Forensic Marijuana : The Science of Medical Cannabinoids...Forensic Marijuana : The Science of Medical Cannabinoids ... Social media is source of information about novel forms of MJ

7/17/17

1

ForensicMarijuana:TheScienceofMedical

Cannabinoids

Dr.MerrillNortonPharm.D.,D.Ph.,ICCDP-DClinicalAssociateProfessorofAddictionPharmacyPractice

[email protected]

News  MoreAmericansareusingmarijuana,accordingtoanewgovernmentreport.About8.4percentofAmericansages12andolderwerecurrentusersofmarijuanalastyear,upfrom7.5percentin2013.Thepercentageofteensages12to17whosmoke,drinkoruseprescriptionnarcoticsnonmedicallyhasfallen,HealthDayreports.

D.C.

Medical marijuana law Decriminalization only

Decriminalization & Medical marijuana law

Decriminalization, Medical marijuana law & Legalization

Decriminalization & CBD only law

High CBD only law

Prohibition

USStateMarijuanaLawsinEffectasofJanuary2017

7/17/17

2

1.   Alzheimer'sDisease2.   Anorexia3.   Arnold-Chiarimalforma9on4.   Arthri9s5.   Ataxia6.   Cachexia7.   Cancer8.   Cardiopulmonaryrespiratorysyndrome9.   Causalgia10.   Cervicaldystonia11.   Crohn'sdisease12.   Decompensatedcirrhosis13.   Dystonia14.   Epilepsy15.   Fibromyalgia16.   Glaucoma17.   Hepa99sC18.   HIV/AIDS19.   Hun9ngton’sdisease20.   Hydrocephalus21.   Inflammatoryautoimmune-mediatedarthri9s22.   Inflammatoryboweldisease(IBS)23.   Inflammatorydemyelina9ngpolyneuropathy24.   Inters99alcys99s25.   LouGehrig’sdisease(amyotrophiclateralsclerosis,

ALS)

26.   Lupus27.   Migraines28.   Mul9pleSclerosis29.   Musclespasms30.   Musculardystrophy31.   Myastheniagravis32.   Myoclonus33.   Nail-patellasyndrome34.   Nauseaorvomi9ng35.   Neurofibromatosis36.   Neuropathy37.   Pain38.   Pancrea99s39.   Parkinson'sdisease40.   Peripheralneuropathy41.   Post-trauma9cstressdisorder(PTSD)42.   Reflexsympathe9cdystrophy43.   Residuallimbpainfromamputa9on44.   Seizuredisorders45.   Sjogren'ssyndrome46.   Spas9city47.   Spinalcorddamagewithintractablespas9city48.   Syringomyelia49.   Terminalillness50.   Toureae’ssyndrome51.   Trauma9cbraininjury

51MedicalCondi9onsForWhichMarijuanaIsApprovedbyaState

Sources:MarijuanaPolicyProject,2014.KeyAspectsofStateandD.C.MedicalMarijuanaLaws,fromNa9onalConferenceofStateLegislatures,“StateMedicalMarijuanaLaws,”www.ncsl.org.;Rahn,B.,2014.QualifyingCondi9onsforMedicalMarijuanabyState,www.Leafly.com

Past Month Marijuana Use exceeds Cigarette use among HS Seniors

0

10

20

30

40

50

60

91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16

Marijuana-12th Cigarettes-12th E-Cigs-12th Alcohol-12th

SOURCE: University of Michigan, 2015 Monitoring the Future Study

WhatAreWeLearningFromtheLegalizationofCannabis

Products?  MJUseandUseDisorders

  MJAttitudes/Perceptions

  MJAvailability/Accessibility

  HealthOutcomes

  OtherDrugUse

  SocialOutcomes

7/17/17

3

MJUseandUseDisorders(1)  USE:

  Adolescents-MJuseremainedconsistentwhileuseofotherdrugs,alcoholandtobaccodeclined

  Adults-IncreasesinMJusebetween2001and2013  ParentcurrentMJuseincreasedlikelihoodofchildpastyearMJuse

  CannabisUseDisorders:  DensityofdispensariesrelatedtohigherratesofMJabuseanddependence

  BUT:80%medicalMJpatientsusedailywithoutcannabisusedisordersymptoms

MJUseandUseDisorders(2)

  Producttypesandmethods:  MMJconsumersusedifferentlythanrecreationalconsumers  Smokingisstillpredominantmethodinyouth,butMMJstatesmorelikelytoconsumeinfoodorotherwaysthannon-MMJstates

  SocialmediaissourceofinformationaboutnovelformsofMJ–e.g.YouTubevideosofdabbing

  Tweetsrelatedtoediblesanddabsgreaterinstateswithmedicaland/orrecreationalMJlaws

TweetsAboutEdibles

Lamy, Daniulaityte, et al. DAD 2016; 164:64-70.

7/17/17

4

MJAttitudesandPerceptions

  MMJlawsnotassociatedwithincreasesinMMJstates,howeverlegislationmaymorebroadlyimpactperceptionsofharm

  Evenamongparentusers,strongoppositiontoteenuse

0

20

40

60

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07 09 11 13 15

Past Year Use Perceived Risk


12th Graders’ Attitudes Regarding Marijuana Laws: What would you be most

likely to do?

0

20

40

60

80

100

95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16

Not use it, even if it were legal and available Try it Use it more often than I do now


MJAvailability/Accessibility

  MMpatientsgreateraccesstodispensariesandformsofuse,morefrequentandintensiveusethannon-patientmarijuanausers

  Lackofunderstandingaboutageandpossessionlimits

  Medicalmarijuanaprogramsvaryinadherenceto“goodmedicalpractice”withenrollmenthigherin“lessmedicalized”programs

  Noincreaseinperceivedavailabilityamongyouth

7/17/17

5

HealthOutcomes

  IncreaseinMJdependenthospitaldischargesandpoisoncentercalls

  MedicalMJpatientsreportedreasonsforMJuseassleep,anxiety,pain

  PersistentMJuseinyoungadulthoodpositivelyassociatedwithgeneralizedanxietydisorder,substanceuse(incl.alcoholandtobacco)disorders

OtherDrugUse  Alcohol:

  Evidenceofbothsubstitutionandcomplementarity  Concurrentusemorecommonamongrecreationalusersandsomewhatrareamongmedicalusers

  Tobacco:  TeensmokingpredictedlaterMJuse

  RxOpioids:  Trendstowardslessmisuseofprescriptionopioids

SocialOutcomes  Densityofdispensariesrelatedtohigherviolentandpropertycrime,childneglectandabuse

  EarlyadolescentuseofMJassociatedwithlowereducationandeconomicoutcomes

  Driving/ridingafterMJusecommoninunderageMJ-usingcollegestudents

7/17/17

6

Percent of Students Reporting Daily Use of Marijuana, by Grade and Potency (%∆-9 THC)

0

5

10

15

20

95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14

%∆-

9 TH

C

SOURCE: University of Michigan, 2013 Monitoring the Future Study; University of Mississippi Marijuana Project, NIDA 2013

SoWhatDoesAllOfThisMeantoHealthcare

Practitioners?

NASReport–releasedJan2017

PURPOSE:Toprovideacomprehensivereviewofthecurrentevidenceregardingthehealtheffectsofusingcannabisandcannabis-derivedproducts

Reportmade4recommendations.

7/17/17

7

1.AddressResearchGaps

  Examinehealtheffectsofcannabisinat-riskorunder-researchedpopulations(e.g.youth,elderly,pregnant/breastfeedingwomen)

  Determinebenefits&harmsassociatedwithunderstudiedMJproducts(e.g.edibles,topicals)

  Investigateeconomicimpactofrecreational/medicalMJusonhealthcaresystems,healthinsuranceproviders,&patients

2.ImproveResearchQuality

  Developminimumdatasetforobservational&clinicalstudies,standardsforresearchmethods&designs,guidelinesfordatacollectionmethods

  AdaptexistingresearchreportingstandardstoneedsofMJresearch

  Developuniformterminologyforclinical&epidemiologicalMJresearch

  Developstandardized&evidence-basedquestionbanksforclinicalresearch&publichealthsurveillancetools

3.ImproveSurveillanceCapacity

  Developquestionbanksonbeneficial&harmfuleffectsoftherapeutic&recreationalMJuse&incorporatethemintomajorpublichealthsurveyssuchasNHANES,NHIS,BRFSS,NSDUH,YRBS,NVSS,MEPS,NSFG

  StrategiesforsurveillanceofharmfuleffectsofMJfortherapeuticuse

  Developnoveldiagnostictechnologiesforrapid,accurate,non-invasiveassessmentofMJexposure&impairment.

7/17/17

8

4.AddressResearchBarriers

  Proposestrategiesforexpandingaccesstoresearch-gradeMJ

  Identifynontraditionalfundingsources&mechanismstosupportcomprehensivenationalMJresearchagenda

  Investigatestrategiesforimprovingquality,diversity,&externalvalidityofresearch-gradeMJproducts

PhysicianPrescribingBackground

  TheHealthEffectsofCannabisandCannabinoids:TheCurrentStateofEvidenceandRecommendationsforResearch

  440pages|6x9|PAPERBACK

  ISBN978-0-309-45304-2|DOI:10.17226/24625

  CommitteeontheHealthEffectsofMarijuana:AnEvidenceReviewandResearchAgenda;BoardonPopulationHealthandPublicHealthPractice;HealthandMedicineDivision;NationalAcademiesofSciences,Engineering,andMedicine

TheHealthEffectsofCannabisandCannabinoids:TheCurrentStateofEvidenceandRecommendations

forResearch(2017)

  TheNationalAcademiesofSciences,Engineering,andMedicine(theNationalAcademies)willappointanadhoccommitteetodevelopacomprehensive,in-depthreviewofexistingevidenceregardingthehealtheffectsofusingmarijuanaand/oritsconstituents.

  Thecommitteewilldevelopaconsensusreportwithtwoprimarysections:(1)asectionofthereportwillsummarizewhatcanbedeterminedaboutthehealtheffectsofmarijuanauseand,(2)asectionofthereportwillsummarizepotentialtherapeuticusesofmarijuana.

7/17/17

9

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and

Recommendations for Research (2017)

  Aftercarefulconsideration,thecommitteechosenottoattempttoreviewbasic,non-humanresearchinordertoattempttobolsterevidenceforidentifiedhealthoutcomesfromcannabisexposure.

  Giventhemethodologicvariationinthestudiesreviewed,aswellaspotentialdeficienciesinstudydesignandexecution,thecommitteefocuseditsattentionandenergyonidentifyinghighqualitystudieswiththebestinformationandlowestriskofbiasasthewaytoensurethatreportfindingsandconclusionswereasinformativeandrelevantaspossible.

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and

Recommendations for Research (2017)

  Exposuremeasurementisalwaysanadditionalconcernwhenevaluatingcomprehensivereviewsofobservationalstudies.

  Assessmentofcannabisexposureisparticularlychallengingbecauseofitsillegalstatus(inmostsettings)andtherelianceonself-report.Inherentdifficultiesinaccuratelyassessingtheexposureintermsofdose,specifictypeofcannabisproductused,modeofintake,duration,frequency,andothervariablesresultinthevariabilityindefinitionsusedtooperationalizecannabisexposure.

  Riskofpolysubstanceuse

GUIDELINESONPRESCRIBINGMARIJUANA

  TheFederationofStateMedicalBoards(September2016)recommendationssetforthsomebasicgroundrulesfordoctorswhochoosetoprescribeormakeareferralformedicalmarijuana:

  •Thedoctorshouldadheretocurrentstandsofpracticeandcomplywithstatelaws,rulesandregulations,whichmayspecifyconditionsforwhichapatientmayquality.

  •Thedoctor’sofficeshouldnotbelocatedatamarijuanadispensaryorcultivationcenter.Thedoctorshouldnotreceivefinancialcompensationfromorholdafinancialinterestinmarijuana-relatedbusinessesorbeaffiliatedwiththeminanyway.

  •Thephysicianshouldnotusemarijuanaeithermedicinallyorrecreationallywhileactivelyengagedinthepracticeofmedicine.

  Fitzgerald,S.NationalBoardOffersGuidanceforDoctorsPrescribingMedicalMarijuana,NeurologyToday;September22,2016

7/17/17

10


  Therecommendationsalsofocusonspecificsoftheofficevisit:

  Thereshouldbeanestablisheddoctor-patientrelationshipbeforethedoctorconsiderstheuseofmedicalmarijuana.

  •Thedoctorshoulddoaphysicalexamandgatherhealthhistory,includingdocumentationofprevioustherapiesusedbythepatientandinformationonanypersonalorfamilyhistoryofsubstanceabuse,mentalillnessorpsychoticdisorders.

  Thediagnosisshouldjustifytheconsiderationofmedicalmarijuana.



  •Thedoctorshouldreviewothertreatmentoptions.Theknownbenefitsandrisksofmarijuanashouldbepresented,alongwiththewarningthat,unlikewithFDA-approveddrugs,thereisvariabilityandlackofstandardizationinmarijuanapreparation.

  •Ifthemedicalmarijuanaischosen,aspecifictreatmentplanforalimitedperiodoftimeshouldbeagreedon,withdetailsdocumentedinthemedicalrecord.Thedoctorshouldinstructthepatientnottodriveoroperateheavymachinerywhileusingmarijuana.

  •Thepatientshouldbeseenforfollow-upvisitstomonitorforefficacyandsideeffectsofmedicalmarijuana.

  •Patientswithahistoryofmentalhealthproblems,substanceabuseoraddictionshouldbereferredforfurtherevaluationasneeded.


WillIGetArrestedforPrescribing(Recommending)MedicalCannabinoids?

  In2013,theJusticeDepartmentdeclaredU.S.attorneyswouldnolongerpursueactionsagainstphysiciansforrecommendingmedicalmarijuanainstateswhereithasbeenmadelegal,arulingsupportedbytheAmericanCollegeofPhysicians…….

  Thismaychange…………

7/17/17

11

WhatShouldAPrescriberKnowAboutMedicalCannabinoids?

Terms  Pharmacokinetics–whatthebodydoestoadrug.Referstothemovementofadruginto,through,andoutofthebody

  ADME(Absorption,Distribution,Metabolism,andElimination)

  Absorption–aftertakingadrug,itmustcrossoneormorebiologicalmembranesbeforeitreachesthesystemiccirculation.  Exception:DrugsadministeredIVenterthesystemiccirculationdirectly

–noabsorptionstep.

  Distribution–thepassageofdrugmoleculesfrombloodtotissues.

  Metabolism–chemicallychangingdrugcomponentsintometabolites.

  Excretion–thepassageofmoleculesfromthebloodtotheoutsideofthebodythroughurine,bile,orotherroutes.

Terms  Bioavailability–amountofdrugabsorbedcomparedtothedrugdose.  Example:afractionofthedosemaybemetabolizedduringtheearlypassagethroughthegastrointestinaltractorliver.

  HalfLife–amountoftimerequiredfortheconcentrationoramountofdruginthebodytobereducedby50%.

Cmax–peakconcentrationofdrug.

  Pharmacodynamics–thestudyoftheactionoreffectsofdrugsonthebody.

7/17/17

12

Psychoactive(Personal)vsNon-Psychoactive(Medical)

Cannabinoids

Delta-9-THC“PSYCHOACTIVE”

CBD“NOTPSYCHOACTIVE”

AreYouFamiliarWithTHCMedicationsYouCan

Prescribe?

Marinol(Dronabinol)  Chemicallyas(6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol.

  Issyntheticdelta-9-tetrahydrocannabinol(delta-9-THC)**

  Availableinroundsoftgelationcapsulesin2.5mg,5mg,or10mgcapsules

  Pharmacodynamics:primarilycentralsympathomimeticactivity

  Onset:0.5-1.0hours

  Peak:2-4hours

  Duration:4-6hourswithappetitestimulationlastingupto24hoursafteradministration

7/17/17

13

Marinol(Dronabinol)  Pharmacokinetics

  AbsorptionandDistribution:95%absorbedaftersingledosebutonly10-20%reachessystemiccirculation,largevolume(Vd)ofdistributionduetohighlipidsolubility

  Metabolism:Undergoesfirstpasshepaticmetabolism,yieldingbothactiveandinactivemetabolites.Primarymetaboliteis11-OH-delta-9-THCwhichconcentrationspeakat0.5to4hoursafteroraldosing-clearanceaverageis0.2L/kgbutvariesanddeclinesoverseveraldays.

  Elimination:initialhalflifeis4hoursandterminalhalflifeis25-36hours-duetolargeVd,Marinolisexcretedatlowlevelsforprolongedperiodsoftime.Excretedinfecesandurine(lowlevelsofMarinoldetectedinurineafter5weeks).

Syndros(Dronabinol)OralSolution

  FDAApprovedin1985

  OralSolution5mg/ml

Syndrosisacannabinoidindicatedinadultsforthetreatmentof:anorexiaassociatedwithweightlossinpatientswithAIDS(1);andnauseaandvomitingassociatedwithcancerchemotherapyinpatientswhohavefailedtorespondadequatelytoconventionalantiemetictreatments.

  Dosing:Calibratedoralsyringewith5mgSyndrosmax-ifmorethan5mgnecessarymustgiveindivideddoseswith6-8ouncesofwater

  Updated2016Guideslines:Startingdoseof2.1mgorallytwicedaily,onehourbeforelunchanddinner.

  ADEs:Dizziness,Euphoria,ParanoidReaction,AbnormalThinking,AbdominalPain,Nausea,andVomiting

  FDACenterWatch2016

OtherTHCMedicationsBeingConsideredforFDAApprovalSativex(THCandCBD)-OromucosalsprayformulationusedforthetreatmentofmoderatetoseverespasticityofMS

Epidiolex(CBD)-isplant-derivedCBD,indevelopmentforthetreatmentofanumberofrarepediatricepilepsydisorders

7/17/17

14

SoWhatIsAlloftheControversyAboutPrescribingTHC/CBD

Medications?

TheUseofLeafMarijuanaasaMedication!!!!!

•  CannabinoidConcentra8on–  30,000cannabisprepara8ons

confiscatedintheU.S.between1980and1997were

•  AverageConcentra8ons–  3.1%THC–  0.3%CBD

–  InfluencingFactors•  Plantsex,age/developmental

stage,environment,gene8cmakeup

•  MedicalspeciesaregrowntoproducesimilarlevelsofTHCandCBD

•  Sinsemillaisderivedfromtheunpollinatedfemalecannabisplant

–  preferredforitshighTHCcontent(upto17%THC)

•  Concentra8onsofcannabinoidsinthebody(parentormetabolite)aredependentuseanddose

CannabisPlantAnatomy

P:hYps://www.leafly.com/news/cannabis-101/cannabis-anatomy-the-parts-of-the-plant

Na8onalHighwayTrafficSafetyAdministra8on,Cannabis/Marijuana(Δ9-Tetrahydrocannabinol,THC),2012,DrugsandHumanPerformanceFactSheets,hYp://www.nhtsa.gov/people/injury/research/job185drugs/cannabis.htm,(August3,2015)

7/17/17

15

Classifying Marijuana • Marijuana produces some excitatory effects but it

is not generally regarded as a stimulant.

• Marijuana produces sedative effects, but a person faces no risk of slipping into a coma or dying.

• Marijuana produces mild analgesic effects (pain relief), but it is not related pharmacologically to opiates like drugs.

• Marijuana produces hallucinations at high doses, but its structure does not resemble LSD or any other drug formally categorized as hallucinogen.

Chemistry was established over 100 years ago by two chemists, the Smith Brothers. 50 cannabinoid-based compounds, with 4 major cannabinoids in the plant: •  2 isomers, a trans-delta-9-THC and a delta-8-THC •  A cannabidiol [CBD] (the 2nd most abundant psychoactive

ingredient after THC) •  A cannabinol is a decomposition product of THC that

accumulates as cannabis samples age. After ingestion, delta-9 is converted in the liver to 11-Hydroxy THC which is equally as potent and active.

Ë  Delta-9-tetrahydrocannabinol (THC) is the active ingredient of marijuana

major metabolites OH-THC (11-delta-9-THC) and THC-COOH (11-nor-delta-9-THC-carboxylic acid, inactive)

Levo is the more active isomer

O

OH

11-OH-THC (active) THC

7/17/17

16

Chemical constituents of Cannabis Chemical classes

Cannabinoids (66)Nitrogenous compounds (27)Amino acids(18)Proteins/ enzymes (11)Sugars (34)Hydrocarbons (50)Simple alcohols (7)Simple aldehydes (12)Simple ketones (13)Simple acids (21)Fatty acids (22)Simple esters/lactones (13)Steroids (11)Terpenes (20)Non-cannabinoid phenols (25)Flavoroids (21)Vitamins (1)Pigments (2)Elements (9) Total known compounds (483)

Picture: Nature Reviews Cancer 3, 745-755 (October 2003)

CB1 and CB2: presynaptic receptors Depending on site, inhibit neurotransmitter release

(GABA, glutamate, 5HT, DA, ACh)

?

Endocannabinoid System

Sites of Action *affects nearly every major organ system*

As-of yet unidentified receptors? Activity on non-cannabinoid receptors?

CB2: Immune cells (T cells, B cells, monocytes) Spleen Tonsils Brain Heart Liver Lungs Other?

CB1: Brain Kidneys Liver Heart GI Tract Pancreas Adipose Muscle Reproductive organs Other?

7/17/17

17

http://www.drugabuse.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects

Effects of Cannabis on the Brain

https://www.drugabuse.gov/publications/drugfacts/marijuana

51

The Ubiquitous CB1

• Endogenous CBs are a major class of neuromodulators, acting through receptors, CB1 and CB2

• CB1 receptors are primarily located on CNS neurons

  Levels exceed those of nearly all neurotransmitter receptors

• Exogenous CBs exert their effects by driving this innate system, often mimicking and enhancing its natural functions

7/17/17

18

52

The Ubiquitous CB1

• The omnipresent central distribution of CB1, has led to the term, Omnineuromodulator, to describe CB action

• Therapeutic effects are primarily due to agonist action in brain regions that mediate nausea/vomiting, appetite, and neuropathic pain

Endocannabinoids are the body’s endogenous cannabinoids. “The Bliss Molecules” Anandamide (Sanskrit ananda inner bliss) is one endocannabinoid. It is found in chocolate (though there is some controversy over whether the small quantity has any effect on the body). It is about as potent as THC. Chocolate tree

TypicalMarijuanaPreparations

7/17/17

19

Marijuana  Cheaperandlesspotentsubstance

  Preparedfromtheleavesandfloweringtopsoftheplant

  AverageTHCconcentrationinmarijuanais1–5%

  THCDose=10–40mgusually  <100mgpercigarette  Howdoyoudosethisformulation?

Hashish   Resinextractedfromtheflowerclustersandtopleavesofthehempplant,Cannabissativa,andC.indica

  mostpotentgradeofcannabis

  Obtainedfromcultivatedplantsgrowninhot,moistclimates

  Hashoilisanextractofhashishthatcanbesmokedoraddedtothetobacco

  Produceseuphoriaandexaggerationsofsensations

  [THC]=8–12%byweight

  Hashoil:[THC]=25–60%byweight

PriyamvadaSharma,PratimaMurthy,M.MSrinivasBharath.“Chemisty,Metabolism,andToxicologyofCannabis:ClinicalImplications”.IranianJournalofPsychiatry.October1,2012.pg.149http://eds.b.ebscohost.com/eds/pdfviewer/pdfviewer?sid=14587b3e-f585-4dce-af43-007de0074755%40sessionmgr110&vid=16&hid=104

7/17/17

20

Cannabinoids

Hues8s,M.2009,HumanCannabinoidPharmacokine8cs,Na+onalIns+tuteofHealth:ChemBiodivers,v.4(8),p.1770-1804.

Cannabinoids•  THC

–  psychoac8ve,euphoria,increasedreac8on8me,lossofmemory/cogni8vefunc8oningdecreases,clearancehalf-lifeoflessthan30minutesandisnotdetectableinurine

•  CBN–  Painrelief,An8-insomnia,Promotesgrowthofbonecells,

An8bacterial,An8-inflammatory,An8-convulsive,Appe8tes8mulant•  CBD

–  maymodifyTHCeffects,inhibitsconversionofTHCto11-OH-THC(CYP450),forma8onofCBDfromTHCdoesnotoccurbyheatfromsmokingnorbyhumanmetabolism,blocksanxietyandpsychologicalsideeffectsproducedbyTHCintake

•  THC-COOH–  Lipidsolublecomponent(metabolite),canbestoredinfatcellsfor

weekstomonths,foundinbloodandurine,typicallyappearsintheurinewithin60minutes,butcantakeaslongas4hours,presenceofthemajorTHC-COOH>LOQindicatesexposuretoTHCwithin3daysaeerasingleuse,toapproximately30daysinheavychronicusers


MarijuanaΔ9-Tetrahydrocannabinol(THC),2015,MayoClinic:DrugsofAbuseTes8ng,hYp://www.mayomedicallaboratories.com/test-info/drug-book/marijuana.html(August10,2015)

THC:PharmacodynamicsDrugtoBody

  Causesdisinhibitionofdopamine(DA)neuronsbypresynapticinhibitionofGABAneuronsintheVTA

  Causeseuphoriaandrelaxation

  Feelingsofwell-being,grandiosity,andalteredperceptionofpassageoftime

  Dose-dependentperceptualchanges,drowsiness,diminishedcoordination,andmemoryimpairment

  Hash(concentratedTHC)mayresultinvisualhallucinations,depersonalization,andfrankpsychoticepisodes

7/17/17

21

THC:Pharmacodynamics

  apartialagonistatbothCB1&2receptors,hasactivityatnon-CBreceptorsandothertargets,andisresponsibleforthepsychoactiveeffectsofcannabisthroughitsactionsattheCB1receptor.

  smokingrouteorbyvaporization:centralnervoussystemandphysiologicaleffectsoccurwithinminutes

  Thepsychotropiceffector"high"occursmuchmorequicklybythesmokingthanbytheoralroute

  Physiologicaleffectsincluderapidchangesinheartrateanddiastolicbloodpressure,conjunctivalsuffusion,drymouthandthroat,vasodilatation,anddecreasedrespiratoryrate

THC-PharmacokineticsBodytoDrug–Absorption

A.Inhalation/Smoking

  90%ofTHCinbloodcirculatesinplasmaandrestsinRBCs

  Delta-9-THCisdetectableinplasmawithinsecondsafterthefirstpuff

  Peakplasmaconcentrationattainedwithin3–10minutes

  Bioavailabilityvariesaccordingtodepthofinhalation,puffduration,andbreath-hold

  systemicbioavailabilityis~23–27%forheavyusersand10–14%foroccasionalusers

  MaximumTHCplasmaconcentrationisobserved8minutesafteronsetofsmoking

  Delta-9-THCplasmaconcentrationrapidlydecreasesto1–4ng/mLwithin3–4hours

THC:Pharmacokinetics–Absorption

B.OralIngestion

  relativelyslowersystemicabsorption:1to2hoursbutcanbedelayedbyafewhours

  extensivelivermetabolismreducesoralbioavailabilityofTHCby4–12%

  maximumTHCplasmaconcentration4.4011ng/mLfor20mgand2.7–6.3ng/mLfor15mg

7/17/17

22

THC:Pharmacokinetics–Distribution

  ExtensivetissuebindingduetolipophilicnatureoftheTHC

  rapidlydistributedintohighlyvascularizedtissuesandlipophilictissuessuchasfat

  slowredistributionduetoitsdeepfatdeposits

  terminalphaseisreached~10hoursafterintake

NOTE:ThisiswhyTHClevelsaremaintainedinthebodyforalongtimefollowingabuse!Ex)clinicalstudyamong52volunteersshowedthatTHC-COOHwasdetectableinserumfrom3.5to74.3hours

**THC:Pharmacokinetics–Metabolism

Active,Psychoactivecomponent Inactive;Diagnostic

*THCismetabolizedintheliverbycytochromeP450s–2C9,2C19,and3A

http://eds.b.ebscohost.com/eds/pdfviewer/pdfviewer?sid=14587b3e-f585-4dce-af43-007de0074755%40sessionmgr110&vid=16&hid=104

Peak3-8minutes

Peak15-81minutes

Peaks81-240minutes

THC:Pharmacokinetics–Excretion/Elimination

  >65%excretedinthefeces(intheformof11-OH-THC)

  ~20%excretedinurine

  80–90%ofcannabisexcretedwithin5daysashydroxylatedandcarboxylatedmetabolites

  Mostmetabolitesformaconjugatewithglucuronicacidtoincreasewatersolubility(THCCOOHistheprimaryglucuronideconjugateinurine)

  Lowrenalclearanceduetoreabsorption  Clearancelevel:11.8+/-3L/hr(women)and14.9+/-3.7L/hrformen36L/hrfornaïvecannabisusersand60L/hrforregularusers

  Halflife:infrequentusers:1.3daysfrequentusers:5-15days

7/17/17

23

AdverseDrugEffectsofLeafMarijuana

Psychological Effects

Ø  Euphoria Ø  Relaxation

Ø  Altered time and space perception

Ø  Lack of concentration

Ø  Impaired memory/learning

Ø  Mood changes Ø  Disorientation

Ø  Sense of well-being

Ø  Drowsiness

Physiological effects

Ø  Tachycardia Ø  Reddened conjuctiva

Ø  Dry mouth and throat

Ø  Increased appetite

Ø  Vasodilation

Ø  Bronchodilation Ø  Decreased respiratory rate

7/17/17

24

Duration of Effects on Driving

Ø  Effects from smoking are felt within minutes Ø  Effects reach their peak in 10-30 minutes

Ø  Most users experience a “high” that last about 2-3 hours

Ø  Most behavioral and physiological effects last 3-6 hours after drug use

Ø  Researchers have shown that some residual effects may last up to 24 hours

Ø  Psychomotor impairment can persist after the perceived high has dissipated

Drug Interactions

Ø  Marijuana combined with stimulants (cocaine, amphetamines, etc.) can lead to increased hypertension, tachycardia and possible cardiotoxicity

Ø  Depressants (Benzodiazepines, barbiturates, muscle relaxants, etc.) can increase drowsiness and CNS depression

Ø  Marijuana used in combination with ethanol leads to additive effects

Ø  Marijuana and ethanol use makes the user more likely to be a traffic safety risk than when consumed alone

How much should a person use to get 25 mg of THC? •  20% THC •  Net weight 1/8 oz or

3.5 gm

•  Single serving 50 mg

http://onehumanbeing.com/the_mmj_project/2009/03/granddaddy-purple-at-cclb/

http://bothcollective.com/page/6/?app-download=windowsphone

7/17/17

25

ButIsTHCToxic???

•  2009studyfromAmericanScien9stontherela9vetoxicityofrecrea9onaldrugsshowedthatusingonly109mesthe"effec9ve"doseofalcoholcouldbefatal,whereasmorethan1,0009mestheeffec9vedoseofmarijuanawouldhavetobeusedtobepossiblyfatal.

•  ThetoxicdoseofTHCina65kgadultwouldbe8.45kg.

Dr.MerrillNorton,Pharm.D.,D.Ph.,ICCDP-DandCaitlinPayne,ResearchAssistant 73

ButisTHCToxic???•  Thetachycardiaalmostinvariablyproducedinacute

intoxica9on,combinedwiththesensoryaltera9onsandincreasedtremorcommonlyreported,probablycontributetotheaffec9vecomponentsofthesereac9ons.CNSandrespiratorydepressionarenotedwithhighdoses,whichinsevereoverdosemaybelife-threatening(Rosencrantz,1983).Theseeffectsare,ofcourse,moredangeroustothosewithpre-exis9ngcardiacirregulari9es.Becauseofthelargeeffec9vetolethaldosera9oinhumans(probablyinexcessof1:1000innon-tolerantusers)theriskofexperiencingseveretoxiceffectsofcannabisislimitedbytheaversivepsychotropiceffectsofhighdoses,whichusuallyleadtocessa9onofusebeforetheonsetofdangerousphysicalconsequences.


ModifyingConcentra8ons•  Why

–  SeekingbeYerhigh– MoreTHCandlessCBD

•  CBDlimtspsychoac8veeffectsofTHC•  terpenes,delayormodulatetheonsetofeffectsofcannabinoids

–  an8-inflammatoryterpenesthatprotectthelungsfromirrita8on

•  What–  HoneyOil,Wax,HashOil

•  How–  UsingburningtechniquesandsolventstoridplantandplantresinsofCBD

–  pureTHCprepara8onsmaybethepresenceofresidualsolvents(e.g.,ethanol)thatareneededtosolubilizethes8ckypureTHC


DeBacker,B.,Maebe,K.,Verstraete,A.,Charlier,C.,2012,Evolu8onoftheContentofTHCandOtherMajorCannabinoidsinDrug-TypeCannabisCumngsandSeedlingsDuringGrowthofPlants,JournalofForensicSciences,v.57(4)

7/17/17

26

EvolvingCannabisAdministra9on•  What?

–  Newroutes•  Why?

–  Providemoredirectdelivery

•  Considera9ons:

– Mathema9calmodelshavebeendevelopedtoes9matethe9meofmarijuanaexposurewithina95%confidenceintervalbasedonbloodconcentra9ons

– Marijuanahasbeenshowntoimpairperformanceondrivingsimulatortasksandonopenandcloseddrivingcoursesforuptoapproximately3hours


MedicalMarijuanaStandards

What is in medical cannabis?

www.fullspectrumlabs.com Accessed 07/18/2011

7/17/17

27

Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders

Disorder Target Symptoms Therapeutic Cannabinoid

Clinical Outcome

Multiple Sclerosis Spasticity Oral THC, CBD In progress Neurogenic pain Sublingual THC, CBD Phase II trial in progress Bladder dysfunction Sublingual THC, CBD Phase II trial in progress

Parkinsons’s disease Dystonia Nabilone No effect Dyskinesia Nabilone ↓ Dyskinesia Tremor Δ9-THC No effect

Cancer Pain Sublingual THC, CBD Phase III trial in progress

Postoperative pain Pain IM levonantradol ↓ pain, but less effective than existing therapies

Croxford, JL. CNS Drugs 2003; 17(3) CBD = cannabidiol

THC = tetrahydrocannabinol

Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders (cont’d)

Disorder Target Symptoms Therapeutic Cannabinoid

Clinical Outcome

Spinal cord injury Pain Sublingual THC, CBD

Phase II trial in progress

GI tract pain Pain THC ↓ Morphine requirement

Traumatic Brain Injury / Stroke

Neurodegeneration IV dexanabinol (HU-211)

↓ Intracranial pressure, ↓  mortality, phase III trial in progress

Neurodegeneration CBD In progress

HIV wasting syndrome

Appetite loss, nausea Smoked cannabis In progress

Appetite loss, nausea Dronabinol ↑ appetite, ↓ nausea

Tourette’s syndrome Behavioural disorders THC undetermined

Croxford, JL. CNS Drugs 2003; 17(3)

Pharmacology

hYps://cbdbrothers.com/wp-content/uploads/2014/05/tumblr_mmt475oMxO1s85ojqo1_500.png

7/17/17

28

hYp://steephilllab.com/wp-content/uploads/2014/01/Understanding-Medical-Cannabis-2.jpg

Pharmacology•  Marinol

–  Reduc8onofnauseaandvomi8nginchemotherapy–  Increaseappe8teinHIV-was8ngdisease–  Poten8alNewIndica8ons

•  Reduc8onofspas8city,analgesia,agonist-replacementincannabisdependency

Kine8cProfileaeerasingleoraldose(10mgofTHC)–  meanpeakconcfound1-2hourspostdose

•  THC:3.8ng/ml(1.1-12.7ng/ml)•  11-OH-THC:3.4ng/ml(1.2-5.6ng/ml)•  THC-COOH:26ng/ml(14-46ng/ml)

Pharmacology

•  Cul8va8onmethodshavebeendevelopedtoreproduciblyproduceplantswithdefinedTHCorCBDconcentra8ons.GWPharmaceu+calshasproducedtwostandardizedextractprepara8ons,Tetranabinex®,whichishighinTHC,andNabidiolex®,whichishighinCBD.Sa+vex®containsequalpropor8onsofTetranabinex®andNabidiolex®,and,hence,almostequalamountsofTHCandCBD


7/17/17

29

DrugInterac8ons•  S8mulants

–  Cocaine,Amphetamines,etc•  increasedhypertension•  tachycardia•  cardiotoxicity.

•  Depressants–  Benzodiazepines,Barbiturates,Ethanol,Opioids,An8histamines,musclerelaxants,etc.

•  increasedrowsiness•  CNSdepression

•  Alcohol•  greaterimpairment•  decreasesinfunc8on•  lesslikelytoreactappropriately•  increasedreac8on8mes


ButWhatAboutCannabisOil?

• Assesstheefficacyofmarijuana,oroneofmarijuana’sconstituentsinthetreatmentofpeoplewithepilepsy

Objective

• 4randomizedreportsincludingatotalof48patients,eachofwhichusedcannabidiolasthetreatmentagent

Inclusion

• Noreliableconclusionsonefficacybut200–300mgdailyofcannabidiolwassafelyadministeredtoasmallnumberofpatientsforashortperiodoftime

Results

Cannabinoidsforepilepsy:CochraneReview

GlossD,VickreyB.CochraneDatabaseofSystematicReviews2012,Issue6

7/17/17

30

AmericanAcademyofNeurology

Concludethat“forpatientswithepilepsy,dataareinsufficienttosupportorrefutetheefficacyofcannabinoidsforreducingseizurefrequency”

ThereisNOTsufficientevidencetoprescribeCBDorrecommendself-treatmentwithsmokedmarijuana

KoppelBSetal.Neurology2014;82:1556-1563

Anecdotalcasesofchildrensuccessfullytreatedwith

medicalmarijuana(CBD

enrichedpreparations)

Prominentinternetand

nationalmediaattention

Beliefthattreatmentsderivedfrom

naturalproductsaresaferormore

effectiveiscommonandpotentiallydangerous

Whyareparentsusingcannabis?

CilioMRetal.Epilepsia.2014.55(6):787-790

Charlotte§  CharlotteisalittlegirlfromColorado

withDravetsyndrome

§  Frequentboutsoffebrileandafebrilestatusepilepticus

§  Failedmultiplemedications:Levetiracetam,oxcarbazepine,topiramate,zonisamide,valproate,clobazam,clonazepam,anddiazepam

§  At5yearsofage,hadsignificantcognitiveandmotordelays,requiredafeedingtube,andneededfullassistancewithactivitiesofdailyliving

§  50generalizedtonic-clonicseizuresperday

http://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/

7/17/17

31

Charlotte’sWeb

  AhighconcentrationCBD/THCstrainofcannabisproducedbyamedicalmarijuanagroupinColorado

  Charlotte’sWeb,suppliedbyRealmofCaring,isbasedoutofColoradoandparentsandfamiliesaremovingtheretoattempttreatment

ParentsbegangivingCharlottelowdosesofplantextractandslowly

increasedthedoseovertime

Month3:>90%reductionin

generalizedtonic-clonicseizuresandweanedfromother

AEDs

Month20:2-3nocturnalgeneralizedtonic-clonicseizurespermonth,feedsanddrinksbymouthbyherselfandautisticbehaviorshave

improvement,walkingandtalking

http://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/

ParentSurveyofCannabidiol-EnrichedCannabisUse

§  StanfordUniversity

§  Surveyof24questions§  Diagnosisandseizuretypes§  Parental-reportedeffectofcannabidiol-enriched

cannabisonthechild’sseizurefrequencyandsideeffects

§  AdministeredtoFacebookgroupof150parentssupportingtheuseofcannabidiol-enrichedcannabistotreatchildrenwithtreatment-resistantepilepsy

PorterBEetal.EpilepsyBehav.2013;29(3):574-577

ParentSurveyofCannabidiol-EnrichedCannabisUse

PorterBEetal.EpilepsyBehav.2013;29(3):574-577

• Agerange:2–16yearsold• SeizureTypes:• Dravetsyndrome=13• Doose=4• Lennox-Gastautsyndrome=1• Idiopathicearly-onsetepilepsy=1

• 18/19patientsexperiencedtreatmentresistantepilepsyformorethan3yearsbeforetryingCBD

• Unsuccessfullytriedmedian12otherantiepileptics

• SeizureFrequencypre-CBD:2perweekto250perday

PopulationDemographics

• DoseRanges:0.5mg/kg/dayto28.6mg/kg/day• THC:0to0.8mg/kg/day

Intervention

• 16/19(84%)reportedareductionintheirchild’sseizurefrequency• 2/16reportedtobeseizurefree• 8/16reportedagreaterthan80%reductioninseizurefrequency

• 3/16reportedagreaterthan50%reductioninseizurefrequency

• 12/19patientsweanedtheirchildfromanotherAED

• Othereffects:• Bettermood(15/19,79%)• Increasedalertness(14/19,74%)• Bettersleep(13/19,68%)• Drowsiness(7/19,37%)• Fatigue(3/19,16%)

Results

7/17/17

32

Cannabidiol:CBD

Cannabinoids

Delta-9-THC“ACTIVE”CBD“INACTIVE

Cannabidiol (CBD) versus THC •  THC and CBD molecules present in largest amounts in cannabis.

Most recognized and studied. •  Classed as phytocannabinoids (as opposed to endocannabinoids

and cannabinoids that are manufactured artificially), both CBD and THC interact with specific cells in our brains.

•  THC – Psychoactive cannabinoid, THC is responsible for the “high” from smoking marijuana so production and usage are strictly regulated (even in WA, OR, CO and AK).

•  CBD – naturally occurring cannabinoid, and the second most abundant molecule in Cannabis plant.

•  CBD is legal and safe to consume, yet has long been in the shadow of THC.

CBD:Pharmacodynamics

  LacksdetectablepsychoactivityanddoesnotappeartobindtoeitherCB1orCB2receptorsatphysiologicallymeaningfulconcentrations.

  Affectstheactivityofasignificantnumberofothertargetsincludingionchannels,receptors,andenzymes.

  Mayhaveanti-inflammatory,analgesic,anti-nausea,anti-emetic,anti-psychotic,anti-ischemic,anxiolytic,andanti-epileptiformeffects.

7/17/17

33

CBD:PharmacokineticsAbsorption

  OralBioavailability:13–19%duetomarkedfirstpasseffect

  IVpreferable

Distribution

  LikeTHC,itishighlylipophilic–rapidlydistributedandeasilypassesthebloodbrainbarrier(BBB)

CBD:PharmacokineticsMetabolism

  undergoesmultiplehydroxylations,oxidationstocarboxylicacids,beta-oxidation,conjugation,andepoxidataion

Excretion/Elimination

  prolongedduetolipophilicity(staysinsystemlonger)

  excretedfromurine,bothinfreestateandasitsglucuronide

  ****Halflife=9hours

Cannabidiol(CBD)Absorp8on•  Smoked/inhaled

•  AverageBioavailability:31.13%•  IntravenousAdministra8on(upto72hourspostdosing)

–  PlasmaClearance:960−1560ml/min•  OralApplica8on(40mgofCBD)

–  BloodConcentra8on:1.1−11ng/ml•  1haeerdosechocolatecookies

–  CBDconcentra8onsof0.30−2.57ng/ml•  1haeeroralintakeof5.4mgofCBD,remaineddetectablefor3−4haeer

•  Followingadministra8onofequivalentamountsofTHCandCBD,lowerplasmaconcentra8onsofCBDwerealwaysobserved

•  Studiessuggest: –  Iden8fica8onandquan8fica8onofCBDcouldbeanaddi8onalproofofcannabis

exposure–  Couldimproveinterpreta8onofTHCeffectsconsideringthepoten8alabilityof

CBDtomodifyTHCeffects


7/17/17

34

Cannabidiol(CBD)Metabolism•  Significantfirst-passeffect

–  UnlikeTHC,alargepropor8onisexcretedunchangedinthefeces•  Co-administra8onofCBDwithTHCdidnotsignificantlyimpactTHCorTHC

metabolitekine8cs,including:–  thetotalclearance,–  volumeofdistribu8on–  terminalelimina8onhalf-lives

•  CBDonlypar8allyinhibitedthehydroxyla8onofTHCto11-OH-THCcatalyzedbyCYP2C–  Studybasedonconcentra8onvs8mecurves,ra8osofmax.average

concentra8ons,andAUCvaluesof:•  11-OH-THC/THC•  THC-COOH/THC•  THC-COOH/11-OH-THC


CannabisElimina8on•  5dayspostdose:80−90%ofTHCisexcreted

–  65%isexcretedinthefeces•  Primaryfecalmetabolite:11-OH-THC

–  20%beingeliminatedintheurine•  primaryurinarymetabolite:acid-linkedTHC-COOHglucuronideconjugate

•  Urineconcentra8ondropsrapidlyun8lreachingaconcentra8onof20−50ng/ml,thenbeginsdecreaseatamuchslowerrate

•  Longterminalhalf-lifeofTHCinplasma–  Reportedtobegreaterthan4.1dinchroniccannabisusers

•  MeanplasmaTHC-COOHelimina8onhalf-lives:–  FrequentUsers:5.2±0.8–  InfrequentUsers:6.2±6.7d

•  However,nosignificantpharmacokine8cdifferencesbetweenchronicandoccasionalusershavebeensubstan8ated


PharmacodynamicsofOtherCannabinoids

  Δ8-THC(anisomerofΔ9-THC):partialagonistatbothCBreceptorsandsharesrelativelysimilarefficacyandpotencywithΔ9-THC.Morepotentanti-emeticthanΔ9-THC.

Cannabinol(aproductofΔ9-THCoxidation):has10%oftheactivityofΔ9-THC.Appearstohavesomepossibleimmunosuppressiveproperties.

Cannabigerol:partialCB1/2receptoragonist.Mayhavesomeanti-inflammatoryandanalgesicproperties.Itmayalsoblock5-HT1Areceptorsandactasanα2-adrenoceptoragonist.

Tetrahydrocannabivarin:actsasaCB1receptorantagonistandCB2receptorpartialagonist.Itmayhaveanti-epileptiform/anti-convulsantproperties.

7/17/17

35

Pharmacology(2015)

•  Cul9va9onmethodshavebeendevelopedtoreproduciblyproduceplantswithdefinedTHCorCBDconcentra9ons.GWPharmaceu,calshasproducedtwostandardizedextractprepara9ons,Tetranabinex®,whichishighinTHC,andNabidiolex®,whichishighinCBD.Sa,vex®containsequalpropor9onsofTetranabinex®andNabidiolex®,and,hence,almostequalamountsofTHCandCBD


DifferentRoutesofAdministrationandthe

EffectonPlasmaConcentrations

A.  IntravenousRoute

B.  OralRoute

C.  Vaporization/Inhalation

D.  Dabbing

  IntravenousRoute-Researchprimarily

  HowCannabisCausesParanoia:UsingtheIntravenousAdministrationof∆9-Tetrahydrocannabinol(THC)toIdentifyKeyCognitiveMechanismsLeadingtoParanoiaDanielFreeman*,1,GrahamDunn2,RobinM.Murray3,NicoleEvans1,RachelLister1,AngusAntley1,MelSlater4,5,BeataGodlewska1,RobertCornish6,JonathanWilliams7,MartinaDiSimplicio8,ArtemisIgoumenou9,RudolfBrenneisen10,ElizabethM.

Tunbridge1,PaulJ.Harrison1,CatherineJ.Harmer1,PhilipCowen1andPaulD.Morrison3+

7/17/17

36

Edibles

Edibles•  Gela9ncapsules,glycocholate,sesameoil:improvedbioavailability

–  Considerablevaria9onsinpeakconcentra9onsandratesofabsorp9on

»  Occurredevenwhenadministerinthesamevehiclemorethanonce

–  SesameOilbasedAdministra9on»  OralTHCbioavailability:10-20%

•  Meningested20mg•  Womeningested15mg

»  PlasmaPeakat4-6hours,butwereconsideredoveres9matedbecauseofradioac9velabelingnotbeingsubjecttoonlyTHCandextendingtoitsmetabolites


OralAdministration–ClinicalStudyExample

  ingestionofbrowniescontainingalowdoseofΔ9-THC(9mgTHC/brownie)àmeanpeakplasmaΔ9-THClevelsof5ng/mL

  IngestionofbrowniescontainingahighdoseofΔ9-THC(~13mgΔ9-THC/brownie)àmeanpeakplasmaΔ9-THClevelsof6to9ng/mL

NOTE:only10–20%oftheadministereddoseentersbloodstreamduetoextensivefirstpasseffect

7/17/17

37

Inhala8onandSmoking•  Absorp8on

–  Rapidandefficientdeliveryfromlungstobrain–  ExposingdrugeffectstoCNS(abusepoten8al)–  Slightlylowerpeakconcentra8onsthatIVadministeredTHC–  Bioavailability:2-56%

•  Duetovariabilityinsmokingdynamics/ability–  Number,dura8on,spacingbetweenpuffs,hold8me,inhala8onvolume,smokingtopography,and

expecta8on–  Forma8onof11-OH-THCandTHC-COOHoccurredlaterandwithmuchlowerconcentra8ons

•  TechniqueandStudyDesign–  THCdisposi8onfollowedfor7daysaeersmokingasinglecannabiscigareYecontaining1.75%or3.55%THC

•  ImmediatelyfollowingfirstcigareYepuff–  MeanTHCconc1.75%(16mg):7.0+/-8.1ng/ml–  MeanTHCconc3.55%(34mg):18.1+/-12.0ng/ml

•  Peakconcoccurredat9minutespriortostoppingsmokingat9.8minutes–  PeakTHCconc1.75%(16mg):84.3ng/ml(range50-129)–  PeakTHCconc3.55%(34mg):162.2ng/ml(range76-267)

•  Within2hoursofcessa8onalllevelsfellbelow5ng/ml•  Dosedetec8on(levelabove0.5ng/ml)

–  1.75%(16mg):3to12hours–  3.55%(34mg):6to27hours

•  Thoughtsonsafety/delivery–  AllsubjectsusinghashishbasedcigareYesexperiencedhigherTHCconcentra8onsinplasma–  THCconcentra8onstypicallypeakduringtheactofsmoking,whilepeak11-OHTHCconcentra8onsoccurapproximately

9-23minutesaeerthestartofsmokingHues8s,M.2009,HumanCannabinoidPharmacokine8cs,Na+onalIns+tuteofHealth:ChemBiodivers,v.4(8),p.1770-1804.

Vaping•  Absorp8on

–  vaporizersreportedtheonsetofeffectsmorerapidlywithpureTHC(mean2.5min)thanherbalcannabis(mean6.5min)

–  vaporizerresultedinhigherplasmaconcentra8onsofTHCcomparedtosmokedmarijuanaat30and60minateachstrength

•  Technique–  hea8ngcannabistoatemperaturebetween180and2001C,itispossibleto

vaporizethecannabinoidsthatresideonthetrichomesonthesurfaceofcannabisflowersandleaves,whileavoidingcombus8on

•  Thoughtonsafety/delivery–  vola8zescomponentssuchasTHC,CBD,andterpenes,butwithsignificant

reduc8onofpyroly8cbyproducts–  releasesubstan8al–  amountsoftheTHCwhileproducingnomeasurableamountsofthebenzene,

toluene,andnaphthalene,whicharegeneratedwhenmarijuanaissmoked–  vaporizertoinhalesomeformofpureTHC(likelydissolvedinalcoholor

anothersolvent)

Hazekamp,A.,Ware,M.,Muller-Vahl,K.,Abrams,D.,Grotenhermen,F.,2013,Themedicinaluseofcannabisandcannabinoids--aninterna8onalcross-sec8onalsurveyonadministra8onforms,JournalofPsychoac8veDrugs,45(3),p.199-210

Vaporization-clinicalstudyexample

  32Adultcannabissmokersdrankplaceboorlow-dosealcohol10minbeforeinhaling500mgplacebo,low-dose(2.9%)THC,orhigh-dose(6.7%)THCvaporizedcannabis.

  Bloodandplasmaconcentrationswereobtainedbeforeandupto8.3hafteringestion

  “ControlledCannabisVaporizerAdministration:BloodandPlasmaCannabinoidswithandwithoutAlcohol”RebecaL.Hartman,TimothyL.Brown,GaryMilavetz,AndrewSpurgin,DavidA.Gorelick,GaryGaffneyandMarilynA.Huestis.ClinicalChemistry.June2015vol61no.6p.850-869.

  http://www.clinchem.org.proxy-remote.galib.uga.edu/content/61/6/850.full

7/17/17

38

Dabbing  Inhalationofaconcentratedtetrahydrocannabinol(THC)productcreatedthroughbutaneextraction

  Blasting-passbutanethroughasteelorglasstubepackedwithdriedcannabistrimmings-THCandotherhydrophobiccompoundsintheplant’strichomesdissolveintothebutane-butane-THCsolutionleavesthetubethroughfilterandiscollectedinadishortray-butaneevaporatesandleavesresinsthatcanhaveTHCconcentrationupto80%

SoWhatIstheProblemWithMedicalMarijuana

ForPrescribers?

7/17/17

39

NewTypesofConcentrates

•  Kief•  WaterHash•  CO2Oil•  ButaneHashOil(BHO)•  Rosin

Concentra9on:Kief•  Alsoknownasdrysieve(some9mes“drysip”)hash,kiefisthe

simplestofconcentrates.Kiefiscomposedofthetrichomes(thecrystallinestructurescoa9ngtheoutsidesurfaceoftheflowers)brokenawayfromthedriedplantmaterial,usuallyviaspecializedfilteringscreensandalialeelbowgrease.Kiefisgenerallyconsideredalower-qualityextract,butsometop-flightextractorscanproduceanextremelycleanandflavorfulproductusingthismethod.THCcontentcanrangefrom20percentto60percent.Thisprocessatitshighestlevelyieldsnothingbutthelargest,mostperfecttrichomeglandheadsandnoneoftheglandstems,plantmaaer,etc.thatgenerallycloudsthequicker,lower-qualitykiefextrac9ons.WhileitiscertainlyavailableinColoradodispensaries,comparedtothreeyearsago,itismuchhardertofindbecauseoftheprevalenceofsolventextractsandthelowreturnthatitprovidestocommercialgrowers.

DeBacker,B.,Maebe,K.,Verstraete,A.,Charlier,C.,2012,Evolu8onoftheContentofTHCandOtherMajorCannabinoidsinDrug-TypeCannabisCumngsandSeedlingsDuringGrowthofPlants,JournalofForensicSciences,v.57(4)

ConcentratesofWaterHash•  Therearevarioustechniquesusedintheproduc9onofwaterhash,and

theresul9ngproductshavemanyforms(bubblehash,solventlesswax,icewax,amongothers).Thebasicprincipleisthis:plantmaterial(eitherdryorfresh-frozengenerally)ismixedwithcoldwaterandice,thenagitatedmanuallyormechanicallyinordertobreakoffthenow-brialetrichomeheads.Thissolu9onisthenfilteredthroughspecifically-sizedscreenstoremoveanythingundesirable,leavingbehindarela9velypurefinishedproductthattypicallytestsbetween50percentand80percentTHC.Themostcommonwaythatwaterhashisextractedisusingaseriesofmicroscreenfabricbags(generallyreferredtoas“bubblebags”)whichremovevariousgradesofproductaccordingtothesizeofpar9clestheyallowthrough.

7/17/17

40

ConcentratesofCO2Oil

•  Thisvarietyofextractiscreatedusingcarbondioxidecompressedathighpressuresun8litbecomeswhatisknownasa“supercri8calfluid,”whichthenisabletostriptheessen8aloilsofthecannabisplantmuchlikehydrocarbonsolvents.CO2oilisgenerallyaloose,orange-8ntedoilthatcanbeeitherclearoropaquedependinguponthefinishingprocessesusedaeerextrac8on,andTHCcontenttestsbetween50percentand75percent.Theappealofthismethodformanyisthatitisnon-flammableandcontainsnochemicalsolvents.ThemachinesrequiredtodoCO2extrac8onsatanykindofcommercialscalecancosthundredsofthousandsofdollars.

ConcentratesofButaneHashOil(BHO)

•  Perhapsthemostcommontypeofextractonthemarket,BHOhasavarietyofnames(wax,shaYer,crumble,oil,errl,honeycomb,moonrock,nectar,etc.)butlikewaterhash,thebasicprinciplesofextrac8onarethesameacrossallofthem,withthevaria8onsinappearanceandtexturemostlycominginfinishingprocesses.Tomakeabutaneconcentrate,butaneispressurizedinavesselandwashedoverplantmaterial(usuallydry,butsome8mesfresh-frozen—moreonthatbelow),thentheresul8ngsolu8oniscollected.Thehashmakermustremoveanyresidualsolventfromthissolu8on,sothenextstepgenerallyisapplyingheat(butanehasalowboilingpoint)andvacuum(whichlowerstheboilingpointfurther)inordertomakethisprocesseasierandfasterwhileretainingthehighestamountofflavorfulterpenesandcannabinoidsinthefinishedproduct.BHOgenerallytestsbetween60percentand90percentTHC,makingitperhapsthestrongestconcentrateonthemainstreammarket.

ConcentratesofRosin•  ThenewestandhoYesttypeofextractonthescenerightnow,rosinisextractedfromeitherdriedbuds,trim,orlower-gradewaterhash/kief.Whatisuniqueaboutrosinisthatitcanbemadewithnothingmorethanastandardhairstraightener,parchmentpaperandsomehand-appliedpressure.Whenthematerialissmashedandheatedquicklybetweentheparchmentsheets,itextrudessomeoftheessen8aloilspresentintheplant,resul8nginagoldenshaYeroroil-likeextractthatlookssimilartopressedhigh-qualitywaterhashorevensolvent-extractedshaYer.Rosinisafairlyrecentdevelopment,soitsavailabilityindispensariesiss8llsomewhatlimited,asisdataaboutitspotency;butearlyreportsonsomerosinextractshaveshowednumbersbetween50percentand70percentTHC,similartothatofhigh-qualitywaterhash.

7/17/17

41

Inhala9onandSmoking•  Absorp9on

–  Rapidandefficientdeliveryfromlungstobrain–  ExposingdrugeffectstoCNS(abusepoten9al)–  Slightlylowerpeakconcentra9onsthatIVadministeredTHC–  Bioavailability:2-56%

•  Duetovariabilityinsmokingdynamics/ability– Number,dura9on,spacingbetweenpuffs,hold9me,inhala9onvolume,smokingtopography,andexpecta9on

–  Forma9onof11-OH-THCandTHC-COOHoccurredlaterandwithmuchlowerconcentra9ons


ColoradoMarijuanaAnalysis–March2015

  Denverlabanalyzedmorethan600samplesofbudprovidedbycertifiedgrowersandsellers

  averageTHClevelwas18.7%,andsomeretailpotcontained30%THCormore

  Littleornocannabidiol(CBD)—theaverageCBDamount:0.1%  Recall:CBDlacksdetectablepsychoactivityandinsteadhas

anti-inflammatory,analgesic,anti-nausea,anti-emetic,anti-psychotic,anti-ischemic,anxiolytic,andanti-epileptiformeffects–the“medical”inmedicalmarijuana.

OtherAdministra9ons•  Routes

–  Oromucosal•  Sa,vex®isadministeredsublinguallytoavoidfirst-passmetabolismbytheliver.Sa,vex®is

approvedinCanadaforthetreatmentofneuropathicpainassociatedwithmul9plesclerosis,andinthreeEuropeancountriesforanumberofindica9ons.

–  Rectal•  THC-hemisuccinateprovidedthehighestbioavailabilityof13.5%(Marinolsuppository)•  bioavailabilityoftherectalroutewasapproximatelytwicethatoftheoralroute•  THCdidnotaccumulateinthebloodfollowing10−15mgdailydoses•  administra9onof2.5−5mgofTHCproducedmaximumplasmaconcentra9onsof1.1−4.1ng/ml

within2−8h.–  Transcutaneous

•  meansteady-stateplasmaconcentra9onofΔ8-THCwas4.4ng/mlwithin1.4h,andwasmaintainedforatleast48h

•  Permeabili9esofCBDandCBNwerefoundtobe10-foldhigherthanforΔ8-THC•  Lowabusepoten9alduetoslowdeliveryofTHCtothebrain

–  Intravenous•  THCproducedschizophrenia-likeposi9veandnega9vesymptomsandeuphoria,andaltered

aspectsofcogni9vefunc9on–  Acuteparanoia,panic,hypotension,withdrawal,behaviorandcogni9vedefects

(endogenouspsychosis)


7/17/17

42

124

Impact of Addiction

■  MARIJUANA:

16 y.o. 2 year history of daily abuse

underside surface view of prefrontal and temporal lobe activity © 2006 Amen Clinics Inc

Normal

7/17/17 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

WithdrawalAccordingtotheDSM5

•  A.Cessa8onofcannabisusethathasbeenheavyandprolonged•  B.3ormoreofthefollowingdevelopwithinseveraldaysaeer

CriterionA•  1.Irritability,angeroraggression•  2.Nervousnessoranxiety•  3.Sleepdifficulty(insomnia)•  4.Decreasedappe8teorweightloss•  5.Restlessness•  6.Depressedmood•  7.Physicalsymptomscausingsignificantdiscomfort:must

reportatleastoneofthefollowing:stomachpain,shakiness/tremors,swea8ng,fever,chills,headache

125Dr.MerrillNorton,Pharm.D.,D.Ph.,ICCDP-DandCaitlinPayne,ResearchAssistant

Ques9ons???????


Documents

Forensic Marijuana : The Science of Medical Cannabinoids...Forensic Marijuana : The Science of Medical Cannabinoids ... Social media is source of information about novel forms of MJ