Submitted28June2016Accepted9September2016Published5October2016Correspo

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Submitted28June2016Accepted9September2016Published5October2016Correspo - Description


Copyright2016AlrashedyandMolinaDistributedunderCreativeCommonsCC-BY40OPENACCESSTheethnobotanyofpsychoactiveplantuseaphylogeneticperspectiveNashmiahAidAlrashedyandJeanmaireMolinaDepartmentofBiologyLong Download

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1 Submitted28June2016Accepted9September201
Submitted28June2016Accepted9September2016Published5October2016CorrespondingauthorJeanmaireMolina,jeanmaire.molina@liu.eduAcademiceditorMichaelWinkAdditionalInformationandDeclarationscanbefoundonpage23DOI10.7717/peerj.2546 Copyright2016AlrashedyandMolinaDistributedunderCreativeCommonsCC-BY4.0 OPENACCESSTheethnobotanyofpsychoactiveplantuse:aphylogeneticperspectiveNashmiahAidAlrashedy*andJeanmaireMolina*DepartmentofBiology,LongIslandUniversity,Brooklyn,NY,UnitedStates*Theseauthorscontributedequallytothiswork. ABSTRACT Psychoactiveplantscontainchemicalsthatpresumablyevolvedasallelochemicalsbuttargetcertainneuronalreceptorswhenconsumedbyhumans,alteringperception,emotionandcognition.Theseplantshavebeenusedsinceancienttimesasmedicinesandinthecontextofreligiousritualsfortheirvariouspsychoactiveeffects(e.g.,ashallucinogens,stimulants,sedatives).Theubiquityofpsychoactiveplantsinvariousculturesmotivatesinvestigationofthecommonalitiesamongtheseplants,inwhichaphylogeneticframeworkmaybeinsightful.Aphylogenyofculturallydiversepsy-choactiveplanttaxawasconstructedwiththeirpsychotropiceffectsandaffectedneu-rotransmittersystemsmappedonthephylogeny.Thephylogeneticdistributionshowsmultipleevolutionaryoriginsofpsychoactivefamilies.TheplantfamiliesMyristicaceae(e.g.,nutmeg),Papaveraceae(opiumpoppy),Cactaceae(peyote),Convolvulaceae(morningglory),Solanaceae(tobacco),Lamiaceae(mints),Apocynaceae(dogbane)haveadisproportionatenumberofpsychoactivegenerawithvariousindigenousgroupsusinggeographicallydisparatemembersoftheseplantfamiliesforthesamepsychoactiveeffect,anexampleofculturalconvergence.Pharmacologicaltraitsrelatedtohallucinogenicandsedativepotentialarephylogeneticallyconservedwithinfam-ilies.Unrelatedfamiliesthatexertsimilarpsychoactiveeffectsalsomodulatesimilarneurotransmittersystems(i.e.,mechanisticconvergence).However,pharmacologicalmechanismsforstimulanteffectswerevariedevenwithinfamiliessuggestingthatstimulantchemicalsmaybemoreevolutionarilylabilethanthoseassociatedwithhallucinogenicandsedativeeffects.Chemicallysimilarpsychoactivechemicalsmayalsoexistinphylogeneticallyunrelatedlineages,suggestingconvergentevolutionordifferentialgeneregulationofacommonmetabolicpathway.Ourstudyhasshownthatphylogeneticanalysisoftraditionallyusedpsychoactiveplantssuggestsmultipleethnobotanicaloriginsandwidespreadhumandependenceontheseplants,motivatingpharmacologicalinvestigationintotheirpotentialasmoderntherapeuticsforvariousneurologicaldisorders. SubjectsAnthropology,Biodiversity,EvolutionaryStudie

2 s,Neuroscience,PlantScienceKeywordsEthno
s,Neuroscience,PlantScienceKeywordsEthnopharmacology,Drugdiscovery,Traditionalmedicine,Evolutionaryethnob-otany,Neuropsychopharmacology,PsychotropicINTRODUCTIONPlantsconstantlyevolvetoproducevariousdefensivesecondarymetabolitesagainsttheirequallyadaptivepredators(Polya,2003;Wink,2003;Wink,2016).Somewell-knownpsychoactivecompoundssuchasatropine,caffeine,cocaine,nicotineandHowtocitethisarticleAlrashedyandMolina(2016),Theethnobotanyofpsychoactiveplantuse:aphylogeneticperspective.PeerJ4:e2546;DOI10.7717/peerj.2546 morphinearebelievedtohavebeenproductsofthisevolutionaryarmsrace(Howe&Jander,2008;Fürstenberg-Hägg,Zagrobelny&Bak,2013).Psychoactive,alternativelypsychotropic,substancesactonthenervoussystemaffectingmentalprocessesandbehavior(Spinella,2001;Rätsch,2005).Theyincludehallucinogensthatdistortreality,sedatives/narcoticsthatinducesleep,calmativeoranxiolytics,antidepressants,andstimulantsthatwakethemind(Spinella,2001;Rätsch,2005;VanWyk&Wink,2014).Interestingly,humanshaveexploitedalternateusesforplantscontainingpsychoactivephytochemicalsthathavepurportedlyevolvedtowardoffplantpredators.However,theaffinityofthesephytochemicalswithinthehominidnervoussystemmayalsoindicatesomekindofmutualisticco-evolution,withancienthumansseekingandperhapscultivatingplantpsychotropicstofacilitatesurvival,byalleviatingstarvation,fatigueandpain(Sullivan&Hagen,2002).Psychoactivecompoundshavespecificmoleculartargetsinthenervoussystem,andinteractinaparticularwaywithneuronalreceptorstoproducevariouspsychoactiveeffects(Spinella,2001;Polya,2003).Forinstance,morphineinopiumpoppy(Papaversomniferum,Papaveraceae)eliminatespainbybindingtoopioidreceptors(Polya,2003),butsimultaneouslypromotessedationandeuphoria,bydisinhibitingdopamine-containingneuronsinthelimbicsystem(Johnson&North,1992).Dopamineisultimatelyresponsibleforfeelingsofelationandsatisfaction,whichoccuraftersomerewardingactlikesexorfoodsatiety.Addictionarisesfromwantingtore-experiencethepleasureduetothedrug'sabilitytocausedopaminebuildup(Lüscher&Ungless,2006).Compoundsthatmimicserotoninandactasreceptoragonistslikemescalineinthepeyotecactus(Lophophorawilliamsii,Cactaceae),triggerhallucinationsandcognitivebreakdown(Polya,2003).Stimulatingsubstances,suchasthealkaloidnicotineintobacco,Nicotianatabacum(Solanaceae),mimictheendogenousneurotransmitteracetylcholinestimulatingmusclecontractionsandcholinergicareasofthebraininvolvedinarousalandattention(Polya,2003).Yet,theconfamilialAtropabelladonna,containsachemicallydifferentalkaloid,atropine,

3 whichpromotessedationandincapacitationvi
whichpromotessedationandincapacitationviaitsactionasmuscarinicacetylcholineantagonist,blockingneuromuscularcommunication(Spinella,2001).Itiswellestablishedthatallcultures,ancientormodern,havesomekindofdrugculture,relyingonpsychoactivesforrecreational,ritualand/ormedicinaluses(Schultes,1976;Schultes,Hofmann&Rätsch,2001;Rätsch,2005).ShamanisticreligionshaveexistedintheOldWorldofEurope,AsiaandAfrica,believingthatpsychoactiveplantsarecapableofhealingthroughdivinepower.Marijuana(Cannabisspp.,Cannabaceae)andopiumpoppyareamongthemostpopularpsychoactiveplantsusedbyOldWorldshamans.MarijuanawasusedinancientChinaforvariousafflictionslikemalariaandconstipation,andevenasanarcoticinsurgeries.InIndia,theplantwasconsideredsacredpromotingpleasurablesensationsintheuser(Clarke&Merlin,2013).Tetrahydrocannabinol(THC)inmarijuana,exertstheseactionsbybindingtocannabinoidreceptors,mediatingsensorypleasure(Mahler,Smith&Berridge,2007).Anotherfamiliarpsychoactive,opiumpoppywasusedformedicinalandrecreationalpurposes.ItprobablyoriginatedintheMediterranean,butwidespreadusehasconfoundeditsevolutionaryorigin(Merlin,2003).ItwasrecordedintheEberpapyrus,anancientEgyptianscroll,thatopiumpoppywasusedtostopthe AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 2/30 excessivecryingofchildren(Vetulani,2001).Theplantcontainsmorphineandcodeinethatareresponsibleforitshypnoticandanalgesicproperties(Heinrichetal.,2012).IndigenouspeopleoftheNewWorldhavealsousedpsychotropicsubstances,includingtobacco,ayahuasca,andcoca,evenmoresothanculturesoftheOldWorld(Schultes,1976).TobaccofromtheleavesofN.tabacumhaslongbeenusedintheAmericas,withcultivationinpre-ColumbianMexicoorPeru(Rätsch,2005).AmericanIndiansbelievedinthemedicinalpoweroftobacco,anditwassmokedinceremonialpeacepipestosealcovenants.IntheAmazonBasinofSouthAmerica,thehallucinogenicbeverage,ayahuasca,ismadebyhealersfromtheboiledcrushedstemsofthecaapi,Banisteropsiscaapi(Malpighiaceae),alongwiththeleavesofchacruna,Psychotriaviridis(Rubiaceae).ChacrunacontainsserotonergicN,N-dimethyltryptamine(DMT),thatisactivatedbythebeta-carbolinesincaapi(McKenna,1996).IntheAndes,indigenouspeopleschewcocaleavesofErythroxylumcoca(Erythroxylaceae)tocopewithhardlabor,removingsymptomsoffatigueandhunger(Nigg&Seigler,1992).Itscocainecontentpreventsdopaminereuptakeproducingincreasedenergyandmoodelevation(Spinella,2001).Theubiquityofpsychoactiveplantsinvariousculturesmotivatesinvestigationofthecommonalitiesamongtheseplants,inwhichaphylogeneticframeworkmaybeinsightful.Informationi

4 sassignedtonodesofthephylogeny,insteadof
sassignedtonodesofthephylogeny,insteadofonespeciesatatime,facilitatingthestudyoftraitdistributions(Saslis-Lagoudakisetal.,2015).Phylogeneticstudiesofculturallydiversemedicinalplantshaverepeatedlyshownthatmedicinalusesandphytochemicaltraitsarenotrandomlydistributedonthephylogeny,butaresharedbycloselyrelatedplants,regardlessoftheseplants'culturalandgeographicdesignations(Saslis-Lagoudakisetal.,2012;Saslis-Lagoudakisetal.,2015;Xavier&Molina,2016).Inthisstudyweaimedtounderstandifthereisasimilarpatternofculturalconvergence(Xavier&Molina,2016)inpsychoactiveplantsusingphylogeneticanalysisdoesthephylogenyofculturallyimportantpsychoactiveplantsrevealapreferenceforcertainplantfamiliesandforspecificpsychoactiveeffects(hallucinogenic,sedative,stimulant,etc.)?Additionally,wesoughttounderstandifthereisalsoapatternofmechanisticconvergence,suchthatunrelatedplantswithsimilarpsychoactiveeffectsultimatelyaffectsimilarneurotransmittersystems.Ourstudyprovidesinsightintotheethnobotanicaloriginsofpsychoactiveplantuseandsuggestsnewplantsourcesofpsychopharmacologicaldrugs.MATERIALSANDMETHODSPyschoactivetaxaofseedplants(126genera)usedbyvariousindigenousgroupswerecompiledforthisstudy(Table1),butplantswithpsychoactiveusesonlyafteralcoholicfermentationwereexcluded(e.g.,winefromgrapes,Vitisvinifera).Congenericspecieswereonlyrepresentedonceinthephylogeny,e.g.,Daturaspp.includedD.discolorBernh.,D.feroxL.,D.innoxiaMill.,D.metelL.,D.stramoniumL.,D.wrightiiRegel.Thisistoaccountfortaxonomicuncertaintiesthatarecommoninspeciescircumscriptions,andalsonottovisuallybiasthephylogenytowardsacertainfamilywithmulti-speciesgenera(e.g.,Datura).Theplants'nameswereverifiedin(ThePlantList,2013),aworkinglist AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 3/30 Table1Psychoactiveplanttaxainthisstudy.Culturallydiversepsychoactiveplanttaxa,theiruses,indigenouspsychoactiveculturalorigin,andcorrespondingGenbanknumbers. Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Acanthaceae(Lamiales)JusticiapectoralisJacq.justiciaNativeAmerican(Rätsch,2005)Hallucinogen,antidepres-sant,sedative,aphrodisiac(Rätsch,2005)AJ879453 Acoraceae(Acorales)AcoruscalamusL.sweetflagIndomalayan,TemperateAsian(Rätsch,2005)Stimulant,antidepressant,sedative(Rätsch,2005)AJ879453 Aizoaceae(Caryophyl-lales)Sceletiumspp.kougoedAfricanandMiddleEastern(Gericke&Viljoen,2008)Sedative,analgesic(Gericke&Viljoen,2008)HM850175 Apiaceae(Apiales)Angelicasinensis(Oliv.)DielsdongquaiTemperateA

5 sian(Rätsch,2005)Stimulant,sedative(O'M
sian(Rätsch,2005)Stimulant,sedative(O'Mahony,2010)GQ436632 Apiaceae(Apiales)Centellaasiatica(L)Urb.gotukolaIndomalayan,TemperateAsian(Rätsch,2005)Antianxiety,antidepressant(Mamedov,2005)GQ436635 Apocynaceae(Gentianales)Alstoniascholaris(L.)R.Br.ditaAfricanandMiddleEastern,Australasian,Indomalayan(Rätsch,2005;Arulmozhietal.,2012)Stimulant,antianxiety,an-tidepressant,sedative,anal-gesic,aphrodisiac(Rätsch,2005;Arulmozhietal.,2012)EU916739 Apocynaceae(Gentianales)ApocynumvenetumLluobumaTemperateAsian(Grundmannetal.,2007)Antianxiety,antidepressant(Grundmannetal.,2007;Zheng,Fan&Liu,2013)KP088474 Apocynaceae(Gentianales)Carissaedulis(Forssk.)VahlArabiannumnumAfricanandMiddleEastern(Rätsch,2005)Hallucinogen,aphrodisiac(Rätsch,2005)JF265327 Apocynaceae(Gentianales)Rauvolfiaserpentina(L.)Benth.exKurzsnakerootIndomalayan(Mamedov,2005)Antianxiety,antidepres-sant,sedative,analgesic(Spinella,2001;Mamedov,2005;Rätsch,2005)KJ667614 Apocynaceae(Gentianales)Tabernaemontanaspp.milkweedIndomalayan,African,NativeAmerican(Rätsch,2005)Hallucinogen,stimulant,antidepressant,sedative,analgesic(Rätsch,2005;Pratchayasakuletal.,2008;Cardosoetal.,2015)EU916740 Apocynaceae(Gentianales)TabernantheibogaBaill.ibogaAfricanandMiddleEastern(Sayin,2014)Hallucinogen,stimulant,an-tianxiety,antidepressant,analgesic,aphrodisiac(Nigg&Seigler,1992;Sayin,2014)AJ419763 (continuedonnextpage) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 4/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Apocynaceae(Gentianales)Voacangaspp.voacangobushAfricanandMiddleEastern(Rätsch,2005)Hallucinogen,stimulant,aphrodisiac(Rätsch,2005)KC628529 Aquifoliaceae(Aquifoliales)Ilexspp.yerbamateNativeAmerican(Rätsch,2005)Stimulant(Rätsch,2005)FJ394625 Araliaceae(Apiales)PanaxginsengC.A.Mey.ginsengTemperateAsian(Rätsch,2005)Stimulant,antidepressant,aphrodisiac(Rätsch,2005)KM088019 Arecaceae(Arecales)ArecacatechuL.betelnutIndomalayan(Rätsch,2005)Stimulant,sedative,aphro-disiac(Rätsch,2005)JX571781 Asteraceae(Asterales)Artemisiaspp.wormwoodEuropean;TemperateAsian(Rätsch,2005;Sayin,2014)Hallucinogen,stimulant,analgesicaphrodisiac(Rätsch,2005;Sayin,2014)KM360653 Asteraceae(Asterales)CaleaternifoliaOlivdreamherbNativeAmerican(Rätsch,2005)Hallucinogen,sedative(Rätsch,2005)AY215089 Asteraceae(Asterales)LactucavirosaHabl.wildlettuceAfricanandMiddleEastern(Rätsch,2005)Sedative,aphrodisiac(Rätsch,2005)KM360888 Asteraceae(Asterales)Tagetesspp

6 .MexicanmarigoldNativeAmerican(Rätsch,2
.MexicanmarigoldNativeAmerican(Rätsch,2005)Hallucinogen,stimulant,antianxiety,antidepressant,aphrodisiac(Rätsch,2005)AY215184 Bignoniaceae(Lamiales)Bignonianocturna(Barb.Rodr.)L.G.Lohmann[DTanaeciumnocturnum(Barb.Rodr.)Burea&K.Schum.]koriboNativeAmerican(Rätsch,2005)Sedative,analgesicandaphrodisiac(Rätsch,2005)KR534325 Burseraceae(Sapindales)BoswelliasacraFlueck.olibanumtreeAfricanandMiddleEastern(Rätsch,2005)Hallucinogen(Rätsch,2005)KT934315 Cactaceae(Caryophyl-lales)Ariocarpusfissuratus(Engelm.)K.Schum.chautleNativeAmerican(Rätsch,2005)Hallucinoge,analgesic(Rätsch,2005)KC777009 Cactaceae(Caryophyl-lales)Echinopsisspp.(incl.TrichocereuspachanoiBritton&Rose)SanPedrocactusNativeAmerican(Rätsch,2005)Hallucinogen,stimulant(Rätsch,2005)FR853367 (continuedonnextpage) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 5/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Cactaceae(Caryophyl-lales)Lophophorawilliamsii(Lem.ExSalm-Dyck)J.M.Coult.peyoteNativeAmerican(Vetulani,2001)Hallucinogen(Vetulani,2001)KC777011 Cactaceae(Caryophyl-lales)Mammillariaspp.falsepeyoteNativeAmerica(Rätsch,2005)Hallucinogen(Rätsch,2005)KC777008 Cactaceae(Caryophyl-lales)Pachycereuspecten-aboriginum(Engelm.exS.Watson)Britton&RosepitayoNativeAmerican(Schultes,1976)Hallucinogen(Schultes,1976)JN191499 Campanulaceae(Asterales)LobeliatupaL.tupaNativeAmerican(Schultes,1976)Hallucinogen,sedative(Schultes,1976;Rätsch,2005)EF174606 Cannabaceae(Rosales)Cannabisspp.marijuanaIndomalayan,TemperateAsian(Rätsch,2005)Hallucinogen,stimulant,an-tianxiety,antidepressant,sedative,analgesic,aphro-disiac(Rätsch,2005)AF500344 Cannabaceae(Rosales)HumuluslupulusL.hopsEuropean(Rätsch,2005)Antianxiety,sedative(Hein-richetal.,2012)KT266264 Caprifoliaceae(Dipsacales)Nardostachysjatamansi(D.Don)DC.jatamansiIndomalaya(Chaudharyetal.,2015)Antidepressant,sedative(Chaudharyetal.,2015)AF446950 Caprifoliaceae(Dipsacales)ValerianaofficinalisL.valerianEuropean(Heinrichetal.,2012)Antianxietyandsedative(Heinrichetal.,2012)AY362490 Celastraceae(Calastrales)Cathaedulis(Vahl)Endl.khatAfricanandMiddleEastern(Rätsch,2005)Stimulant,antidepressant,aphrodisiac(Rätsch,2005)JQ412336 Columelliaceae(Bruniales)DesfontainiaspinosaRuiz&Pav.taiqueNativeAmerican(Rätsch,2005)Hallucinogen(Rätsch,2005)Z29670 Combretaceae(Myrtales)Terminaliabellirica(Gaertn.)Roxb.bellerianmy-robalanIndomalaya(Rätsch,2005)Hallucinogen,sedative(Rätsch,2005)KT279740 Convolvul

7 aceae(Solanales)Argyreianervosa(Burm.F.)
aceae(Solanales)Argyreianervosa(Burm.F.)Bojer(DArgyreiaspeciosa(L.f.)Sweet)HawaiianbabyNativeAmerican(Rätsch,2005)Hallucinogen,analgesic,aphrodisiac(Rätsch,2005;Galani,Patel&Patel,2010)KF242477 Convolvulaceae(Solanales)ConvolvulustricolorL.dwartmorninggloryEuropean(Rätsch,2005)Sedative,analgesic(Rätsch,2005)L11683 (continuedonnextpage) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 6/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Convolvulaceae(Solanales)Ipomoeaspp.morninggloryNativeAmerican(Rätsch,2005)Hallucinogen,stimulant,aphrodisiac(Rätsch,2005;Meiraetal.,2012)KF242478 Convolvulaceae(Solanales)Turbinacorymbosa(L.)Raf.ololiuquivineNativeAmerican(Rätsch,2005)Hallucinogen,analgesic(Rätsch,2005)AY100966 Cupressaceae(Pinales)JuniperusrecurvaBuch.-Ham.exD.DonHimalayanweepingjuniperIndomalayan,TemperateAsian(Rätsch,2005)Hallucinogen(Rätsch,2005)JQ512552 Ephedraceae(Ephedrales)Ephedraspp.ephedraTemperateAsian(Heinrichetal.,2012)Stimulant(Rätsch,2005)AY056562 Ericaceae(Ericales)LedumpalustreL.wildrose-maryTemperateAsian(Rätsch,2005)Hallucinogen,sedative,analgesic(Rätsch,2005)AF419831 Ericaceae(Ericales)RhododendronmolleG.Don.yangzhizhuTemperateAsian(Mamedov,2005)Antidepressant(Mamedov,2005)AF421101 Erythroxylaceae(Malpighiales)Erythroxylumspp.CocaNativeAmerican(Rätsch,2005)Stimulant,antianxiety,analgesicandaphrodisiac(Rätsch,2005)AB925614 Fabaceae(Fabales)Acaciaspp.wattleAfrican/MiddleEasternAustralasian,Indomalayan,NativeAmerican(Rätsch,2005)Hallucinogen,aphrodisiac(Rätsch,2005)HM849736 Fabaceae(Fabales)Anadenantheraspp.vilca,yopoNativeAmerican(Rätsch,2005)Hallucinogenandanalgesic(Schultes,1976)KJ082119 Fabaceae(Fabales)Astragalusspp.milkvetchNativeAmerica(Rätsch,2005)Hallucinogen(Rätsch,2005)KU666554 Fabaceae(Fabales)Calliandraanomala(Kunth)J.F.Macbr.cabellitoNativeAmerican(Rätsch,2005)Hallucinogenandanalgesic(Rätsch,2005)AM234255 Fabaceae(Fabales)Desmanthusillinoensis(Michx.)MacMill.prairiebundleflowerNativeAmerican(Halpern,2004)Hallucinogen(Halpern,2004)KP126868 Fabaceae(Fabales)Erythrinaspp.coraltreesNativeAmerican,Indomalaya(Rätsch,2005).Hallucinogenandsedative(Rätsch,2005)AB045801 Fabaceae(Fabales)LonchocarpusviolaceusBenth.balche'treeNativeAmerican(Rätsch,2005)Hallucinogen(Rätsch,2005)JQ626245 Fabaceae(Fabales)Mimosaspp.mimosaNativeAmerican,Indomalayan(Rätsch,2005)Hallucinogenic,sedative,aphrodisiac(Rätsch,2005)KJ773686 (continuedonnextpage) Alrash

8 edyandMolina(2016),PeerJ,DOI10.7717/peer
edyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 7/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Fabaceae(Fabales)Mucunapruriens(L.)DC.velvetbeanIndomalayan(Lamparielloetal.,2012)Hallucinogen,aphrodisiac(O'Mahony,2010;Lamparielloetal.,2012)EU128734 Fabaceae(Fabales)Rhynchosiapyramidalis(Lam.)Urb.bird'seyesNativeAmerican(Rätsch,2005)Sedative(Rätsch,2005)KJ594450 Fabaceae(Fabales)Sophorasecundiflora(Ortega)DC.mescalbeanNativeAmerican(Schultes,1976)Hallucinogen(Schultes,1976)Z70141 Hypericaceae(Malpighiales)HypericumperforatumL.St.John'swortEuropean(Spinella,2001)Antianxiety,antidepressant(Spinella,2001;Heinrichetal.,2012)AF206779 Iridaceae(Asparagales)CrocussativusL.saffronEuropean(Rätsch,2005)Antianxiety,sedative,aphro-disiac(Rätsch,2005;Hossein-zadeh&Noraei,2009)KF886671 Lamiaceae(Lamiales)LavandulaangustifoliaMill.(DLavandulaof-ficinalisChaix)lavenderEuropean(Rätsch,2005)Antianxiety,sedative,anal-gesic(Lis-Balchin&Hart,1999;Hajhashemi,Ghannadi&Sharif,2003)KT948988 Lamiaceae(Lamiales)Leonotisleonurus(L.)R.Br.lion'stailAfricanandMiddleEastern(Rätsch,2005)Hallucinogen,sedative,analgesic(Rätsch,2005)AM234998 Lamiaceae(Lamiales)LeonuruscardiacaL.motherwortEuropean(Rauwaldetal.,2015)Antianxiety,antidepres-sant,sedative(Rauwaldetal.,2015)KM360848 Lamiaceae(Lamiales)MelissaofficinalisL.lemonbalmEuropean(Vogletal.,2013)Antianxiety,sedative(Hein-richetal.,2012)KM360879 Lamiaceae(Lamiales)Plectranthusscutellarioides(L.)R.Br.(DColeusblumeiBenth.)coleusIndomalayan(Rätsch,2005)Hallucinogen,analgesic(Rätsch,2005)JQ933273 Lamiaceae(Lamiales)RosmarinusofficinalisL.rosemaryEuropean(Ferlemietal.,2015)Antianxiety,antidepressant,analgesic(Ferlemietal.,2015)KR232566 Lamiaceae(Lamiales)SalviadivinorumEpling&JativayerbadelapastoraNativeAmerican(Rätsch,2005)Hallucinogen,analgesic(Rätsch,2005)AY570410 Lamiaceae(Lamiales)ScutellarialaterifloraL.skullcapNativeAmerican(Awadetal.,2003)Antianxiety,sedative(Awadetal.,2003)HQ590266 Lauraceae(Laurales)Cinnamomumcam-phora(L.)J.PreslcamphorIndomalayan,TemperateAsian(Rätsch,2005)Stimulant,sedative(Rätsch,2005)L12641 (continuedonnextpage) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 8/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Lauraceae(Laurales)Sassafrasalbidum(Nutt.)NeessassafrasNativeAmerican(Rätsch,2005)Stimulant(Rätsch,2005)AF206819 Loganiaceae(Gentianales)Strychnos

9 nux-vomicaL.strychninetreeIndomalaya(Rä
nux-vomicaL.strychninetreeIndomalaya(Rätsch,2005)Stimulant,antianxiety,an-tidepressant,aphrodisiac(Rätsch,2005)L14410 Lythraceae(Myrtales)Heimiasalicifolia(Kunth)LinksinicuicheNativeAmerican(Rätsch,2005)Hallucinogen,sedative(Rätsch,2005)AY905410 Malpighiaceae(Malpighiales)Banisteriopsisspp.ayahuascaNativeAmerican(Sayin,2014)Hallucinogen(Sayin,2014)HQ247440 Malpighiaceae(Malpighiales)Diplopteryscabrerana(Cuatrec)B.GateschalipongaNativeAmerican(Sayin,2014)Hallucinogen(O'Mahony,2010)HQ247482 Malvaceae(Malvales)Colaspp.kolanutAfricaandMiddleEastern(McClatcheyetal.,2009)Stimulant(McClatcheyetal.,2009)AY082353 Malvaceae(Malvales)SidaacutaBurm.f.broomweedNativeAmerica(Rätsch,2005)Stimulant(Rätsch,2005)KJ773888 Malvaceae(Malvales)Theobromaspp.cacaoNativeAmerican(Rätsch,2005)Stimulant(Rätsch,2005)JQ228389 Malvaceae(Malvales)Tiliaspp.lindenEuropean(Rätsch,2005)Antianxiety,sedative(Rätsch,2005)KT894775 Melanthiaceae(Liliales)VeratrumalbumL.whitehelleboreEuropean(Rätsch,2005)Hallucinogen(Rätsch,2005)KM242984 Myristicaceae(Magnoliales)HorsfieldiaaustralianaS.T.BlakenutmegAustralasian(Rätsch,2005)Hallucinogen(Rätsch,2005)KF496315 Myristicaceae(Magnoliales)MyristicafragransHoutt.nutmegAustraliasia,Indomalaya(Rätsch,2005)Hallucinogen,stimulant,sedativeaprhodisiac(Rätsch,2005)AF206798 Myristicaceae(Magnoliales)Osteophloeumplatyspermum(SpruceexA.DC.)Warb.huapaNativeAmerican(Rätsch,2005)Hallucinogen(Rätsch,2005)JQ625884 Myristicaceae(Magnoliales)Virolaelongata(Benth.)Warb.epenaNativeAmerican(Rätsch,2005)Hallucinogen,stimulant(Rätsch,2005)JQ626043 Myrtaceae(Myrtales)PsidiumguajavaL.guavaAfricanandMiddlEastern(Rätsch,2005)Sedative,analgesic(Rätsch,2005)JQ025077 Nitrariaceae(Sapindales)PeganumharmalaL.harmalAfricanandMiddleEastern(Sayin,2014)Hallucinogen,stimulant,analgesic(Vetulani,2001;Farouketal.,2008)DQ267164 (continuedonnextpage) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 9/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Nymphaeaceae(Nymphaeales)Nupharlutea(L.)Sm.yellowwaterlilyEuropean(Rätsch,2005)Sedative(Rätsch,2005)DQ182338 Nymphaeaceae(Nymphaeales)Nymphaeaspp.waterlilyAfricanandMiddleEastern(Rätsch,2005)Sedative(Rätsch,2005)GQ468660 Olacaceae(Santalales)Ptychopetalumola-coidesBenth.marapuamaNativeAmerican(Piatoetal.,2008)Stimulant,Antidepressant(Piatoetal.,2008)FJ038139 Orchidaceae(Asparagales)VanillaplanifoliaJacks.exAndrewsvanillaNativeAmerica(Rätsch,2005)Stim

10 ulant,sedative,aphrodisiac(Rätsch,2005;
ulant,sedative,aphrodisiac(Rätsch,2005;O'Mahony,2010)KJ566306 Orobanchaceae(Lamiales)CistanchedeserticolaK.C.MaroucongrongTemperateAsian(Wang,Zhang&Xie,2012)Stimulant,aphrodisiac(O'Mahony,2010)KC128846 Pandanaceae(Pandanales)Pandanusspp.screwpineAustralasian(Rätsch,2005)Hallucinoge,analgesic(Rätsch,2005)JX903247 Papaveraceae(Ranuncu-lales)ArgemonemexicanaL.MexicanpoppyNativeAmerican(Rätsch,2005)Hallucinogen,sedative,anal-gesic,aphrodisiac(Rätsch,2005;Brahmachari,Gorai&Roy,2013)U86621 Papaveraceae(Ranuncu-lales)EschscholziacalifornicaCham.CaliforniapoppyNativeAmerican(Rollandetal.,1991)Antianxiety,sedative,anal-gesic(Rollandetal.,1991)KM360775 Papaveraceae(Ranuncu-lales)MeconopsishorridulaHook.f.&ThomsonpricklybluepoppyTemperateAsian(Fanetal.,2015)Sedative,analgesic(Fanetal.,2015)JX087717 Papaveraceae(Ranuncu-lales)PapaversomniferumL.opiumpoppyAfricanandMiddleEastern(Vetulani,2001)Hallucinogen,sedative,anal-gesic,aphrodisiac(Rätsch,2005)KU204905 Passifloraceae(Malpighiales)Passifloraspp.passionflowerNativeAmerican(Rätsch,2005)Antianxiety,sedative(Hein-richetal.,2012)HQ900864 Passifloraceae(Malpighiales)TurneradiffusaWilld.exSchult.damianaNativeAmerican(Rätsch,2005)Stimulant,antianxiety,aphrodisiac(Rätsch,2005)JQ593109 Phytolaccaceae(Caryophyl-lales)PhytolaccaacinosaRoxb.pokeweedTemperateAsian(Rätsch,2005)Hallucinogen(Rätsch,2005)HM850257 Piperaceae(Piperales)ArundodonaxL.giantreedAfricanandMiddleEastern;NativeAmerican(Rätsch,2005)Hallucinogen(Rätsch,2005)U13226 Piperaceae(Piperales)Piperspp.pepper,kavaNativeAmerican,Indomalayan,Australasian(Rätsch,2005)Stimulant,antianxiety,seda-tive,analgesic,aphrodisiac(Rätsch,2005)AY032642 (continuedonnextpage) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 10/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Plantaginaceae(Lamiales)Bacopamonnieri(L.)Wettst.brahmiIndomalayan(Shinomol,Muralid-hara&Bharath,2011)Antianxiety,aphrodisiac(Shinomol,Muralidhara&Bharath,2011)KJ773301 Poaceae(Po-ales)LoliumtemulentumL.beardeddarnelAfricanandMiddleEastern(Rätsch,2005)Hallucinogen(Rätsch,2005)KM538829 Ranunculaceae(Ranuncu-lales)Aconitumspp.monkshoodEuropean,Indomalayan,TemperateAsian(Rätsch,2005)Hallucinogen,analgesic,aphrodisiac(Rätsch,2005)EU053898 Ranunculaceae(Ranuncu-lales)HydrastiscanadensisL.goldensealNativeAmerican(Foster&Duke,2000)Stimulant,sedative,analgesic(O'Mahony,2010)L75849 Rubiaceae(Gentianales)Catunaregamnilot-ica(Stapf)Ti

11 rveng.(DRandianiloticaStapf)chibraAfrica
rveng.(DRandianiloticaStapf)chibraAfricaandMiddleEastern(Danjumaetal.,2014)Antianxiety,antidepressant(Danjumaetal.,2014)AJ286700 Rubiaceae(Gentianales)CoffeaarabicaL.coffeeAfricanandMiddleEastern(Rätsch,2005)Stimulant(Rätsch,2005)EF044213 Rubiaceae(Gentianales)Corynanthespp.pampramaAfricanandMiddleEastern(Rätsch,2005)Stimulantandaphrodisiac(Rätsch,2005)AJ346977 Rubiaceae(Gentianales)Mitragynaspeciosa(Korth.)HavilkratomIndomalaya(Idayuetal.,2011;Suhaimietal.,2016)Stimulant,analgesic,sedative(Rätsch,2005;Suhaimietal.,2016)AJ346988 Rubiaceae(Gentianales)Pausinystaliajohimbe(K.Schum.)PierreexBeilleyohimbeAfricanandMiddleEastern(Rätsch,2005)Hallucinogen,stimulant,antidepressant,aphrodisiac(Rätsch,2005)AJ346998 Rubiaceae(Gentianales)Psychotriaspp.chacrunaNativeAmerican(Rätsch,2005)Hallucinogen,sedative,anal-gesic(Rätsch,2005)KJ805654 Santalaceae(Santalales)SantalummurrayanumC.AGardnersandalwoodAustralasian(Rätsch,2005)Sedative(Rätsch,2005)L26077 Sapindaceae(Sapindales)Paulliniaspp.guaranaNativeAmerican(McClatcheyetal.,2009)Stimulant(McClatcheyetal.,2009)AY724365 Solanaceae(Solanales)AtropabelladonnaL.belladonnaEuropean(Schultes,1976)Hallucinogen,stimulant,sedative,aphrodisiac(Rätsch,2005)AJ316582 Solanaceae(Solanales)Brugmansiaspp.angel'strumpetNativeAmerican(Rätsch,2005)Hallucinogen,sedative,aphrodisiac(Rätsch,2005)HM849829 (continuedonnextpage) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 11/30 Table1(continued)Family(Order)AcceptedbinomialnameCommonnameIndigenouspsychoactivecultureMechanismofactionGenbanknumbers Solanaceae(Solanales)Brunfelsiaspp.raintreeNativeAmerican(Rätsch,2005)Hallucinogen,analgesic(Rätsch,2005)AY206720 Solanaceae(Solanales)Cestrumspp.floweringjessamineNativeAmerican(Rätsch,2005)Hallucinogen,sedative,anal-gesic(Rätsch,2005)JX572398 Solanaceae(Solanales)Daturaspp.toloacheNativeAmerican,Indomalayan,European(Rätsch,2005)Hallucinogen,sedative,anal-gesic,aphrodisiac(Rätsch,2005)JX996059 Solanaceae(Solanales)Duboisiaspp.pituriAustralasian(Rätsch,2005)Hallucinogen,stimulant,aphrodisiac(Rätsch,2005)KM895868 Solanaceae(Solanales)Hyoscyamusspp.HenbaneEuropean(Rätsch,2005)Hallucinogen.sedative(Rätsch,2005)KF248009 Solanaceae(Solanales)Iochromafuchsioides(Bonpl.)MiersyasNativeAmerican(Rätsch,2005)Sedative(Rätsch,2005)KU310432 Solanaceae(Solanales)Mandragoraspp.mandrakeEuropean,AfricanandMiddleEastern(Rätsch,2005;Sayin,2014)Hallucinogen,sedative,analgesic,aphrodisiac(Rätsch,2005;Sayin,2014)U08614 Solanaceae(Solanales)Nic

12 otianaspp.tobaccoNativeAmerican,Australa
otianaspp.tobaccoNativeAmerican,Australasian(Vetulani,2001;Rätsch,2005)Stimulant,antianxiety(Rätsch,2005)KU199713 Solanaceae(Solanales)PetuniaviolaceaLindl.shaninNativeAmerican(Schultes,1976)Hallucinogen(Schultes,1976)HQ384915 Solanaceae(Solanales)Physalisspp.groundcherryNativeAmerican(Rätsch,2005)Sedative,analgesic(Rätsch,2005)KP295964 Solanaceae(Solanales)ScopoliacarniolicaJacq.scopoliaEuropean(Rätsch,2005)Hallucinogen,sedative,aphrodisiac(Rätsch,2005)HQ216145 Solanaceae(Solanales)Solandraspp.arboldelvientoNativeAmerican(Knab,1977;Rätsch,2005)Hallucinogen,aphrodisiac(Knab,1977;Rätsch,2005)U08620 Solanaceae(Solanales)Solanumspp.nightshadeEuropean,NativeAmerican(Rätsch,2005)Sedative,analgesic(Rätsch,2005)KC535803 Solanaceae(Solanales)Withaniasomnifera(L.)DunalashwagandhaIndomalayan(Rätsch,2005)Sedative,aphrodisiac(Rätsch,2005)FJ914179 Theaceae(Ericales)Camelliasinensis(L.)KuntzeteaTemperateAsian(Rätsch,2005)Stimulant,aphrodisiac(Rätsch,2005)EU053898 Urticaceae(Rosales)UrticaurensL.nettleAfricanandMiddleEastern(Doukkalietal.,2015)Hallucinogen,antianxiety,sedative(O'Mahony,2010;Doukkalietal.,2015)KM361027 AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 12/30 ofallknownplantspeciesthatismaintainedbytheRoyalBotanicGardensandtheMissouriBotanicalGarden.Thepsychoactiveusesofeachplantwerecategorizedasfollows:hallucinogen,sedative(Dnarcotic/hynotic),stimulant,anxiolytic(Drelaxant),andantidepressant.Aspsychotropicplantsmayalsoexertanalgesiaand/oraphrodisiaceffects,theseeffectsweredeterminedforeachplantinadditiontotheiroriginalpsychoactiveuse.Multipleeffectsbasedonliteraturewerenotuncommon.Thus,plantswereassignedmultiplepsychoactiveattributes,ifapplicable.Forcongenerictaxa,usesforeachspecieswereallnoted.The126psychoactiveplanttaxawerecategorizedaccordingtotheethnicgroupstheywereassociatedwith:NativeAmerican(includingNorth,CentralandSouthAmerica,49genera),European(15),TemperateAsian(includingChina,Russia,10),MiddleEasternandAfrican(19),Indomalayan(includingIndiaandSoutheastAsia,10),Australasia(includingAustralia,NewGuinea,NewZealand,PacificIslands,4).Taxawithtraditionalpsychoactiveusesinatleasttwoofthesegroupsweredesignatedmulti-cultural(19).Theusesoftheplantswerebasedontheoriginatingindigenouscultures.Forexample,harmal,Peganumharmala(Nitrariaceae),isnativeintheMediterranean(Europe),butitwasusedasastimulantintheMiddleEastandinAfrica,soharmalwasassignedtothelatter.Guava,Psidiumguajava(Myrtaceae),isnativetotropicalAmerica,butwasonlyusedaspsychoactiveinAfri

13 ca(Rätsch,2005).Argyreianervosa(DA.spec
ca(Rätsch,2005).Argyreianervosa(DA.speciosa),thoughofIndianorigin,isconsideredmulti-culturalhere.IthasbeenusedinAyurvedicmedicineasananalgesicandaphrodisiac(Galani,Patel&Patel,2010),butHawaiians(Australasia)havebeenusingitasalternativetomarijuana(Rätsch,2005).Culturaldesignationsforeachplantwereallnoted,withoverlappingorigins,ifapplicable,indicated.Toconstructthephylogeny,thesequenceofrbcL(thegenethatcodesforthephotosyntheticenzymerubisco;Clegg,1993)foreachpsychoactiveplanttaxonwasobtainedfromtheGenBankdatabase(http://www.ncbi.nlm.nih.gov/genbank)usingBLASTN(e-valueD0,querycoverage�50%;Altschuletal.,1990).Iftherearemultiplespecieswithinthegenus,onlythegenusnamewasindicated.TherbcLsequenceswerenotavailableinGenBankforthefollowingspecies:Caleaternifolia,Calliandraanomala,Crocussativus,Horsfieldiaaustraliana,Iochromafuchsioides,Juniperusrecurva,Justiciapectoralis,Lactucavirosa,Ledumpalustre,Lonchocarpusviolaceus,Nymphaeaampla,Pachyceruspectenaboriginum,Psychotriaviridis,Ptychopetalumolacoides,Psidiumguajava,Rhynchosiapyramidalis,Sassafrasalbidum,Sceletiumtortuosum,Tanaeciumnocturnum,Tiliatomentosa,Urticaurens,Veratrumalbum,andVirolaelongata.Inthesecases,therbcLsequenceforanyspecieswithinthecorrespondinggenuswasdownloadedinstead.TherbcLsequencesofthepsychoactiveplantswerealignedusingdefaultparametersinMAFFTv.7(Katoh&Standley,2013).PhyML(Guindon&Gascuel,2003)wasutilizedtoreconstructthephylogenyapplyingthegeneraltimereversible(GTR)DNAmodel(Tavaré,1986)withaLRT(approximatelikelihoodratiotest)Shimodaira-Hasegawa-like(SH-like)branchsupport(Simmons&Norton,2014)and100bootstrapreplicates.ITOL(InteractiveTreeofLife,http://itol.embl.de),aweb-basedtoolusedforthedisplayandmanipulationofphylogenetictrees(Letunic&Bork,2006),wasusedtohighlightandmapthetraitsinTable1(indigenousculture,psychoactiveuses).Affectedneurotransmitter AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 13/30 (NT)systems(Table2)forthemainpsychoactivefamilieswerealsoaddedtothephylogeny.CosmeticeditingoftheITOLresultswascompletedinAdobeIllustratorCS4.RESULTSThe126psychoactiveseedplanttaxabelongto56familiesand31orders(Table1)andtogethercomprise1.6%ofthetotalgenericdiversityforthesefamilies.Thephylogenyreflectsexpectedrelationships(TheAngiospermPhylogenyGroup,2016).Withineudicotsthereseemstobeculturalbiasofpsychotropicusetowardasteridmembers(61)vs.rosids(31).Nonetheless,thescattereddistributionofpsychoactivetaxathroughouttheangiospermphylogenysuggeststhatpsychoactivephytochemicalshaveevolvedmultiple

14 timesthroughoutangiospermevolution.Howev
timesthroughoutangiospermevolution.However,certainfamiliesaremorediversewithatleast3ormoregenera:Myristicaceae,Papaveraceae,Malvaceae,Fabaceae,Cactaceae,Asteraceae,Convolvulaceae,Solanaceae,Lamiaceae,Rubiaceae,Apocynaceae.However,psychoactivediversitywithinthesefamiliesmaybepositivelycorrelatedwiththefamily'sgenericdiversity.Totestthis,aPearson'sproductmomentcorrelationcoefficientwascalculatedtotesttherelationshipbetweenthenumberofpsychoactivegenerainourstudyversusthegenericdiversityofeachfamily(fromChristenhusz&Byng,2016).TaxonomicallydiversefamilieslikeAsteraceaeandRubiaceae(�500generaeach)didnotalwayshaveproportionallyhighernumberofpsychoactivegenerawiththecorrelationcoefficientveryweaklypositive(rD0:004).However,Myristicaceae(4psychoactivegeneraoutof21total),Papaveraceae(4/42),Cactaceae(5/127),Convolvulaceae(4/53),Solanaceae(16/100),Lamiaceae(8/241),Apocynaceae(7/366)haveadisproportionatenumber(�1.6%)oftheirfamily'sgenericdiversitypsychoactive.WefocusedontheneurotransmittersystemsaffectedbypsychotropicmembersofthesefamiliesaswellaspsychoactivemembersintheinherentlydiversefamiliesofFabaceae,Malvaceae,Rubiaceae,andAsteraceae(Fig.1).Unrelatedfamiliesmayexertsimilarpsychoactiveeffects(Fig.1).Cactaceae,Fabaceae,Myristicaceae,Convolvulaceae,andSolanaceaearemainlyhallucinogens,thoughtheyareunrelated.Ofthefiveculturalgroups,NativeAmericanshavetraditionallyusedthemostpsychoactives(49/126)withpredilectionforhallucinogens(Fig.2)inCactaceae,Fabaceae,Convolvulaceae.Thesefamiliesmainlyworkasserotoninreceptoragonists(Fig.1;Table2),thesamemechanismashallucinogenicMyristicaceaethathasbeenusedinAustralasiaandIndomalaya.MembersofSolanaceaehavealsobeenusedashallucinogens,predominantlybyNativeAmericansandEuropeans,butactviaadifferentmechanismasacetylcholineantagonists.Hallucinogenicasteridsarealsooftenusedasaphrodisiacs(16=30D53%vs.4=18D22%hallucinogenicrosids).TheunrelatedPapaveraceaeandLamiaceaesimilarlyshowsedative/narcoticqualities,anotherpopularpsychoactiveeffectamongdifferentculturalgroups(Fig.2).However,theyaffectdifferentneurotransmittersystemswithPapaveraceaeworkingmainlyasopioidreceptoragonists.Lamiaceaeworkasreceptoragonistsofgamma-aminobutyricacid(GABA),whichalsomediatesthefamily'sanxiolyticeffects.Psychoactivemembersofthesefamiliesalsotendtoexhibitanalgesiceffects.Plantswithanxiolyticandantidepressantpropertiesarerelativelysparse(Figs.1and2),withEuropeansshowingslightlyincreaseduseoftheseplants.MembersofApocynaceae AlrashedyandMolina(2016),PeerJ,

15 DOI10.7717/peerj.2546 14/30 Table2Mainps
DOI10.7717/peerj.2546 14/30 Table2Mainpsychoactivefamilies(cf.Fig.1),theirprimarypsychoactiveeffect,suspectedphytochemicalconstituentsproducingtheeffect,andtheprimaryneu-rotransmitter(NT)systemspotentiallyaffected.``''referstotheactivation(receptoragonist)andinhibition(receptorantagonist),respectively,ofcertainNTrecep-torsbythepsychoactivesubstance. FamilyMainpsychoactiveeffectActivephytochemicalsNeurotransmittersystemsaffected ApocynaceaeAntidepressantIndolealkaloids,e.g.,ibogaine,rauwolscine,reserpine,yohimbine(Spinella,2001;Polya,2003;Rätsch,2005;Pratchayasakuletal.,2008;Sayin,2014;Cardosoetal.,2015)Serotonin(C),dopamine(C),noradrenaline(C)(Wells,Lopez&Tanaka,1999;Spinella,2001;Polya,2003;Grundmannetal.,2007;Arulmozhietal.,2012;Zheng,Fan&Liu,2013;Sayin,2014;Cardosoetal.,2015)(exceptreserpinebutotherindolealkaloidsmaycounteractitseffects(Polya,2003) AsteraceaeHallucinogen,aphrodisiacSesquiterpenelactones(Rätsch,2005;Sayin,2014)Unknownmechanismsforvarioussesquiterpenelactones(Chadwicketal.,2013) CactaceaehallucinogenPhenethylaminealkaloids,e.g.,hordenine,mescaline,pectenine(Rätsch,2005;Sayin,2014)Serotonin(C)(Polya,2003) ConvolvulaceaehallucinogenErgotindolealkaloids(Rätsch,2005;McClatcheyetal.,2009)Serotonin(C)(Polya,2003;Kennedy,2014) FabaceaeHallucinogenIndolealkaloids,e.g.,bufotenin,DMT;tryptamines(Polya,2003;Wink,2003;Halpern,2004;Rätsch,2005)Serotonin(C) LamiaceaeAnxiolytic,sedative,analgesicTerpenoidse.g.,baicalin,linalool,labdane,rosmarinicacid,salvinorinA,wogonin,etc.(Lis-Balchin&Hart,1999;Awadetal.,2003;Awadetal.,2009;Polya,2003;Wink,2003;Heinrichetal.,2012);leonurinealkaloid(Rauwaldetal.,2015)GABA(C)(Awadetal.,2003;Awadetal.,2009;Hajhashemi,Ghannadi&Sharif,2003;Shietal.,2014;Rauwaldetal.,2015) MalvaceaeStimulantXanthinealkaloids,e.g.,caffeine,theobromine(inCola,Theobroma;Rätsch,2005;McClatcheyetal.,2009);phenethylamineephedrine(inSida;Prakash,Varma&Ghosal,1981)Adenosine(�)byxanthinealkaloids(Polya,2003;McClatcheyetal.,2009);adrenaline(C)byephedrine(Polya,2003) MyristicaceaeHallucinogenDMT(indolealkaloidinVirola);phenylpropenee.g.,myristicin,elemicine,safrole(Polya,2003;Rätsch,2005)Serotonin(C)(Spinella,2001;Polya,2003) PapaveraceaeHallucinogenIsoquinolinealkaloids,e.g.,codeine;morphine;reticuline;thebaine(Polya,2003;Heinrichetal.,2012;Fedurcoetal.,2015;Shangetal.,2015)Opioid(C)(Rollandetal.,1991;Polya,2003;Shangetal.,2015) RubiaceaeStimulantcaffeine(xanthinealkaloidinCoffea;Polya,2003);indolealkaloidsinothers,e.g.,corynanthine,mitragyn

16 ine,yohimbine(indolealkaloid;Polya,2003;
ine,yohimbine(indolealkaloid;Polya,2003;Rätsch,2005;Suhaimietal.,2016)Adenosine(�)byxanthinealkaloids(Polya,2003;McClatcheyetal.,2009);adrenaline(C)andserotonin(C)byindolealkaloids(Polya,2003) SolanaceaeHallucinogen,sedative,Tropanealkaloids,e.g.,atropine,hyoscyamine,scopolamine(Polya,2003;Wink,2003;Rätsch,2005)Acetylcholine(�)(Polya,2003) AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 15/30 Figure1Thephylogeny(cladogram)oftraditionallyusedpsychoactiveplanttaxa.Thephylogenycon-formstoexpectedgroupings(APGIV,2016).The11mainplantfamiliesarehighlighted(toptobottom):Myristicaceae,Papaveraceae,Malvaceae,Fabaceae,Cactaceae,Asteraceae,Convolvulaceae,Solanaceae,Lamiaceae,Rubiaceae,Apocynaceae.GreycirclesnexttotheirfamilynamesareproportionaltototalgenericdiversitywithinthefamilywithlowestcountforMyristicaceae(21genera),andhighestwith1623generaforAsteraceae(Christenhusz&Byng,2016).Branchesarecodedaccordingtothedifferentcultures(NativeAmerican:redsolidline;MiddleEasternandAfrican:orangedashedline;European:bluesolidline;Indomalayan:greendottedline;TemperateAsia:pinksolidline,Australasia:yellowsolidline;Multi-cultural:greysolidline).Branchesinboldrepresentbootstrapnodesupport�50%andSH-likebranchsupport�0.9.Psychoactiveuseswereoverlainnexttotaxonnamesincolumns(Ha,hallucinogen;Sm,stimulant;Ax,anxiolytic;Ad,antidepressant;Sd,sedative;Ag,analgesic;Ap,aphrodisiac;alongwiththeprimaryneurotransmittersaffectedbythephytochemical/sexertingthedominantpsychoactiveeffect(de-lineatedwithboxes;cf.Table2).Shadedplantfamilieswithphytochemicalsthatactivatecertainneuro-transmittersystems(e.g.,receptoragonists)showtheneurotransmitter/sinvolvedwithgreen(bright)background;phytochemicalswithinhibitoryeffectstotheNThavered(dark)background.InAsteraceae,neuropharmacologyisunclear(???). AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 16/30 Figure2Culturaldistributionofpsychoactiveapplications.Psychoactiveplantswerecategorizedac-cordingtoculturalaffiliationandpsychoactiveuses.Eachrowshowsthedistributionofpsychoactiveusesforplantswithinaculturalgroup.Ofthe126psychoactiveplantgenera,morethanhalfoftheplantsareusedashallucinogensmostlybyNativeAmericans.Plantswithsedative/narcoticqualitiesarealsocom-monlysoughtafter.Plantswithanxiolyticandantidepressanteffectsaretheleastpopularamongdifferentcultures. andRubiaceaethatshowanantidepressanteffectfacilitatethiseffectbyincreasingsynapticlevelsofmonoamineneurotransmitters(serotonin,dopamine,noradrenaline;Fig.1andTable2).Incontrast

17 ,plantswithstimulatingeffectsarenumerous
,plantswithstimulatingeffectsarenumerousandrandomlydistributedthroughoutthephylogeny,exhibitingvaryingmechanismsofaction(seeMalvaceaeandRubiaceae,Fig.1andTable2).DISCUSSIONThephylogeneticdistributionofpsychoactiveplantsshowsmultipleevolutionaryoriginsandprovidesevidencefortheadaptivebenefitofphytochemicalsthatarepsychoactiveinanimals.Ithasbeenhypothesizedthatmammalsmayhavesoughtplantswiththesephytochemicalsthatwerechemicallysimilartoendogenousneurotransmitterstoaugmenttheirnutrition,aswellastofacilitatesurvival,alleviatingpainandhunger(Sullivan&Hagen,2002).Whetherthisphylogeneticdistribution,showingmultipleindependentoriginsofpsychoactiveplants,isduetoco-evolutionarymutualismwithanimalsremainstobetested.However,itisclearthatcertainpsychoactiveeffectsareconcentratedincertaingroups,whichdemonstratesthatpsychoactivephytochemicalsarephylogeneticallyclustered.Phylogeneticclusteringofcertainsecondarymetabolites(Wink,2003;Winketal.,2010;Wink,2013)andofmedicinaltraits(Saslis-Lagoudakisetal.,2012;Saslis-Lagoudakisetal.,2015;Xavier&Molina,2016)havealsobeenrevealedinotherstudies. AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 17/30 Inthephylogeny,11of56plantfamilieshavemorepsychoactivegenera(threeormore)comparedtoothers.Accountingforthesefamilies'totalgenericdiversityshowsthatMyristicaceae,Papaveraceae,Cactaceae,Convolvulaceae,Solanaceae,Lamiaceae,andApocynaceaehaveadisproportionatenumberofpsychoactivegenera.Thepsychoactivediversityoftheotherfamilies,Fabaceae,Malvaceae,Asteraceae,andRubiaceae,maybeanartifactoftheiroverallhighergenericdiversity.Nonetheless,weseeapatternwheretheseplantfamiliesarebeingusedforsimilarpsychoactiveapplicationsbydifferentcultures,apatternofculturalconvergence(Xavier&Molina,2016)withbias,interestingly,forplantswithhallucinogenicandsedative/narcoticpotential.PharmacologyofhallucinogenicplantsTheuseofhallucinogensiswidespreadincultureswhichassignedpositivemeaningtotheexperiencedalteredstateofconsciousness,suchasallowingtheuseraccesstothespiritualworld(Júnioretal.,2015).Hallucinogensusedindivinationandreligioushealing(i.e.,entheogens)mayhaveplayedasignificantroleinhumanevolution(Schultes,Hofmann&Rätsch,2001).NativeAmericansprolificallyusedhallucinogens,buthallucinogenicuseseemstobelowerintemperateAsia.IncreasedhallucinogenicuseamongindigenouspeoplesofBrazil(SouthAmerica)wasalsoreportedbyRodrigues&Carlini(2006).InourstudywefindhallucinogenicplantsinMyristicaceae,Fabaceae,Cactaceae,andConvolvulaceaemainlyactingasserotoninreceptoragonists,acaseo

18 fmechanisticconvergencewhereunrelatedfam
fmechanisticconvergencewhereunrelatedfamiliesexertthesamepsychoactiveeffectbyaffectingidenticalneurotransmittersystems.MescalineistheserotonergicchemicalinCactaceae,whileDMT(N,N-dimethyltryptamine)andbufotenin(Polya,2003)havethesameeffectandevolvedindependentlyinhallucinogenictaxainFabaceae(Wink,2013).SerotoninitselfoccursinfabaceousMucunapruriens(Polya,2003),ahallucinogenandaphrodisiacinAyurvedicmedicine(Lamparielloetal.,2012).DMTalsoexistsinVirolaoftheunrelatedMyristicaceae(Polya,2003),andthealkaloid,elemicine,inconfamilialMyristicafragranstransformsintoamescaline-likemolecule(Rätsch,2005).TheunrelatedConvolvulaceaeexertshallucinogeniceffectspossiblythroughitsergotalkaloidsthatworkalsoasserotoninreceptoragonists(Polya,2003;Kennedy,2014).Yetinterestingly,theseergotalkaloidsoriginatefromascomycetoussymbioticfungi(Beaulieuetal.,2013).Thoughendophyticfungicanproducesomeactivemetabolitesoriginallyattributedtoplants(Wink,2008;Winketal.,2010;Nicoletti&Fiorentino,2015),whichmayconfoundinterpretationofthephylogeny,thiswasnotthecase,sofar,fortheothermainpsychoactivefamiliesinourstudy.Ontheotherhand,hallucinogenictaxainthecloselyrelatedSolanaceaeworkonadifferentmechanism.Itstropanealkaloidssuchasscopolamineandatropineactasmuscarinicreceptorantagonists,inhibitingacetylcholinetransmission(Spinella,2001).Interestingly,inanotherasteridmember,Salviadivinorum(Lamiaceae),thediterpene,salvinorinA,possiblyworksasahallucinogenthroughitsactiononspecificopioidreceptors(kappa)(Willmore-Fordhametal.,2007),thesamereceptormodulatedbythealkaloidibogaineinhallucinogenicTabernantheiboga(Apocynaceae; AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 18/30 Spinella,2001).Variousunrelatedtaxaseeminglyachievetheirhallucinogeniceffectsbymodulatingserotonin,acetylcholine,and/orendogenousopioids.Itisinterestingthatinmanyhallucinogenicasterids,aphrodisiaceffectsarequitecommon(seeAsteraceae,Solanaceae,Apocynaceae).InmembersofSolanaceaethiseffectmaybeduetodopamineincreasefromcholinergicantagonism(Spinella,2001).Dopamineisimportantinsexualarousalandorgasm(Krüger,Hartmann&Schedlowski,2005).ThisneurotransmitterisalsomodulatedbyibogaineinT.iboga(Wells,Lopez&Tanaka,1999),whichisalsotraditionallyusedasanaphrodisiacalongwithotherApocynaceaemembers.Inanotherasteridfamily,Asteraceae,itisnotclearwhichofitsphytochemicalconstituentsproducepsychoactiveeffects,exceptperhapsforwormwood(Artemisiaspp.)whereinthemonoterpenoid,thujone,antagonizesthemaininhibitoryneurotransmitter,gamma-aminobutyricacid(GABA),resu

19 ltinginitsstimulant,almostconvulsant,eff
ltinginitsstimulant,almostconvulsant,effects(Höldetal.,2000).However,thegreatdiversityofsesquiterpenelactonesprevalentinthefamily(Chadwicketal.,2013)arelikelyimplicatedinitshallucinogenicandaphrodisiacpotential(Fig.1andTable2).Thesefindingsmotivatefurtherresearchintotheseasteridfamiliesasnewtherapeuticsforsexualdysfunction.PharmacologyofplantswithsedativeandanalgesiceectsDr.WEDixon,well-knownBritishpharmacologistofhistime,oncecommentedthatnarcoticindulgencesreflectthesadparadoxthathumansseemedtogettheir``chiefpleasuresinlifebyescapingoutoflife''(NarcoticPlants,1928:252).Theremaybetruthtothisasnarcotic/sedativeeffectswerecommonlysoughtforbyvariouscultures,secondtohallucinogens,withmembersofPapaveraceaeandLamiaceaetraditionallyusedforthispurpose.OpiumpoppyofPapaveraceaehaslongbeenknowntoancientGreeksandSumeriansandisconsideredoneofthemostimportantmedicinalplantsinhistory.Itsopiumlatexisthesourceof�30alkaloidsincludingmorphineandcodeine,whichbindtoopioidreceptors,promotingsedationandanalgesia(Heinrichetal.,2012).ThoughthereareothermembersofPapaveraceaethathavebeenusedbyAsiansandNativeAmericansforsedationandpainrelief(Rollandetal.,1991;Brahmachari,Gorai&Roy,2013;Shangetal.,2015),thesubstancesresponsiblefortheireffectsarenotwellcharacterizedasinopiumpoppy,butitispossiblethattheireffectsarealsomediatedviaopioidreceptors(Shangetal.,2015)andatleastinEschscholziacalifornica(Californiapoppy)viatheGABAergicsystem(Fedurcoetal.,2015).Inasterids,sedationisproducedbymembersofSolanaceaeandLamiaceaepossiblyviadifferentpathways.TropanealkaloidsinSolanaceae(Wink,2003),particularlyscopolamine,promotesedationthroughdepressionofthecentralnervoussystemresultingfromanticholinergicactivity(Renner,Oertel&Kirch,2005).InLamiaceae,thiseffectismainlyfacilitatedviatheGABAergicpathway(Shietal.,2014),withleonurine(Rauwaldetal.,2015)andessentialoilcomponents(Lisbalchin&Hart,1999;Wink,2003;Awadetal.,2009;Shietal.,2014;Ferlemietal.,2015)astheprimarychemicalsthatincreaseGABA.Coincidentally,Lamiaceaemembersalsopossessanalgesiceffects,butthepharmacologyisunclear(Hajhashemi,Ghannadi&Sharif,2003;Dobetsberger&Buchbauer,2011)andmayreflecttheantinociceptivepropertiesofactivationofGABA AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 19/30 receptors(Enna&McCarson,2006).Salviadivinorumhowever,doesnotcontainessentialoils(Rätsch,2005),buthasbeenpharmacologicallyshowntoexertanalgesicqualitythroughactivationofthesameopioidreceptors(kappa)implicatedinitshallucinogeniceffect(Willmore-Fordhameta

20 l.,2007),amechanismdifferentfromtheother
l.,2007),amechanismdifferentfromtheotherLamiaceaespecieshere.SomemembersofthedistantlyrelatedRubiaceae,includingPsychotriacolorata(Elisabetskyetal.,1995)andMitragynaspeciosa(Suhaimietal.,2016),havealsoshownsimilaropiate-likeantinociceptiveproperties,confirmingtheirtraditionaluses.Repeatedevolutionofphytochemicalswithaffinityforanimalopioidreceptorsmayimplysomeadaptivebenefittoplants.PharmacologyofplantswithanxiolyticandantidepressanteectsTherelativelysparsedistributionofanxiolyticandantidepressantplantsinthephylogenycomparedtohallucinogensandsedatives,suggeststhatthereislessculturalutilityforplantswiththesepsychoactiveproperties.IntheUSthereisaculturalaspecttothepathogenesisofanxietyanddepressionwithminoritygroupsreportinglowerincidencecomparedtowhites(Hofmann,Asnaani&Hinton,2010).ThedefinitionitselfofdepressioniswroughtwithWesternassumptionsofindividualhappiness,whichisincontrasttoothercultures'viewofhappinessarisingfromsocialinterdependence(Chentsova-Dutton,Ryder&Tsai,2014).Thismayexplainwhythesepsychoactiveuseswerelessprevalentcomparedtohallucinogenic,stimulantandsedativeapplications.SedativemembersofLamiaceaeoftenpossessanxiolyticqualities(Fig.1),andthisisprobablyduetooverlappingeffectsonGABA(Tallmanetal.,2002).Phytol,analcoholinessentialoils(Costaetal.,2014)hasbeenshowntoincreaseGABA.Rosmarinicacidinrosemary(R.officinalis)andlemonbalm(M.officinalis),bothLamiaceae,alsoworksasGABAtransaminaseinhibitorpreventingGABAcatabolism(Awadetal.,2009).InmembersofApocynaceaeandRubiaceae(Gentianales)thatshowanxiolyticandantidepressanteffects,anothermechanismmaybeinvolved.Rauvolfiaserpentina(Apocynaceae)isusedinAyurvedicmedicinetotreatdepression(Mamedov,2005).InAfrica,theconfamilialT.ibogaisusedasastimulanttocombatfatigueandhunger,butmayhavepotentialineasingdepressivesymptoms(Nigg&Seigler,1992).Pausinystaliayohimbe(Rubiaceae)hasstimulatingeffectsonthenervoussystemandhasbeenusedtoincreaselibidobymenincentralAfrica(Rätsch,2005).TheconfamilialM.speciosahasalsobeenusedasstimulanttocounteractfatigueandincreaseenduranceforworkinSoutheastAsia(Idayuetal.,2011).Themainchemicalconstituentsofthesecloselyrelatedfamiliesareindolealkaloidsthatgenerallyincreasesynapticlevelsofthemonoamineneurotransmitters,serotonin,dopamineandnoradrenalinebyvariousmechanismsincludinginhibitionoftransportandreuptake(Wells,Lopez&Tanaka,1999;Zheng,Fan&Liu,2013;Kennedy,2014).Theunrelatedbutpopularherbalantidepressant,St.John'swort(Hypericumperforatum,Hypericaceae;Spinella,2001),aswellaspharmaceuticala

21 ntidepressants,producesitseffects(Feighn
ntidepressants,producesitseffects(Feighner,1999)viathesamemechanismofreuptakeinhibition.MonoaminetransportinhibitorsmayberifeinApocynaceae(orGentianales).InherethnopharmacologicalstudiesofplantsfromSouthAfrica,Jäger(2015)alsodiscoveredtwootherApocynaceaespeciesthatexhibitedhighaffinitytotheserotonintransporter. AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 20/30 Interestingly,theseplantswerealsobeingusedbytraditionalhealerstotreatthosewhowere``beingputdownbythespirits.''Aprimarysideeffectofmanyconventionalantidepressantsissexualdysfunction(Higgins,Nash&Lynch,2010),whichseemstocontradicttheaphrodisiaceffectexhibitedbyT.ibogaandP.yohimbe,inadditiontotheirantidepressanteffects.ThissuggeststhatmembersofGentianalesmaybeexploitedasnovelpharmaceuticalsfordepressionwithouttheknownsideeffectsofsexualdysfunction.PharmacologyofplantswithstimulatingeectsPlantstraditionallyusedasstimulantsarenumerousandscatteredthroughoutthephylogeny,indicatingthatstimulantphytochemicalshaveevolvedmultipletimesindependentlyindifferentlineagesandmayconfersomeevolutionarybenefit.Afewdisplayparadoxicaleffectsasbothstimulatingandsedating,suchasmarijuana(Blocketal.,1998)andM.speciosa(Rätsch,2005),whichmaybeattributedtodosage,idiosyncrasies,orantagonisticphytochemicals.Albeitbelongingtodiversefamilies,coffee(Coffeaarabica,Rubiaceae),yerbamate(Ilexparaguariensis,Aquifoliaceae),kola(Colaspp.,Malvaceae),tea(Camelliasinensis,Theaceae),andguarana(Paulliniacupana,Sapindaceae),allcontaincaffeine,axanthinealkaloid,whichactsasastimulantthroughantagonismofadenosinereceptors,interferingwiththebindingoftheinhibitoryendogenousadenosine(Rätsch,2005).Yohimbe(P.yohimbe),thoughconfamilialwithcoffee,containstheindolealkaloid,yohimbine,whichbindstoadrenergicandserotoninreceptors(Polya,2003),andisstructurallyandmechanisticallysimilartootherstimulantalkaloidsfoundindiverseplantgroupssuchasergotalkaloidsinConvolvulaceae,ibogaineinT.ibogaandVoacangasp.(Apocynaceae),andharmalineinPeganumharmala(Nitrariaceae)(Polya,2003).Withinthesamefamily,particularlySolanaceae,contrastingeffectsandmechanismsmayalsobeobserved.Thoughmanysolanaceousmemberscontaintropanealkaloidsthatworkasanticholinergichallucinogenswithincapacitatingeffects,tobaccoexertsstimulantactivitythroughanoppositemechanism,withnicotine,apyrrolidinealkaloid,promotingacetylcholinetransmission.However,tropanealkaloidsarenotuniquetoSolanaceae.Cocaine,foundintheunrelatedE.coca(Erythroxylaceae),suggeststhatchemicallysimilaralkaloidsmayevolveindivergentlin

22 eages(i.e.,convergentevolution)oralterna
eages(i.e.,convergentevolution)oralternatively,certainmetabolicpathwayshavebeenevolutionarilyconservedthroughoutplantevolutionanddifferentialgeneregulationisresponsiblefortheexpressionofthispathway(Wink,2003;Wink,2008;Winketal.,2010;Weng,2014).ThesemayaccountforthepresenceofephedrineinthegymnospermEphedraspp.(Ephedraceae;Polya,2003)andtheunrelatedangiospermsSidaacuta(Malvaceae;Prakash,Varma&Ghosal,1981)andCathaedulis(Celastraceae;Polya,2003).Ephedrine,aphenethylaminethatmimicsnoradrenaline,stimulatestheadrenergicreceptorsystem,andthusthesympatheticnervoussystemresponsibleforthe``fight-and-flight''response(Polya,2003;Rätsch,2005).Itisnotablethat,evenwithinthesamefamily,thestimulantphytochemicalsarechemicallydiverse.Thisphylogeneticpatternmayindicatethatstimulantchemicalsmaybemoreevolutionarilylabilethanhallucinogenicandsedativephytochemicalsthatseemtobemorephylogeneticallyconservedwithinthefamily.Astowhythisisbegsfurther AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 21/30 inquiry,buthintsattheevolutionarybenefitsofthesechemicallydiverseplantpsychoactivecompoundsthathaveevolvedmultipletimesamongseedplants,possiblywithmultifariousrolesotherthantofunctionsolelyasallelochemicals.CONCLUSIONPhylogeneticanalysishasdemonstratedmultipleevolutionaryoriginsoftraditionallyusedpsychoactiveplantgroups.Whetherthispatternisduetorepeatedco-evolutionarymutualismwithanimalsremainstobetested.Psychoactivediversityofsomehighlightedfamiliesisprobablyduetotheinherentelevateddiversityinthesefamilies.However,otherplantfamilieshaveadisproportionatenumberofpsychoactivegenera,andtheirphytochemicalandpsychoactivetraitsshowphylogeneticclustering,withdifferentculturesconvergingongeographically-disparatemembersofthesefamiliesforsimilaruses:Myristicaceae,Cactaceae,Convolvulaceae,andSolanaceaeashallucinogens;Papaveraceae,Lamiaceaeforanalgesiaandsedation;Apocynaceaeforantidepressanteffects.Incertainunrelatedfamilieswiththesamepsychoactiveeffect,thesameneurotransmittersystemswerealsoaffected,i.e.,mechanisticconvergence.However,thiswasnotthecaseforplantswithstimulanteffects,whereconfamilialtaxapossesschemicallydiversestimulantalkaloids,andchemicallysimilarstimulantalkaloidsexistindiverselineages.Endophyticfungicanalsoproducesomeactivemetabolitesoriginallyattributedtoplants(Wink,2008;Winketal.,2010;Nicoletti&Fiorentino,2015),andthisshouldbeconsideredwheninterpretingthephylogeny.Thoughwemayhavemissedotherpsychotropictaxa,ourstudystillprovidesinsightintotheethnobotanicaloriginsofpsychoactivepla

23 ntuse.Theadditionofthesemissingtaxamayon
ntuse.Theadditionofthesemissingtaxamayonlyservetocorroborateourconclusionofwidespreadhumandependenceonpsychoactiveplantsandhighlightotherimportantpsychoactivefamiliesandtheirpharmacology.Thebrainisperhapsthemostcomplexdomainofthehumanbody(Singer,2007),andthereforebraindisordersarecomplexpathologiesthemselves(Margineanu,2016).Ethnobotanicalresearchonhowvarioushumancultureshaveexploitedherbaltherapythroughtimetotreatneurologicalafflictionswillcontinuetoprovideinsightintotheetiologyofthesediseasesandthesuccessoffolklorictreatments.Yet,theastoundingdiversityofplant-basedmedicinesmaybebetterappreciatedwithinanevo-lutionarycontextthatcanrevealphylogeneticpatternsthatmayguidefuturedrugdiscovery(Saslis-Lagoudakisetal.,2012;Xavier&Molina,2016).Thoughchemicallysimilarpsychoactivechemicalsmayexistinphylogeneticallyunrelatedlineages,suggestingconvergentevolutionordifferentialgeneregulationofcommonmetabolicpathways(Wink,2003;Wink,2008;Winketal.,2010),themajorityoftraditionallyusedpsychoactiveplantsgenerallydisplayphylogeneticconservatisminphytochemistryandpharmacology,andmaybeexploredasnoveltherapeuticsforneurologicaldisorderssuchasdepression,anxiety,pain,insomniaandsexualdysfunction,reinforcingthepotentialofplantpsychoactivesas``springboardsforpsychotherapeuticdrugdiscovery''(McKenna,1996). AlrashedyandMolina(2016),PeerJ,DOI10.7717/peerj.2546 22/30 ACKNOWLEDGEMENTSThisresearchwasconceivedaspartofNA'sMScthesis,andwearegratefultotheKingAbdullahscholarshipprogram(ofSaudiArabia)forsponsoringNA.WealsothankNA'sfamilyandMichaelPuruggananforvariousformsofsupport.WealsothankJosephMorinandTimothyLeslieforreviewingearlierdraftsofthismanuscript.Weareequallygratefultothereviewersfortheirconstructivecomments. ADDITIONALINFORMATIONANDDECLARATIONSFundingTheauthorsreceivednofundingforthiswork.CompetingInterestsTheauthorsdeclaretherearenocompetinginterests.AuthorContributionsNashmiahAidAlrashedyperformedtheexperiments,analyzedthedata,contributedreagents/materials/analysistools,wrotethepaper,preparedfiguresand/ortables,revieweddraftsofthepaper.JeanmaireMolinaconceivedanddesignedtheexperiments,performedtheexperiments,analyzedthedata,contributedreagents/materials/analysistools,wrotethepaper,preparedfiguresand/ortables,revieweddraftsofthepaper.DataAvailabilityThefollowinginformationwassuppliedregardingdataavailability:Theresearchinthisarticledidnotgenerate,collectoranalyseanyrawdataorcode.REFERENCESAltschulSF,GishW,MillerW,MyersEW,LipmanDJ.1990.Basiclocalalignmentsearchtool.JournalofM

24 olecularBiology215:403410DOI10.1016
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