medical€uses€of€marijuana.€€Recent€(November€1996)€ballotÏâ °(#°(#d(#d(#âinitiatives€in€California€and€Arizona€had€sparked€a€public€health€and€policy€debate€on€the€medicalÏutility€of€marijuana€Ô#ccddÔand€the€desirability€of€allowing€healthcare€providers€to€prescribe,€and€patientsÐ € Ð Ðto€receive,€marijuanaÔ#ddccWÔ€for€medicinal€purposes.Ð l ¼ ÐÌFor€some€years€the€principal€psychoactive€ingredient€of€marijuana,€delta„9„tetrahydrocannabinolÐ D ” Ð(ðˆðòò9óó„THC),€has€been€available€to€healthcare€providers€in€an€oral€form€as€dronabinol€(trade€nameÐ 0 €  ÐÔ#aaddÔMarinol)€for€the€treatment€of€emesis€associated€with€cancer€chemotherapy€and€for€appetite€stimulationÔ#ddaaÎXÔÐ l  ÐÔ#ccddÔin€the€treatment€of€AIDS€wasting€syndrome.€€The€current€debate€centers€primarily€on€the€potentialÔ#ddccpYÔÐ X  Ðfor€other€treatment€indications€and€the€claims€that,€when€smoked,€marijuana€offers€therapeuticÏÔ#aaddÔadvantages€over€the€currently€available€oral€form.€€As€the€Federal€Governmentððs€principal€biomedicalÔ#ddaamZÔÔ#ccZddÔÐ à0  ÐÔ#ddccüZÔÔ#aaddÔresearch€agency,€the€NIH€believed€that€the€public€debate€could€benefit€from€an€impartial€examinationÔ#ddaa=[ÔÔ#cc¹YddÔÐ Ì  Ðof€all€the€data€available€to€date€concerning€these€issues.€€As€the€claims€for€benefits€were€wideÏranging,€10€major€components€of€the€NIH€participated€in€the€planning€for€the€conferenceÔ#ddccÉ[Ô.Ð ¤ô ÐÌThe€NIH€planning€group€focused€the€meeting€on€the€following€four€questions€concerningÏmarijuana€as€a€potential€therapeutic€agent:ÌÌòòQuestion€1€„€óóWhat€research€has€been€done€previously€and€what€is€currently€known€about€theÐ @ Ðpossible€medical€uses€of€marijuana?ÌÌòòQuestion€2€„€óóWhat€are€the€major€unanswered€scientific€questions?Ð T ÐÌòòQuestion€3€„€óóWhat€are€the€diseases€or€conditions€for€which€marijuana€might€have€potential€as€aÐ Ü, Ðtreatment€and€that€merit€further€study?ÌÌòòQuestion€4€„€óóWhat€special€issues€have€to€be€considered€in€conducting€clinical€studies€of€theÐ  ð Ðtherapeutic€uses€of€marijuana?ÌÔ‡Xò:XXXò:ÔÌThe€meeting€was€formatted€as€a€scientific€workshop.€€It€was€not€an€attempt€to€render€a€consensus.€ÏTherefore,€it€was€structured€so€that€speakers€with€experience€in€the€relevant€therapeutic€areasÏwould€present€to€a€group€of€eight€expert€consultants€who€possessed€broad€expertise€in€clinicalÏstudies€and€therapeutics€and€who€had€no€public€positions€on€the€potential€use€of€marijuana€as€aÏtherapeutic€agent.€€Each€presentation€was€followed€by€a€session€for€questions€and€answers€fromÏthe€Expert€Group.€€The€second€day€was€allotted€for€the€public€to€present€their€views€and€forÏdiscussion€by€the€Expert€Group.€€This€report€represents€a€compilation€of€the€views€of€the€ExpertÏGroup.€€Since€this€report€was€not€intended€as€a€general€review€of€the€literature€on€marijuana€andÏTHC,€only€a€few€selected€references€from€among€the€thousands€that€exist€are€cited.€€Each€of€theÏmembers€in€the€Expert€Group€chose€those€references€relevant€to€their€own€contributions€to€theÏreport.Ð  œ+ì&* ÐÔ/†X €XXXXXX/X_/ÔòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þ…cÝà@ ìàÝ  ÝClinical€Pharmacology€of€Marijuanaóó݃„þ…cácÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚Õ²dÝÝ  ÝThe€Pharmacology€of€Natural€Products݃ղdeÝŒÐ Ê ÐŒÔ€X5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌÓ/€d/ÓââIâââ  ât€is€important€to€keep€in€mind€that€marijuana€is€not€a€single€drug.€€Marijuana€is€a€mixture€of€theÐ À Ðâ :(#:(#°(#°(#âdried€flowering€tops€and€leaves€from€the€plant€cannabis€sativa€(Agurell€et€al.€1984;€GrahamÏâ °(#°(#:(#:(#â1976;€Jones€1987;€Mechoulam€1973).€€Like€most€plants,€marijuana€is€a€variable€and€complexÏmixture€of€biologically€active€compounds€(Agurell€et€al.€1986;€Graham€1976;€Mechoulam€1973).€ÏCharacterizing€the€clinical€pharmacology€of€the€constituents€in€any€pharmacologically€activeÏplant€is€often€complicated,€particularly€when€the€plant€is€smoked€or€eaten€more€or€less€in€itsÏnatural€form.€€Marijuana€is€not€unusual€in€this€respect.€€Cannabis€sativa€is€a€very€adaptive€plant,Ïso€its€characteristics€are€even€more€variable€than€most€plants€(Graham€1976;€Mechoulam€1973).€ÏSome€of€the€seeming€inconsistency€or€uncertainty€in€scientific€reports€describing€the€clinicalÏpharmacology€of€marijuana€results€from€the€inherently€variable€potency€of€the€plant€materialÏused€in€research€studies.€€Inadequate€control€over€drug€dose€when€researching€the€effects€ofÏsmoked€and€oral€marijuana,€together€with€the€use€of€research€subjects€who€vary€greatly€in€theirÏÔ#aaddÔpast€experience€with€marijuana,€contribute€differing€accounts€of€what€marijuana€does€or€does€not€do.Ô#ddaaÛjÔÐ P ÐÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚Õ}kÝÝ  ÝThe€Plant݃Õ}kÙk݌Рà0 ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌMarijuana€contains€more€than€400€chemicals.€€Approximately€60€are€called€cannabinoids;€i.e.,ÏCòò21óó€terpenes€found€in€the€plant€and€their€carboxylic€acids,€analogs,€and€transformation€productsÐ Æ Ð(Agurell€et€al.€1984,€1986;€Mechoulam€1973).€€Most€of€the€naturally€occurring€cannabinoidsÏhave€been€identified.€€Cannabinoids€appear€in€no€other€plant.€€Cannabinoids€have€been€theÏsubject€of€much€research,€particularly€since€the€mid€1960s€when€Mechoulam€and€his€colleaguesÏfirst€isolated€delta„9„tetrahydrocannabinol€(ðˆðòò9óó„THC)€(Mechoulam€1973;€Mechoulam€et€al.€1991).€Ð †Ö ÐTHC€in€the€scientific€literature€is€termed€ðˆðòò9óó„THC€or€ðˆðòò1óó„THC€depending€on€whether€the€pyran€orÐ vÆ Ðmonoterpinoid€numbering€system€is€used.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕŽoÝÝ  ÝCannabinoids€of€Importance݃Վoêo݌РF – ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌTHC,€the€main€psychoactive€cannabinoid€in€marijuana,€is€an€optically€active€resinous€substance.€ÏTHC€is€not€soluble€in€water€but€is€extremely€lipid€soluble€(Agurell€et€al.€1984,€1986;€MechoulamÏ1973).€€Varying€proportions€of€other€cannabinoids,€mainly€cannabidiol€(CBD)€and€cannabinolÏ(Ô#ccddÔCBN),€are€also€present€in€marijuana,€sometimes€in€quantities€that€might€modify€the€pharmacologyÔ#ddcc»qÔÐ  %\ " ÐÔ#ccddÔof€THC€or€cause€effects€of€their€own.€€CBD€is€not€psychoactive€but€has€significant€¢anticonvulsant£Ô#ddccWrÔ,Ð ü%L!# Ðsedative,€and€other€pharmacologic€activity€likely€to€interact€with€THC€(Adams€and€Martin€1996;ÏAgurell€et€al.€1984,€1986;€Hollister€1986òòa)óó.Ð Ü',#% ÐÌThe€concentration€of€THC€and€other€cannabinoids€in€marijuana€varies€greatly€depending€onÏgrowing€conditions,€plant€genetics,€and€processing€after€harvest€(Adams€and€Martin€1996;ÏAgurell€et€al.€1984;€Graham€1976;€Mechoulam€1973).€€In€the€usual€mixture€of€leaves€and€stemsÏdistributed€as€marijuana,€concentration€of€THC€ranges€from€0.3€percent€to€4€percent€by€weight.€Ïâ âHowever,€specially€grown€and€selected€marijuana€can€contain€15€percent€or€more€THC.€€Thus,€aÐ |-Ì(+ Ðmarijuana€cigarette€weighing€1€gram€(g)€might€contain€as€little€as€3€milligrams€(mg)€of€THC€orÏas€much€as€150€mg€or€more.Ìâ âÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕvÝÝ  ÝPotency€of€¢Tetrahydrocannabinol£ÝƒÕvjv݌Р€Ð ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌTHC€is€quite€potent€when€compared€to€most€other€psychoactive€drugs.€€An€intravenous€(IV)€doseÏof€only€a€milligram€or€two€can€produce€profound€mental€and€physiologic€effects€(Agurell€et€al.Ï1984,€1986;€Fehr€and€Kalant€1983;€Jones€1987).€€Large€doses€of€THC€delivered€by€marijuana€orÏadministered€in€the€pure€form€can€produce€mental€and€perceptual€effects€similar€to€drugs€usuallyÏtermed€hallucinogens€or€psychomimetics.€€However,€the€way€marijuana€is€used€in€the€UnitedÏStates€does€not€commonly€lead€to€such€profound€mental€effects.€€Despite€potent€psychoactivityÏand€pharmacologic€actions€on€multiple€organ€systems,€cannabinoids€have€remarkably€low€lethalÏtoxicity.€€Lethal€doses€in€humans€are€not€known.€€Given€THCððs€potency€on€some€brain€functions,Ïthe€clinical€pharmacology€of€marijuana€containing€high€concentrations€of€THC,€for€exampleÏgreater€than€10€percent,€may€well€differ€from€plant€material€containing€only€1€or€2€percent€THCÏsimply€because€of€the€greater€dose€delivered.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕÿzÝÝ  ÝSome€Limitations€of€Previous€Marijuana€Research݃Õÿz[{݌Р¶ ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌUnfortunately,€much€of€what€is€known€about€the€human€pharmacology€of€smoked€marijuanaÏcomes€from€experiments€with€plant€material€containing€about€2€percent€THC€or€less,€orÏoccasionally€up€to€4€percent€THC.€€In€addition,€human€experiments€typically€are€done€inÏlaboratory€settings€where€only€one€or€two€smoked€doses€were€administered€to€relatively€young,Ïmedically€screened,€healthy€male€volunteers€well€experienced€with€the€effects€of€marijuana.€ÏFemales€rarely€participated€in€past€marijuana€research€because€of€prohibitions€(now€removed)Ïagainst€their€inclusion.€€Thus€the€clinical€pharmacology€of€single€or€repeated€smoked€marijuanaÏdoses€given€to€older€people€or€to€people€with€serious€diseases€has€hardly€been€researched€at€all€inÏa€controlled€laboratory€or€clinic€setting.€€Some€of€the€very€few€reports€of€experiments€that€haveÏincluded€older€or€sicker€people,€particularly€patients€less€experienced€in€using€marijuana,€suggestÏthe€profile€of€adverse€effects€may€differ€from€healthy€student€volunteers€smoking€in€a€laboratoryÏexperiment€(¢Hollister£€¢1986òòa£óó,€¢1988òòa£óó).Ð ü L ÐÌTHC€administered€alone€in€its€pure€form€is€the€most€thoroughly€researched€cannabinoid.€€MuchÏof€what€is€written€about€the€clinical€pharmacology€of€marijuana€is€actually€inferred€from€theÏresults€of€experiments€using€only€pure€THC.€€Generally,€in€experiments€actually€using€marijuana,Ïthe€assumed€dose€of€marijuana€was€based€only€on€the€concentration€of€THC€in€the€plant€material.€ÏThe€amounts€of€cannabidiol€and€other€cannabinoids€in€the€plant€also€vary€so€that€pharmacologicÏinteractions€modifying€the€effects€THC€may€occur€when€marijuana€is€used€instead€of€pure€THC.€ÏÔ#ccddÔOnly€rarely€in€human€experiments€using€marijuana€was€the€content€of€CBD€or€other€¢cannabinoids£Ô#ddcc±‚ÔÐ |(Ì#& Ðspecified€or€the€possibility€of€interactive€effects€between€THC€and€other€cannabinoids€or€otherÏmarijuana€constituents€actually€measured.ÌÌThe€result€of€this€research€strategy€is€that€a€good€deal€is€known€about€the€pharmacology€of€THC,Ïbut€experimental€confirmation€that€the€pharmacology€of€a€marijuana€cigarette€is€indeed€entirelyÏor€mainly€determined€by€the€amount€of€THC€it€contains€remains€to€be€completed.€€The€scientificÐ .l), Ðliterature€contains€occasional€hints€that€the€pharmacology€of€pure€THC,€although€similar,€is€notÏalways€the€same€as€the€clinical€pharmacology€of€smoked€marijuana€containing€the€same€amountÏof€THC€(Graham€1976;€Harvey€1985;€Institute€of€Medicine€1982).€€Proponents€of€therapeuticÏapplications€of€marijuana€emphasize€possible€but€not€well€documented€or€proven€differencesÏÔ#aaddÔbetween€the€effects€of€the€crude€plant€and€pure€constituents€like€THC€(Grinspoon€and€¢Bakalar£€1993).Ô#ddaa~†ÔÐ pÀ ÐÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚Õ!‡ÝÝ  ÝRoute„Dependent€¢Pharmacokinetics£ÝƒÕ!‡}‡ÝŒÐ P   ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌRoute€of€administration€determines€the€pharmacokinetics€of€the€cannabinoids€in€marijuana,Ïparticularly€absorption€and€metabolism€(Adams€and€Martin€1996;€Agurell€et€al.€1984,€1986).€ÏTypically,€marijuana€is€smoked€as€a€cigarette€(a€joint)€weighing€between€0.5€and€1.0€g,€or€in€aÏpipe€in€a€way€not€unlike€tobacco€smoking.€€Marijuana€can€also€be€baked€in€foods€and€eaten,€orÏethanol€or€other€extracts€of€plant€material€can€be€taken€by€mouth.€€Some€users€claim€marijuanaÏÔ#ccddÔcontaining€adequate€THC€can€be€heated€without€burning€and€the€resulting€vapor€inhaled€to€produceÔ#ddcc ŠÔÐ öF  Ðthe€desired€level€of€intoxication.€€This€has€not€been€studied€under€controlled€conditions.€€PureÏÔ#ccddÔpreparations€of€THC€and€other€cannabinoids€can€be€administered€by€mouth,€by€rectal€suppositoryÔ#ddcc ‹Ô,Ð Ö& Ðby€IV€injection,€or€smoked.€€IV€injection€of€crude€extracts€of€marijuana€plant€material€would€beÏquite€toxic,€however.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕŒÝÝ  ÝMarijuana€Smoking€and€Oral€Administration݃ՌyŒÝŒÐ –æ ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌSmoking€plant€material€is€a€special€way€of€delivering€psychoactive€drugs€to€the€brain.€€SmokingÏhas€different€behavioral€and€physiologic€consequences€than€oral€or€IV€administration.€€What€isÏwell€known€about€tobacco€(nicotine)€and€coca€(cocaine)€clinical€psychopharmacology€andÏtoxicity€illustrates€this€point€all€too€well.€€When€marijuana€is€smoked,€THC€in€the€form€of€anÏaerosol€in€the€inhaled€smoke€is€absorbed€within€seconds€and€delivered€to€the€brain€rapidly€andÏefficiently€as€would€be€expected€of€a€very€lipid„soluble€drug.€€Peak€venous€blood€levels€of€75€toÏ150€nanograms€per€milliliter€(ng/mL)€of€plasma€appear€about€the€time€smoking€is€finishedÏ(Agurell€et€al.€1984,€1986;€Huestis€et€al.€1992òòaóó,€1992òòbóó).€€Arterial€concentrations€of€THC€haveÐ l Ðnot€been€measured€but€would€be€expected€to€be€much€higher€initially€than€venous€levels,€as€is€theÏcase€with€smoked€nicotine€or€smoked€cocaine.ÌÌOral€ingestion€of€THC€or€marijuana€is€quite€different€than€smoking.€€Maximum€THC€and€otherÏcannabinoid€blood€levels€are€only€reached€1€to€3€hours€after€an€oral€dose€(Adams€and€MartinÏ1996;€Agurell€et€al.€1984,€1986).€€Onset€of€psychoactive€and€other€pharmacologic€effects€is€rapidÏafter€smoking€but€much€slower€after€oral€doses.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚Õ#’ÝÝ  ÝMarijuana€Smoking€Behavior€and€Dose€Control݃Õ#’’݌РŒ'Ü"% ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌAs€with€any€smoked€drug€(e.g.,€nicotine€or€cocaine),€characterizing€the€pharmacokinetics€of€THCÏand€other€cannabinoids€from€smoked€marijuana€is€a€challenge€(Agurell€et€al.€1986;€Heishman€etÏal.€1989;€Herning€et€al.€1986;€Heustis€et€al.€1992òòaóó).€€A€personððs€smoking€behavior€during€anÐ b+²&) Ðexperiment€is€difficult€for€a€researcher€to€control.€€People€differ.€€Smoking€behavior€is€not€easilyÏquantified.€€An€experienced€marijuana€smoker€can€titrate€and€regulate€dose€to€obtain€the€desiredÏacute€psychological€effects€and€to€avoid€overdose€and/or€minimize€undesired€effects.€€Each€puffÐ 2.‚), Ðdelivers€a€discrete€dose€of€THC€to€the€body.€€Puff€and€inhalation€volume€changes€with€phase€ofÏsmoking,€tending€to€be€highest€at€the€beginning€and€lowest€at€the€end€of€smoking€a€cigarette.€ÏSome€studies€found€frequent€users€to€have€higher€puff€volumes€than€did€less€frequent€marijuanaÏÔ#ccddÔusers.€€During€smoking,€as€the€cigarette€length€shortens,€the€concentration€of€THC€in€the€remainingÔ#ddccÒ–ÔÐ €Ð Ðmarijuana€increases;€thus,€each€successive€puff€contains€an€increasing€concentration€of€THC.ÌÌÔ#ccddÔOne€consequence€of€this€complicated€process€is€that€an€experienced€marijuana€smoker€can€regulateÔ#ddccЗÔÐ P   Ðalmost€on€a€puff„by„puff€basis€the€dose€of€THC€delivered€to€lungs€and€thence€to€brain.€€A€lessÏÔ#aaddÔexperienced€smoker€is€more€likely€to€overdose€or€underdose.€€Thus€a€marijuana€researcher€attemptingÔ#ddaa̘ÔÐ 0 € Ðto€control€or€specify€dose€in€a€pharmacologic€experiment€with€smoked€marijuana€has€only€partialÏcontrol€over€drug€dose€actually€delivered.€€Postsmoking€assay€of€cannabinoids€in€blood€or€urineÏcan€partially€quantify€dose€actually€absorbed€after€smoking,€but€the€analytic€procedures€areÏmethodologically€demanding,€and€only€in€recent€years€have€they€become€at€all€practical.ÌÌAfter€smoking,€venous€blood€levels€of€THC€fall€precipitously€within€minutes,€and€an€hour€laterÏthey€are€about€5€to€10€percent€of€the€peak€level€(Agurell€et€al.€1986;€Huestis€et€al.€1992òòaóó,€1992òòbóó).€Ð À ÐPlasma€clearance€of€THC€is€quite€high,€950€milliliters€per€minute€(mL/min)€or€greater;€thusÏapproximating€hepatic€blood€flow.€€However,€the€rapid€disappearance€of€THC€from€blood€isÏlargely€due€to€redistribution€to€other€tissues€in€the€body€rather€than€simply€because€of€rapidÏcannabinoid€metabolism€(Agurell€et€al.€1984,€1986).€€Metabolism€in€most€tissues€is€relativelyÏslow€or€absent.€€Slow€release€of€THC€and€other€cannabinoids€from€tissues€and€subsequentÏmetabolism€makes€for€a€very€long€elimination€half„time.€€The€terminal€half„life€of€THC€isÏestimated€to€be€from€about€20€hours€to€as€long€as€10€to€13€days,€though€reported€estimates€varyÏas€expected€with€any€slowly€cleared€substance€and€the€use€of€assays€with€varied€sensitivity.ÌÌCannabinoid€metabolism€is€extensive€with€at€least€80€probably€biologically€inactive€but€notÏcompletely€studied€metabolites€formed€from€THC€alone€(Agurell€et€al.€1986;€¢Hollister£€¢1988òòa£óó).€Ð ` Ð11„hydroxy„THC€is€the€primary€active€THC€metabolite.€€Some€inactive€carboxy€metabolitesÏhave€terminal€half„lives€of€50€hours€to€6€days€or€more€and€thus€serve€as€long€persistence€markersÏof€prior€marijuana€use€by€urine€tests.€€Most€of€the€absorbed€THC€dose€is€eliminated€in€feces€andÏabout€33€percent€in€urine.€€THC€enters€enterohepatic€circulation€and€undergoes€hydroxylationÏand€oxidation€to€11„nor„9„carboxy„delta„9„THC€(9„COOH„ð¬ðòò9óó„THC).€€The€glucuronide€isÐ À! Ðexcreted€as€the€major€urine€metabolite€along€with€about€18€nonconjugated€metabolites.€€FrequentÏand€infrequent€marijuana€users€are€similar€in€the€way€they€metabolize€THC€(Agurell€et€al.€1986;ÏKelly€and€Jones€1992).ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕA¢ÝÝ  ÝRoute€of€Use€Bioavailability€and€Dose݃ÕA¢¢ÝŒÐ p&À!$ ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌTHC€bioavailability,€i.e.,€the€actual€absorbed€dose€as€measured€in€blood,€from€smoked€marijuanaÏvaries€greatly€among€individuals.€€Bioavailability€can€range€from€1€percent€to€24€percent€with€theÏfraction€absorbed€rarely€exceeding€10€percent€to€20€percent€of€the€THC€in€a€marijuana€cigaretteÏÔ#ccddÔor€pipe€(Agurell€et€al.€1986;€¢Hollister£€¢1988òòa£óó).€€This€relatively€low€and€quite€variable€¢bioavailability£Ô#ddcc~¤ÔÐ 6+†&) Ðresults€from€significant€loss€of€THC€in€sidestream€smoke,€from€variation€in€individual€smokingÏbehaviors,€from€incomplete€absorption€from€inhaled€smoke,€and€from€metabolism€in€lung€andÏcannabinoid€pyrolysis.€€A€smokerððs€experience€is€probably€an€important€determinant€of€doseÐ .V), Ðactually€absorbed€(Herning€et€al.€1986;€Johansson€et€al.€1989).€€Much€more€is€known€about€theÏdynamics€of€tobacco€(nicotine)€smoking.€€Many€of€the€same€pharmacokinetic€considerationsÏapply€to€marijuana€smoking.ÌÌOral€bioavailability€of€THC,€whether€given€in€the€pure€form€or€as€THC€in€marijuana,€also€is€lowÏand€extremely€variable,€ranging€between€5€percent€and€20€percent€(Agurell€et€al.€1984,€1986).€ÏGreat€variation€can€occur€even€when€the€same€individual€is€repeatedly€dosed€under€controlledÏand€ideal€conditions.€€THCððs€low€and€variable€oral€bioavailability€is€largely€a€consequence€ofÏÔ#ccddÔlarge€first„pass€hepatic€elimination€of€THC€from€blood€and€due€to€erratic€absorption€from€stomachÔ#ddcc«¨ÔÐ 0 € Ðand€bowel.€€Because€peak€effects€are€slow€in€onset€and€variable€in€intensity,€typically€at€least€anÏhour€or€two€after€an€oral€dose,€it€is€more€difficult€for€a€user€to€titrate€dose€than€with€marijuanaÏsmoking.€€When€smoked,€THCððs€active€metabolite€11„hydroxy„THC€probably€contributes€littleÏÔ#ccddÔto€the€effects€since€relatively€little€is€formed,€but€after€oral€doses€the€amounts€of€11„hydroxy„THCÔ#ddccnªÔÐ ð@  Ðmetabolite€may€exceed€that€of€THC€and€thus€contribute€to€the€pharmacologic€effects€of€oral€THCÏor€marijuana.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚Õ}«ÝÝ  ÝMental€and€Behavioral€Effects݃Õ}«Ù«ÝŒÐ ° ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌÝ‚"9ÿÝÔ€(XnXXX €ÔÝ  ÝòòÝ‚"9¬ÝÝ  ÝCommon€Acute€Effectsóó݃"9¬Ì¬ÝŒÐ ¦ö ЌԀX €XX(XnÔÝ  ÝÌUsually€the€mental€and€behavioral€effects€of€marijuana€consist€of€a€sense€of€well„being€(oftenÏtermed€euphoria€or€a€high),€feelings€of€relaxation,€altered€perception€of€time€and€distance,Ïintensified€sensory€experiences,€laughter,€talkativeness,€and€increased€sociability€when€taken€inÏasocial€setting.€€Impaired€memory€for€recent€events,€difficulty€concentrating,€dreamlike€states,Ïimpaired€motor€coordination,€impaired€driving€and€other€psychomotor€skills,€slowed€reactionÏÔ#ccddÔtime,€impaired€goal„directed€mental€activity,€and€altered€peripheral€vision€are€common€associatedÔ#ddcc6¯ÔÐ 6† Ðeffects€(Adams€and€Martin€1996;€Fehr€and€Kalant€1983;€¢Hollister£€¢1988òòa£óó;€Institute€of€MedicineÐ &v Ð1982;€Tart€1971).ÌÌWith€repeated€exposure,€varying€degrees€of€tolerance€rapidly€develops€to€many€subjective€andÏphysiologic€effects€(Fehr€and€Kalant€1983;€Jones€1987).€€Thus,€intensity€of€acute€effects€isÏdetermined€not€only€by€THC€dose€but€also€by€past€experience,€setting,€expectations,€and€poorlyÏunderstood€individual€differences€in€sensitivity.€€After€a€single€moderate€smoked€dose€mostÏmental€and€behavioral€effects€are€easily€measurable€for€only€a€few€hours€and€are€usually€noÏlonger€measurable€after€4€to€6€hours€(¢Hollister£€¢1986òòa£óó,€¢1988òòa£óó).€€A€few€published€reports€describeÐ ¦$ö" Ðlingering€cognitive€or€behavioral€changes€24€hours€or€so€after€a€single€smoked€or€oral€dose€(FehrÏand€Kalant€1983;€Institute€of€Medicine€1982;€Yesavage€et€al.€1985).€€Venous€blood€levels€ofÏTHC€or€other€cannabinoids€correlate€poorly€with€intensity€of€effects€and€character€of€intoxicationÏ(Agurell€et€al.€1986;€Barnett€et€al.€1985;€Huestis€et€al.€1992òòaóó).Ð f(¶#& ÐÌÝ‚"9ÿÝÔ€(XnXXX €ÔÝ  ÝòòÝ‚"98´ÝÝ  ÝAdverse€Mental€Effectsóó݃"98´u´ÝŒÐ F*–%( ЌԀX €XX(XnÔÝ  ÝÌÔ#ccddÔLarge€smoked€or€oral€marijuana€doses€or€even€ordinary€doses€taken€by€a€sensitive,€inexperiencedÔ#ddccµÔ,Ð &,v'* Ðor€predisposed€person€can€produce€transient€anxiety,€panic,€feelings€of€depression€and€otherÏÔ#aaddÔdysphoric€mood€changes,€depersonalization,€bizarre€behaviors,€delusions,€illusions,€or€hallucinationsÔ#ddaaÿµÔÐ .V), Ð(Adams€and€Martin€1996;€Fehr€and€Kalant€1983;€¢Hollister£€¢1986òòa£óó,€¢1988òòa£óó;€Institute€of€MedicineÐ ° Ð1982).€€Depending€on€the€mix€of€symptoms€and€behaviors,€the€state€has€been€termed€an€acuteÏpanic€reaction,€toxic€delirium,€acute€paranoid€state,€or€acute€mania.€€The€unpleasant€effects€areÏusually€of€sudden€onset,€during€or€shortly€after€smoking,€or€appear€more€gradually€an€hour€orÏtwo€after€an€oral€dose,€usually€last€a€few€hours,€less€often€a€few€days,€and€completely€clearÏÔ#ccddÔwithout€any€specific€treatment€other€than€reassurance€and€a€supportive€environment.€€A€subsequentÔ#ddccœ¸ÔÐ ` ° Ðmarijuana€dose,€particularly€a€lower€one,€may€be€well€tolerated.€€In€a€large€survey€of€regularÏmarijuana€users,€17€percent€of€young€adult€respondents€reported€experiencing€at€least€one€of€theÏpreceding€symptoms€during€at€least€one€occasion€of€marijuana€use,€usually€early€in€their€useÏ(Tart€1971).ÌÌWhether€marijuana€can€produce€or€trigger€lasting€mood€disorders€(depression€or€mania)€orÏschizophrenia€is€less€clearly€established€(Fehr€and€Kalant€1983;€Gruber€and€Pope€1994;€¢Hollister£Ï¢1986òòa£óó,€¢1988òòa£óó;€Institute€of€Medicine€1982).€€A€psychotic€state€with€schizophrenic„like€and€manicÐ à0  Ðfeatures€lasting€a€week€or€more€has€been€described.€€Marijuana€can€clearly€worsen€schizophrenia.€ÏChronic€marijuana€use€can€be€associated€with€behavior€characterized€by€apathy€and€loss€ofÏmotivation€along€with€impaired€educational€performance€even€without€obvious€behavioralÏchanges€(Pope€and€Yurgelun„Todd€1996;€Pope€et€al.€1995).€€The€explanation€and€mechanisms€forÏthis€association€are€still€not€well€established.ÌÌÝ‚"9ÿÝÔ€(XnXXX €ÔÝ  ÝòòÝ‚"9G½ÝÝ  ÝCardiovascular€and€Autonomic€Effectsóó݃"9G½„½ÝŒÐ pÀ ЌԀX €XX(XnÔÝ  ÝÌA€consistent,€prominent,€and€sudden€effect€of€marijuana€is€a€20€to€100€percent€increase€in€heartÏrate€lasting€up€to€2€to€3€hours€(¢Hollister£€¢1986òòa£óó,€¢1988òòa£óó;€Jones€1985).€€After€higher€smoked€or€oralÐ @ Ðdoses€postural€hypotension€and€associated€faintness€or€dizziness€can€occur€upon€standing€upÏfrom€a€supine€or€prone€position.€€Tolerance€to€these€effects€appears€after€only€a€few€days€of€twoÏto€three€times€per€day€dosing€(Benowitz€and€Jones€1981;€Jones€1985).€€Typical€is€a€modestÏÔ#ccddÔincrease€in€supine€blood€pressure.€€Cardiac€output€can€increase€30€percent€when€supine.€€PeripheralÔ#ddcc$ÀÔÐ P Ðvascular€resistance€decreases€with€the€greatest€drop€in€resistance€in€skeletal€muscles.€€SkinÏtemperature€drops€are€large;€4€to€6€degrees€centigrade,€even€after€a€modest€smoked€dose€andÏroughly€parallel€to€plasma€norepinephrine€increases.€€With€a€few€days€of€repeated€exposure€toÏfrequent€doses€of€oral€THC€or€marijuana€extract,€supine€blood€pressure€falls,€the€sometimesÏmarked€initial€orthostatic€hypotension€disappears,€blood€volume€increases,€and€heart€rate€slowsÏ(Benowitz€and€Jones€1981).€€Thus€like€other€system€effects,€the€intensity€and€character€of€manyÏhemodynamic€effects€of€single€smoked€doses€in€humans€are€a€function€of€recent€marijuanaÏexposure,€dose,€and€even€body€position.ÌÌThe€cardiovascular€effects€of€smoked€or€oral€marijuana€have€not€presented€any€health€problemsÏÔ#ccddÔfor€healthy€and€relatively€young€users.€€However,€marijuana€smoking€by€older€patients,€particularlyÔ#ddcc×ÃÔÐ P( #& Ðthose€with€some€degree€of€coronary€artery€or€cerebrovascular€disease,€is€likely€to€pose€greaterÏÔ#aaddÔrisks€because€of€the€resulting€increased€cardiac€work,€increased€catecholamines,€¢carboxyhemoglobin£Ô#ddaa×ÄÔ,Ð 0*€%( Ðand€postural€hypotension€(Benowitz€and€Jones€1981;€¢Hollister£€¢1988òòa£óó).€€Such€issues€have€notÐ  +p&) Ðbeen€well€addressed€in€past€marijuana€research.ÌÌÐ  ð-@), ÐÝ‚"9ÿÝÔ€(XnXXX €ÔÝ  ÝòòÝ‚"98ÆÝÝ  ÝRespiratory€System€Effectsóó݃"98ÆuÆ݌Р° ЌԀX €XX(XnÔÝ  ÝÌPulmonary€effects€associated€with€marijuana€smoking€include€transient€bronchodilation€afterÏacute€exposure.€€Chronic€bronchitis€and€pharyngitis€are€associated€with€repeated€exposure€withÏan€increased€frequency€of€pulmonary€illness.€€With€chronic€marijuana€smoking,€large„airwayÏobstruction€is€evident€on€pulmonary€function€tests,€and€cellular€inflammatory€histopathologicalÏabnormalities€appear€in€bronchial€epithelium€(Adams€and€Martin€1996;€Hollister€1986òòaóó).€€TheseÐ P   Ðeffects€appear€to€be€additive€to€those€produced€by€tobacco€smoking.ÌÌÝ‚"9ÿÝÔ€(XnXXX €ÔÝ  ÝòòÝ‚"9<ÉÝÝ  ÝEndocrine€Systemóó݃"9<ÉyÉ݌Р p  ЌԀX €XX(XnÔÝ  ÝÌEndocrine€system€effects€include€a€moderate€depression€of€spermatogenesis€and€sperm€motilityÏand€a€decrease€in€plasma€testosterone€in€males.€€Prolactin,€FSH,€LH,€and€GH€levels€are€decreasedÏÔ#ccddÔin€females.€€Although€suppressed€ovulation€and€other€ovulatory€cycle€changes€occur€in€nonhumanÔ#ddccÁÊÔÐ à0  Ðprimates,€a€study€of€human€females€smoking€marijuana€in€a€research€hospital€setting€did€not€findÏhormone€or€menstrual€cycle€changes€like€those€in€the€monkeys€given€THC€(Mendelson€andÏMello€1984;€Mendelson€et€al.€1984òòaóó).€€Relatively€little€research€has€been€done€on€experimentallyÐ ° Ðadministered€marijuana€effects€on€human€female€endocrine€and€reproductive€system€function.ÌÌÝ‚"9ÿÝÔ€(XnXXX €ÔÝ  ÝòòÝ‚"9êÌÝÝ  ÝImmune€Systemóó݃"9êÌ'Í݌Р€Ð ЌԀX €XX(XnÔÝ  ÝÌÔ#ccddÔTHC€and€other€cannabinoids€in€marijuana€have€immunosuppressant€properties€producing€impairedÔ#ddcc®ÍÔÐ `° Ðcell„mediated€and€humoral€immune€system€responses.€€A€large€literature€describes€the€results€ofÏexperiments€with€animal€and€animal€tissue€in€in€vivo€and€in€vitro€model€systems.€€THC€and€otherÏcannabinoids€suppress€antibody€formation,€cytokine€production,€leukocyte€migration€and€naturalÏkiller„cell€activity.€€Cannabinoids€decrease€host€resistance€to€infection€from€bacterial€and€viralÏinfection€in€animals.€€Marijuana€smokers€show€evidence€of€impaired€immune€function:€€forÏexample,€decreased€leukocyte€blastogenesis€in€response€to€mitogens.€€Marijuana€smokers,€whenÏcompared€to€nonmarijuana€smokers,€have€more€respiratory€illness€(Polen€et€al.€1993).ÌÌÔ#ccddÔThe€cannabinoids€have€been€characterized€as€immunomodulators€because€although€they€generallyÔ#ddccÕÐÔÐ Ð  Ðsuppress,€they€occasionally€enhance€some€immune€responses€(Friedman€et€al.€1995).€€Reviews€ofÏmarijuana€immune€system€effects€have€characterized€the€effects€as€complicated€or€conflicting€orÏcontroversial€(Adams€and€Martin€1996;€¢Hollister£€¢1988òòb£óó).€€The€clinical€significance€or€relevanceÐ  #ð! Ðof€these€findings€remains€uncertain.€€Much€of€the€complexity€and€controversy€results€from€theÏuse€of€mostly€in€vitro€animal€models,€or€in€vitro€animal€and€human€cell€cultures,€or€in€vivoÏanimal€studies.€Generally€in€most€studies€the€cannabinoid€doses€or€concentrations€used€have€beenÏquite€high€when€compared€to€reasonable€levels€of€exposure€in€human€marijuana€smoking.€€ÌÌSuppressed€or€impaired€immune€mechanisms€would€likely€have€negative€effects€on€health€byÏincreasing€susceptibility€to€infection€or€to€tumors.€€People€with€compromised€immune€systems€orÏÔ#aaddÔexisting€malignancies€may€be€at€higher€risk€than€healthy€people.€€For€example,€the€risk€of€developingÔ#ddaaØÔÔÐ  +p&) ÐÔ#ccddÔAIDS€may€be€higher€with€HIV€infection,€with€a€higher€risk€for€infection€by€opportunistic€bacteriaÔ#ddcczÕÔ,Ð ,`'* Ðâ âfungi,€or€viruses.€€On€the€other€hand,€some€have€suggested€that€the€immunosuppressive€effects€ofÐ -P(+ Ðcannabinoids€might€be€useful€clinically;€for€example,€in€treating€multiple€sclerosis,€mostlyÏreasoning€from€theoretical€assumptions€or€experimental€disease€models€in€animals.Ìâ âÌÔ#aaddÔIn€summary,€there€is€good€evidence€that€THC€and€other€cannabinoids€can€impair€both€cell„mediatedÔ#ddaaR×ÔÐ €Ð Ðand€humoral€immune€system€functioning,€leading€to€decreased€resistance€to€infection€by€virusesÏand€bacteria.€€However,€the€health€relevance€of€these€findings€to€human€marijuana€use€remainsÏuncertain.€€Conclusive€evidence€for€increased€malignancy,€or€enhanced€acquisition€of€HIV,€or€theÏdevelopment€of€AIDS,€has€not€been€associated€with€marijuana€use.ÌÌThere€is€a€need€for€further€research,€particularly€in€circumstances€where€long„term€administrationÏof€marijuana€might€be€considered€for€therapeutic€purposes;€for€example,€in€individuals€who€areÏHIV„positive€or€who€have€tumors,€malignancies,€or€diseases€where€immune€system€function€mayÏbe€important€in€the€genesis€of€the€disease.€€Clinical€studies€with€smoked€marijuana€in€patientsÏwith€compromised€immune€systems€may€offer€a€sensitive€index€of€adverse€immune€systemÏeffects€associated€with€cannabinoid€exposure.€€Direct€measures€of€viral€load€and€other€sensitiveÏindices€of€immune€system€function€are€now€more€practical€than€in€past€years€when€most€of€theÏÔ#ccddÔcannabinoid€immune€system€research€was€carried€out.€€The€possibility€that€frequent€and€prolongedÔ#ddccàÛÔÐ ° Ðmarijuana€use€might€lead€to€clinically€significant€impairments€of€immune€system€function€isÏgreat€enough€that€such€studies€should€be€part€of€any€marijuana€medication€development€research,Ïparticularly€when€marijuana€will€be€used€by€patients€with€compromised€immune€systems.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕÝÝÝ  ÝTolerance€and€Physical€Dependence݃ÕÝìÝ݌Р`° ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌAfter€repeated€smoked€or€oral€marijuana€doses,€marked€tolerance€is€rapidly€acquired€(after€a€dayÏor€two)€to€many€marijuana€effects,€e.g.,€cardiovascular,€autonomic,€and€many€subjective€effects.€ÏAfter€exposure€is€stopped,€tolerance€is€lost€with€similar€rapidity€(Jones€et€al.€1981).€€MeasurableÏÔ#aaddÔtolerance€or€tachyphalaxis€is€evident€for€some€hours€after€smoking€even€a€single€marijuana€cigaretteÔ#ddaaÍßÔ.Ð &v ÐÌWithdrawal€symptoms€and€signs€appearing€within€hours€after€cessation€of€repeated€marijuanaÏuse€have€been€occasionally€reported€by€patients€in€clinical€settings€(Duffy€and€Milin€1996;ÏMendelson€et€al.€1984òòbóó).€€A€withdrawal€syndrome€was€reliably€produced€by€as€little€as€5€days€ofÐ æ 6 Ðmodest€but€frequent€oral€doses€of€THC€or€marijuana€extract€in€double„blind,€placebo„controlledÏexperiments€(Jones€et€al.€1981).€€THC€decreased€or€relieved€the€symptoms.€€Typical€symptomsÏand€signs€were€restlessness,€insomnia,€irritability,€salivation,€tearing,€nausea,€diarrhea,€increasedÏbody€temperature,€anorexia,€weight€loss,€tremor,€sweating,€sleep€brainwave€rapid€eye€movementÏÔ#aaddÔrebound,€and€subjective€sleep€disturbance.€€Increased€dreaming€contributing€to€the€sleep€disturbanceÔ#ddaa ãÔÐ –%æ # Ðsometimes€persisted€for€weeks,€but€the€other€signs€and€symptoms€were€gone€or€markedlyÏdiminished€within€48€hours€after€the€last€oral€marijuana€dose.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕWäÝÝ  ÝDrug€Interactions€With€Marijuana݃ÕWä³ä݌РV)¦$' ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  Ýò òÌó óTobacco,€ethanol,€and€other€psychoactive€and€therapeutic€drugs€commonly€consumed€togetherÐ L+œ&) Ðwith€marijuana€share€metabolic€pathways€with€cannabinoids,€so€metabolic€interactions€are€likely.€ÏBoth€THC€and€CBD€inhibit€the€metabolism€of€drugs€metabolized€by€hepatic€mixed„functionÏoxidase€enzymes€(Benowitz€and€Jones€1977;€Benowitz€et€al.€1980;€Hollister€1986òòbóó).Ð .l), ЇThe€absorption€or€clearance€of€other€drugs€taken€with€marijuana€may€be€slowed€or€hastenedÏdepending€on€timing€and€sequence€of€drug€ingestion€and€past€exposure.€€For€example,€ethanolÏconsumed€just€after€smoking€a€marijuana€cigarette€produces€a€much€lower€peak€blood€level€thanÏthe€same€dose€of€ethanol€taken€an€hour€before€marijuana€smoking€because€THC€slows€gastricÏemptying€time,€thus€slowing€absorption€of€ethanol.ÌÌTHC€is€highly€bound€to€plasma€proteins€(97€percent€to€99€percent)€and€thus€is€likely€to€interactÏwith€other€highly€bound€drugs€because€of€competition€for€binding€sites€on€plasma€proteins.ÌÌFinally,€there€is€experimental€evidence€for€drug€interactions€at€the€functional€(neural)€adaptationÏlevel€(Adams€and€Martin€1996).ÌÌBy€those€and€possibly€by€other€mechanisms,€recent€or€concurrent€THC€or€CBD€exposureÏmeasurably€alters€the€pharmacokinetics€and/or€effects€of€ethanol,€barbiturates,€nicotine,Ïamphetamines,€cocaine,€phencyclidine,€opiates,€atropine,€and€clomipramine€(Fehr€and€KalantÏ1983;€Institute€of€Medicine€1982).€€Marijuana€use€is€likely€to€alter€the€pharmacology€of€someÏconcurrently€used€therapeutic€drugs,€e.g.,€cancer€chemotherapeutic€agents€or€anticonvulsants.ÌÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚Õ¯ëÝÝ  Ý¢Cannabinoid£€Receptors݃կë ì݌Рà ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌMechanisms€of€psychoactive€cannabinoid€action€were€long€suspected€to€be€through€interactionsÏof/with€lipid€components€of€cell€membranes€(Adams€and€Martin€1996;€¢Hollister£€¢1988òòa£óó).€€TheÐ vÆ Ðdiscovery€of€cannabinoid€receptors€in€the€human€brain€in€the€late€1980s€led€to€renewed€interest€inÏthe€pharmacology€and€potential€therapeutic€uses€of€cannabinoids€(Adams€and€Martin€1996;ÏHerkenham€1992).€€The€mechanisms€of€action€of€THC€are€now€assumed€to€be€mainly€receptorÏmediated.€€So€far,€it€still€is€a€relatively€simple€receptor€family€(CB€1€and€CB€2).€€Receptors€areÏÔ#aaddÔabundant€in€brain€areas€concerned€with€memory,€cognition,€and€motor€coordination.€€An€endogenousÔ#ddaaïÔÐ &v Ðligand,€a€fatty€acid€derivative€named€anandamide,€has€been€identified€but€not€yet€studied€inÏhumans€(Thomas€et€al.€1996).€€A€specific€THC€antagonist,€SR141716A,€provokes€intenseÏwithdrawal€signs€and€behaviors€in€rodents€that€have€been€exposed€to€THC€for€even€relativelyÏbrief€periods€(Adams€and€Martin€1996).€€The€clinical€pharmacology€of€the€antagonist€has€notÏbeen€studied€in€humans.ÌÐ  Æ"  ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þ=ñÝà@KK%ìàÝ  ÝReferencesóó݃„þ=ñ™ñÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‘™X°,X°‚,` ˜X6Óà0 ‘ àà ° àAdams,€I.B.,€and€Martin,€B.R.€Cannabis:€Pharmacology€and€toxicology€in€animals€and€humans.ÏòòAddictionóó€91(11):1585-1614,€November€1996.к ‘(#‘(# Ðà0 ‘ àà ° àAgurell,€S.,€Dewey,€W.L.,€and€Willett,€R.E.,€eds.€òòThe€Cannabinoids:€Chemical,€Pharmacologic,Ð ªú Ðand€Therapeutic€Aspectsóó.€New€York:€Academic€Press,€1984.Ô‡X/XXX €ÔК ê‘(#‘(# Ðà0 ‘ àà ° 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€ÔÐè 8 ‘(#‘(# Ðà0 ‘ àà ° àJohansson,€E.;€Halldin,€M.M.;€Agurell,€S.;€Hollister,€L.E.;€and€Gillespie,€H.K.€TerminalÏelimination€plasma€half-life€of€delta€1-tetrahydrocannabinol€(delta€1-THC)€in€heavy€users€ofÏmarijuana.€òòEur€J€Clin€Pharmacolóó€37(3):273-277,€1989.Ьü ‘(#‘(# Ðà0 ‘ àà ° àJones,€R.T.€Drug€of€abuse€profile:€Cannabis.€òòClin€Chemóó€33€(11€Suppl):72B-81B,€October€1987.Ð˜è ‘(#‘(# Ðà0 ‘ àà ° àJones,€R.T.€Cardiovascular€effects€of€cannabinoids.€In:€Harvey,€D.J.,€ed.€òòMarihuana,€'84:Ð „Ô  ÐProceedings€of€the€Oxford€Symposium€on€Cannabis.óó€Oxford:€IRL€Press,€1985.€pp.€325-334.ÐpÀ‘(#‘(# Ðà0 ‘ àà ° àJones,€R.T.;€Benowitz,€N.L.;€and€Herning,€R.I.€Clinical€relevance€of€cannabis€tolerance€andÏdependence.€òòJ€Clin€Pharmacolóó€21:143S-152S,€1981.ÐH˜‘(#‘(# Ðà0 ‘ àà ° àKelly,€P.,€and€Jones,€R.T.€€Metabolism€of€tetrahydrocannabinol€in€frequent€and€infrequentÏmarijuana€users.€òòJ€Anal€Toxicolóó€16:228-235,€1992.Ð p‘(#‘(# ÐÔ#†X €XXX/ #ÔÔ‡X/XXX €Ôà0 ‘ àà ° àMechoulam,€R.,€ed.€òòMarijuana:€Chemistry,€Pharmacology,€Metabolism€and€Clinical€Effects.óóÐ  \ ÐNew€York:€Academic€Press,€1973.Ð ‘(#‘(# ÐÔ#†X €XXX/Ì#ÔÔ‡X/XXX €Ôà0 ‘ àà ° àMechoulam,€R.;€Devane,€W.A.;€Breuer,€A.;€and€Zahalka,€J.€A€random€walk€through€a€cannabisÐ ä4 Ðfield.€Special€Issue:€Pharmacological,€chemical,€biochemical€and€behavioral€research€onÏcannabis€and€the€cannabinoids.€òòPharmacol€Biochem€Behavóó€40(3):461-464,€November€1991.м ‘(#‘(# Ðà0 ‘ àà ° àMendelson,€J.H.,€and€Mello,€N.K.€Effects€of€marijuana€on€neuroendocrine€hormones€in€humanÏmales€and€females.€In:€Braude,€M.C.,€and€Ludford,€J.P.,€eds.€òòMarijuana€Effects€on€theÐ ”ä ÐEndocrine€and€Reproductive€Systems.óó€National€Institute€on€Drug€Abuse€Research€MonographÐ €Ð Ð44.€DHHS€Pub.€No.€(ADM)84„1278.€Washington,€DC:€Supt.€of€Docs.,€U.S.€Govt.€Print.€Off.,Ï1984.€pp.€97-114.Ð ‘(#‘(# Ðà0 ‘ àà ° àMendelson,€J.H.;€Mello,€N.K.;€Cristofaro,€P.;€Ellingboe,€J.;€and€Benedikt,€R.€Acute€effects€ofÏmarijuana€on€pituitary€and€gonadal€hormones€during€the€periovulatory€phase€of€the€menstrualÏcycle.€In:€Harris,€L.S.,€ed.€òòProblems€of€Drug€Dependence,€1984:€Proceedings€of€the€46òòthóóÐ #l! ÐAnnual€Scientific€Meeting,€The€Committee€on€Problems€of€Drug€Dependence,€Inc.€NationalÏInstitute€on€Drug€Abuse€Research€Monograph€55.óó€DHHS€Pub.€No.€(ADM)85„1393.Ð ô$D # ÐWashington,€DC:€Supt.€of€Docs.,€U.S.€Govt.€Print.€Off.,€1984òòaóó.€pp.€24-31.Ðà%0!$‘(#‘(# Ðà0 ‘ àà ° àMendelson,€J.H.;€Mello,€N.K.;€Lex,€B.W.;€and€Bavli,€S.€Marijuana€withdrawal€syndrome€in€aÏwoman.€òòAm€J€Psychiatryóó€141(10):1289-1290,€October€1984òòbóó.и'#&‘(#‘(# Ðà0 ‘ àà ° àPolen,€M.R.;€Sidney,€S.;€Tekawa,€I.S.;€Sadler,€M.;€and€Friedman,€G.D.€Health€care€use€byÏfrequent€marijuana€smokers€who€do€not€smoke€tobacco.€òòWest€J€Medóó€158(6):596„601,€JuneÐ )à$( Ð1993.Ð ‘(#‘(# Ðà0 ‘ àà ° àPope,€H.G.,€Jr.,€and€Yurgelun-Todd,€D.€The€residual€cognitive€effects€of€heavy€marijuana€use€inÏcollege€students.€òòJAMAóó€275(7):521-527,€February€21,€1996.ÐT,¤'+‘(#‘(# Ðà0 ‘ àà ° àPope,€H.G.;€Gruber,€A.J.;€and€Yurgelun-Todd,€D.€The€residual€neuropsychological€effects€ofÏcannabis:€The€current€status€of€research.€òòDrug€Alcohol€Dependóó€38(1):25-34,€April€1995.Ð,.|)-‘(#‘(# Ðà0 ‘ àà ° àTart,€C.T.€òòOn€Being€Stoned:€A€Psychological€Study€of€Marijuana€Intoxication.óó€Palo€Alto,€CA:Ð ° ÐScience€and€Behavior€Books,€1971.Ð ‘(#‘(# Ðà0 ‘ àà ° àThomas,€B.F.;€Adams,€I.B.;€Mascarella,€S.W.;€Martin,€B.R.;€and€Razdan,€R.K.€Structure-activityÏanalysis€of€anandamide€analogs:€Relationship€to€a€cannabinoid€pharmacophore.€òòJ€Med€ChemóóÐ tÄ Ð39(2):471-497,€January€19,€1996.Ð ‘(#‘(# Ðà0 ‘ àà ° àYesavage,€J.A.;€Leirer,€V.O.;€Denari,€M.;€and€Hollister,€L.E.€Carry-over€effects€of€marijuanaÏintoxication€on€aircraft€pilot€performance:€A€preliminary€report.€òòAm€J€PsychiatryóóÐ 8 ˆ Ð142(11):1325-1329,€November€1985.Ô#†X €XXX/Î#ÔÐ $ t‘(#‘(# ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þDÝà@ªª&ìàÝ  ÝAnalgesiaóó݃„þD ÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌòòÓ6°,X°‚,` ˜X°,X°‘™X6Ó1.à0 Ü àWhat€research€has€been€done€and€what€is€known€about€the€possible€medical€uses€ofÐ Ê Ðmarijuana?óóк Ü(#Ü(# ÐÌÓ/€d/ÓââAââ€â  ânumber€of€studies€have€been€conducted€on€the€antinociceptive€or€analgesic€effect€ofÐ š ê Ðâ ø(#ø(#°(#°(#âtetrahydrocannabinol€(THC)€or€marijuana€in€both€animals€and€human€subjects;€the€resultsÏâ °(#°(#ø(#ø(#âhave€been€conflicting.€€Of€interest€is€the€recent€identification€of€cannabinoid€receptors€as€well€asÏan€endogenous€ligand,€anandamide.€€There€is€some€evidence€that€they€are€part€of€a€natural€painÏcontrol€system€distinct€from€the€endogenous€opioid€system.€€Recognizing€that€some€studies€haveÏdemonstrated€an€antinociceptive€(analgesic)€effect€of€THC€and€related€compounds€in€rodents,€itÏmay€be€useful€to€identify€what€specific€kinds€of€pain€may€be€relieved€by€marijuana€or€THC.ÌÌAnimal€studies€on€the€analgesic€effect€of€marijuana€have€produced€inconsistent€results.€€WhereasÏone€study€shows€that€delta„9„tetrahydrocannibinol€(ðˆðòò9óó„THC)€is€equipotent€to€morphine€in€ratsÐ  Z  Ð(tailflick€test),€and€more€potent€than€morphine€in€mice€(hotplate€test),€other€studies€showed€thatÏðˆðòò9óó„THC€was€less€potent€than€morphine€in€both€mice€and€rats.€€Cannabinoids€have€been€shown€toÐ ê: Ðbe€possibly€analgesic€in€animal€models€of€neuropathic€pain.ÌÌÔ#ccddÔThere€have€been€a€few€studies€of€marijuana/ðˆðòò9óó„THC€employing€different€models€of€experimentallyÔ#ddccR#ÔÐ º  Ðinduced€pain€in€volunteer€subjects,€and€these€studies€have€also€yielded€conflicting€results.€€RaftÏÔ#ccddÔand€colleagues€(1977)€found€that,€in€oral€surgery€patients,€premedication€with€intravenous€ðˆðòò9óó„THCÔ#ddccY$ÔÐ šê Ðwas€less€effective€than€diazepam€or€placebo€in€reducing€two€kinds€of€experimentally€inducedÏpain.€€Another€study€showed€that€smoked€marijuana€increased€pain€tolerance,€while€othersÏÔ#aaddÔshowed€either€no€effect€or€a€lowering€of€pain€threshold€after€oral€or€intravenous€dosing€with€ðˆðòò9óó„THCÔ#ddaaµ%ÔÐ jº Ðor€smoking€marijuana.€€The€current€ð ðFDA€Guideline€for€the€Clinical€Evaluation€of€AnalgesicÐ Zª ÐDrugsðð€(FDA€1992)€notes€that€ð ðEvidence€is€still€inadequate€to€establish€that€any€experimentalÐ Jš ÐÔ#aaddÔpain€model€will€consistently€and€accurately€predict€the€clinical€efficacy€of€new€analgesics,€.€.€.€[andÔ#ddaaI'Ô]Ð :Š Ðthey€cannot€substitute€for€controlled€trials€in€patients€with€pathologic€pain€[naturally€occurringÏpain€caused€by€disease€or€tissue€injury]€in€producing€substantial€evidence€of€analgesia€.€.€.ðð€€ThisÐ  j Ðis€also€the€overwhelming€consensus€of€investigators€who€conduct€controlled€clinical€trials€ofÏanalgesic€efficacy.€€Therefore,€the€above€studies€contribute€little€information€about€the€analgesicÏefficacy€of€marijuana/ðˆðòò9óó„THC€in€patients€with€pain.Ð ê":  ÐÌThere€appear€to€be€no€controlled€analgesic€studies€of€smoked€marijuana€in€patients€with€naturallyÏoccurring€pain.€€However,€Noyes€and€his€colleagues€conducted€two€studies€of€oral€ðˆðòò9óó„THC€inÐ º% !# Ðinpatients€with€cancer€pain.€€Both€of€these€studies€used€the€same€standard€single„dose€analgesicÏstudy€methodology€and€met€the€criteria€for€well„controlled€clinical€trials€of€analgesic€efficacy,Ïbut€with€small€sample€sizes.€€Both€were€randomized,€double„blind,€crossover€comparisonsÏemploying€a€full„time€nurse„observer,€who€collected€hourly€subjective€ratings€of€pain€intensityÏand€pain€relief.€€Observed€and€reported€side€effects€were€recorded,€as€were€the€responses€to€anÏ11„item€subjective€effects€questionnaire.ÌÌÔ#aaddÔThe€first€study€in€10€cancer€patients€compared€a€placebo€and€5,€10,€15,€and€20€mg€doses€of€ðˆðòò9óó„THCÔ#ddaaÁ,ÔÐ :-Š(+ Ðover€a€6„hour€observation€period€(Noyes€et€al.€1975òòaóó).€€The€slope€of€the€dose„response€curve€forÐ *.z), Ðpain€relief€was€significant,€as€was€a€pairwise€comparison€of€pain€relief€after€the€two€lower€dosesÏÔ#ccddÔcombined€versus€the€two€higher€doses€combined.€€There€was€also€a€clear€dose„response€relationshipÔ#ddccF.ÔÐ  ð Ðfor€sedation,€mental€clouding,€and€other€central€nervous€system€(CNS)€related€side€effects.€ÏBecause€of€sedation,€the€20„mg€dose€was€judged€to€be€ð ðof€limited€value€for€most€patients.ððÐ €Ð ÐÌThe€second€study€in€36€cancer€patients€compared€placebo,€10,€and€20€mg€of€ðˆðòò9óó„THC€and€60€andÐ ` ° Ð120€mg€of€codeine€over€a€7„hour€observation€period€(Noyes€et€al.€1975òòbóó).€€Codeine€120€mg€andÐ P   Ððˆðòò9óó„THC€20€mg€were€similar€to€each€other€and€significantly€superior€to€placebo€for€the€sum€of€theÐ @  ÐÔ#ccddÔpain€intensity€differences€and€total€pain€relief,€while€other€pairwise€contrasts€were€not€significantÔ#ddcc%1Ô.€Ð 0 € ÐRelative€potency€analysis€was€not€performed.ÌÌThe€time„effect€curves€for€both€doses€of€codeine€and€for€ðˆðòò9óó„THC,€10€mg,€peaked€at€the€thirdÐ P  Ðhour.€€As€in€the€first€study,€the€20€mg€dose€of€ðˆðòò9óó„THC€peaked€at€the€fifth€hour,€which€probablyÐ ð@  Ðreflects€the€delayed€absorption€of€oral€THC.€€ð ðPatients€receiving€20€mg€of€THC€were€heavilyÐ à0  Ðsedated€and€even€at€10€mg€reported€considerable€drowsiness.€€Other€dose€limiting€side€effectsÏincluded€dizziness,€ataxia€and€blurred€visionðð€(Noyes€et€al.€1975òòbóó).€€Mental€clouding,€thinkingÐ À Ðimpairment,€disconnected€thought,€disorientation,€slurred€speech,€and€impaired€memory€wereÏmuch€more€prominent€after€both€doses€of€ðˆðòò9óó„THC€than€after€codeine€administration,€and€patientsÐ  ð Ðexpressed€particular€concern€over€their€ð ðloss€of€controlðð€over€thought€and€action.€€Five€patientsÐ à Ðexperienced€very€unpleasant€psychic€effects€after€ðˆðòò9óó„THC;€three€patients€said€they€felt€as€if€theyÐ €Ð Ðwere€dying,€one€patient€experienced€depressed€mood,€and€one€patient€suffered€paranoid€ideation.€ÏIn€two€patients,€the€adverse€mood€effects€persisted€3€or€4€days.ÌÌThese€studies€indicate€that€ðˆðòò9óó„THC€has€some€analgesic€activity€in€humans.€€They€also€indicateÐ @ Ðthat€there€is,€at€best,€a€very€narrow€therapeutic€window€between€doses€that€produce€usefulÏanalgesia€and€those€that€produce€unacceptable€adverse€CNS€effects.ÌÌòò2.à0 Ü àWhat€are€the€major€unanswered€scientific€questions?óóÐPÜ(#Ü(# ÐÌSince€oral€ðˆðòò9óó„THC€has€some€analgesic€activity,€it€is€highly€likely€that€smoked€marijuana€hasÐ à0 Ðsome€analgesic€activity€in€some€kinds€of€clinical€pain.€€Because€ðˆðòò9óó„THC€from€smoked€marijuanaÐ Ð  ÐÔ#ccddÔis€absorbed€directly€into€the€pulmonary€circulation,€this€route€of€administration€results€in€a€ðˆðòò9óó„THCÔ#ddcc'9ÔÐ À! Ðblood€level€curve€much€more€like€that€produced€by€an€intravenous€injection€than€that€after€oralÏadministration.€€It€is€therefore€likely€that€smoked€marijuana€potentially€allows€a€more€preciseÏtitration€to€effect€than€oral€administration€of€ðˆðòò9óó„THC€with€its€delayed,€poor,€and€erraticÐ $à" Ðbioavailability.€€Theoretically,€smoked€marijuana€or€inhaled€THC€potentially€has€some€of€theÏcharacteristics€of€a€patient„controlled€analgesia€(PCA)€pump.€€It€is€therefore€possible€that€someÏpain€patients€could€use€smoked€marijuana€to€titrate€themselves€into€the€therapeutic€window€ofÏadequate€pain€relief€while€avoiding€unacceptable€adverse€effects.€€Although€the€above€scenario€isÏpharmacologically€reasonable,€only€properly€designed€controlled€clinical€analgesic€studies€canÏdetermine€if€it€actually€works€and€is€practically€useful.€€For€example,€it€is€also€possible€that€theÏminimum€blood€level€of€ðˆðòò9óó„THC€that€produces€useful€analgesia€also€usually€produces€a€level€ofÐ  +p&) Ðsedation,€mental€clouding,€and€thinking€impairment€that€is€unacceptable€to€most€patients.Ìâ âÐ -P(+ ÐThere€are€currently€available€a€great€variety€of€both€opioid€and€nonsteroidal€anti„inflammatoryÏâ âÔ#aaddÔdrug€(NSAID)€analgesics€in€various€dosage€formulations€suitable€for€many€routes€of€administrationÔ#ddaa«>Ô.€Ð  ð ÐAdroit€use€of€these€can€manage€most€acute€pain€and€even€chronic€cancer€pain€satisfactorily.€€IfÏmarijuana€is€to€be€a€useful€analgesic,€healthcare€providers€need€to€know€how€it€compares€inÏefficacy€and€safety€to€at€least€a€few€of€the€standard€analgesics€that€would€be€used€in€managing€aÏparticular€kind€of€pain.ÌÌòò3.à0 Ü àWhat€are€the€diseases€or€conditions€for€which€marijuana€might€have€potential€as€a€treatmentÐ @  Ðand€which€merit€further€study?Ð Ü(#Ü(# ÐÌóóNeuropathic€pain€represents€a€treatment€problem€for€which€currently€available€analgesics€are,€atÐ `  Ðbest,€marginally€effective.€€Since€ðˆðòò9óó„THC€is€not€acting€by€the€same€mechanism€as€either€opioidsÐ P  ÐÔ#aaddÔor€NSAIDs,€it€may€be€useful€in€this€inadequately€treated€type€of€pain.€€Evaluation€of€¢cannabinoids£Ô#ddaa/BÔ€inÐ ð@  ÐÔ#ccddÔthe€management€of€neuropathic€pain,€including€HIV„associated€neuropathy,€should€be€undertakenÔ#ddccÓBÔ.€Ð à0  ÐA€few€animal€studies€support€this€idea.€€Another€potentially€useful€role€for€marijuana/ðˆðòò9óó„THCÐ Ð  Ðmight€be€as€an€adjuvant€when€added€to€a€regimen€of€standard€analgesics.Ð  À ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þIDÝà@KK%ìàÝ  ÝReferencesóó݃„þID¥DÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‘™X°,X°‚,` ˜X6Óòòà0 ‘ àà ° àFDA€Guideline€for€the€Clinical€Evaluation€of€Analgesic€Drugs.óó€DHHS€Pub.€No.€93„3093.Ð Ê ÐRockville,€MD:€U.S.€Department€of€Health€and€Human€Services,€Public€Health€Service,€FoodÏand€Drug€Administration,€1992.ò òЪú‘(#‘(# Ðó óà0 ‘ àà ° àNoyes,€R.,€Jr.;€Brunk,€S.F.;€Baram,€D.A.;€and€Canter,€A.€Analgesic€effect€of€delta„9„Ð š ê Ðtetrahydrocannabinol.€òòJ€Clin€Pharmacolóó€15(2„3):139„143,€February„March,€1975òòaóó.Њ Ú‘(#‘(# Ðà0 ‘ àà ° àNoyes,€R.,€Jr.;€Brunk,€S.F.;€Avery,€D.A.H.;€and€Canter,€A.C.€The€analgesic€properties€of€delta„9„¼tetrahydrocannabinol.€òòClin€Pharmacol€Theróó€18(1):84„89,€July,€1975òòbóó.Ðj º‘(#‘(# Ðà0 ‘ àà ° àRaft,€D.;€Gregg,€J.;€Ghia,€J.;€and€Harris,€L.€Effects€of€intravenous€tetrahydrocannabinol€onÏexperimental€and€surgical€pain.€òòClin€Pharmacol€Theróó€21(1):26„33,€1977.Ð Jš ‘(#‘(# ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þ}IÝà@hhìàÝ  ÝUse€of€Marijuana€in€Neurological€and€Movement€Disordersóó݃„þ}IÙIÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‚,` ˜X°,X°‘™X6Óòò1.à0 Ü àWhat€research€has€been€done€and€what€is€known€about€the€possible€medical€uses€ofÐ Ê Ðmarijuana?Ð Ü(#Ü(# ÐÌÓ/€d/ÓóóââTâââ  âhere€have€been€numerous€studies€both€in€animals€and€in€various€clinical€states€on€the€use€ofÐ š ê Ðâ ø(#ø(#°(#°(#âcannabinoids€on€neurological€and€various€movement€disorders.€€These€results€range€fromÏâ °(#°(#ø(#ø(#âanecdotal€reports€to€surveys€and€clinical€trials.€€Marijuana€or€tetrahydrocannabinol€(THC)€isÏreported€to€have€some€¢antispasticity£,€analgesic,€¢antitremor£,€and€¢antiataxia£€actions,€as€well€asÏsome€activity€in€multiple€sclerosis€(MS)€and€in€spinal€cord€injury€patients.ÌÌThe€spasticity€and€nocturnal€spasms€produced€by€MS€and€partial€spinal€cord€injury€have€beenÏreported€to€be€relieved€by€smoked€marijuana€and€to€some€extent€by€oral€THC€in€numerousÏanecdotal€reports.€€The€effect€seems€to€appear€rapidly€with€smoked€marijuana;€patients€are€ableÏto€titrate€the€dose€by€the€amount€they€smoke.€€No€large„scale€controlled€studies€or€studies€toÏcompare€either€smoked€or€oral€THC€with€other€available€therapies€have€been€reported.€€SeveralÏÔ#ccddÔrelatively€good€therapeutic€alternatives€exist.€€There€is€no€published€evidence€that€the€¢cannabinoid£Ô#ddccÇOÔÐ ê: Ðdrugs€are€superior€or€even€equivalent.ÌÌSubstantial€experimental€animal€literature€exists€showing€that€various€cannabinoids,€givenÏprimarily€by€parenteral€routes,€have€a€substantial€anticonvulsant€effect€in€the€control€of€variousÏmodels€of€epilepsy,€especially€generalized€and€partial€tonic„clonic€seizures.€€Scant€information€isÏavailable€about€the€human€experience€with€the€use€of€marijuana€or€cannabinoids€for€the€treatmentÏof€epilepsy.€€This€is€an€area€of€potential€value,€especially€for€cannabis€therapies€by€other€than€theÏsmoked€route.ÌÌSeveral€single€case€histories€have€been€reported€indicating€some€benefit€of€smoked€marijuana€forÏdystonic€states.€€It€must€be€remembered€that€dystonia€is€a€clinical€syndrome€with€numerousÏpotential€causes,€and€the€information€available€now€does€not€differentiate€which€causes€are€mostÏlikely€to€be€improved.€€Smoked€marijuana€and€oral€THC€have€been€tested€in€the€treatment€ofÏParkinsonððs€disease€and€Huntingtonððs€chorea€without€success.ÌÌThe€cannabinoids€also€have€been€used€as€experimental€immunologic€modifiers€to€treat€suchÏconditions€as€the€animal€models€of€experimental€allergic€encephalomyelitis€(EAE)€and€neuritis.€ÏParenteral€cannabinoids€have€been€successful€in€modifying€EAE€in€animals,€suggesting€thatÏ¢cannabinoids£€may€be€of€value€in€a€more€fundamental€way€by€altering€the€root€cause€of€a€diseaseÏÔ#ccddÔsuch€as€MS€rather€than€simply€treating€its€symptoms.€€Smoked€marijuana€would€not€be€acceptableÔ#ddccºUÔÐ ª&ú!$ Ðfor€such€a€role€because€of€the€variability€of€dose€with€the€smoked€route.ÌÌòò2.à0 Ü àWhat€are€the€major€unanswered€scientific€questions?Ðz)Ê$'Ü(#Ü(# ÐÌóóThe€discovery€of€dedicated€systems€of€central€nervous€system€(CNS)€neurons€approximatelyÐ Z+ª&) Ð8years€ago,€which€express€receptors€specific€for€the€cannabinoids,€is€of€major€scientific€interestÏand€importance.€€The€distribution€of€these€cannabinoid€receptor„bearing€neurons€correspondsÏwell€with€the€clinical€effects€of€smoked€marijuana;€for€instance,€their€presence€in€the€forebrainÐ *.z), Ðmay€relate€to€adverse€changes€in€short„term€memory,€but€perhaps€positively€in€the€control€ofÏepilepsy.€€Cannabinoid€receptors€in€the€brainstem€and€cerebellum€may€relate€to€the€recognizedÏ¢incoordination£€that€accompanies€smoked€marijuana€use.€€The€discovery€of€intrinsic€ligands€forÏthese€receptors€in€the€mammalian€brain€is€also€of€great€importance.€€This€system€of€cannabinoidÏreceptors€and€ligands€may€be€analogous€to€the€discovery€of€opiate€receptors€and€¢endorphins£,Ïwhich€linked€various€opium€derivatives€(heroin€and€morphine)€to€an€intrinsic€system€of€neuronsÏin€the€CNS.€€That€discovery€was€of€major€importance€for€pain€researchòò.óóÐ P   ÐÌThe€major€unanswered€scientific€questions€are:ÌÌÝ‚FcÿÝÝ  ÝÝ‚Fct[Ýð"ðà0 Ü àÝ  ÝHow€useful€is€smoked€marijuana€of€known€specific€potency€in€controlling€various€neurologicÐ `  Ðconditions?݃Fct[[݌РÜ(#Ü(# ÐŒÝ  ÝÌÝ‚FcÿÝÝ  ÝÝ‚Fcs\Ýð"ðà0 Ü àÝ  ÝIn€comparative€studies,€how€useful€is€smoked€marijuana€in€altering€objective€abnormalitiesÐ à0  Ðsuch€as€spasticity€versus€current€standard€therapies€that€have€already€been€approved€forÏhuman€use?݃Fcs\Ž\݌РÜ(#Ü(# ÐŒÝ  ÝÌÝ‚FcÿÝÝ  ÝÝ‚FcÊ]Ýð"ðà0 Ü àÝ  ÝCan€alternative€delivery€systems€(other€than€the€oral€route)€be€developed€to€provide€rapidityÐ  ð Ðof€action€with€more€safety€than€smoked€marijuana?݃FcÊ]å]݌РÜ(#Ü(# ÐŒÝ  ÝÌÝ‚FcÿÝÝ  ÝÝ‚Fcò^Ýð"ðà0 Ü àÝ  ÝCan€available€or€newly€developed€synthetic€cannabinoids€be€used€more€effectively€toÐ pÀ Ðstimulate€or€block€receptor€activity€in€the€cannabinoid€system€of€the€CNS?݃Fcò^ _݌РÜ(#Ü(# ÐŒÝ  ÝÌÝ‚FcÿÝÝ  ÝÝ‚Fc)`Ýð"ðà0 Ü àÝ  ÝWhat€are€the€immune„modulating€characteristics€of€the€cannabinoids€and€can€they€be€used€forÐ @ Ðtherapeutic€human€benefit?݃Fc)`D`݌РÜ(#Ü(# ÐŒÝ  ÝÌÝ‚FcÿÝÝ  ÝÝ‚Fc8aÝð"ðà0 Ü àÝ  ÝCan€the€long„term€risks€of€daily€smoked€marijuana€be€quantified€so€that€useful€risk€versusÐ ` Ðbenefit€ratios€can€be€determined,€especially€when€considering€treatment€of€long„termÏconditions€such€as€spasticity€or€epilepsy?݃Fc8aSa݌РÜ(#Ü(# ÐŒÝ  ÝÌòò3.à0 Ü àWhat€are€the€diseases€or€conditions€for€which€marijuana€might€have€potential€as€a€treatmentÐ Ð  Ðand€which€merit€further€study?óóÐÀ!Ü(#Ü(# ÐÌMarijuana€or€the€use€of€other€cannabinoids€as€human€therapies€might€be€considered€for€treatingÏspasticity€and€nocturnal€spasms€complicating€MS€and€spinal€cord€injury,€for€various€activeÏepilepsy€states,€for€some€forms€of€¢dystonia£,€and€perhaps€most€interestingly,€for€treatingÏneuropathic€pain€(Zeltser€et€al.€1991).€€(Also€see€the€chapter€titled€òòAnalgesiaóó.)€€NeuropathicÐ p&À!$ Ðpain€complicates€many€CNS€diseases.€€Few€available€therapies€provide€even€partial€relief.ÌÐ  P( #& ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þneÝà@&ìàÝ  ÝReferenceóó݃„þneÊeÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‘™X°,X°‚,` ˜X6Óà0 ‘ àà ° àZeltser,€R.;€Seltzer,€Z.;€Eisen,€A.;€¢Feigenbaum£,€¢J.J.£;€and€Mechoulam,€R.€Suppression€ofÏneuropathic€pain€behavior€in€rats€by€a€non„psychotropic€synthetic€cannabinoid€with€NMDAÏreceptor„blocking€properties.€òòPainóó€47(1):95„103,€October€1991.Ð ªú‘(#‘(# ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þêgÝà@CC!ìàÝ  ÝNausea€and€Vomitingóó݃„þêgFhÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‚,` ˜X°,X°‘™X6Óòò1.à0 Ü àWhat€research€has€been€done€and€what€is€known€about€the€possible€medical€uses€ofÐ Ê Ðmarijuana?óóк Ü(#Ü(# ÐÌÓ/€d/ÓââTâââ  âhere€is€a€large€body€of€clinical€research€on€the€use€of€cannabinoids€for€chemotherapy„relatedÐ š ê Ðâ ø(#ø(#°(#°(#ânausea€and€vomiting.€€Most€of€this€work€was€conducted€during€the€early€1980s.€€TheÏâ °(#°(#ø(#ø(#âmajority€of€reports€deal€with€oral€dronabinol€rather€than€smoked€marijuana.€€These€studiesÏdemonstrated€that€dronabinol€was€superior€to€placebo€in€controlling€nausea€and€vomiting€causedÏby€chemotherapy€that€induces€a€moderate€amount€of€emesis€(Sallan€et€al.€1975).€€Several€studiesÏcompared€oral€dronabinol€with€prochlorperazine€(Sallan€et€al.€1980).€€Mixed€results€wereÏreported€from€these€studies,€but€generally€dronabinol€was€found€equivalent.ÌÌGralla€and€colleagues€(1984)€examined€metoclopramide€versus€dronabinol€in€patients€givenÏcisplatin€in€a€randomized€double„blind€trial.€€These€investigators€reported€poorer€antiemeticÏcontrol€and€more€side€effects€with€dronabinol€than€with€the€metoclopramide.ÌÌNone€of€these€studies€compared€oral€dronabinol€or€smoked€marijuana€with€what€are€nowÏconsidered€the€most€effective€antiemetic€regimens,€the€combination€of€a€specific€serotoninÏantagonist€(like€ondansetron,€granisetron,€or€dolasetron)€plus€dexamethasone,€which€wereÏintroduced€in€the€early€1990s.€€This€combination€has€demonstrated€complete€protection€fromÏvomiting€during€the€initial€24€hours€after€cisplatin€(the€most€potent€emetic€stimulus)€in€79Ïpercent€of€patients€treated€(Italian€Group€for€Antiemetic€Research€1995).€€Without€antiemeticÏprotection,€98€percent€of€similar€patients€vomit€a€median€of€six€times€within€the€first€24€hoursÏalone€after€cisplatin€(Kris€1996).€€Side€effects€of€these€newer€antiemetic€regimens€are€negligibleÏand€would€permit€a€patient€to€drive€or€return€to€his€or€her€job€immediately€after€receivingÏchemotherapy.ÌÌOnly€two€clinical€trials€have€formally€addressed€the€effectiveness€of€smoked€marijuana.€€LevittÏand€colleagues€(1984)€conducted€a€random„order€assignment€crossover€study€comparing€smokedÏmarijuana€and€dronabinol€in€20€subjects,€15€men€and€5€women.€€Twenty„five€percent€of€theÏsubjects€were€free€of€vomiting€and€15€percent€were€free€of€nausea.€€As€to€individual€preferenceÏfor€the€route€of€administration,€45€percent€of€the€patients€had€no€preference,€35€percent€preferredÏoral€dronabinol,€and€20€percent€preferred€smoked€marijuana.ÌÌVinciguerra€and€colleagues€(1988)€studied€smoked€marijuana€in€an€open€trial€in€74€patients€whoÏpreviously€had€no€improvement€with€standard€antiemetic€agents.€€Nearly€25€percent€of€patientsÏÔ#aaddÔwho€initially€consented€to€participate€later€refused€treatment€citing€bias€against€smoking,€harshnessÔ#ddaatÔ€ofÐ š'ê"% Ðsmoke,€and€preference€for€oral€dronabinol.€€Of€the€remaining€56€patients,€18€(34percent)€rated€itÏvery€effective€and€26€(44€percent)€moderately€effective.€€Twelve€(22€percent)€noted€no€benefit.€ÏSedation€occurred€in€88€percent,€dry€mouth€in€77€percent,€and€dizziness€in€39€percent.€€OnlyÏ13percent€were€free€of€adverse€effects.ÌÌÐ  :-Š(+ Ðòò2.à0 Ü àWhat€are€the€major€unanswered€scientific€questions?аÜ(#Ü(# ÐóóÌNo€scientific€questions€have€been€definitively€answered€about€the€efficacy€of€smoked€marijuanaÏÔ#ccddÔin€chemotherapy„related€nausea€and€vomiting.€€A€comparison€of€the€efficacy€of€smoked€marijuanaÔ#ddccâvÔÐ €Ð Ðversus€oral€dronabinol€would€also€be€of€interest.€€In€addition,€further€information€on€appropriateÏdosage€and€frequency,€side€effects,€tolerability,€and€patient€acceptability€for€smoked€marijuanaÏwould€need€to€be€established.ÌÌòò3.à0 Ü àWhat€are€the€diseases€or€conditions€for€which€marijuana€might€have€potential€as€a€treatmentÐ 0 € Ðand€which€merit€further€study?óóÐ p Ü(#Ü(# ÐÌInhaled€marijuana€has€the€potential€to€improve€chemotherapy„related€nausea€and€vomiting.€ÏBecause€the€combination€of€a€serotonin€antagonist€plus€dexamethasone€prevents€chemotherapy„¼related€nausea€and€vomiting€in€the€majority€of€patients,€investigation€of€smoked€marijuana€as€aÏtreatment€for€the€minority€of€patients€who€vomit€despite€receiving€the€current€best€regimensÏ(i.e.,rescue€therapy€in€refractory€patients)€might€be€an€initial€focus.€€Another€line€of€investigationÏcould€be€the€efficacy€of€inhaled€marijuana€in€delayed€nausea€and€vomiting€due€to€chemotherapy.ÌÌAn€add„on€design€in€which€smoked€marijuana€or€placebo€would€be€administered€to€incompleteÏresponders€to€standard€combination€therapy€would€be€appropriate.€€A€dronabinol€capsule€groupÏshould€also€be€included.€€Stratification€should€be€done€for€naive€versus€experienced€marijuanaÏsmokers.€€Nausea€severity,€vomiting€prevention,€and€CNS€effects€assessments€should€be€primaryÏendpoints.ÌÌInhaled€marijuana€merits€testing€in€controlled,€double„blind,€randomized€trials€for€the€aboveÏindications.Ð   p ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þ_}Ýà@KK%ìàÝ  ÝReferencesóó݃„þ_}»}ÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‘™X°,X°‚,` ˜X6Óà0 ‘ àà ° àGralla,€R.J.;€Tyson,€L.B.;€Bordin,€L.A.;€Clark,€R.A.;€Kelsen,€D.P.;€Kris,€M.G.;€Kalman,€L.B.;Ïand€Groshen,€S.€Antiemetic€therapy:€A€review€of€recent€studies€and€a€report€of€a€randomÏassignment€trial€comparing€metoclopramide€with€delta„9„tetrahydrocannabinol.€òòCancer€TreatÐ ªú ÐRepóó€68(1):163„172,€January€1984.К ê‘(#‘(# Ðà0 ‘ àà ° àItalian€Group€for€Antiemetic€Research.€Ondansetron€versus€granisetron,€both€combined€withÏdexamethasone,€in€the€prevention€of€cisplatin„induced€emesis.€òòAnn€Oncolóó€6:805„810,€1995.Ðz Ê‘(#‘(# Ðà0 ‘ àà ° àKris,€M.G.;€Cubeddu,€L.X.;€Gralla,€R.J.;€Cupissol,€D.;€Tyson,€L.B.;€Venkatraman,€E.,€andÏHomesley,€H.D.€Are€more€antiemetic€trials€with€a€placebo€necessary?€Report€of€patient€dataÏfrom€randomized€trials€of€placebo€antiemetics€with€cisplatin.€òòCanceróó€78:2193„2198,€1996.ÐJš ‘(#‘(# Ðò òà0 ‘ àà ° àó óLevitt,€M.;€Faiman,€C.;€Hawks,€R.;€and€Wilson,€A.€Randomized€double„blind€comparison€ofÐ :Š  Ðdelta„9„tetrahydrocannabinol€(THC)€and€marijuana€as€chemotherapy€antiemetics.€òòProc€AmÐ *z  ÐSoc€Clin€Oncolóó€3:91,€1984.Ðj ‘(#‘(# Ðà0 ‘ àà ° àSallan,€S.E.;€Zinberg,€N.E.;€and€Frei,€III,€E.€Antiemetic€effect€of€delta„9„tetrahydrocannabinol€inÏpatients€receiving€cancer€chemotherapy.€òòN€Engl€J€Medóó€293:795„797,€1975.ÐúJ‘(#‘(# Ðà0 ‘ àà ° àSallan,€S.E.;€Cronin,€C.;€Zelen,€M.;€and€Zinberg,€N.E.€Antiemetics€in€patients€receivingÏchemotherapy€for€cancerð"ða€randomized€comparison€of€delta„9„tetrahydrocannabinol€andÐ Ú* Ðprochlorperazine.€òòN€Engl€J€Medóó€302:135„138,€1980.ÐÊ‘(#‘(# Ðà0 ‘ àà ° àVinciguerra,€V.;€Moore,€T.;€and€Brennan,€E.€Inhalation€marijuana€as€an€antiemetic€for€cancerÏchemotherapy.€òòNY€State€Med€Jóó€88(10):525„527,€October€1988.Ð ªú‘(#‘(# ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þ‡†Ýà@¡¡&ìàÝ  ÝGlaucomaóóòò݃„þ‡†ã†ÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‚,` ˜X°,X°‘™X6Ó1.à0 Ü àWhat€research€has€been€done€and€what€is€known€about€the€possible€medical€uses€ofÐ Ê Ðmarijuana?Ð Ü(#Ü(# ÐóóÌÓ/€d/ÓÔ#aaddÔââMâââ  âarijuana€is€not€generally€accepted€as€a€safe€and€effective€treatment€for€glaucoma.€€The€AmericanÔ#ddaašˆÔÐ š ê Ðâ F(#F(#°(#°(#âÔ#^^ddÔAcademy€of€Ophthalmology€(1992)€stated:€ð ðThere€is€evidence€that€marijuana€(or€its€componentsÔ#dd^^z‰Ô),Ð Š Ú Ðâ °(#°(#F(#F(#âtaken€orally€or€by€inhalation€can€lower€intraocular€pressure.€€However,€there€are€no€conclusiveÏstudies€to€date€to€indicate€that€marijuana€(or€its€components)€can€safely€and€effectively€lowerÏintraocular€pressure€enough€to€prevent€optic€nerve€damage.€.€.€.€€The€dose€of€marijuana€necessaryÏto€produce€a€clinically€relevant€effect€in€the€short€term€appears€to€produce€an€unacceptable€levelÏÔ#ccddÔof€undesirable€side€effects€such€as€euphoria,€systemic€hypotension,€and/or€dry€eye€and€conjunctivalÔ#ddcc¸‹ÔÐ :Š  Ðhyperemia€in€the€majority€of€glaucoma€patients€in€whom€the€drug€has€been€carefully€studied.€€NoÏdata€have€been€published€on€studies€of€long„term€ocular€and€systemic€effects€of€the€use€ofÏmarijuana€by€glaucoma€patients.ÌÌð ð.€.€.€Because€the€possibility€exists€that€marijuana€(or€its€components)€may€be€useful€in€treatingÐ ê: Ðglaucoma,€the€American€Academy€on€Ophthalmology€Committee€on€Drugs€believes€that€a€longÏterm€clinical€study,€designed€to€test€the€safety€and€efficacy€of€marijuana€in€the€prevention€ofÏprogressive€optic€nerve€damage€and€consequent€visual€field€loss,€appears€appropriate.ððÐ º  ÐÌThe€National€Eye€Institute€(1997)€has€recently€stated€much€the€same€thing.€€ð ðStudies€in€the€earlyÐ šê Ð1970s€showed€that€marijuana,€when€smoked,€lowers€intraocular€pressure€in€people€with€normalÏpressure€and€those€with€glaucoma.€.€.€.€€However,€none€of€those€studies€demonstrated€thatÏmarijuanað"ðor€any€of€its€componentsð"ðcould€safely€and€effectively€lower€intraocular€pressure€anyÐ jº Ðmore€than€a€variety€of€drugs€then€on€the€market.€.€.€.€[and]€some€potentially€serious€side€effectsÏÔ#ccddÔwere€noted.€.€.€.€€Research€to€date€has€not€investigated€whether€marijuana€use€offers€any€advantagesÔ#ddccàÔÐ Jš Ðover€currently€available€glaucoma€treatments€or€if€it€is€useful€when€used€in€combination€withÏstandard€therapies.€.€.€.€[¢t]he£€National€Eye€Institute€stands€ready€to€evaluate€any€well„designedÏÔ#aaddÔstudies€for€treatment€of€eye€diseases,€including€those€involving€marijuana€for€treatment€of€glaucomaÔ#ddaaC’Ô.ððÐ  j ÐÌThe€initial€observation€that€smoked€marijuana€lowered€intraocular€pressure€(IOP)€in€humans€inÏacute€experiments€was€made€by€Hepler€and€Frank€in€1971.€€Hepler€and€Petrus€(1976)€laterÏreported€in€greater€detail€that€4€percent€(¢tetrahydrocannabinol£€(THC))€marijuana€cigarettesÏlowered€the€IOP€about€27€percent€more€than€did€a€placebo€Ô#ccddÔat€30€minutes€in€normal€volunteers,€andÐ Ê$ " Ðthat€20€mg€of€oral€THC€lowered€the€IOP€about€17€percentÔ#ddcc7”Ô€more€than€placebo€at€30€minutes.€€TheyÐ º% !# ÐÔ#ccddÔalso€reported€that€smoked€marijuana€lowered€IOP€much€more€dramatically€in€patients€with€poorlyÔ#ddcc•ÔÐ ª&ú!$ Ðcontrolled€glaucoma,€with€10€of€12€responding,€and€presented€graphs€showing€the€timecourse.€ÏOne€patient€demonstrated€a€reduction€from€40€mm€Hg€to€10€mm€Hg€in€one€eye€and€from€35€mmÏHg€to€15€mm€Hg€in€the€other.€€Since€patients€with€severe€glaucoma€did€not€discontinue€theirÏcurrent€therapy€(pilocarpine€„€4€percent,€epinephrine€„€2€percent,€or€oral€acetazolamide)€HeplerÏand€Petrus€concluded€that€smoked€marijuana€or€oral€THC€were€additive€to€the€then„knownÏclasses€of€therapeutic€agents,€and€presumably€worked€by€an€independent€mechanism€(Hepler€andÏPetrus€1976).€€In€these€short„term€studies,€lasting€up€to€4€hours,€2€cigarettes€were€as€effective€asÏ20€cigarettes,€and€intoxication€occurred.€€Others€confirmed€that€the€marijuana€could€have€aÐ *.z), Ðsignificant€adjunctive€effect€in€glaucoma€patients,€with€Cuendet€and€colleagues€reporting€thatÏ12/16€eyes€of€10€patients€had€a€reduction€of€15€percent€or€more€(Cuendet€et€al.€1976).ÌÌFlom€and€colleagues€(1975)€concluded€that€in€normal€volunteers€in€acute€studies€the€lowering€ofÏIOP€was€proportional€to€the€ð ðhigh,ðð€and€that€experienced€users€who€did€not€experience€a€ð ðhighððÐ pÀ Ðdid€not€have€a€lowering€of€IOP.€€Merritt€and€colleagues€(1980)€studied€the€blood€pressure€(BP)Ïand€IOP€of€18€glaucoma€patients€in€short„term€studies,€which€compared€smoking€a€singleÏ2percent€THC€cigarette€versus€a€placebo€cigarette€of€the€same€smell€and€taste€and€concluded€thatÏthe€IOP€was€reduced€by€4€mm€Hg€at€30€minutes€and€by€6€mm€Hg€at€90€minutes€(in€patients€withÏeither€open„angle€or€synechial€angle„closure€glaucoma),€returning€to€baseline€by€4€hours€withÏTHC,€while€there€was€no€change€with€the€placebo,€but€that€the€pulse€rose€from€82€beats€perÏminute€(bpm)€to€123€bpm€at€15€minutes,€and€the€systolic€BP€fell€11€mm€Hg€and€diastolic€BP€fellÏ5€mm€Hg,€suggesting€that€reduced€perfusion€of€the€ciliary€body€accounted€for€the€reduction€inÏIOP€and€that€the€adverse€systemic€effects,€including€postural€hypotension,€would€limit€theÏpotential€usefulness€of€marijuana.€€Indeed,€Merritt€concluded€in€an€editorial€in€the€òòJournal€of€theÐ Ð  ÐNational€Medical€Associationóó€(1982)€that€ð ðSystemic€delta„9€THC€therapies€invariably€produce€aÐ À Ðdecreased€perfusion€pressure€to€the€eye.€€This€decreased€perfusion€to€an€already€damaged€opticÏÔ#ccddÔnerve€may€not€be€of€long„term€benefit€to€glaucoma€victims.ðð€€However,€there€are€several€anecdotalÔ#ddccÒžÔÐ  ð Ðreports€that,€on€continued€use,€tolerance€develops€to€the€undesirable€cardiovascular€and€moodÏeffects€of€marijuana,€while€tolerance€does€not€develop€to€the€beneficial€effects€on€IOP€in€patientsÏwith€glaucoma€(Palmberg€1997).ÌÌÔ#aaddÔEfforts€to€avoid€systemic€effects€of€THC€in€glaucoma€treatment€led€to€studies€of€topical€preparationsÔ#ddaaU Ô,Ð P  Ðsuch€as€1€percent€THC€in€peanut€oil.€€However,€no€effect€of€the€preparation€on€IOP€was€found€byÏJay€and€Green€(1983).ÌÌAnimal€studies€have€yielded€conflicting€results€about€the€mechanism€of€action€of€THC€on€theÏIOP.€€The€studies€by€Green€in€rabbits€suggested€central€effects€mediated€through€the€adrenergicÏnervous€system€(Green€1979),€but€the€studies€of€Colasanti€(1990)€in€cats€indicated€no€effect€ofÏeither€sympathetic€or€parasympathetic€denervation€on€the€action€of€THC.€€She€also€found€thatÏTHC€has€no€effect€on€aqueous€production€in€anesthetized€cats,€but€rather€increased€aqueousÏoutflow€facility€threefold.ÌÌÔ#^^ddÔThe€mechanism€in€humans€has€never€been€investigated€by€modern€means,€including€¢fluorophotometry£Ô#dd^^`£Ô,Ð  #ð! Ðcoupled€with€the€older€method€of€tonography,€which€could€yield€clear€information€about€theÏmechanism€of€action,€whether€on€inflow,€conventional€outflow,€or€uveo„scleral€outflow.€€InÏaddition,€it€would€now€be€possible€to€test€the€additivity€of€marijuana€to€a€wide€variety€of€agentsÏÔ#aaddÔnow€available,€including€beta„1€and€beta„2€agonists€and€antagonists,€alpha„2€agonists,€¢dorzolamide£Ô#ddaa¥ÔÔ#cc­ddÔ,Ð `'°"% Ðand€latanoprost,€to€see€whether€or€not€THC€works€by€a€separate€mechanismÔ#ddcc¤¥Ô.Ð P( #& ÐÌòò2.à0 Ü àWhat€are€the€major€unanswered€scientific€questions?óóÐ0*€%(Ü(#Ü(# ÐÌResearchers€do€not€know€the€mechanism€of€action€of€cannabis€on€IOP,€given€either€as€smokedÏmarijuana€or€as€oral€THC.ÌÐ ð-@), ÐAdditional€studies€of€long„term€marijuana€use€are€needed€to€determine€if€there€are€or€are€notÏimportant€adverse€pulmonary,€central€nervous€system€(CNS),€or€immune€system€problems.ÌÌIt€needs€to€be€determined€if€smoked€or€eaten€marijuana€is€more€effective€in€lowering€IOP€on€aÏchronic€basis€than€THC€alone,€as€marijuana€advocates€maintain€on€the€basis€of€anecdotalÏexperience,€or€if€pure€THC,€without€the€particulates€and€carcinogens€of€marijuana€smoke,€couldÏbe€inhaled€by€means€other€than€smoking,€or€taken€orally,€with€equal€long„term€effect€on€IOP.ÌÌÔ#ccddÔResearchers€do€not€know€if€marijuana€would€be€additive€to€the€new,€very€potent€types€of€¢eyedrops£Ô#ddcc^©ÔÐ 0 € Ðnow€available€to€treat€glaucoma,€including€alpha„2€agonists,€dorzolamide€and€latanoprost€(aÏprostaglandin€that€increases€uveoscleral€outflow€and,€like€THC,€causes€conjunctival€hyperemia).€ÏIf€marijuana€were€not€to€be€additive€to€one€of€these€agents,€marijuana€would€be€obsolete,€sinceÏthese€agents€have€no€systemic€side€effects€(other€than€slightly€dry€mouth€in€some€patients€withÏapraclonidine€and€bromonidine),€and€they€have€a€duration€of€action€of€12€to€24€hours.ÌÌØ€ ØòòÝ‚ )NÿÝÝ  ÝÝ‚ )Nð«ÝÚƒ Ú3Ú  Ú.à0 Ü àÝ  ÝWhat€are€the€diseases€or€conditions€for€which€marijuana€might€have€potential€as€a€treatmentÐ À Ðand€which€merit€further€study?݃ )Nð« ¬ÝÛ€ یРÜ(#Ü(# ÐŒÝ  ÝÌóóFurther€studies€to€define€the€mechanism€of€action€and€to€determine€the€efficacy€of€delta„9„Ð à Ðtetrahydrocannabinol€and€marijuana€in€the€treatment€of€glaucoma€are€justified.ÌÌIn€glaucoma,€there€does€not€appear€to€be€any€obvious€reason€to€use€smoked€marijuana€as€aÏprimary€ð ð€stand€aloneðð€investigational€therapy,€as€there€are€many€available€agents€for€treatment,Ð P  Ðand€these€topical€preparations€seem€to€be€potentially€ideal.€€An€approach€that€may€be€useful€is€toÏstudy€smoked€marijuana€in€incomplete€responders€to€standard€therapies.€€The€suggested€designÏfor€clinical€studies€is€to€add€marijuana,€oral€THC,€or€placebo€to€standard€therapy€under€double„¼blind€conditions.€€Studies€proposed€should€consider€the€following€measures:ÌÌÝ‚AûbÿÝÝ  ÝÝ‚Aûb8°Ýððà0 Ü àÝ  ÝEstablish€dose„response€and€dose„duration€relationships€for€IOP€and€CNS€effects.݃Aûb8°S°ÝŒÐð@Ü(#Ü(# ÐŒÝ  ÝÌÝ‚AûbÿÝÝ  ÝÝ‚Aûb±Ýððà0 Ü àÝ  ÝRelate€IOP€and€blood€pressure€measurements€longitudinally€to€evaluate€potential€toleranceÐ Ð  Ðdevelopment€to€cardiovascular€effects.݃Aûb±0±ÝŒÐ Ü(#Ü(# ÐŒÝ  ÝÌÝ‚AûbÿÝÝ  ÝÝ‚Aûb.²Ýððà0 Ü àÝ  ÝEvaluate€CNS€effects€longitudinally€for€tolerance€development.݃Aûb.²I²ÝŒÐ #ð!Ü(#Ü(# ÐŒÝ  ÝÐ  $à" ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þ³Ýà@KK%ìàÝ  ÝReferencesóó݃„þ³l³ÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÓ6°,X°‘™X°,X°‚,` ˜X6Óà0 ‘ àà ° àAmerican€Academy€of€Ophthalmology.€ð ðThe€Use€of€Marijuana€in€the€Treatment€of€Glaucoma.ððÐ Ê ÐStatement€by€the€Board€of€Directors€of€the€American€Academy€of€Ophthalmology,€PO€BoxÏ7424,€San€Francisco,€CA,€June€1992.Ð ‘(#‘(# Ðà0 ‘ àà ° àColasanti,€B.K.€Review:€Ocular€hypotensive€effect€of€marijuana€cannabinoids:€Correlate€ofÏcentral€action€or€separate€phenomenon?€òòJ€Ocular€Pharmacolóó€6(4):259„269,€1990.Њ Ú‘(#‘(# Ðà0 ‘ àà ° àCuendet,€J.F.;€Saprio,€D.;€Calanca,€A.;€Faggioni,€R.;€and€Ducrey,€N.€Action€of€delta„9„¼tetrahydrocannabinol€on€ophthalmotonus.€òòOpthalmologicaóó€172:122„127,€1976.Ðj º‘(#‘(# Ðà0 ‘ àà ° àFlom,€M.C.;€Adams,€A.J.;€and€Jones,€R.T.€Marijuana€smoking€and€reduced€pressure€in€humanÏeyes:€Drug€action€or€epiphenomenon?€òòInvest€Ophthalmolóó€14(1):52„55,€1975.ÐJš ‘(#‘(# Ðà0 ‘ àà ° àGreen,€K.€Marihuana€in€ophthalmologyð"ðpast,€present€and€future.€(Editorial).€òòAnn€OphthalmolóóÐ :Š  Ð11(2):203„205,€1979.Ð ‘(#‘(# Ðà0 ‘ àà ° àHepler,€R.S.,€and€Frank,€I.R.€Marijuana€smoking€and€intraocular€pressure.€(Letter).€òòJAMAóóÐ j  Ð217:1392,€1971.Ð ‘(#‘(# Ðà0 ‘ àà ° àHepler,€R.S.,€and€Petrus,€R.J.€Experiences€with€administration€of€marihuana€to€glaucomaÏpatients.€In:€Cohen,€S.,€and€Stillman,€R.C.,€eds.€òòThe€Therapeutic€Potential€of€Marihuana.óó€NewÐ ê: ÐYork:€Plenum€Medical€Books,€1976.€pp.€63„75.Ð ‘(#‘(# Ðà0 ‘ àà ° àJayÔ#aaddÔ,€W.M.,€and€Green,€K.€Multiple„drop€study€of€topically€applied€1%€delta€9„¢tetrahydrocannabinol£Ô#ddaaƺÔÐ Ê Ðin€human€eyes.€òòArch€Ophthalmolóó€101(4):591„593,€1983.к ‘(#‘(# Ðà0 ‘ àà ° àMerritt,€J.C.€Glaucoma,€hypertension,€and€marijuana.€(Editorial).òò€J€Natl€Med€Assnóó€Ðªú‘(#‘(# Ðà ‘ à74(8):715„716,€1982.Ìà0 ‘ àà ° àMerritt,€J.C.;€Crawford,€W.J.;€Alexander,€P.C.;€Anduze,€A.L.;€and€Gelbart,€S.S.€Effect€ofÏÔ#ccddÔmarihuana€on€intraocular€and€blood€pressure€in€glaucoma.€òòOphthalmologyóó€87(3):222„228,€1980.Ô#ddccÞ¼ÔÐzÊ‘(#‘(# Ðà0 ‘ àà ° àNational€Eye€Institute.€ð ðThe€Use€of€Marijuana€for€Glaucoma.ðð€€Statement€of€the€National€EyeÐ jº ÐInstitute€of€the€National€Institutes€of€Health,€February€18,€1997.Ð ‘(#‘(# Ðà0 ‘ àà ° àPalmberg,€P.€Unpublished€observations€presented€at€the€Workshop€on€the€Medical€Utility€ofÏMarijuana,€National€Institutes€of€Health,€Bethesda,€MD,€February€20,€1997.Ð :Š‘(#‘(# ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þK¿Ýà@  ìàÝ  ÝAppetite€Stimulation/Cachexiaóó݃„þK¿§¿ÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  Ý̜؀ ØñÞñÝ‚ )NÿÝÝ  ÝñÞñÓ6°,X°‚,` ˜X°,X°‘™X6ÓñÜñÝ‚ )NÿÝÝ  ÝñÜñòòñÜñÝ‚ )N›ÀÝÚƒ Ú4Ú  Ú.à0 Ü àÝ  ÝñÜññÞññÝñ1.ñÝññÝñà0 Ü àñÝññÞññÞñÝ‚ )N•ÀÝÚƒ Ú1Ú  Ú.à0 Ü àÝ  ÝñÞñWhat›€research€has€been€done€and€what€is€known€about€the€possible€medical€uses€ofÐ Ê Ðmarijuana?óó݃ )N•À’ÁÝÛ€ یк Ü(#Ü(# ÐŒÝ  ÝÌÓ/€d/ÓââIâââ  ât€has€been€shown€that€there€is€a€strong€relationship€between€smoking€marijuana€and€increasedÐ š ê Ðâ :(#:(#°(#°(#âfrequency€and€amount€of€eating.Ìâ °(#°(#:(#:(#âÌSurvey€data€on€appetite€stimulation€(Haines€and€Green€1970)€(N€=€131)€showed€that€91€percentÏof€marijuana€users€eat€every€time€they€smoke.€€Tart€(1970)€found€that€93€percent€of€marijuanaÏÔ#ccddÔusers€(131)€reported€that€marijuana€made€them€enjoy€eating€very€much€and€that€they€consequentlyÔ#ddcc…ÄÔÐ Jš  Ðate€a€lot€more.€€Foltin€and€colleagues€(1986)€reported€that€marijuana€users€eat€more€often.€€AÏstudy€by€Farrow€and€associates€(1987)€reported€no€hematologic€changes€or€signs€of€nutrientÏdeficiencies€in€marijuana€users.ÌÌMarijuana€is€reported€to€enhance€the€sensory€appeal€of€foods.€€Taste€does€not€seem€to€be€alteredÏas€measured€by€indexes€of€sourness€(citric€acid€in€lemonade),€saltiness€(NaCl€in€tomato€juice),Ïsweetness€(sucrose€in€cherry„flavored€drink),€and€bitterness€(urea€in€tonic€water).€€There€does€notÏappear€to€be€impairment€in€the€normal€satiety€mechanisms€following€marijuana€ingestion.ÌÌFoltin€and€colleagues€(1988)€saw€signs€of€a€general€increase€in€food€intake€on€smoked€marijuanaÏdays€versus€placebo€days.€€The€effect€may€not€persist€over€an€extended€period€of€time,€but€long„¼term€studies€have€not€been€done.€€Setting€is€important€in€appetite€enhancement€and€socialÏsettings€contribute€heavily.€€Williams€and€associates€(1946)€did€a€chronic€dosing€study.€€TheyÏfound€that€body€weight€went€up€and€stayed€up,€possibly€due€to€an€effect€of€marijuana€on€fluidÏretention.€€Greenberg€and€colleagues€(1976)€saw€a€sharp€increase€in€food€intake€followed€by€aÏleveling€off.€€The€increase€in€body€weight€may€reflect€a€reduction€in€energy€expenditure.ÌÌFood€intake€was€greater€after€smoking,€compared€to€oral€and€sublingual€administration,€but€thereÏwas€much€individual€variability.€€Marijuana€seems€to€enhance€appetite€in€the€evening,€whereasÏmany€cancer€patients€report€having€most€of€their€appetite€in€morning.€€This€would€suggest€aÏpotential€complementary€use€of€marijuana.ÌÌCachexia€or€wasting€due€to€HIV€infection€is€increasingly€prevalent€in€the€era€of€effectiveÏprophylaxis€for€òòPneumocystis€cariniióó€pneumonia€(Hoover€et€al.€1993).€€Significant€weight€loss,Ð Ê$ " Ðmore€than€20€percent€of€ideal€body€weight,€is€associated€with€shortened€survival€of€HIV„infectedÏpatients€(Kotler€et€al.€1989).€The€major€causes€of€weight€loss€in€HIV„infected€patients€areÏopportunistic€infections,€enteric€infections€associated€with€malabsorption,€and€reduced€caloricÏintake.€€The€latter€is€the€most€important€cause€of€wasting€in€the€absence€of€opportunisticÏinfections€and€malabsorption€(MacCallan€et€al.€1995).ÌÌÔ#bbddÔAdministration€of€the€appetite€stimulants€megestrol€acetate€(VonRoenn€et€al.€1994)€and€¢dronabinol£Ô#ddbbÕÍÔÐ Z+ª&) Ð(¢Gorter£€et€al.€1992)€is€associated€with€weight€gain€in€HIV„infected€patients.€€Anabolic€steroidsÏand€recombinant€human€growth€hormone€produce€an€increase€in€lean€body€mass€(Mulligan€et€al.ÏÔ#ccddÔ1993).€€In€published€studies,€the€weight€gain€produced€by€appetite€stimulants€or€hormonal€therapyÔ#ddcc4ÏÔÐ *.z), Ðhas€not€been€shown€to€be€associated€with€an€improved€immunologic€status€or€clinical€outcome.€ÏAll€investigations,€however,€have€been€relatively€short,€12€to€24€weeks€in€length.€€Although€thereÏis€much€anecdotal€evidence€of€weight€gain€produced€by€use€of€smoked€marijuana,€no€objectiveÏdata€relative€to€body€composition€alterations,€HIV€replication,€or€immunologic€function€in€HIV„¼infected€patients€are€available.€€An€epidemiologic€study€demonstrated€no€alteration€in€the€naturalÏhistory€of€HIV€infection€with€use€of€smoked€marijuana€(Kaslow€et€al.€1989),€although€otherÏinvestigations€in€uninfected€volunteers€and€animal€models€indicated€that€there€are€effects€onÏcomponents€of€the€immune€system.€€There€have€been€no€recent€published€studies€of€the€impact€ofÏsmoked€marijuana€on€the€immune€system€in€HIV„infected€patients€using€state„of„the„artÏimmunologic€assays.ÌÌMegestrol€acetate€(Oster€et€al.€1994,€VonRoenn€et€al.€1994)€produces€weight€gain€that€isÏpredominantly€fat,€with€very€little€increase€in€lean€body€mass.€€Dronabinol€(ðˆðòò9óó„THC)€has€beenÐ ð@  Ðstudied€in€patients€with€cancer€(Nelson€et€al.€1994;€Plasse€et€al.€1991)€and€AIDS€(Gorter€et€al.Ï1992),€who€showed€increased€weight€gain.ÌÌBeal€and€colleagues€(1995)€studied€dronabinol€as€treatment€for€anorexia€associated€with€weightÏloss€in€patients€with€AIDS.€€A€significant€increase€in€appetite€was€seen€with€a€decrease€in€nausea,Ïand€a€mood€increase€that€was€not€significant.€€The€6„week€study€may€have€been€too€short€to€fullyÏcapture€the€effects€of€dronabinol.ÌÌIn€a€survey€looking€at€physiciansðð€choice€of€drugs€to€treat€wasting,€the€first€line€choice€ofÏ80percent€of€the€care€providers€was€megestrol€with€dronabinol€being€used€by€54€percent.€ÏDronabinol€was€also€the€second€line€choice€of€most€providers.ÌÌProblems€that€have€been€identified€with€dronabinol€are€that€patients€feel€ð ðtoo€stonedðð;€are€unableÐ  p ÐÔ#bbddÔto€titrate€their€dose€properly;€note€delayed€onset€of€effect,€prolonged€duration€of€effect,€or€problemsÔ#ddbbS×ÔÐ ` Ðwith€malabsorption;€and€ð ðnot€the€same€feeling€as€smoked€marijuana.ððÐ P ÐÌSeveral€panelists€pointed€out€that€the€weight€gain€is€primarily€an€accumulation€of€waterÏ(sometimes€of€fat),€but€not€of€lean€body€mass.€€On€the€other€hand,€oncologists€heard€fromÏpatients€with€advanced€cancer€that€increased€appetite€and€weight€gain€are€psychologicallyÏhelpful,€regardless€of€the€nature€of€the€added€weight,€and€regardless€of€the€impact€(if€any)€onÏsurvival.€€Panelists€also€commented€that€very€likely€weight€loss€is€an€indicator€rather€than€aÏcauseof€impending€death.ÌÌòò2.à0 Ü àWhat€are€the€major€unanswered€scientific€questions?Ðp&À!$Ü(#Ü(# ÐÌóóSome€questions€that€need€to€be€answered€in€future€studies€are:Ð P( #& ÐÌØ€ ØÝ‚ )NÿÝÝ  ÝÝ‚ )NÛÝÚƒ Ú1Ú  Ú.à0 Ü àÝ  ÝDoes€smoking€marijuana€increase€total€energy€intake€in€patients€with€catabolic€illness?݃ )NÛ/ÛÝÛ€ ÛŒÐ0*€%(Ü(#Ü(# ÐŒÝ  ÝÌÝ‚ )NÿÝÝ  ÝÝ‚ )N'ÜÝÚƒ Ú2Ú  Ú.à0 Ü àÝ  ÝDoes€marijuana€use€alter€energy€expenditure?݃ )N'ÜBÜÝÛ€ ÛŒÐ,`'*Ü(#Ü(# ÐŒÝ  ÝÌÝ‚ )NÿÝÝ  ÝÝ‚ )NÝÝÚƒ Ú3Ú  Ú.à0 Ü àÝ  ÝDoes€marijuana€use€alter€body€weight,€and€to€what€extent?݃ )NÝ*ÝÝÛ€ ÛŒÐð-@),Ü(#Ü(# ÐŒÝ  ÝÝ‚ )NÿÝÝ  ÝÝ‚ )NÞÝÚƒ Ú4Ú  Ú.à0 Ü àÝ  ÝDoes€marijuana€use€alter€body€composition,€and€to€what€extent?݃ )NÞÞÝÛ€ یаÜ(#Ü(# ÐŒÝ  ÝÌSo€far,€it€has€not€been€shown€that€reversing€wasting€changes€mortality€risk.€€Another€question€isÏwhether€weight€gain€is€associated€with€positive€changes€in€psychological€status.€€It€seems€relatedÏbut€has€not€been€systematically€addressed.ÌòòÌ3.à0 Ü àWhat€are€the€diseases€or€conditions€for€which€marijuana€might€have€potential€as€a€treatmentÐ P   Ðand€which€merit€further€study?Ð Ü(#Ü(# ÐóóÌAreas€of€study€for€the€potential€appetite„stimulating€properties€of€marijuana€include€the€cachexiaÏof€cancer,€HIV/AIDS€symptomatology,€and€other€wasting€syndromes.€€With€an€appropriateÏdelivery€system€designed€to€minimize€the€health€risks€of€smoking,€studies€of€the€appetite„¼stimulating€potential€of€cannabinoids€are€justified.€€Such€investigations€should€be€designed€toÏassess€long„term€effects€on€immunologic€status,€the€rate€of€viral€replication,€and€clinicalÏoutcomes€in€participants€as€well€as€weight€gain.ÌÌIn€therapeutic€trials€for€cachexia,€research€should€attempt€to€separate€out€the€effect€of€marijuanaÏon€mood€versus€appetite.€€Complex€interactions€likely€are€involved.Ð   ð ÐÓ6°,X°‘™X°,X°‚,` ˜X6ÓòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þŸãÝà@KK%ìàÝ  ÝReferencesóó݃„þŸãûãÝŒˆÐ ° ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌà0 ‘ àà ° àBeal,€J.E.;€Olson,€D.O.;€Laubenstein,€L.;€et€al.€Dronabinol€as€a€treatment€for€anorexia€associatedÏwith€weight€loss€in€patients€with€AIDS.òò€J€Pain€Symptom€Manageóó€10:89„97,€1995.к ‘(#‘(# Ðà0 ‘ àà ° àFarrow,€J.A.;€Rees,€J.M.;€and€Worthington„Roberts,€B.S.€Health,€developmental,€and€nutritionalÏstatus€of€adolescent€alcohol€and€marijuana€abusers.€òòPediatricsóó€79:218,€1987.К ê‘(#‘(# Ðà0 ‘ àà ° àFoltin,€R.W.;€Brady,€J.V.;€and€Fischman,€M.W.€òòPharmacol€Biochem€Behavóó€25:577„582,€1986.ò òЊ Ú‘(#‘(# Ðó óà0 ‘ àà ° àFoltin,€R.W.;€Fischman,€M.W.;€and€Byrne,€M.F.€Effects€of€smoked€marijuana€on€food€intake€andÐ z Ê Ðbody€weight€of€humans€living€in€a€residential€laboratory.€òòAppetiteóó€11:1„14,€1988.Ðj º‘(#‘(# Ðà0 ‘ àà ° àGorter,€R.;€Seifried,€M.;€and€Volberding,€P.€Dronabinol€effects€on€weight€in€patients€with€HIVÏinfection.€òòAIDSóó€6:127,€1992.ÐJš ‘(#‘(# Ðà0 ‘ àà ° àGreenberg,€I.;€Kuehnle,€J.;€Mendelson,€J.H.;€and€Bernstein,€J.G.€Effects€of€marijuana€use€onÏbody€weight€and€caloric€intake€in€humans.€òòPsychopharmacologyóó€49:79„84,€1976.Ð*z ‘(#‘(# Ðà0 ‘ àà ° àHaines,€L.,€and€Green,€W.€Marijuana€use€patterns.€òòBr€J€Addictóó€65:347,€1970.Ðj ‘(#‘(# Ðà0 ‘ àà ° àHoover,€D.R.;€Saah,€A.J.;€Bacellar,€H.;€et€al.€Clinical€manifestations€of€AIDS€in€the€era€ofÏPneumocystis€prophylaxis.€Multicenter€AIDS€Cohort€Study.€òòN€Engl€J€Medóó€329:1922„1929,Ð úJ Ð1993.Ð ‘(#‘(# Ðà0 ‘ àà ° àKaslow,€R.A.;€Blackwelder,€W.C.;€Ostrow,€D.G.;€et€al.€No€evidence€for€a€role€of€alcohol€or€otherÏpsychoactive€drugs€in€accelerating€immunodeficiency€in€HIV„1„positive€individuals:€A€reportÏfrom€the€Multicenter€AIDS€Cohort€Study.€òòJAMAóó€26:3424„3429,€1989.к ‘(#‘(# Ðà0 ‘ àà ° àKotler,€D.P.;€Tierney,€P.R.;€Wang,€J.;€and€Pierson,€R.N.,€Jr.€The€magnitude€of€body€cell€massÏdepletion€determines€the€timing€of€death€from€wasting€in€AIDS.€òòAm€J€Clin€Nutróó€50:444„447,Ð šê Ð1989.Ð ‘(#‘(# Ðà0 ‘ àà ° àMacCallan,€D.C.;€Noble,€C.;€Baldwin,€C.;€et€al.€Energy€expenditure€and€wasting€in€humanÏimmunodeficiency€virus€infection.€òòN€Engl€J€Medóó€333:83„88,€1995.Ðjº‘(#‘(# Ðà0 ‘ àà ° àMulligan,€K.;€Grunfeld,€C.;€Hellerstein,€M.K.;€et€al.€Anabolic€effects€of€recombinant€humanÏgrowth€hormone€in€patients€with€wasting€associated€with€human€immunodeficiency€virusÏinfection.€òòJ€Clin€Endocrinol€Metabóó€77:956„962,€1993.Ð:Š‘(#‘(# Ðà0 ‘ àà ° àÔ#aaddÔNelson,€K.;€Walsh,€D.;€Deeter,€P.;€and€Sheehan,€F.€A€phase€II€study€of€delta„9„¢tetrahydrocannabinol£Ô#ddaa–ïÔÐ *z Ðfor€appetite€stimulation€in€cancer„associated€anorexia€(Review).€òòJ€Palliat€Careóó€10(1):14„18,Ð  j ÐSpring€1994.Ð ‘(#‘(# Ðà0 ‘ àà ° àOster,€M.H.;€Enders,€S.R.;€Samuels,€S.J.;€Cone,€L.A.;€et€al.€Megestrol€acetate€in€patients€withÏAIDS€and€cachexia.€òòAnn€Intern€Medóó€121:400„408,€1994.Ðê": ‘(#‘(# Ðà0 ‘ àà ° àPlasse,€T.F.;€Gorter,€R.W.;€Krasnow,€S.H.;€Lane,€M.;€Shepard,€K.V.;€and€Wadleigh,€R.G.€RecentÏclinical€experience€with€dronabinol.€òòPharmacol€Biochem€Behavóó€40:695„700,€1991.ÐÊ$ "‘(#‘(# Ðà0 ‘ àà ° àTart,€C.T.€Marijuana€intoxication:€Common€experiences.€òòNatureóó€226:701,€1970.к% !#‘(#‘(# Ðà0 ‘ àà ° àVonRoenn,€J.;€Armstrong,€D.A.;€Kotler,€D.P.;€et€al.€Megestrol€acetate€in€patients€with€AIDS„¼related€cachexia.€òòAnn€Intern€Medóó€121:393„399,€1994.К'ê"%‘(#‘(# Ðà0 ‘ àà ° àWilliams,€E.G.;€Himmelsbach,€C.K.;€Wikler,€A.;€and€Rudle,€D.C.€Studies€on€marihuana€andÏpyrahexyl€compound.€òòPubl€Health€Repóó€61(29):1059,€July€19,€1946.Ð z)Ê$'‘(#‘(# ÐòòÝ‚„þÿÝÔ€X5§XàX €ÔԀîàX5§Ôò òÝ  ÝÝ‚„þ¹ôÝà@ŽŽìàÝ  ÝQuestion€4.€€What€Special€Issues€Have€ñáñTñáññáñtñáño€œñâñBñâññâñbñâñe›€Considered€inˆÐ ° ÐConducting€Clinical€Trials€of€the€Therapeutic€Uses€of€Marijuana?óó݃„þ¹ôõ݌РÚ* ЌԀîîî½­ÔÔ€X €Xîî³¼Ôó óÝ  ÝÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚Õ~öÝÝ  ÝBenefit€and€Risk€Considerations݃Õ~öÚö݌РôD ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌÓ/€d/ÓââTâââ  âhere€are€a€number€of€guidelines€and€specific€issues€related€to€smoked€marijuana€that€areÐ ê : Ðâ ø(#ø(#°(#°(#âimportant€in€planning€trial€designs€and€carrying€out€clinical€studies.€€The€current€state€ofÏâ °(#°(#ø(#ø(#âknowledge€regarding€the€efficacy€of€smoked€marijuana€for€a€given€disease/condition€should€beÏtaken€into€account€in€designing€clinical€protocols.€€Investigators€should€give€consideration€to€theÏrange€of€potential€questions€that€could€be€addressed€and€propose€to€address€the€most€pertinentÏquestion(s)€with€the€most€appropriate€study€designs.€€This€strategy€should€enhance€the€possibilityÏof€National€Institutes€of€Health€(NIH)€funding€support.€€In€some€instances,€the€initial€question€toÏbe€addressed€may€be€whether€smoked€marijuana€is€efficacious€in€the€treatment/management€of€aÏclinical€condition.€€Such€a€proposed€study€may€be€a€validation€of€clinical€anecdotes€or€beÏproposed€from€basic€research€findings€that€suggest€a€potential€benefit.€€In€either€case,€theÏquestion€should€be€formulated€as€a€testable€hypothesis.€€In€other€instances,€the€more€germaneÏquestion€may€be€whether€smoked€marijuana€possesses€specific€advantages€over€dronabinolÏcapsules€or€other€pharmacological€therapies,€has€additional€therapeutic€effects€in€combinationÏwith€standard€therapies,€has€benefit€in€patients€refractory€to€standard€medications,€or€has€benefitÏprimarily€in€marijuana„experienced€patients.ÌÌÔ#ccddÔThe€risks€of€concern€associated€with€the€investigational€use€of€marijuana€differ€depending€on€theÐ ê: ÐpatientÔ#ddcc‹ýÔ€populations€being€studied€and€with€the€proposed€duration€of€administration.€€For€example,Ð Ú* Ðthere€is€a€Ô#ccddÔdifferent€level€of€risk€of€developing€bacterial€pneumonia€associated€with€marijuanaÐ Ê ÐadministrationÔ#ddccªþÔ€to€immune„compromised€patients€compared€with€nonimmune„compromisedÐ º  Ðsubjects.€€On€the€other€hand,€some€risks€may€decrease€with€continued€use€due€to€the€rapidÏtolerance€development€to€certain€central€nervous€system€(CNS)€and€cardiovascular€effects€ofÏmarijuana.€€Marijuana„experienced€subjects€may€already€have€some€level€of€tolerance€to€certainÏeffects.€€Hence,€it€is€critical€to€consider€the€side€effects€of€marijuana,€the€proposed€duration€ofÏadministration,€the€previous€and€current€level€of€marijuana€use€in€the€proposed€study€population,Ïand€any€additional€risks€that€may€be€conferred€by€the€disease€status€of€the€population€in€theÏassessment€of€risks€and€the€appropriate€type€and€frequency€of€safety€monitoring.€€ConcernsÏregarding€the€long„term€risks€associated€with€smoking€are€less€important€in€conditions€whereÏshort„term€use€is€being€proposed€or€patients€are€terminally€ill.€€However,€such€risks€are€ofÏconcern€for€conditions€where€chronic€administration€of€smoked€marijuana€is€likely.€€RegardlessÏÔ#aaddÔof€whether€short„term€or€long„term€use€is€being€studied,€all€clinical€trials€must€monitor€side€effectsÔ#ddaaMÔ.Ð  &Z!# ÐÌÝ‚ÕÿÝÔ€ŠUV ‹XX €ÔÔ€Šù ‹ ‹ŠUVÔò òÝ  ÝÝ‚ÕòÝÝ  ÝStudy€Design€Considerations݃ÕòN݌Рê':#% ЌԀX5§X ‹ŠùÔÔ€X €XXX5§Ôó óÝ  ÝÌBeyond€the€benefit€and€risk€considerations,€there€are€some€general€and€specific€study€designÏissues€regarding€the€evaluation€of€the€therapeutic€effects€of€smoked€marijuana.ÌÌThere€are€two€basic€types€of€control€groups€to€be€considered€in€designing€studies€of€the€medicalÏuse€of€smoked€marijuana:€€placebo€control€and€active€control€groups.€€A€placebo€control€isÏimportant€in€studying€clinical€conditions€where€there€is€no€known€effective€therapy.€€PlaceboÐ .à), Ðcontrols€are€also€desirable€in€studies€where€the€question€is€whether€smoked€marijuana€is€effectiveÏor€whether€it€is€equivalent€to€another€drug,€and€many€study€designs€utilize€both€placebo€andÏactive€control€groups.€€This€allows€a€determination€as€to€whether€a€valid€conclusion€can€be€drawnÏabout€the€efficacy€of€the€test€drug€by€providing€a€measure€of€assay€sensitivity€for€the€study;€i.e.,Ïdid€any€treatment€show€superiority€to€placebo.€€This€design€also€allows€comparison€of€marijuanaÏwith€a€standard€therapy.€€If€an€effective€standard€treatment€exists,€there€are€conditions€such€asÏchemotherapy„related€nausea€and€vomiting€in€which€it€would€be€unethical€to€include€a€placeboÏcontrol€group.€€On€the€other€hand,€in€single„dose€analgesic€studies€a€placebo€group€can€beÏincorporated€in€the€design€if€appropriate€provision€is€made€for€administration€of€a€ð ðrescueððÐ 0 € Ðanalgesic€if€the€study€medication€proves€ineffective.€€Adding€a€placebo€group€increases€theÏÔ#ccddÔcomplexity€of€the€study€design€and€the€number€of€subjects€required€and€presents€ethical€questionsÔ#ddccx ÔÐ `  Ðthat€must€be€confronted€and€answered€on€a€study„by„study€basis,€but€a€study€without€a€placeboÏgroup€may€yield€uninterpretable€results€unless€some€other€measure€of€assay€sensitivity€isÏincorporated€in€the€study.ÌÌIf€smoked€marijuana€is€being€compared€to€a€standard€of€care,€placebo€may€not€be€needed€ifÏobjective€endpoints€are€being€measured;€e.g.,€number€of€vomiting€episodes€per€day.€€Since€manyÏof€the€potential€therapeutic€uses€of€marijuana€involve€the€use€of€the€drug€as€an€ð ðadd€onðð€orÐ  ð Ðadjunctive€therapy€administered€concomitantly€with€a€standard€therapeutic€regimen,€a€practicalÏstrategy€for€avoiding€a€placebo€group€is€to€administer€the€standard€therapy€to€all€patients€in€theÏstudy,€and€ò òin€additionó ó€administer€marijuana€to€half€the€patients€and€a€placebo€marijuana€to€theÐ pÀ Ðother€half.€€In€that€way,€no€patient€would€be€deprived€of€standard€effective€therapy.ÌÌSome€investigations€address€whether€an€effect€is€dose€related.€€This€type€of€design€allows€for€theÏassessment€of€the€dose€range€that€produces€therapeutic€effects€and€the€relationship€between€theseÏeffects€and€dose„related€side€effects.€€Although€these€designs€do€not€exclude€the€addition€ofÏplacebo€groups,€a€placebo€is€often€not€used€because€the€determination€of€a€positive€dose„responseÏcurve€for€an€effect€provides€an€internal€measure€of€assay€sensitivity.€€An€obvious€difficulty€withÏthis€type€of€design€for€smoked€marijuana€is€the€inability€to€standardize€dose€delivery€due€to€theÏÔ#ccddÔinherent€variability€associated€with€pulmonary€administration.€€One€possible€design€is€to€compareÔ#ddcc÷ÔÐ à0 Ðself„titrated€smoking€with€several€fixed€doses€of€THC€capsules.ÌÌÝ‚ÕÿÝÔ€Šµ`‹XXê”ÔÔ€Š¹s ‹‹Šµ`Ôò òÝ  ÝÝ‚ÕÖÝÝ  ÝSelection€of€Patient€Population݃ÕÖ2݌Р°"  ЌԀX¥ŽX ‹Š¹sÔÔ€Xê”XXX¥ŽÔó óÝ  ÝÌThe€selection€of€the€patient€population€to€be€studied,€and€the€inclusion€/exclusion€criteria€for€theÏdefined€population,€are€another€critical€set€of€decisions.€€Design€choices€include€patients€who€areÏÔ#ccddÔthe€general€population€of€patients€with€the€disorder,€or€one€of€the€following€groups:€€¢nonresponders£Ô#ddcc³ÔÐ †&Ö!$ ÐÔ#ccddÔor€incomplete€responders€to€other€therapies,€patients€selected€in€open„trial€designs€who€respondedÔ#ddccVÔÐ v'Æ"% Ðto€marijuana,€and€naive€versus€experienced€marijuana€smokers.ÌÌÔ#aaddÔOne€proposed€strategy,€selecting€subsets€responsive€to€marijuana€in€an€open€manner€(i.e.,€ð ðenrichmentÔ#ddaa4ÔÐ F*–%( Ðdesignðð),€assumes€that€there€may€be€subpopulations€that€are€difficult€to€recognize,€except€on€theÐ 6+†&) Ðbasis€of€their€prior€putative€response€to€marijuana.€€Once€identified,€such€patients€are€randomlyÏassigned€to€a€study€drug€or€control€group€and€are€evaluated€in€a€prospective€manner.€€ThisÏapproach€is€useful€in€situations€where€responses€are€variable€and/or€modest,€making€it€difficult€toÐ .V), Ðdemonstrate€an€effect,€and€where€it€would€be€of€interest€to€know€if€a€drug€was€useful€even€in€aÏsubset€of€the€patient€population.€€However,€the€limitation€of€this€approach€is€the€difficulty€ofÏestimating€the€size€of€the€population€to€which€study€results€can€be€generalized.ÌÌSingle„patient€(N€=€1)€studies€utilize€multiple€periods€of€a€study€drug„control,€within„subject,Ïcrossover€design.€€Evidence€of€efficacy€in€single€patients€can€be€determined€in€such€designs,Ïalthough€carryover€effects€from€the€long€plasma€half„life€of€cannabinoids€may€confoundÏinterpretation€of€results.ÌÌÝ‚ÕÿÝÔ€Šµ`‹XXê”ÔÔ€Š¹s ‹‹Šµ`Ôò òÝ  ÝÝ‚ÕÌÝÝ  ÝBlinding€or€Masking€Treatment€Assignments݃ÕÌ(݌Р p  ЌԀX¥ŽX ‹Š¹sÔÔ€Xê”XXX¥ŽÔó óÝ  ÝÌÔ#ccddÔThe€issue€of€ð ðblindingðð€or€ð ðmaskingðð€marijuana€cigarettes€was€discussed€at€some€length.€€BlindingÔ#ddccêÔÐ f  Ðmay€be€difficult,€even€with€identical„looking€placebo€cigarettes.€€Experienced€marijuana€usersÏmay€be€able€to€discern€from€the€subjective€effects€whether€they€received€active€or€placeboÏcigarettes.€€Nonetheless,€there€should€be€an€effort€to€mask€treatment€assignment€from€both€theÏpatient€and€investigator,€i.e.,€the€double„blind€technique.€€The€effectiveness€of€blinding€can€beÏevaluated€to€some€extent€by€querying€patients€after€the€study€about€their€guess€as€to€the€identityÏof€their€treatment.€€In€order€to€maintain€double„blind€conditions€when€comparing€smokedÏmarijuana€with€a€control€treatment€in€tablet€or€capsule€form,€a€double„dummy€technique€is€used.€ÏThe€marijuana€treatment€group€would€receive€active€marijuana€plus€dummy€tablets€or€capsules,Ïwhile€the€control€group€would€receive€dummy€marijuana€(i.e.,€with€little€or€no€THC)€plus€activeÏtablets€or€capsules.ÌÌÝ‚ÕÿÝÔ€Šµ`‹XXê”ÔÔ€Š¹s ‹‹Šµ`Ôò òÝ  ÝÝ‚ÕþÝÝ  ÝSelection€of€Clinical€Endpoints݃ÕþZ݌РV¦ ЌԀX¥ŽX ‹Š¹sÔÔ€Xê”XXX¥ŽÔó óÝ  ÝÌÔ#ccddÔThe€choice€of€clinical€endpoints€for€evaluation€of€potential€efficacy€should€be€guided€by€the€desireÔ#ddcc ÔÐ Lœ Ðto€obtain€objective€data,€if€such€endpoints€can€be€obtained€and€are€clinically€relevant.€€ExamplesÏof€such€endpoints€would€be€the€number€of€vomiting€episodes€associated€with€a€particularÏchemotherapy,€intraocular€pressure€(IOP)€measurements€in€glaucoma€trials,€and€weight€gain€andÏpercent€changes€in€body€composition€in€AIDS„wasting€syndrome€studies.€€The€frequency€ofÏmeasurements€should€be€dictated€by€the€clinical€condition€being€studied.ÌÌWhile€blinding€may€not€be€as€important€in€studies€with€clear€objective€endpoints,€some€potentialÏindications€for€marijuana€are€in€conditions€that€involve€subjective€responses,€e.g.,€treating€theÏsymptoms€and€improving€the€quality€of€life€in€very€sick€or€dying€patients.€€Scientific€evidenceÏcan€be€generated€on€the€basis€of€subjective€responses.€€These€therapeutic€areas€should€not€beÏavoided€on€the€grounds€that€studies€involving€objective€endpoints€would€be€easier€to€quantitateÏor€would€be€more€immune€to€bias.ÌÌBecause€of€the€importance€of€the€questions€of€the€medical€utility€of€marijuana€and€the€inherentÏdifficulties€in€designing€a€definitive€study€with€clinically€important€endpoints,€a€mechanismÏcould€be€considered,€such€as€a€forum€where€experts€in€the€subject€areas€and€experts€in€clinicalÏtrial€methodology,€Government€scientists,€and€applicable€physicians€and€patients€could€engage€inÏdialog€regarding€appropriate€study€designs€prior€to€their€adoption.ÌÐ .l), ÐÝ‚ÕÿÝÔ€Šµ`‹XXê”ÔÔ€Š¹s ‹‹Šµ`Ôò òÝ  ÝÝ‚ÕI&ÝÝ  ÝPossible€Role€of€the€NIH€in€Facilitating€Clinical€Evaluation€of€the€Medical€UtilityÐ ° Ðof€Marijuana݃ÕI&¥&݌̌Ô€X¥ŽX ‹Š¹sÔÔ€Xê”XXX¥ŽÔó óÝ  ÝÔ‡X{XXXê”ÔÌTÔ#†Xê”XXX{'#ÔÔ‡=Xê”XXXê”Ôhere€are€several€mechanisms€whereby€the€NIH€can€facilitate€clinical€trials€with€marijuana.Ð ¨ø ÐÌAdequate€supplies€of€marijuana€of€various€and€consistent€strengths€and€placebos€should€be€madeÏavailable€to€investigators.€€The€NIH€should€consider€using€its€facilities€and€influence€to€assureÏthe€availability€of€comparator€compounds€and€appropriate€placebos€(e.g.,€active€and€identicalÏplacebo€amitriptyline€tablets€to€permit€a€randomized€trial€versus€smoked€marijuana/smokedÏmarijuana€placebo€for€the€control€of€neuropathic€pain).ÌÌBecause€of€the€broad€range€of€potential€uses€of€marijuana€cutting€across€many€NIH€Institutes,€aÏcentralized€mechanism€should€be€considered€to€facilitate€the€design,€approval,€and€conduct€ofÏtrials€supported€by€the€NIH.€€Consideration€should€be€given€to€supporting€mechanisms€wherebyÏexperts€in€multiple€areas€and€physicians€and€patients€could€engage€in€dialog€regarding€studyÏdesigns€prior€to€their€commencement.€€In€addition,€to€permit€the€most€rapid€and€accurateÏdetermination€of€marijuanaððs€medical€utility,€the€NIH€should€coordinate€with€efforts€in€individualÏStates€and€by€research€organizations€also€conducting€peer„reviewed€research€studying€marijuanaÏ(e.g.,€American€Cancer€Society,€Multiple€Sclerosis€Society).€€The€NIH€should€also€work€closelyÏwith€the€Drug€Enforcement€Administration€(DEA)€and€the€U.S.€Food€and€Drug€AdministrationÏ(FDA)€to€ensure€that€FDA€regulations€are€followed€and€that€clinical€trials€supported€are€adequateÏfor€submission€as€part€of€an€FDA€approval€package€should€marijuana€prove€effective€for€aÏparticular€indication.ÌÌThe€NIH€should€use€its€resources€and€influence€to€rapidly€develop€a€smoke„free€inhaled€deliveryÏsystem€for€marijuana€or€THC.€€This€effort€will€remove€a€significant€health€hazard€during€clinicalÏtesting€and€future€potential€use.€€This€will€also€bring€this€research€effort€in€line€with€otherÏGovernment€initiatives€to€curtail€cigarette€smoking,€the€number„one€preventable€cause€ofÏpremature€death€and€disability€in€America.€€Until€this€is€done,€the€testing€of€smoked€marijuanaÏwould€be€difficult€in€smoke„free€healthcare€and€municipal€facilities.€€In€addition,€study€ofÏsmoked€marijuana€in€private€facilities€such€as€community€medical€offices€or€patientsðð€homes,Ïwhere€smoking€is€not€prohibited,€would€still€present€an€environmental€hazard€of€secondhandÏsmoke€for€healthcare€workers€and€family€members.€€ð ðTaking€the€smokeðð€out€of€an€inhaled€dosageÐ è"8  Ðform€of€marijuana€or€THC€would€remove€an€important€obstacle€to€the€accurate€determination€ofÏinhaled€marijuanaððs€beneficial€and€deleterious€effects.Ô#†Xê”XX=Xê”á'#ÔÐ  È$ " ÐòòÝ‚„þÿÝÔ€X¥ŽXàXê”ÔÔ€î±îàX¥ŽÔò òÝ  ÝÓ  ÓÝ‚„þ€2Ýà@@RR ìàÝ  ÝAppendix:€€The€Effect€of€Controlled€Substances€Scheduling€onÐ ° ÐMarijuana€Researchóó݃„þ€2è2݌РÚ* ЌԀî“Åîîî±ÔÔ€Xê”Xîî“ÅÔó óÝ  ÝÓÜ2ÓÌòò(Although€not€discussed€at€the€meeting,€this€section€is€provided€as€background€regardingÐ ôD Ðresearch€with€Schedule€I€substances.)ÌóóÌÓ/€d/ÓÔ#aaddÔâ âIâ ââ  ân€addition€to€the€requirements€of€the€U.S.€Food€and€Drug€Administration€(FDA)€and€sponsoringÔ#ddaaÒ4ÔÐ Ä  Ðâ 2(#2(#°(#°(#âorganizations€such€as€the€National€Institutes€of€Health€(NIH)€concerning€the€conduct€of€clinicalÏâ °(#°(#2(#2(#âresearch,€U.S.€investigators€are€subject€to€specific€FDA€and€Drug€Enforcement€Agency€(DEA)Ïregulations€concerning€research€with€controlled€substances.€€Under€the€Controlled€SubstancesÏAct€(21€USC€822€(a)(1))€and€implementing€DEA€regulations,€persons€conducting€clinicalÏresearch€with€any€controlled€substance€must€register€with€the€DEA,€keep€specific€types€ofÏrecords,€and€periodically€report€to€the€DEA.€€Marijuana€is€currently€classified€at€the€highestÏ(most€restrictive)€level€as€a€Schedule€I€drug€(no€accepted€medical€use,€high€potential€for€abuse).€ÏAttempts€by€various€petitioners€to€have€marijuana€rescheduled€have€not€been€successful.ÌÌTherefore,€there€is€at€least€one€extra€layer€(many€States€have€their€own€laws€modeled€after€theÏÔ#ccddÔControlled€Substances€Act€(CSA),€which€add€further€complexity)€for€any€investigator€undertakingÔ#ddcc9ÔÐ d ÐÔ#aaddÔclinical€trials€with€controlled€substances.€€In€the€case€of€research€conducted€under€an€InvestigationalÔ#ddaaª9ÔÐ T ÐNew€Drug€Application€(IND),€recordkeeping€requirements€are€exempt€from€the€CSA€but€must€beÏkept€in€accordance€with€the€Food,€Drug€and€Cosmetic€Act€(FDCA).€€Under€the€FDCA,€a€sponsorÏor€investigator€must€make€its€records€concerning€shipment,€delivery,€receipt,€and€dispositionÏavailable€for€inspection€and€copying€at€¢DEA£ððs€request.€€Additionally,€FDA€regulations€requireÏthat€sponsors€and€investigators€conducting€clinical€trials€take€special€precautions€to€preventÏÔ#aaddÔdiversion,€including€storage€in€a€secure€place€with€limited€access.€€In€the€case€of€some€investigatorÔ#ddaa$<ÔÐ ¤ô ÐÔ#aaddÔsites,€this€may€require€acquisition€of€a€safe€and/or€other€physical€space€changes€and/or€proceduresÔ#ddaaÆ<Ô€toÐ ”ä Ðinsure€security€and€accountability€of€the€substance.ÌÌÔ#ccddÔThe€CSA€also€mandates€reporting€procedures€when€conducting€research€with€controlled€substancesÔ#ddccŸ=Ô.€Ð d´ ÐA€DEA€registration€for€controlled€substances€also€authorizes€(within€specified€limits)€theÏmanufacture€and€distribution€of€the€substances.€€If€a€researcher€engages€in€manufacture€orÏdistribution,€then€he€or€she€is€held€to€the€reporting€standard€of€manufacturers€and€distributors.€ÏPresumably,€the€manufacturer/distributor€reporting€requirements€would€not€apply€in€mostÏstudies,€as€the€source€of€marijuana€would€be€the€National€Institute€on€Drug€Abuse€(NIDA)€andÏmost€studies€would€not€be€using€the€plant€material€to€manufacture€other€forms€or€products.ÌÌWhere€research€studies€of€Schedule€I€substances€are€not€conducted€under€an€IND,€the€DEAÏrequires€a€copy€of€the€research€protocol€be€submitted€for€approval€and€identify€in€the€registrationÏapplications€the€extent€to€which€the€research€will€involve€manufacture€or€importation.€€WhereÏresearch€is€conducted€under€an€IND,€however,€the€sponsor€need€only€provide€the€DEA€with€aÏcopy€of€the€IND€and€a€statement€of€security€precautions.€€The€FDA€has€ultimate€authority€toÏdecide€whether€the€research€may€proceed€either€under€its€jurisdiction€over€INDs€(FDCA)€or€inÏthe€case€of€non„IND€research,€under€the€CSA€(21CFR1301.42).€€Where€non„IND€research€isÏundertaken,€the€FDA€must€consult€with€the€DEA€concerning€the€adequacy€of€the€applicantððsÏdiversion€control€procedures.€€If€a€researcher€desires€to€increase€the€amount€of€Schedule€IÐ d.´), Ðmaterial€it€has€previously€received€permission€to€use,€it€must€apply€to€the€DEA€for€the€increase,Ïand€the€DEA€will€forward€the€request€to€the€FDA€for€approval/denial,€taking€into€account€DEAÏcomments€on€the€adequacy€of€the€researcherððs€security€against€diversion€control.ÌÌSome€States€may€have€their€own€registration€requirements€for€Schedule€I€substances€above€andÏbeyond€the€Federal€requirements.€€Each€researcher€must€check€his€or€her€own€State€authorities€toÏsee€if€other€regulatory€requirements€need€to€be€met.€€Given€the€small€amounts€of€researchÏmaterial€used€by€researchers€in€comparison€to€the€additional€regulatory€burden€and€time€delays,Ïmany€researchers€have€been€discouraged€from€pursuing€research€with€these€substances.€€Indeed,Ïone€of€the€recommendations€of€the€Institute€of€Medicine€Report€entitled€òòThe€Development€ofÐ  p  ÐMedications€for€the€Treatment€of€Opiate€and€Cocaine€Addictions:€€Issues€for€the€GovernmentÏand€Private€Sector€óó(National€Academy€Press,€Washington,€DC€1995,€pp.€168„171)€was€that€theÐ P  Ðcurrent€regulatory€system€be€modified€to€remove€barriers€to€undertaking€clinical€research€withÏcontrolled€substances.Ð  à0  Ðò òÔ‡î“ÅîXXê”ÔòòÔ‡î±îXî“ÅÔAd€Hoc€Group€of€ExpertsñÕñ€GroupñÕñÔ#†î“ÅîXH#ÔóóÔ#†Xê”Xîî“ÅlH#ÔÐ ° ÐßA€,) °°xdE°ÙxAßÐ Ú* Ðó óÌÒ(¦Â/ °(#°(#(ÒWilliam€T.€Beaver,€M.D.ÌProfessor€Emeritus€ofÌPharmacology€and€AnesthesiaÌGeorgetown€University€School€of€MedicineÌWashington,€DCÌÌJulie€Buring,€Sc.D.ÌAssociate€Professor€of€Preventive€MedicineÌHarvard€Medical€SchoolÌandÌDeputy€DirectorÌDivision€of€Preventive€MedicineÌBrigham€and€Womenððs€HospitalÌBoston,€MAÌÌAvram€Goldstein,€M.D.ÌProfessor€Emeritus€of€PharmacologyÌStanford€UniversityÌStanford,€CAÌÌKenneth€Johnson,€M.D.ÌProfessor€and€ChairmanÌDepartment€of€NeurologyÌUniversity€of€Maryland€HospitalÌBaltimore,€MDÌÌReese€Jones,€M.D.ÌProfessor€of€PsychiatryÌLangley€Porter€Psychiatric€InstituteÌUniversity€of€California,€San€FranciscoÌSan€Francisco,€CAÌÌMark€G.€Kris,€M.D.ÌAttending€PhysicianÌMemorial€Sloan„Kettering€Cancer€CenterÌandÌProfessor€of€MedicineÌCornell€University€Medical€CollegeÌNew€York,€NYÌÌÐ Y,©'+ ÐKathi€Mooney,€Ph.D.ÌProgram€DirectorÌGraduate€Programs€in€OncologyÌNursingÌandÌProfessorÌUniversity€of€Utah€College€of€NursingÌSalt€Lake€City,€UTÌÌPaul€Palmberg,€M.D.,€Ph.D.ÌProfessor€of€OphthalmologyÌBascom„Palmer€Eye€InstituteÌUniversity€of€Miami€School€of€MedicineÌMiami,€FLÌÌJohn€Phair,€M.D.ÌProfessor€of€MedicineÌNorthwestern€University€Medical€SchoolÌChicago,€IL