Bernhard-Michael(Bernd)Mayer,PhD

Professor&ChairDepartmentofPharmacology&Toxicology

InstituteofPharmaceuticalSciences,UniversityofGraz,Humboldtstraße46,A-8010Graz,Austria

NicotineToxicityandAddiction– DebunkingofTwoPopularMyths

PotentialConflictofInterestsØ Ihavebeenadvocatingelectroniccigarettesfortobaccoharmreductionsince2006.Ø Ihavewrittenhonoredexpertopinionsforpharmaceuticalandvapeindustries.Ø Iservedasunpaidexpertwitnessinpolicydecision-makingontheregulationofvaping(since

2014).Ø Iservedashonoredexpertwitnessinapatentcaseone-liquids(USA,2017).Ø Iamfinancially,legallyandpersonallyindependentofmyclientsandreceivednofundingfrom

thetobaccoorvapeindustry.

Cancer

COPD

otherrespiratorydiseases

strokeandmyocardialinfarction

prematuredeath(~10yreducedlifespan)

Perceptionoftheroleofnicotineincancercausedbysmoking

bycourtesyofJoeGitchell

FourCrucialMisconceptions inTobacco Control

1. smoking=abuseofnicotine[med.:nicotineabusus]

2. smokingcessation=therapyofnicotinedependence

3. electroniccigarette=tobaccoproduct(WHO,FDA)

4. goalofpublichealth=tobacco-freeworld

X

X

X

smoke

Harmreductionshelf– Condoms andNicotineProducts

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EstablishedBiological EffectsofNicotine

Ø slight,short-termincreases inbloodpressureandheartrate(similartocaffeineorexercise);

Ø angiogenesis (growthofnewbloodvessels);

Ø inhibitionofinflammationassociatedwithimmunesuppression;

Ø psychoactive,enhancedcognitiveperformance;

Ø activationofdopaminergicreward-pathwaysassociatedwithpleasure(basisfordependence incombinationwithtobaccosmoke;seelater);

Ø numerousothereffectsobservedinvitro andinrodentsbutnotinhumans.

PotentialBenefitsofNicotineConsumption

Ø improvedcognitiveperformance(self-treatmentofschizophrenicpatientsbysmoking?);

Ø protectionagainstneurodegenerativediseases (M.Alzheimer,M.Parkinson);

Ø protectionagainstulcerativecolitis,anastyinflammatoryboweldisease.

PotentialRisksofNicotineConsumption

Ø Pregnancy: Noevidenceforadversebirthoutcomes inclinicalstudies(observationofchildrenforupto2years);

Ø CardiovascularDiseases:potentialhealthriskforpatientswithseverecoronaryarterydisease,e.g.survivedmyocardialinfarction(controversial);

Ø Cancer: nicotine isnotcancerogenic,butacceleratedgrowthofestablished tumorswasobservedinanimalstudies(duetoangiogenesis);noclinicaldata.

Myth#1– Nicotine ishighlytoxic,60mgwillkillanadult

Thetoxicityofnicotinehasbeenoverestimatedfor>100yearsbecauseofanuntenableestimateofthelethaldosebasedonself-experiments thatwereperformedinViennaaround

1850andledtothe60-mgestimatepublishedbyRudolfKobertinatextbookin1905.

Ø Rapidmetabolism anddistributionofnicotinekeepsplasmalevelsfarbelowtoxictresholdswhenappliedatsmallamountsatatime(smoking,vaping).

Ø firstsignsofoverdosing(headache,dizziness)resultinstopofconsumption;

Ø veryslowresorptionofnicotinethroughskin(nicotinepatch:tmax ~12hours,cmax

CaveatØ Smallchildrenareathigherrisk(accordingtolowerbodyweight).

Ø Therefore,nicotinecontainingliquidshavetobekeptoutofthereachofchildren.(liketoiletcleaners,guns,medicinalproducts,tobaccocigarettes,alcoholicdrinks,matchesetc)

20"shots"à10ml(TPD2version)

SummaryoftheHardFactsonToxicity (beyonddispute)

Ø Inhalationofnicotine(via smokingorvaping)isnottoxic.

Ø Unintentionalswallowingofafewdrops(orevenafewml)ofliquidiscompletelyharmless.

Ø Therearenoadverseeffectsofliquidsunintentionallyspilledonskin.

Ø Mostsuicideattemptsbyingestinglargeamountsofconcentratednicotinesolutionswereunsuccessfulduetovomitting.

Myth#2- Nicotine ishighlyaddictive

Smokersdon'tdieoftheirdependence butofthesmoke!

Ø Ifatall,animalsdonotself-administer nicotineasreadilyasharddrugslikecocaineorheroin.

Ø Therewardingeffectsofnicotinearemarkedlypotentiated byotherconstituents oftobaccosmoke.

Ø Thelong-termefficiencyofNRTforsmokingcessation isclosetoplacebo(>95%failureafter12months).

Ø Never-smokerstreatedforupto6monthswithnicotinepatchesdidnotbecomedependent.

Ø Basedontheseandotherfacts,KarlFagerströmrenamedhisfamousandwidelyappliedtestfornicotinedependenceto"Fagerströmtestforcigarettedependence".

Factsarguingagainstasignificantaddictivepotentialofpurenicotine:

DeterminantsofCigaretteDependence(adaptedfromFagerström,2012)

Ø drug-inducedpleasurereward(nicotine incombinationwithotherconstituents oftobaccosmoke);

Ø throathit(via activationofnicotinergicreceptorsonsensoryC-fibersintheupperairways);

Ø habitandconditioning(smoking-associatedbehavior).

NicotineTob.Res. 14,1382-90,2012

E-cigarettesprovidenicotine+throathit+behavior.