QuantitativeAnalysisofNarrativeReportsofPsychedelicDrugs

JeremyR.Coyle1 DavidE.Presti2 MatthewJ.Baggott3

1GraduateGroupinBiostatistics,UniversityofCalifornia,Berkeley,California947207358

USA 2UniversityofCalifornia,DepartmentofMolecularandCellBiology,Berkeley,California 947203200USA 3HumanBehavioralPharmacologyLaboratory,DepartmentofPsychiatryandBehavioral Neuroscience,UniversityofChicago,Chicago,Illinois60637USA Tel:(773)7020563,Email:matthew@baggott.net ABSTRACT BACKGROUND:Psychedelicdrugsfacilitateprofoundchangesinconsciousnessandhave potentialtoprovideinsightsintothenatureofhumanmentalprocessesandtheirrelation tobrainphysiology.Yetpublishedscientificliteraturereflectsaverylimited understandingoftheeffectsofthesedrugs,especiallyfornewersyntheticcompounds.The numberofclinicaltrialsandrangeofdrugsformallystudiedisdwarfedbythenumberof writtendescriptionsofthemanydrugstakenbypeople.Analysisofthesedescriptions usingmachinelearningtechniquescanprovideaframeworkforlearningaboutthesedrug useexperiences. METHODS:Wecollected1000reportsof10drugsfromthedruginformationwebsite Erowid.organdformedatermdocumentfrequencymatrix.Usingvariableselectionanda randomforestclassifier,weidentifiedasubsetofwordsthatdifferentiatedbetweendrugs. RESULTS:Arandomforestusingasubsetof110predictorvariablesclassifiedwith accuracycomparabletoarandomforestusingthefullsetof3934predictors.Our estimatedaccuracywas51.1%,whichcomparesfavorablytothe10%expectedfrom chance.ReportsofMDMAhadthehighestaccuracyat86.9%;thosedescribingDPThadthe lowestat20.1%.Hierarchicalclusteringsuggestedsimilaritiesbetweencertaindrugs,such asDMTandSalviadivinorum. CONCLUSION:Machinelearningtechniquescanrevealconsistenciesindescriptionsof druguseexperiencesthatvarybydrugclass.Thismaybeusefulfordeveloping hypothesesaboutthepharmacologyandtoxicityofnewandpoorlycharacterizeddrugs. INTRODUCTION Psychedelicsubstancessuchaslysergicaciddiethylamide(LSD)and3,4 methylenedioxymethamphetamine(MDMA;streetnameecstasy)arewidelyconsumed. Anestimated14.8%ofAmericansovertheageof12yearshaveusedpsychedelicsatsome point,commonlyLSD(9.2%ofthepopulation)andecstasy(6.3%)[1].InEurope, Narrativereportsofpsychedelics1

psychedelicusevariesgreatlybycountry:across22countries,thebycountrymedian percentoftheadultpopulation(ages1564years)havingusedLSDandecstasyis estimatedat1.3%and2.3%,respectively[2].Despitewidespreaduse,thesedrugsare poorlyunderstood,largelybecauseformalcontrolledexperimentsinhumansarerare.In thisreport,weuseamachinelearningapproachtounderstandingdescriptionsof psychedelicexperiences. Psychedelicsfacilitateavarietyofcomplexmentalstates,includingalterationsin perception,intensificationofemotionsandthoughts,andchangedsenseofboundary betweentheselfandenvironment[3,4].Theyhavebeenusedexperimentallytoimitate psychosis[57]yettheyhavealsobeenreportedtofacilitatemysticalandspiritual experiences[8,9].Thecomplexityofpsychedelicseffectsisunderscoredbythemany termsusedtolabelthem:psychedelics;hallucinogens;psychotomimetics;andentheogens. Becauseofthesecomplexeffects,psychedelicsarepowerfulprobesoftheconnection betweenbrainphysiologyandconsciousness,oneofthemostmysteriousproblemsin neuroscience. Psychedelicusebyhumansmaypredatewrittenhistory.Intheirplantandfungalforms, psychedelicshaveprobablybeenusedformillenniafortherapeutic,ritualistic,and religiouspurposes[10,11].Modernscientificresearchonpsychedelicscanbetracedback toArthurHeffters[12]isolationofmescalinefromthepeyotecactusinthe1890s.The paceofscientificresearchquickenedafterAlbertHofmannsdiscoveryofLSDinthe1940s. ResearchonLSDcontributedtotherecognitionthatserotoninfunctionsasabrain neurotransmitterintimatelyinvolvedintheregulationofmentalprocesses[13].Inthe 1950sand1960s,psychedelicswereextensivelystudiedfortheirpsychotherapeutic potential[14,15].Thishascontinuedinalimitedmanner[16,17].However,themajority ofscientificpublicationsonpsychedelicsusethemtoelucidateneuropharmacological signalingmechanismsinrodentsubjects[18,19]. Thesestudiessupportacentralroleforthe5HT2Areceptorinthemechanismsofwhatare sometimescalledserotonergicorclassicalpsychedelics[3].Theseclassicalcompounds includeLSD,N,Ndimethyltryptamine(DMT),mescaline,andpsilocybin.However,many othercompoundswithdifferentmechanismsofpsychoactivityshareclinicaleffectsand usersdemographicswithclassicalpsychedelics.Examplesofsuchchemicalsarethe monoaminereleaserMDMA(methylenedioxymethamphetamine:streetnameecstasy), thekappaopioidreceptoragonistsalvinorinA(fromtheplantSalviadivinorum),andthe NMDAreceptorantagonistanestheticketamine.Theclinicalsimilaritiesofthesedrugs suggestsconvergentdownstreameffectsonconsciousnessdespiteneurochemically distinctinitialmechanisms[6,20].Thus,documentingtheclinicalandexperientialeffects ofdifferentpsychedelicscanelucidateconnectionsbetweenbrainphysiologyand consciousness. Studyingpsychedelicsalsohaspotentialpracticalvalue.Newpsychedelicsmanyfirst synthesizedasprobesofthebrainmindconnection[2123]havebecomeavailablein theunregulatedmarketinrecentdecades[24].Thesedrugsareoftensoldasresearch chemicalsorlegalhighs,butarealsosometimesdisingenuouslymarketedasbath Narrativereportsofpsychedelics2

salts,herbalincense,orplantfood[25,26].Thisdisingenuousmarketingiscommonin theUS,becausetheFederalControlledSubstanceAnalogueActbansmanynovel hallucinogensonlywhentheyareintendedforhumanconsumption.Useofnovel compoundshasledtoadversereactions,especiallyinsituationswhereunknowndosesof unknowncompoundsareinvolved[2527].Understandingthehumanpharmacologyof thesecompoundscouldaidinreducingandtreatingtheirtoxicities.However,thescientific literatureisvirtuallysilentabouttheeffectsofmostofthesenovelchemicalsinhumansin controlledsettings.Theexpenseassociatedwithdoinghumanresearchensuresthis situationwillchangeonlyveryslowly. Incontrasttothelimitedformalscientificliterature,thereisarobustinformalliterature availableontheWebwrittenbyindividualswhousepsychoactives.Animportantsource ofsuchinformationisthewebsiteErowid.org.Thiswebsitereceivesapproximately95,000 uniquevisitorsperdayandcontainsnarrativedescriptionsofnearly22,000druguse episodes[28].Thesedrugexperiencereportsrangefromdescriptionsofcaffeine,alcohol, andnicotine,tomarijuana,LSD,andmescaline,tolesserknownsubstancessuchas4 bromo2,5dimethoxyphenethylamine(2CB)and2,5dimethoxy4 ethylthiophenethylamine(2CT2).Insomecases,thesedescriptionsrepresenttheonly writtensourcesofinformationabouttheeffectsofaspecificcompoundinhumans. Giventheseconsiderations,wesoughttodevelopamethodforquantitativecomparisonof drugusedescriptionsarchivedonline.Previousstudiesofwrittendescriptionsofdrug effectshavegenerallyusedeitherqualitativemethodsordictionaryapproaches. Qualitativemethodsaretimeconsumingandusuallyinvolveverylimitedsamplesizes[29 31].Dictionaryapproachesinwhichdescriptionsarescoredbasedontheappearanceof wordsfrompreviouslyvalidatedcategoriescanbeappliedtolargerdatasets[32]; however,suchapproachesmayfailtocapturethechangingterminologyusedtodescribe drugexperiences.Machinelearningtechniquessuchasclassificationandvariable selectionavoidsomeofthelimitationsoftheseapproaches,astheycanaccommodatea largesamplesizeandmakeclassificationsbasedoncharacteristicsofthedataset,rather thanonpredeterminedcategories. Weusedclassificationtechniquesinanattempttocharacterizedifferencesinnarrative reportsfrom10psychedelicdrugs.Wehypothesizedthat: i) therewouldbedetectabledifferencesbetweenreportsfordifferentdrugsas indicatedbytheabilityofaclassifiertoaccuratelypredictdrugclass; ii) drugswithsimilareffectswouldhavesimilarreportsasindicatedbyclassifier confusionandclassmeans; iii) inspectionofthediscriminatingvariableswouldallowinsightintothedifferences betweenthesedrugs. Wetestedthesehypothesesusingpreexisting,publicallyavailabledrugexperience reportsfromthewebsiteErowid.org.Wewereabletosuccessfullyclassifyreportsfrom10 differentdrugswithanestimatedoverallaccuracyof51.1%andwefurthermoreidentified asubsetof110variablesthatwereparticularlyusefulindistinguishingdrugclasses.We Narrativereportsofpsychedelics3

concludethatmachinelearningtechniquesprovideapromisingapproachforgaining insightsintothepharmacology,andtoxicityofnewandpoorlycharacterizeddrugs. METHODS DataCollection Wecollectedacorpusof1000narrativereportsfromthedrugexperiencearchivesat Erowid.org.Narrativesrepresented10psychedelicallyactivesubstances(Table1),which wereselectedbecausetheirpharmacologyisatleastpartlyunderstood.Reportswere writtenbetween2000and2010.Foreachsubstance,werandomlychose100reports. Table1:Names,routesofadministration,andpharmacologyforthe10studieddrugs

Chemical/SpeciesName 2CE(2,5dimethoxy4 ethylphenethylamine) StreetNames Europa Routesof PrimaryKnownPharmacological administration Mechanisms oral,insufflated 5HT2Aagonist[33,34]

2CT2(2,5dimethoxy4 T2 ethylthiophenethylamine) 5MeODiPT(N,N diisopropyl5 methoxytryptamine) 5MeODMT(5methoxy N,Ndimethyltryptamine) DMT(N,N dimethyltryptamine) DPT(N,N dipropyltryptamine) foxymethoxy, foxy

oral,insufflated

5HT2Aagonist[34]

oral,insufflated, 5HT2Aagonist,bindsto5HT1A receptors[3336] smoked

5MeO Dimitri

smoked, insufflated

5HT1Aand2Aagonist[33,34,3639]

oral,insufflated, 5HT2Aagonist;sigma1regulator[34, smoked 40,41];traceaminereceptoragonist [42] oral,insufflated, 5HT1Aand2Aagonist[34,35];SERT inhibitor/substrate[33,43] smoked, intramuscular oral oral,insufflated oral 5HT2Aand1AagonistandD2like agonist[44,45] Monoaminereleaser[46] 5HT2Aand1Aagonist[44,47]

thelight

LSD(lysergicacid diethylamide) MDMA(3,4methylene dioxymethamphetamine) PsilocybinMushrooms (psilocinisactive metabolite) Salviadivinorum (SalvinorinAisactive ingredient)

acid,blotter,tabs ecstasy,e,rolls, molly shrooms,magic mushrooms salvia,diviner's sage

smoked

Kappaopioidagonist[48]

Narrativereportsofpsychedelics4

Approach Inordertoidentifythedifferencesbetweenthedrugsinouranalysis,weconducteda classificationanalysisinwhichfrequenciesofindividualwordsineachreportwereusedto predictwhichdrugwasreportedlytaken.Classificationtechniquesallowedustoquantify howdifficultitistodifferentiatebetweendrugs(howsimilartheyare),andwhichwords weremostusefulforpredictionofthedrugbeingdescribed.Weusedvariableselection techniquestodeterminewhichofthelargenumberofwordswereusefulforaccurate reportclassification.Finally,weclusteredselectedwordsbasedontheircooccurrencein reportstovisualizeandformqualitativedescriptionsofthedifferencesbetweendrugsand betweengroupsofdrugs. Preprocessing First,wecheckedreportsforspellingerrorsinawordprocessor.Wethenconvertedeach reporttoavectorwithoneelementforeachuniqueword,containingthenumberof occurrencesofthatwordinthereport.Toreducethedatasettoamoremanageablesize, wedroppedwordsthatoccurredinfewerthanfivereports.Weconvertedallwordsto theirrootformwiththeMorphystemmer[49],allowingallformsofawordtobetreatedas asingleelement.Morphydeterminestherootofawordusingadictionary.Wordsthat werenotpresentinthedictionarywerestemmedmanually.Wetheneliminatedtwotypes ofwordsfromtheremainderoftheanalysis:commonwords[suchaspronouns(e.g.,he) anddeterminers(e.g.,the)]anddrugterminology.Weremovedcommonwordsbecause weconsideredthemunlikelytodifferentiatebetweendocumentsordrugs.Weremoved drugterminology(e.g.,ecstasyandroll)tofocustheanalysisondifferencesindrug effectsinsteadoftrivialdifferences.Thedocumentvectorswerethencombinedintoa termdocumentfrequencymatrixwitharowforeachreportandacolumnforeachunique wordinthecorpus.Tocontrolfordifferencesinreportlengths,weconvertedtheword occurrencecountsintowordfrequencies. Classification WeappliedLeoBreimansrandomforestclassificationalgorithm[50].Randomforestisan ensembleclassifierthatgeneratesagroupofclassificationtreesbasedonpredictor variablesandthenusesthemajorityvoteofthetreestodeterminemembership.Each classificationtreeisfitusingarandomsubsetofpredictorvariablesonarandomsubsetof theobservationsdrawnwithreplacement.Theperformanceofthisclassifiercanbe assessedusingoutofbagaccuracybypredictingeachobservationusingonlythosetrees forwhichtheobservationwasoutofbag,meaningthattheobservationwasnotusedin thetreesconstruction.Variablescanbeselectedonthebasisofanimportancemeasure, definedasthedecreaseinoutofbagaccuracycausedbyrandomlypermutingthevaluesof thatpredictor.Variableselectionusingrandomforestsarecommonlyemployedin microarraygeneticsexperimentstoselectfromalargepoolofcandidategenesthosethat predictacondition[51,52]. FeatureSelection WeusedthevarSelRFpackageinR[53,54]forfeatureselection.Thispackageusesatwo stepalgorithmtodetermineaminimalsubsetofpredictorvariablesthatclassifiesalmost aswellasallavailablepredictors.First,arandomforestisfitusingallpredictorwordsand Narrativereportsofpsychedelics5

thesewordsarerankedusingtheimportancemeasuredescribedabove.Then,new randomforestmodelsarefittoprogressivelysmallersubsetsofvariables,andthe performanceofthesereducedmodelsisassessedusingoutofbagaccuracy,asdescribed above.Thesubsetsaregeneratedbyeliminatingtheleastimportant20%ofvariablesat eachstep.Afterallsubsetsarefit,varSelRFselectedthesmallestsubsetwhichclassifies withanaccuracylessthan1standarderrorunitlowerthanthesubsetwiththehighest accuracy.Thissmallersubset,whilenotbeingsignificantlyworseatdifferentiatingthe classes,allowsforeasierinterpretation. Bootstrapping Tomeasureclassifierperformancewithoutoverfitting,weused.632bootstrapping.Before bootstrapping,weappliedvarSelRFtotheoriginaldataset.Then,ateachof200iterations, wesampledthedatawithreplacementtoformatrainingset,andreservedtheremaining datafortesting.Withthetrainingset,weusedvarSelRFtoselectasetofpredictor variables.Wethenfitarandomforestmodelonthetrainingsetusingtheselected variablesandassessingclassifieraccuracyusingthetestingset. PerformanceAssessment Differentmeasuresofclassifieraccuracyareusedfordifferentpurposes.Mostofthese estimatesarebiasedbecauseresamplingcanleadtooverfitting.Suchestimatesarevalid onlyfordeterminingrelativeperformanceunderdifferentconditions.Weusedoutofbag accuracy(describedabove),tocompareperformanceatdifferentsubsetsizesduring featureselection.Applyingoutofbagaccuracytothebootstrapiterationswouldhave beenproblematicbecausereportsaresampledwithreplacement,andthereforeaduplicate versionofareportcouldmeanthetreesarenottrulyoutofbag.Todetermineaccuracy foreachdrugandcreateaconfusionmatrixbetweendrugs,weusedaccuracyofprediction forthetestingdatafromeachbootstrapiteration.Foranunbiasedestimateofoverall performanceweusedthe.632bootstrapestimator,whichcombinesaccuracyforbootstrap testingdatawiththeoutofbagaccuracyusingthesubsetofvariablesselectedfromthe originaldataset. Stability Weassessedthestabilityofthevariableselectionprocedurebycomparingthewords selectedfromtheoriginaldatasettothoseselectedineachofthebootstrapiterations.We thencalculatedtheproportionofiterationsinwhicheachofthesewordsappearedand usedthemedianasanoverallmeasureofstability[52,54]. Visualization Tofacilitatequalitativeanalysisofdifferencesbetweendrugs,wecreatedaheatmapof meanwordfrequenciesbydrugforthewordsselectedbyvarSelRFfromtheoriginal dataset.Weusedhierarchicalclusteringanalysistoformbothwordanddrugclustersand depictedtheclustersusingdendrograms.Wordclusterswereformedusingallthereports anddrugclusterswereformedusingmeanreportsforeachdrugclass.

Narrativereportsofpsychedelics6

Software AllanalyseswereconductedusingR2.11[55]andtheRevolutionRdevelopment environment.AmazonsElasticComputeCloudwasusedforthecomputationallyintensive resamplingprocedures. RESULTS Weobtainedatotalof1000reportswith22440uniquewords.Ofthese,weremoved 15994wordsthatoccurredinfewerthanfivereports.Stemmingtheremaining6445 wordsresultedin4541uniquestems.Weremoved607ofthesethatwerecommonwords ordrugterminology,leavingafinalcountof3934uniquewordstems.Theinitialrunofthe variableselectionprocedureselected110variables.Thesubsetof110variableshadan outofbagaccuracyof46.2%,similartotheoutofbagaccuracyofthefulldataset (45.5%).Bootstrappingiterationsselectedarangeofpossiblesubsetsizesfrom29 variablestoall3934variables,withamediansizeof138(Figure1).

Figure1Distributionofsubsetsizes:Thenumberofpredictorwordsselectedbyeachofthe200 bootstrappingiterations.Ineachiteration,thealgorithmselectedanumberofwordsthatbalanced parsimonywithaccuracy.Inmostiterations,onlyafewhundredwordswereneededtoclassifythereports withreasonableaccuracy.

Narrativereportsofpsychedelics7

The.632estimatordeterminedthattheclassifierwas51.1%accurate.Individualclass accuracyforbootstraptestingrangedfrom86.9%forMDMAto20.7%forDPT(Figure2A). TheclassifierconfusionmatrixshowninFigure2Bindicateswhichdrugsweremistaken forotherdrugsbytheclassifier.Thesubsetofselectedwordswasrelativelystable.Words selectedfromoriginaldatasetwereselectedinthemajorityofbootstrapiterations(median proportion=0.768,1stquartile=0.532,3rdquartile=0.984).Hierarchicalclusteringof classpredictionsandclassmeansaredepictedinFigures2Band3(includedasan Appendix).Figure3alsodepictsclustersofpredictorwordsfromthesubsetof110 selectedwords.

Figure2Classificationaccuracyandconfusionmatrix:(A)Bootstrapaccuracy(percentofleftout trainingsamplesaccuracyclassified)foreachofthe10drugs.Thereisawiderangeofaccuracies.(B)Each cellrepresentsthepercentofreportsfromagivendrug(incolumns)predictedasbeingfromanothergiven drug(inrows).Thedendrogramatthetopclusterstogetherdrugsthataremisclassifiedaseachother,asthis misclassificationisrelatedtosimilaritiesinreportsfromthesedrugs

DISCUSSION Oursuccessatclassifyingreportssuggeststhatthereareconsistencieswithinnarratives foragivendruganddifferencesbetweennarrativesfordifferentdrugs.Weusedrecursive featureselectiontoidentifysomeoftheseconsistenciesanddifferences.Thisrevealedthat asmallsubsetofwordsthatwasabletoclassifyreportsalmostaswellasthefullsetof 3934words.Theaccuracyofclassifyingreportswiththese110wordswasestimatedas 51.1%.Thiscanbefavorablycomparedto10%,whichwouldbeexpectedfromchance.The smallsubsetofwordsallowsapracticalanalysisofthedifferencesbetweendrugs. Specifically,ourresultssuggestthatnarrativesofMDMAusearemoreconsistentthan Narrativereportsofpsychedelics8

otherpsychedelicsandthatspecificpairsofotherdrugsmayshareinterestingfeatures:for example,DMTandSalvia,LSDandpsilocybinmushrooms,DPTand2CE,and5MeODiPT and2CT2(Figure2B). Toanalyzethe110words,wecreatedaheatmapanddendrogramsofclasscentroid clusteringofwordfrequenciesanddrugs.Thiswasnecessarybecauseitwouldnothave beenpracticaltodepictthemanybinarybranchingclassifiertreesinwhichthese individualwordsappeared.Moreover,theselectedwordsarenotnecessarilyhigh frequencywordsandarenoteasilysummarizedbyfrequency.Instead,theyarewords whosefrequenciesareusefulfordecidingbetweentwopotentialdrugsinthecontextof decisiontreeclassifiers.Thevisualizationofthe110words(Figure3,seeAppendix) thereforeprovidesdifferentinformationfromtheconfusionmatrixofclassifier performance(Figure3).Forexample,theconfusionmatrixindicatesthat5MeODMTwas oftenconfusedforDMTandSalvia,whiletheclasscentroidclusteringvisualizationgroups itwithDPTand2CE.Thisindicatesthatsomeofthedifferencesbetweenthesedrugsis capturedinthosewordsthatweredifficulttointerpretandthereforenotanalyzedwith classcentroids(Figure3). MDMAwasdistinguishedeasilyfromallotherdrugs(estimatedaccuracy86.9%vs52.4% forSalvia,thenextmostaccuratedrug).ThisgroupingofLSDandpsilocybinisconsistent withthehypothesisthatMDMAisamemberofanovelpharmacologicalclass(Nichols 1986).MDMAreportsweredistinguishedfromotherdrugsbyhighfrequenciesofwords withsocialconnotations(e.g.,theclub,hug,rub,smileclusterinFigure3). Examinationofindividualreportssuggeststhatthisreflectsdescriptionsofthesocial contextofMDMAuse(e.g.,nightclubs)aswellasdrugeffectsproper(e.g.,feelingsoflove andfriendliness[56]). LSDandpsilocybinmushroomswerealsogroupedtogether.Thesedrugs(andtoalesser extentDMTandSalvia)weremoststronglyassociatedwiththesee,look,saw,room, tell,ask,walk,housecluster.Thisgroupingisconsistentwithearlyclinical comparisonsfindingthattheyproducesimilareffectsinhumans[57].Alternatively,this clusteringcouldbeaproductofthesesubstanceslongstandingavailabilitycomparedto otherpsychedelics.Thiscouldleadtonarrativedifferencesbetweenthesereportsand thoseofmoreexoticdrugssinceauthorsmayhaveassumedreaderfamiliaritywiththe drugsandbeenlessfocusedondescribingcommonsymptoms. DMTandSalviaweregroupedtogether,withhighfrequencywordclusterssuggesting powerfuleffectsontheperceptionofreality.Thehighestfrequencyclusterforthesedrugs wasthereality,dimension,universe,state,consciousness,form,entitycluster. Bothdrugshavebeenassociatedwithpowerfulalterationsinconsciousnessandfeelingsof alteredreality.RickStrassman[58],summarizinghisstudiesofadministeringDMTto healthyhumanvolunteers,describedhigherdosehallucinatoryexperiencesthatwere morecompellingandconvincingthan'ordinary'realityordreams.Similarly,ina controlledstudyofSalviasprimaryactivechemicalconstituent,salvinorinA,participants reportedintenseexperiencescharacterizedbydisruptionsinvestibularandinteroceptive signals(e.g.,changeinspatialorientation,pressureonthebody)[59].WhileDMTand Narrativereportsofpsychedelics9

Salviahavelittleoverlapintheirknownpharmacologicalmechanisms(DMTisamixed serotonergicagonistandsalvinorinAisakappaopioidagonist),theyarebothtypically takenbysmokingorvaporizing.Thus,theapparentlysimilarintensedrugeffectsmaybe explainedbytheircommonroutesofadministrationandtherapidrisesinblood concentrationsofbothdrugs. DPTand2CEwereclusteredtogetherandwereprimarilyassociatedwithastomach, nausea,vomit,headachecluster,suggestingthesedrugsmayhaveunpleasantphysical effects.Because5HT3receptorstimulationisthoughttoinducenauseaandvomiting[60], wehypothesizethatthesetwosubstances,morethantheotherstudiedpsychedelics,may directlystimulate5HT3receptorsormayinducereleaseof5HTfromenterochromaffin cells.Bothdrugsarecurrentlypoorlycharacterized,althoughitwasreportedthatDPT inhibits[(3)H]5HTtransportattheserotonintransporterwithaKiof0.594M[43]. Limitations Weassumethatmostindividualsactuallyconsumedthedrugsthattheyreportedandare writingingoodfaith.Nonetheless,wecannotknowhowmanydrugreportsaremislabeled orfalsifiedinthecurrentdataset.Notably,however,randomforestsareresistanttothe effectsofafewmislabeledcases(Breiman2001).Consistentwiththisexpectation,our classifierwashighlysuccessfulwithMDMA,despitethewelldocumentedsaleofother drugsasMDMA[61].Duetotheirdistinctiveappearances,itmaybereasonabletoassume thatillicitlyobtainedpsilocybinmushrooms,LSD,andSalviawerelikelytobecorrectly represented.Thesixotherdrugs,beingsoldasresearchchemicals,maybemoreprone tomisrepresentationintheunregulatedmarketingofcrystallineorpowderedchemicals. Thus,itisnoteworthythatoneofthefewavailableanalysesofsimilarsyntheticresearch chemicalspurchasedintheunregulatedmarketplace,werefoundthemtobecorrectly representedastochemicalidentityandalsoofrelativelyhighpurity[33]. Attemptstoinferdrugeffectsfromnarrativeshaveseveralotherinherentlimitations. Differencesbetweendrugnarrativeslikelyalsoreflectauthordemographicsandthe varyingcontextofdruguse.Suchpotentiallimitationscouldbeaddressedbycollectinga newcorpusinwhichauthordemographicinformationisalsoobtained.Additionally,from oneperspective,themixingofeffectsfromuncertaindrugswithcontextisasmucha featureasabugsincesuchreports(ifwritteningoodfaith)reflectdrugexperiencesas theyareunderstoodbyusers,whichisanimportanttopicofstudy. Furtherresearchondrugnarrativesmightprofitablycategorizeindividualnarratives basedonrouteofadministrationandphysicalcontextinordertobetterunderstandthe influenceofthesevariables.Mostexcitingly,perhaps,ourapproachcouldbeusedtolink narrativedescriptionstopharmacology.Dataontheinvitropharmacologyofmanyofthe chemicalsaddressedinthispaperisbeginningtobeassembled[34].Quantitativeanalysis ofdrugnarrativesincombinationwithinvitropharmacologycouldleadtonovel hypothesesconcerningtheeffectsofspecificreceptorsandsignalingpathwayson consciousness. Narrativereportsofpsychedelics10

Inconclusion,wepresentresultsfromanovelapproachtoclassifyingandanalyzingdrug narratives.Wefindthatdrugnarrativescanbesuccessfullyclassifiedusingrandomforest techniques,suggestingthatthiscanbeusedtodevelophypothesesaboutthe pharmacologyandtoxicityofnewandpoorlycharacterizeddrugsastheymayemerge. ACKNOWLEDGEMENTS WearegratefultoSpoon,Earth,andFireErowidfortheirassistanceincollectingand makingavailablethenarrativereportsandforhelpfuldiscussionandinspiration.We thankJuanCarlosLopezforprogrammingassistance,andformerUCBerkeleystudents ConorPenfoldandAndreaPayneforassistanceinearlystagesofthiswork.

Narrativereportsofpsychedelics11

REFERENCES 1. RTIInternational,ResultsFromthe2010NationalSurveyonDrugUseandHealth: SummaryofNationalFindings,inNo.:(SMA)114658.2010.p.156. 2. EMCDDA.StatisticalBulletin.2011;Availablefrom: http://www.emcdda.europa.eu/stats11. 3. Nichols,D.E.,Hallucinogens.PharmacolTher,2004.101(2):p.13181. 4. Studerus,E.,A.Gamma,andF.X.Vollenweider,Psychometricevaluationofthealtered statesofconsciousnessratingscale(OAV).PloSone,2010.5(8):p.e12412. 5. Paparelli,A.,etal.,Druginducedpsychosis:howtoavoidstargazinginschizophrenia researchbylookingatmoreobvioussourcesoflight.FrontBehavNeurosci,2011.5: p.1. 6. Geyer,M.A.andF.X.Vollenweider,Serotoninresearch:contributionsto understandingpsychoses.TrendsPharmacolSci,2008.29(9):p.44553. 7. GouzoulisMayfrank,E.,etal.,History,rationaleandpotentialofhumanexperimental hallucinogenicdrugresearchinpsychiatry.Pharmacopsychiatry,1998.31Suppl2: p.638. 8. Griffiths,R.,etal.,Mysticaltypeexperiencesoccasionedbypsilocybinmediatethe attributionofpersonalmeaningandspiritualsignificance14monthslater.J Psychopharmacol,2008.22(6):p.62132. 9. Griffiths,R.R.,etal.,Psilocybincanoccasionmysticaltypeexperienceshaving substantialandsustainedpersonalmeaningandspiritualsignificance. Psychopharmacology(Berl),2006.187(3):p.26883;discussion28492. 10. Schultes,R.E.andA.Hofmann,PlantsoftheGods:Originsofhallucinogenicuse.1979, NewYork:McGrawHillBookCompany 11. Ott,J.,Pharmacotheon:Entheogenicdrugs,theirplantsourcesandhistory.1993: NaturalProductsCompany. 12. Heffter,A.,Ueberpellote.NaunynSchmiedeberg'sArchivesofPharmacology,1898. 40(5):p.385429. 13. Woolley,D.andE.Shaw,Someneurophysiologicalaspectsofserotonin.British medicaljournal,1954.2(4880):p.122126. 14. Dyck,E.,Psychedelicpsychiatry:LSDfromclinictocampus.2008,Baltimore:Johns HopkinsUniversityPress. 15. Mangini,M.,Treatmentofalcoholismusingpsychedelicdrugs:areviewofthe programofresearch.JPsychoactiveDrugs,1998.30(4):p.381418. 16. Vollenweider,F.X.andM.Kometer,Theneurobiologyofpsychedelicdrugs: implicationsforthetreatmentofmooddisorders.NatRevNeurosci,2010.11(9):p. 64251. 17. Griffths,R.R.andC.S.Grob,Hallucinogensasmedicine.SciAm,2010.303(6):p.769. 18. Fantegrossi,W.E.,K.S.Murnane,andC.J.Reissig,Thebehavioralpharmacologyof hallucinogens.BiochemPharmacol,2008.75(1):p.1733. 19. GonzlezMaeso,J.andS.C.Sealfon,Agonisttraffickingandhallucinogens.Current medicinalchemistry,2009.16(8):p.10171027. Narrativereportsofpsychedelics12

 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

Svenningsson,P.,etal.,Diversepsychotomimeticsactthroughacommonsignaling pathway.Science'sSTKE,2003.302(5649):p.1412. Shulgin,A.,PIHKAL:Achemicallovestory.1991:TransformPress. Shulgin,A.,TIHKAL:thecontinuation.1997:TransformPress. Shulgin,A.,T.Manning,andP.Daley,TheShulginIndexVol1:Psychedelic PhenethylaminesandRelatedCompounds.2011,Berkeley:TransformPress. EMCDDA,Respondingtonewpsychoactivesubstances,inDrugsinfocus,P.Fay, Editor.2011,EuropeanMonitoringCentreforDrugsDrugAddiction:Lisbon, Portugal. Sumnall,H.,M.EvansBrown,andJ.McVeigh,Social,policy,andpublichealth perspectivesonnewpsychoactivesubstances.DrugTestingandAnalysis,2011.3(7 8):p.515523. Spiller,H.A.,etal.,Clinicalexperiencewithandanalyticalconfirmationof'bathsalts' and'legalhighs'(syntheticcathinones)intheUnitedStates.ClinicalToxicology,2011. 49(6):p.499505. Nichols,D.,Legalhighs:thedarksideofmedicinalchemistry.Nature,2011. 469(7328):p.7. Erowid,Thedistillation.ErowidExtracts2011.21:p.2225. Cott,C.andA.Rock,PhenomenologyofN,Ndimethyltryptamineuse:Athematic analysis.JournalofScientificExploration,2008.22:p.359370. Kleinman,J.E.,J.C.Gillin,andR.J.Wyatt,Acomparisonofthephenomenologyof hallucinogensandschizophreniafromsomeautobiographicalaccounts. SchizophreniaBulletin,1977.3(4):p.560. Schifano,F.,etal.,Istherearecreationalmisusepotentialforpregabalin?Analysisof anecdotalonlinereportsincomparisonwithrelatedgabapentinandclonazepamdata. PsychotherPsychosom,2011.80(2):p.11822. Oxman,T.E.,etal.,Thelanguageofalteredstates.JournalofNervousandMental Disease;JournalofNervousandMentalDisease,1988. Nagai,F.,R.Nonaka,andK.SatohHisashiKamimura,Theeffectsofnonmedically usedpsychoactivedrugsonmonoamineneurotransmissioninratbrain.EurJ Pharmacol,2007.559(23):p.1327. Ray,T.S.,Psychedelicsandthehumanreceptorome.PloSone,2010.5(2):p.e9019. Fantegrossi,W.E.,etal.,Hallucinogenlikeactionsof5methoxyN,N diisopropyltryptamineinmiceandrats.PharmacolBiochemBehav,2006.83(1):p. 1229. Winter,J.C.,etal.,Theparadoxof5methoxyN,Ndimethyltryptamine:anindoleamine hallucinogenthatinducesstimuluscontrolvia5HT1Areceptors.PharmacolBiochem Behav,2000.65(1):p.7582. Tricklebank,M.D.,etal.,Subtypesofthe5HTreceptormediatingthebehavioural responsesto5methoxyN,Ndimethyltryptamineintherat.EurJPharmacol,1985. 117(1):p.1524. Spencer,D.G.,T.Glaser,andJ.Traber,Serotoninreceptorsubtypemediationofthe interoceptivediscriminativestimuliinducedby5methoxyN,Ndimethyltryptamine. Psychopharmacology,1987.93(2):p.15866.

Narrativereportsofpsychedelics13

 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56.

KrebsThomson,K.,etal.,Therolesof5HT1Aand5HT2receptorsintheeffectsof5 MeODMTonlocomotoractivityandprepulseinhibitioninrats.Psychopharmacology, 2006.189(3):p.31929. Smith,R.L.,etal.,AgonistpropertiesofN,Ndimethyltryptamineatserotonin5HT2A and5HT2Creceptors.PharmacolBiochemBehav,1998.61(3):p.32330. Fontanilla,D.,etal.,ThehallucinogenN,Ndimethyltryptamine(DMT)isan endogenoussigma1receptorregulator.Science(NewYork,N.Y.),2009.323(5916): p.9347. Bunzow,J.R.,etal.,Amphetamine,3,4methylenedioxymethamphetamine,lysergicacid diethylamide,andmetabolitesofthecatecholamineneurotransmittersareagonistsof arattraceaminereceptor.MolPharmacol,2001.60(6):p.11818. Cozzi,N.V.,etal.,Dimethyltryptamineandotherhallucinogenictryptaminesexhibit substratebehaviorattheserotoninuptaketransporterandthevesiclemonoamine transporter.JNeuralTransm,2009.116(12):p.15919. Watts,V.J.,etal.,LSDandstructuralanalogs:pharmacologicalevaluationatD1 dopaminereceptors.Psychopharmacology(Berl),1995.118(4):p.4019. MaronaLewicka,D.,R.A.Thisted,andD.E.Nichols,Distincttemporalphasesinthe behavioralpharmacologyofLSD:dopamineD2receptormediatedeffectsintherat andimplicationsforpsychosis.Psychopharmacology(Berl),2005.180(3):p.42735. Rothman,R.B.,etal.,Amphetaminetypecentralnervoussystemstimulantsrelease norepinephrinemorepotentlythantheyreleasedopamineandserotonin.Synapse (NewYork,N.Y.),2001.39(1):p.3241. McKenna,D.J.,etal.,Differentialinteractionsofindolealkylamineswith5 hydroxytryptaminereceptorsubtypes.Neuropharmacology,1990.29(3):p.1938. Roth,B.L.,etal.,SalvinorinA:apotentnaturallyoccurringnonnitrogenouskappa opioidselectiveagonist.ProceedingsoftheNationalAcademyofSciencesofthe UnitedStatesofAmerica,2002.99(18):p.119349. Fellbaum,C.WordNet:Anelectroniclexicaldatabase.1998;Availablefrom: http://www.cogsci.princeton.edu/wn. Breiman,L.,Randomforests.Machinelearning,2001.45(1):p.532. Svetnik,V.,etal.,ApplicationofBreiman'srandomforesttomodelingstructure activityrelationshipsofpharmaceuticalmolecules.MultipleClassifierSystems,2004. 3077/2004:p.334343. DazUriarte,R.,GeneSrFandvarSelRF:awebbasedtoolandRpackageforgene selectionandclassificationusingrandomforest.BMCbioinformatics,2007.8(1):p. 328. Breiman,L.andA.Cutler.RandomForestsClassificationManual.2008[cited2012 April18];Availablefrom: http://www.stat.berkeley.edu/~breiman/RandomForests/cc_manual.htm. DazUriarte,R.andS.A.DeAndres,Geneselectionandclassificationofmicroarray datausingrandomforest.BMCbioinformatics,2006.7(1):p.3. RDevelopmentCoreTeam,R:Alanguageandenvironmentforstatisticalcomputing. 2010,RFoundationforStatisticalComputingVienna,Austria. Bedi,G.,D.Hyman,andH.deWit,Isecstasyan"empathogen"?Effectsof+/3,4 methylenedioxymethamphetamineonprosocialfeelingsandidentificationof emotionalstatesinothers.BiolPsychiatry,2010.68(12):p.113440. Narrativereportsofpsychedelics14

 57. 58. 59. 60. 61.

Hollister,L.E.andA.M.Hartman,Mescaline,lysergicaciddiethylamideandpsilocybin: Comparisonofclinicalsyndromes,effectsoncolorperceptionandbiochemical measures.ComprehensivePsychiatry,1962.3(4):p.235241. Strassman,R.J.,HumanpsychopharmacologyofN,Ndimethyltryptamine. Behaviouralbrainresearch,1995.73(12):p.121124. Johnson,M.W.,etal.,HumanpsychopharmacologyanddoseeffectsofsalvinorinA,a kappaopioidagonisthallucinogenpresentintheplantSalviadivinorum.DrugAlcohol Depend,2011.115(12):p.1505. Nichols,D.E.andC.D.Nichols,Serotoninreceptors.ChemRev,2008.108(5):p.1614 1641. Baggott,M.,etal.,Chemicalanalysisofecstasypills.JAMA,2000.284(17):p.2190.

Narrativereportsofpsychedelics15

APPENDIX

Narrativereportsofpsychedelics16

Figure3Classmeanheatmap:Eachcellisthemeanfrequencyofagivenword(columns)inreportsfromagivendrug(rows)inall reportsfromthedataset.Darkercellsrepresenthigherfrequencies.Thesewordswereselectedasimportantfordifferentiatingdrugsby therandomforestalgorithm.Wordsareclusteredbasedoncooccurrenceinreports.Drugsareclusteredbasedonsimilarmean frequenciesforthesewords.Theseclusteringsarerepresentedbydendrogramsattherightandtopsidesoftheplot.