Psychedelics TableofContents
Volume1 Number1 January2025
EDITORIAL
Psychedelics:TheJournalofPsychedelicandPsychoactiveDrugResearch –Chartinganewcourseinpsychedelicscience
INNOVATORS&IDEAS:RISINGSTARS
NicolasGarel:Combiningpsychoactivemoleculesandpsychotherapyforpatientssufferingfrommoodandsubstanceusedisorders:anew therapeuticparadigm NicolasGarel
StephanieKnatzPeck:Novelandinnovativetreatmentforeatingdisorders
BernardLerer:Pre-clinical,translationalandclinicalresearchfocusedontheuseofpsychedelicdrugsandtheirderivativestotreat psychiatricdisorders BernardLerer
Peripheralsignals,centralquestions:Examiningtherelationship betweenpsychedelicsandbrain-derivedneurotrophicfactor(BDNF)
EMERGINGTOPIC
Psychedelictreatmentforanorexianervosa:Afirst-handviewofhowpsilocybintreatmentdidanddidnothelp
StephanieKnatzPeck,HannahFisher…WalterH.Kaye
BENCHTOBEDSIDE
Exploringthetherapeuticpotentialofpsychedelics:Fearextinctionmechanismsandamygdalamodulation
Single-dosepsilocybinaltersrestingstatefunctionalnetworksinpatientswithbodydysmorphicdisorder
XiZhu,ChenZhang…FranklinSchneier
Readingthecrowd:attitudestowardpsychedelicsandpsychedelictherapiesamongattendeesataconference ZacharyBosshardt,JessicaL.Maples-Keller…RomanPalitsky
CoverArt
Thecoverimageillustratesthepotentialofpsychedelictherapytotransformperceptioninpatientswithanorexianervosa.Inthisartisticrepresentation,vibrantcolorsand patternsemanatefromthesilhouetteofaperson’sprofile,symbolizingtheexpandedconsciousnessandalteredself-perceptionreportedbyparticipantsinthefirstclinical trialofpsilocybintreatmentforanorexia.Whilephysicalappearanceremainedunchangedformostparticipants,manydescribedprofoundinternalshifts—experiencing theirbodiesas“vessels”ratherthandefiningfeaturesofidentity.Thisvisualmetaphorcapturestheessenceofwhatoneparticipantdescribed:“Thingsmightnotlookthat differentfromtheoutside,buttheyfeelcompletelydifferentfromtheinside.”ForfurtherinformationonthistopicpleaseseethepaperbyKnatzPeck etalonpages15–18. Coverdesigncreatedthroughextensiveanditerativehuman-AIcollaborationusingClaudeandGrokAIassistants.ThefinalcoverislicensedunderCreativeCommons Attribution-NonCommercial-NoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thiscovermaybereproducedwithoutpermissionunderthe termsofthislicense, providedappropriatecreditisgiventoGenomicPress,andthecontentisnotmodifiedorusedforcommercialpurposes.
Copyright©2025GenomicPress.Allrightsreserved.
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Psychedelics
OPEN
EDITORIAL
Psychedelics:TheJournalofPsychedelicandPsychoactiveDrugResearch –Charting anewcourseinpsychedelicscience
©TheAuthor(s),underexclusivelicencetoGenomicPress2024
Psychedelics January2025;1(1):1–2;doi: https://doi.org/10.61373/pp024d.0007
Welcomehome!Itiswithgreatpleasurethatwepresenttoyouthefirst editorialof“Psychedelics:TheJournalofPsychedelicandPsychoactive DrugResearch.”Thisisalaborofloveandintellectdesignedtoencapsulatetheswirlingcascadesofresearchdiscoveryinpsychedelics.Atamomentwhenempiricalinvestigationhasbeguntoliftthehazesurroundingtheseextraordinarycompounds,thisjournalwillrapidlybecomethe fulcrumforscholarlyconversation,discourse,andenlightenment.Our ambitisbroadinitssweep,ensconcingthemultidisciplinaryessenceof theresearchinquestion.
Ourendeavorencompassesadazzlingarrayofinquiries,fromthe microscopicfacetsofmolecularinteractionstothemacroscopicsocietal implications.Ourquestisnotmerelyrestrictedtothecircuitouscorridors ofneurosciencebutmeandersthroughbiochemistry,psychology,sociology,andmedicine(1).
Thelevelofinnovationweprovideisenrichedbythecollectivewisdom ofawide-rangingeditorialboard,encompassingglobalinsightsfromnumerousacademicspheres,workingcollaborativelytoadvancethefrontiersofknowledgeinthepsychedelicdomain.Wedrawattentiontoour InnovatorsandIdeas section,focusingonindividualswithsignificant contributionstothefield.Twoofoureditorialboardmembershavealreadycontributedtothisengagingsection:KatarinaLeão(auditoryand limbicsystems)asarisingstar(2)andBernardLerer(psychedelicpsychopharmacology)asaresearchleader(3).
Aswewanttoleanmoreonthetherapeuticpotentialofpsychedelics, itispertinenttoscrutinizeresearchsurroundingserotoninreceptorinteractions(4),neuralplasticity(5),andtherelevanceindisorders,such asposttraumaticstressdisorder(PTSD)(6)andmajordepressivedisorder(7).Studiesthatutilizethetoolsofbrainimagingwillbringabout furtherclarity,givingusafullerandmorenuancedpictureoftheeffects ofpsychedelicsonbrainfunction(8).
Concurrentwithclinicalassessmentsandbio-molecularexplorations aretheanthropologicalendeavorsthatdelveintotheintricatemazeof historicalusageandculturalimplications(9).Atatimewhenpublicopinionaboutpsychedelicsisundergoingaseachange,itisindispensablethat werigorouslyexaminetheirsocietalimpact(10).
Youallknowthisisnotjusta“nice-to-have”:forgingrobustresearch methodsthatcancutacrossmultipledisciplinesisdownrightessential.Themosaicofpsychedelicunderstandingisfragmented,andonlyby assemblingpiecesacrossneuroscience,pharmacodynamics,psychology, sociology,andbeyondcanwefathomthefullportrait(11).
AccordingtothefamedpsychiatristStanislavGrof,psychedelics,used responsiblyandwithpropercaution,wouldbeforpsychiatry,whatthe microscopeisforbiologyandmedicine,orthetelescopeisforastronomy (12).Weareconcertedlybreakingbarrierstoenteranewepochinourunderstandingofthemindandconsciousness.Therefore,inthispanorama ofburgeoningscientificinterest, Psychedelics iscommittedtountangling themanythreadsofpsychedelicscholarship.
Restassured;thisjournalaimsformorethanjuststashingawaydata. Wearelayingthecornerstoneofadynamicshiftinacademicdiscourse.
Received:19January2024.Accepted:23January2024. Publishedonline:25January2024.
Wearenotjustattemptingtocollectsubmissions;wearespecificallylookingforyourmostcherisheddiscoveriesaswebuildauniquenewportfoliothatwillanchorthere-birthofthisfield.Wetremendouslyvalueyour trustinustostewardyourscholarshipasweembarkonthisambitious journey.
Considerthisanopeninvitationifyoushareourfascinationwith theuntappedcomplexityandexpandinghorizonsofpsychedelicstudies. Together,letusshedlightonareasobscuredbymisperception,addour insightstothecollectivereservoirofknowledge,andawakenabroader senseofunderstanding.
Yourinvolvementinthismissionisnotjustwelcome–itiscrucial.The pilgrimagetowarddeeperunderstandingisoneweundertakeasacollective,andthatchapterstartstoday.
Psychedelicshavebeenatopicoffascinationformanyindividuals throughouthistory.Fromancientcivilizationstomodern-dayscientists, theuseofpsychedelicshasbeenasubjectofexplorationandresearch. However,thestudyofthesecompoundshasbeenlargelyrestricteddueto legalandsocialbarriers.Butwiththerecentrenaissanceofpsychedelic researchandagrowingshiftinpublicopinion,thereisnowanopportunity toexplorethefullpotentialofthesecompounds.
Asweembarkonthisjourney,itisimportanttoacknowledgethemultidisciplinarynatureofthisfield.Theuseofpsychedelicshasimplications invariousaspectsofhumanlife,rangingfromthemolecularleveltosocietalimplications.Therefore,ourjournalaimstoencompassthebroad rangeofinquiriessurroundingpsychedelics,frombiochemistryandneurosciencetopsychology,sociology,andmedicine.Oneofthemostpromisingaspectsofpsychedelicresearchisitstherapeuticpotential.Studies haveshownthatpsychedelicscouldbeusefulintreatingavarietyofmentalhealthdisorders,includingPTSD,depression,andanxiety.Theexact mechanismsbywhichthesecompoundsworkarestillbeinginvestigated. However,researchhassuggestedthattheymayinteractwithserotonin receptorsinthebrain,leadingtochangesinneuralplasticityandultimately,improvementsinmoodandcognition.
Butitisnotjustthetherapeuticpotentialofpsychedelicsthatwe aimtoexplore.Anthropologicalstudieshaveshownthattheuseof psychedelicshashistoricalandculturalimplications.Bystudyingtheculturalcontextofpsychedelicuse,wecangainadeeperunderstandingof theimpactthatthesecompoundshavehadonhumansocietythroughout history.
Themosaicofpsychedelicunderstandingisfragmented,andonlyby assemblingpiecesacrossneuroscience,pharmacodynamics,psychology, sociology,andbeyondcanwefathomthefullportrait.Therefore,ourjournaliscommittedtountanglingthemanythreadsofpsychedelicscholarship.Westrivetoprovideaplatformforscholarsfromdiverseacademic backgroundstocollaborateandadvancethefrontiersofknowledgeinthe psychedelicdomain.
Inconclusion,ournewjournalaimstobemorethanjustarepository fordata.Weaimtobeacatalystforadynamicshiftinacademicdiscourse andacornerstonefortherebirthofpsychedelicresearch.Weinviteyouto
joinusonthisjourneyandcontributeyourmostcherisheddiscoveriesto ouruniquenewportfolio.Together,letusshedlightonareasobscuredby misperception,addourinsightstothecollectivereservoirofknowledge, andawakenabroadersenseofunderstanding.Yourinvolvementinthis missionisnotjustwelcome–itiscrucial.Thepilgrimagetowarddeeper understandingisoneweundertakeasacollective,andthatchapterstarts today.
JulioLicinio1
1 Editor-in-Chief,Psychedelics,GenomicPress,NewYork,NewYork10036,USA e-mail: julio.licinio@genomicpress.com
References
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2.LeãoK.Linksbetweentheauditoryandlimbicsystems,withafocusontheeffectsof unconventionalnoveltreatmentoptions,suchaspsychedelicsandcannabisextract. Psychedelics.2024.DOI: 10.61373/pp024k.0001
3.LererB.Pre-clinical,translationalandclinicalresearchfocusedontheuseof psychedelicdrugsandtheirderivativestotreatpsychiatricdisorders.Psychedelics. 2024.DOI: 10.61373/pp024k.0004
4.HalberstadtAL.Recentadvancesintheneuropsychopharmacologyofserotonergic hallucinogens.BehavBrainRes.2015;277:99–120.DOI: 10.1016/j.bbr.2014.07.016 PMC4642895
5.LyC,GrebAC,CameronLP,WongJM,BarraganEV,WilsonPC,etal.PsychedelicsPromoteStructuralandFunctionalNeuralPlasticity.CellRep.2018;23(11):3170–3182. DOI: 10.1016/j.celrep.2018.05.022 PMC6082376
6.MithoeferMC,WagnerMT,MithoeferAT,JeromeL,DoblinR.Thesafetyandefficacyof +/ 3,4-methylenedioxymethamphetamine-assistedpsychotherapyinsubjectswithchronic,treatment-resistantposttraumaticstressdisorder:thefirstrandomizedcontrolledpilotstudy.JPsychopharmacol.2011;25(4):439–452.DOI: 10. 1177/0269881110378371 PMC3122379
7.Carhart-HarrisRL,BolstridgeM,RuckerJ,DayCM,ErritzoeD,KaelenM,etal.Psilocybinwithpsychologicalsupportfortreatment-resistantdepression:anopen-labelfeasibilitystudy.LancetPsychiatry.2016;3(7):619–627.DOI: 10.1016/S2215-0366(16) 30065-7
8.Palhano-FontesF,AndradeKC,TofoliLF,SantosAC,CrippaJA,HallakJE,etal.The psychedelicstateinducedbyayahuascamodulatestheactivityandconnectivityofthe defaultmodenetwork.PloSone.2015;10(2):e0118143.DOI: 10.1371/journal.pone. 0118143 PMC4334486
9.SchaeferSB,FurstPT.Peopleofthepeyote:HuicholIndianhistory,religion&survival. 1sted.Albuquerque:UniversityofNewMexicoPress;1996.xiv,560p.p.
10.TupperKW,WoodE,YensenR,JohnsonMW.Psychedelicmedicine:are-emerging therapeuticparadigm.CMAJ.2015;187(14):1054–1059.DOI: 10.1503/cmaj.141124 PMC4592297
11.RossS,BossisA,GussJ,Agin-LiebesG,MaloneT,CohenB,etal.Rapidandsustained symptomreductionfollowingpsilocybintreatmentforanxietyanddepressioninpatientswithlife-threateningcancer:arandomizedcontrolledtrial.JPsychopharmacol. 2016;30(12):1165-1180.DOI: 10.1177/0269881116675512 PMC5367551
12.GrofS.LSDpsychotherapy.2nded.Alameda,CA:HunterHouse;1994.352p.p.
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Psychedelics
INNOVATORS&IDEAS:RISINGSTAR
NicolasGarel:Combiningpsychoactivemoleculesandpsychotherapyforpatients sufferingfrommoodandsubstanceusedisorders:anewtherapeuticparadigm
©TheAuthor(s),2024.ThisarticleisunderexclusiveandpermanentlicensetoGenomicPress
Psychedelics January2025;1(1):3–5;doi: https://doi.org/10.61373/pp024k.0016
Keywords: Ketamine,serotoninergicpsychedelics,addiction,mood disorders,psychotherapy
DrNicolasGarelisanAssistantProfessorintheDepartmentof PsychiatryandAddictologyattheUniversityofMontrealandajunior investigatorattheResearchCenteroftheCentreHospitalierde l’UniversitédeMontréal.DrGareldidhispsychiatryresidencyat McGillUniversitybeforecompletingtheClinician-Investigator ProgramandaMaster’sdegreeatMcGillUniversity,studyingthe potentialroleofketamineinthediscontinuationofbenzodiazepines andrelateddrugs.DrGarelthencompletedaclinicalfellowshipin AddictionMedicineatStanfordUniversity.Hisresearchprogram focusesontheintegrationofpsychoactivemoleculesinconjunction withpsychotherapyasauniquepotentialtreatmentapproachfor patientswithcomorbidmoodandalcohol/sedativeusedisorders.In this“Innovators&Ideas”section,weareexcitedtofeatureDrGarelin ourlatestGenomicPressInterview.Wearethrilledhetookthetimeto answerourquestionsandsharehisvaluableinsightswithourreaders.
Part1:NicolasGarel–LifeandCareer
Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?
Bothmyparentshavebeenphysiciansdeeplyinvolvedinacademia throughouttheircareers.Myfatherhasalreadyretired,andmymotheris settoretirethisyear.Witnessingtheirpassionandfulfilmentintheirwork hashadaprofoundinfluenceonme.Myfatherwasapaediatricinterventionalradiologistandmymotherisachildpsychiatrist,whonaturally sparkedmyfascinationforpsychiatryfromaveryearlyage.Despitethis longitudinalinterest,Ineededhelptochoosebetweeninternalmedicine andpsychiatry.Iwasacceptedinbothprogramsandultimatelydecidedto pursuepsychiatrytheeveningbeforethedeadlinefordeclaringourmedicalspecialtychoices.Duringmyundergraduatestudiesinpsychologybeforestartingmedicalschool,Ibecameparticularlyinterestedinthefield ofpsychedelicsandthenotionthatasingleexperiencecouldprofoundly andmeaningfullymarkandchangeahumanbeing.Itintriguedmehow difficultitwasforpeopletoacceptthisidea,eventhoughwereadilyacceptthatasingletraumaticexperiencecannegativelychangesomeone’s lifeforever.
Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschannelledyoutowardthis opportunity?
Initially,Ibeganmyresearchjourneyinanautismlaboratory.However,the experiencedidnotmeetmyexpectations,andIfoundmyselflostanddisinterestedinresearch.Thischangedwhenmycolleagueandclosefriend, DrKyleGreenway,whowasaresidentinpsychiatrywithmeatMcGill University,knowingmykeeninterestinpsychedelicsandketamine,invitedmetojoinhimindevelopingthefirstketamineclinicwithinthe McGillUniversityHospitalsnetworkfortreatment-resistantdepression. Iacceptedtheinvitationasasecond-yearresidentinpsychiatry,andI
Received:3June2024.Accepted:7June2024. Publishedonline:14June2024.
havebeendedicatedtostudyingketamineandpsychedelicseversince. IeventuallyenteredtheClinician-InvestigatorProgramatMcGillUniversityandpursuedaMasterofSciencedegreefocusingonthepotentialrole ofketamineindiscontinuingbenzodiazepineandrelateddrugs.During thistime,Ialsoco-ledasuccessfulmultisiterandomizedcontrolledtrial, administeringover180ketaminetreatmentsinapsychedelicmodelto patientswithtreatment-resistantdepression.Thispivotalstudy,recently published,solidifiedmydecisiontopursueacareerasaclinicianscientist.
Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea. Inadditiontorefractorymooddisorders,addictionpsychiatryhas emergedasthedisciplinethatIfindthemostinteresting.Thisledmeto completeapostdoctoralfellowshipinaddictionmedicineatStanfordUniversityin2023.Myinterestinaddictionpsychiatryhasshapedmygoals andambitionsasaclinician,ascholar,ateacher,andanactivecitizenof mysociety.Theinteractionsbetweenthispatient’spopulationcomplexity withsignificantclinicalandsocialdilemmasandateam-basedworkenvironmenthavebothchallengedmeonanintellectualandhumanisticbasisandbuiltmymotivationsforanacademiccareerinaddiction.Patients’ decisiontoseekhelpandtheinterventionsthatwecanproposeserveas auniquewindowofopportunitytoaddresscrucialmodifiableriskfactors andimprovelong-termphysicalandmentalhealthoutcomes.Thevarious clinicalpresentationscombinedwithpatients’self-motivatedbehaviours createfascinatingpatient-physicianinteractions.IamfulfilledwhenI seepatientssucceedinginbecomingtheirhealthadvocatesandbravely takingonthechallengesthatcomefromconfrontingtheirdeleterious
Figure1. NicolasGarel,MD,MSc,FRCPC,UniversityofMontreal,Canada.
substanceusebehaviours.Eachencounterwithapatientsufferingfrom addictionrequiresreflectiontoprovideoptimalcaretoanunderserved population.Addictionpsychiatryappearstobeintheprocessofan impressivefermentofideas,givingrisetosocialadvancesandgreatscientificandhumanisticunderstandings.
Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?
Thecurrenttreatmentgapinindividualswithmooddisordersandcomorbidsubstanceusedisorders(SUD)emphasizestheneedfornew,innovative,andmoreeffectiveinterventions.Theco-occurrenceofthesedisorderssignificantlycompoundstheburdenonindividuals,theirfamilies, andsociety.Theseindividualsoftenexperienceexacerbatedsymptoms, increasedriskofrelapse,reducedtreatmentresponse,andhigherrates ofmorbiditycomparedtothosewitheitherconditionalone.Bydevelopingandstudyingnovelinterventionstargetingthisspecificpopulation, wecanbridgethistreatmentgapandprovidemuch-neededsupportto cliniciansandpatientsoftenoverlooked.
Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.
Myresearchprogramwillfocusontheintegrationofpsychoactive molecules,initiallyketamine,inconjunctionwithpsychotherapyasa uniquepotentialtreatmentapproachforpatientswithcomorbidmood andalcohol/sedativeusedisorders.Theprimaryobjectivesaretoevaluate ketamine-assistedpsychotherapy’ssafety,feasibility,and,ultimately,efficacyonkeyclinicaloutcomes,examinechangesinfunctionaloutcomes andqualityoflife,andexploretheunderlyingneurobiologicalmechanismsinvolvedinthistreatmentapproach.
Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?
Throughoutmyacademicstudiesandpostdoctoralexperiences,Ideeply valuecreatingawarmandwelcomingenvironmentwithinmylab.Ibelieve fosteringaculturewherepeoplesupportandhelpeachotheriscrucial.A positiveandsecureatmosphere,combinedwithastrongsenseofcollaborationandteamspiritoverpersonalgains,significantlyenhancescreativityandgeneratesbetterideasandresearchoutcomes.Thiscollaborative ethosnotonlypromotesindividualgrowthbutalsodrivesthecollective successofourresearchendeavours.
AtGenomicPress,weprioritizefosteringresearchendeavoursbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?
Whatdeeplystirsmypassionisthedrivetohelppatientsandfindwaysto improvethelivesofthosewhosuffer.Myprimarymotivationliesinalleviatingtheburdenofmentalillnessandprovidingeffectivetreatmentsfor individualsbattlingsevereconditionsliketreatment-resistantdepressionandalcoholusedisorder.Thegoalofmyresearchistobringhope andtangibleimprovementstothequalityoflifeforpatientswhostruggledailywithdebilitatingmentalhealthissues.
Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?
OneaspectImostenjoyasanacademicandresearcheristheopportunity toworkalongsidebrilliantindividualswhoconstantlyinspireandchallengeme.Everyday,Iamintellectuallystimulatedbyengagingininnovativeprojects.Havingtheunwaveringsupportofmentorsandcolleagues hasbeeninvaluable.Theirguidanceandencouragementhavehelpedme growprofessionallyandenhancedmycreativityandscientificachievements.Thisdynamicandsupportiveatmospheremakesmyworksofulfillingandexciting.
TheGarelKaminskifamilyduringNicolasGarel’spostdoctoralfellowshipatStanfordUniversity,California,USA.
Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?
Iamamanoffamilyandfriendsandlivemybestmomentssurrounded bythepeopleIlove.Sharingtimewiththembringsmeimmensejoyand fulfilment.Additionally,Iampassionateabouttravelingandbackpacking.Ihavehadtheincredibleopportunitytoexplorediverseregions,includingCentralandSouthAmerica,WesternandEasternEurope,theMiddleEast,andAsia,oftenforextendedperiods.Theseadventureshave broadenedmyhorizonsandenrichedmylifewithunforgettableexperiencesandmemories.Giventhechoice,Iwouldalwayschoosetospend myleisuretimewithlovedonesordiscovernewplacesandcultures.
Part2:NicolasGarel–SelectedquestionsfromtheProust Questionnaire1
Whatisyourideaofperfecthappiness?
Happinessisatransientstate,flowingandebbingthroughourlives.Perfecthappiness,therefore,arisesfromtheawarenessofitspresencein thefirstplace.Weoftentakeforgrantedourblessings,forgettingthe fragilityoflifeandhoweverythingcanchangeinstantly.Thus,perfect happinessisthemindfulstateofcontentment,whereonefullyappreciatesthepresentmomentandthebeautyoflife.Itisaboutrecognizing andcherishingthosefleetingmomentsofjoyandpeaceandunderstandingtheirimpermanence.
1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003,Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,ArthurConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.
Figure2.
Whatisyourgreatestfear?
Mygreatestfearisthatwemightreachapointofnoreturnregarding climatechange,ultimatelylosingtheEarthaswehaveknownit.The prospectofreachingastagewherethereisnohopeofreversingthedamagewearecausingisdeeplyunsettling.
Whichlivingpersondoyoumostadmire?
Iadmiremyparentsmost.TheyimmigratedtoCanadaandraisedfive childrenwithoutthesupportofanyextendedfamily.Theyworkedtirelesslythroughouttheirlivestoprovideuswiththemostoptimalenvironmentpossible.Balancingtheirprofessionalandpersonalresponsibilities, theynevercomplainedaboutanything.Tothisday,theyremainasteadfastpresenceinmysiblings’lives,supportingusthrougheverychallenge weface.Theirresilience,dedication,andunwaveringsupportaremyconstantsourceofinspiration.
Whatisyourgreatestextravagance?
AgoodbottleofJapanesewhisky.
Whatareyoumostproudof?
Iammostproudofbalancingmypersonalandprofessionallife.Achieving thisequilibriumallowsmetoenjoymycareerwhilenurturingmeaningful relationshipsandpersonalfulfilment.
Whatisyourgreatestregret?
Nottohavebeen20yearsoldduringthe1960s.
Whatisthequalityyoumostadmireinpeople?
ThequalityImostadmireinpeopleistheirabilitytothinkaboutothers andshowgenuinecare.Thisselflessnessandempathyreflectadepthof characterandcompassionthatIgenuinelyadmire.
Whatisthetraityoumostdislikeinpeople? Fanaticism.
Whatdoyouconsiderthemostoverratedvirtue? Truevirtue,bydefinition,isnotoverrated.
Whatisyourfavouriteoccupation(oractivity)?
TherearetoomanyactivitiesIenjoyedtolistthemall,withoutdoor activitiesbeingatthetopofthelist.
Wherewouldyoumostliketolive? Inmycity,Montreal,orinSanFrancisco.
Whatisyourmosttreasuredpossession?
MymosttreasuredpossessionisapaintingbyParisianartistMicha Tauber,whichIreceivedduringoneofthemostdifficultperiodsofmylife. Thisartworkholdssignificantsentimentalvalueandservesasareminder ofresilienceandhope.
Whenandwherewereyouhappiest?Andwhywereyousohappythen? Ihavelearnedtofindjoyinlittlethings,butletusbehonest:aweekoff withoute-mails,deadlines,anddutydoeshelp!
Whatisyourcurrentstateofmind? Multicentred,includingmyfamily,myprofession,andthestateofthe world.
Whatisyourmostmarkedcharacteristic? Mymostmarkedcharacteristicisprobablymydeepinterestinothersand thetimeIspendconnectingwiththem.
Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Oneofmykeytalentsthatgivesmeacompetitiveedgeismyabilityto strategizeeffectively.
Whatdoyouconsideryourgreatestachievement? Myeducation.
Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Tobeabettersleeper.
Whatdoyoumostvalueinyourfriends? Generosityandsenseofhumour.
Whoareyourfavouritewriters? BorisVian,RomainGary,NaguibMahfouz,andStefanZweig.
Whoareyourheroesoffiction?
Ihavemany,butHectorfromthe Iliad2 hasalwaysbeenagreatheroto mesinceIwasachild.
Whoareyourheroesinreallife?
Myheroesinreallifearemygrandparents.TheyfoughtagainsttheNazis duringWorldWarIIandlostmanyfamilymembersandfriends.They weremembersoftheFrenchresistanceandcreatedanetwork,“lereseau Garel,”thatsavedthousandsofchildren.Theircourageandresiliencein thefaceofimmensedangerandhardshiphavealwaysbeenaprofound sourceofinspirationforme.
Whataphorismormottobestencapsulatesyourlifephilosophy? “LogicwillgetyoufromAtoB.Imaginationwilltakeyoueverywhere.” AlbertEinstein.
NicolasGarel1
1 UniversitédeMontréal,CHUMResearchCentre,Montreal,QuebecH2X0A9, Canada
e-mail: Nicolas.garel@umontreal.ca
Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.
OpenAccess. ThisarticleislicensedtoGenomicPressundertheCreativeCommonsAttribution-NonCommercial-NoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates:(1)Attribution:Credit mustbegiventotheoriginalwork,withalinktothelicenseandnotificationofany changes.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3)NoDerivatives: Modifiedversionsoftheworkcannotbedistributed.(4)Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthelicense.Public domainmaterialsorthosecoveredbystatutoryexceptionsareexemptfromthese terms.Thislicensedoesnotcoverallpotentialrights,suchaspublicityorprivacy rights,whichmayrestrictmaterialuse.Third-partycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunlessotherwisestated.Ifuseexceeds thelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthe copyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/ licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.
2 InGreekmythology,HectorwasthefirstbornchildofKingPriamandQueenHecuba, therulersofTroy.HewastheforemostchampionoftheTrojanforcesandmarried Andromache.Homer’sepicpoem,the Iliad,portraysHectorastheembodimentofa perfectcombatantandthebackboneoftheTrojandefense.
INNOVATORS&IDEAS:RISINGSTAR
StephanieKnatzPeck:Novelandinnovativetreatmentforeatingdisorders
©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.
Psychedelics January2025;1(1):6–9;doi: https://doi.org/10.61373/pp024k.0031
Keywords: Eatingdisorders,anorexianervosa,psilocybintherapy, psychedelictreatment,psilocybintreatment
Dr.StephanieKnatzPeck,Ph.D.,isapracticingclinicalpsychologist andAssociateClinicalProfessorofPsychiatryattheUniversityof California,SanDiego(UCSD).Hercareeruniquelybridgesclinical practicewithinnovativeresearch,focusingondevelopingand evaluatingnovelpsychiatricinterventions,particularlyforeating disorders.Dr.KnatzPeck’sresearchjourneybeganattheUCSDEating DisorderTreatmentandResearchCenter,wheresheskillfully translatedcomplexneuroimagingandgeneticfindingsintopractical, innovativetreatmentapproachesforanorexianervosa(AN).This workculminatedinthedevelopmentandmanualizationof Temperament-BasedTreatmentwithSupports(TBT-S),a groundbreakingbehavioralinterventionforAN.Inrecentyears, Dr.KnatzPeckhasexpandedherresearchintothepromisingfieldof psychedelic-assistedtherapies.Sheservedasco-investigatoronthe firstclinicaltrialevaluatingpsilocybintreatmentforAN,markinga significantmilestoneineatingdisorderresearch.Additionally,she contributesherexpertiseasaseniorclinicalconsultantforCompass Pathways,wheresheleadstraininginitiativesandplaysacrucialrole indevelopingpsychologicalsupportmodelsforpsilocybintherapy acrossvariouspsychiatricconditions.Beyondheracademicpursuits, Dr.KnatzPeckfoundedanddirectsBrightMindTherapy,anoutpatient practiceprovidingevidence-basedtherapyforchildrenand adolescents.Hercomprehensiveapproachseamlesslyintegrates clinicalpracticewithrigorousresearch,utilizingneuroimagingdata, geneticfindings,andhands-onclinicalobservationstodevelop targetedinterventionsfortreatment-resistantpsychiatricconditions. WeareprivilegedtohaveDr.KnatzPeckshareherinvaluableinsights andexperienceswithourreadersinthisGenomicPressInterview.
Part1:StephanieKnatzPeck–LifeandCareer
Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?
Ihavealwaysbeenfascinatedbyhumans.InanysettingIeverfoundmyselfin,Iwasalwaysmoreinterestedinthepeoplearoundmeandtheir reactionsthanintheactualactivity.Thismakespsychologyanaturalfit forme,albeitittooksometimeformetounderstandthatIcouldturn thiscuriosityforhumansintoacareerinvolvingclinicalhumansubjects research.ItwasnotuntilIhadapersonalmentalhealthexperiencethatI wasabletoturnthisintoapursuitdriveninitiallybypersonalpassion.I, likemanyotherswhohavedevotedtheircareerstoeatingdisordertreatment,recoveredfromaverysevereeatingdisorder.Iconsidermyselfincrediblylucky,and,asapointofself-study,Ioftenreflectonpersonal, social,andotherfactorsthatallowedmetobeoneoftheluckyonesto achieveafullrecoveryfromanillnessthatisoftenchronicanddeadly. WhenIwasinitiallytreated,myparentsvoraciouslyconsumedeverybook outtheretounderstandmoreabouteatingdisordersandwerestunned todiscoverhowwellImatchedupwiththeclassicprofileofthosewho
Received:14October2024.Accepted:16October2024. Publishedonline:21October2024.
tendtodevelopaneatingdisorder.Thisgivesmeagoodchucklesince muchofmycareertothispointhasfocusedondevelopingtemperamentcongruenttreatmentsforthoseinrecovery.
Becauseofthis,Ibegangraduateschoolwiththeaimofbeingapracticingclinicalpsychologist.Myearlytrainingexperiencesworkinginclinicaltreatmentresearchlabshelpedmediscoveraninterestinclinicalresearch,specificallytreatmentdevelopment.Thescientificprocesswasa naturalfitforme,andIunderstandthistobedueinsomeparttosomeof myearlychildhoodexperiencesofbeingbornandraisedasathird-culture kid.Iwasbornandraisedoverseasandlivedinfivedifferentcountriesby thetimeIwasnineyearsold.Iliketobelieve(thoughwecanneverknow) thattheseearlyexperienceshaveaffordedmeanaturalcognitiveflexibility.Asathirdculturekid,Iwasnotfirmlyembeddedinculturalidentityinwaysthat,forothers,areimplicitandunconscious.Iwasalways awareofbeingdifferentsimplybyvirtueofbeingraisedinculturesdifferentfrommyown.Beingextractedfrom thisculturalframeworkallowed metobeconsistentlyawareofhowpeopleandperspectivescandiffer throughoutmylife.Movingbetweenmorethanoneculturealsoallowed metoengageinframeshiftsfluidlyandinhabitdifferentperspectivesas Ihadtoadapttodifferentgroupsofpeople.Iamsogratefulforthese experiences,whichallowedmetounderstandthatIwearalensthrough whichIseethingsandtonottakeanyofmyperspectivesasabsolute
Figure1. StephanieKnatzPeck,PhD,UniversityofCalifornia,SanDiego,USA.
truth-anearlyformofpersonalscientificpluralism!Ialsocametounderstandthroughtheseexperiencesthatourlensgaveimportantstructuretomakesenseoftheworldbutwasalsolimitingourabilitytosee thewholetruth.Fromherecamemyfascinationwithaccessingwaysto “undo”or“remove”thatlens,whichledtoanongoingfascinationwith alteredstatesofconsciousness.
Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?
Becauseofmypersonalexperiencewithrecoveringfromasevereeating disorderasatransition-agedyouth,becominginvolvedinthissubfield wasafocalpointofminethroughoutmytraining.Iwasluckyenoughto haveaworldclasseatingdisordercenterinmybackyardattheUniversity ofCalifornia,SanDiego(UCSD)EatingDisorderTreatmentandResearch Center,whichisnowoneofthelargestacademictreatmentcentersinthe USandaprolificneuroimaginglaboratoryresponsibleformanyofthemajorcontributionselucidatingthebiologicalbasisofeatingdisorders.
MyfirstresearchexperiencewasworkinginanotherUCSDlabthat developedandtestednoveltreatmentsforpediatricobesityanddisinhibitedeatingwithamentorwhowastrulyexceptionalinhercreativity.Thisinspiredmebecauseitallowedmetodiscoverthecreative elementsofclinicaltreatmentresearch,whichmakesmetick.Inmypredoctoralinternshipandpostdoctoralfellowship,Iwasexposedtoclinical treatmentresearchandworkedondeveloping,manualizing,anddeliveringnoveltreatmentapproaches.Ireallyenjoyedthecreativityassociated withtranslatingnewresearchfindingsintoclinicalmodelsofcare.This researchnichesuitedmebest,inadditiontoworkingdirectlywithparticipantstoseehowthesetreatmentscamealiveandtocollaboratewith theseexpertsthroughlivedexperiencetorefineanddevelopsomething trulynewandvaluable.
IcontinuedpursuingthisnicheasIprogressedthroughmytraining attheUCSDEatingDisorderCenter.Luckily,myfantasticmentor,Walter Kaye,recognizedmydesireandabilitiesforthistypeofworkandcarved outauniquepathwayforthistobemyfocus.Ireceivedsomeprivategrant fundingfromtheGlobalFoundationforEatingDisorderstotranslateneuroimagingfindingsintotreatmentapproachesforEDs.Thisspurreda pathwayformetoworkondevelopingandtestingnovelinterventions intheclinicalprogramthatIdirected.Theculminationofthisworkis Temperament-BasedTreatmentwithSupports(TBT-S),whichisanovel behavioraltreatmentapproachforanorexianervosa.Myco-developers andIpublishedatreatmentmanualin2022andcontinuetotrainpeople worldwide.Morebroadly,myinteresthasalwaysbeentofindanddevelop newandbetterwaystotreatchroniceatingdisorders.Thenextsteptowardsthiswastheopportunitytogetinvolvedwithpsychedelics,which wasalifelongpersonalinterestofmineandadreamcometrueforsomeonewhowasalwaysfascinatedwiththesubconscious.
Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea. Mycurrentfavoriteresearchtopicispsychedelictreatmentsformental healthconditions.Ihavealwayshadafascinationwithmindstatesand consciousness.Beforeanyformalstudyofthis,Iwasunwittinglyengaginginself-studyandexplorationbyfindingsubtlewaystomanipulatemy consciousness.Asayoungchild,Ilovedplayingwiththeoccult,andby highschool,Iwaspracticingbreath-holding/restrictiontechniques,takingcoldshowers,andmonitoringandrecordingdreams.Inretrospect,it isclearthatIwasinterestedinfindingaccesstoalternativemindstates, andthiswasmywayofexperimentingwiththat.Throughoutcollegeand myearlyyoungadulthood,Ifoundthisthroughdanceasanotherwayto kickoutofourtypicalwaysofoperating.Intheirorigin,dancemusicand dancespacesweresafehavensforpeopletoexpressthemselvesfreely. Toolsthatmaybringoutthisability,likepsychedelics,areoftenused.This wasmyfirstintroductiontopsychedelicsifIambeingradicallygenuine, andwhatpropelledmetograbattheopportunitiesthatcamebeforeme astheresurgenceofpsychedelictreatmentbegan.WhenIdiscoveredthat
psilocybintreatmentresearchwasoccurringatUCSD,Iwasdeterminedto getinvolvedanddidsoquickly.
Onaprofessionalnote,Ihadspentyearsworkinginclinicalsettings delivering“evidence-basedtreatments”tothosewitheatingdisorders, amongstothermentalillnesses,andoftentothosewhowerehighly "treatment-resistant."ItwasclearthatwhatIwasdeliveringsimplywas notgoodenough.Iwasalsostruckbythesecondaryeffectsoftreatment nonresponsiveness,whichfeltsodeleterious.Whenpeopletrytheirbest toengageinavailableoptionstonoavail,ironically,thiscanoftenenhancefeelingsofintensehopelessness,mayresultinnegativetherapeuticexperiences,andcanleaveaninternalizedsenseoffailure.Thatfelt unacceptabletome,anditmadenosensetokeepdirectingpeopletodo thesamethingsoverandover,whichisoftenthepathpeoplearedirected totakeinmentalhealth.Forme,thestudyofpsychedelicsrepresentsa commitmenttoevaluatingnewmodelsofcare.
Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?
Myhopeistosupportthecausetofindbettertreatmentsforthosesufferingfromtreatment-resistantmentalhealthconditions,especiallyeating disorders.Ialsohopetocontributetothedevelopmentandimplementationofhigh-qualitystandardsforpsychedelicpsychotherapyandadjunctivepsychologicalsupport.Idelivertrainingandmentorshiptoclinicaltrialtherapistsrelatedtodrug-adjunctivetherapeuticsupport.Ihave workedwithCompassPathwaystodevelopanddeliverpsychologicalsupportmodelsforpsilocybin.
Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?
Iwassopleasedtohavecomeintotheopportunitytoformallyevaluate psilocybintreatmentforanorexianervosaafterreceivingfundingfrom CompassPathways.Oursmallphase1trialwasthefirsteverpublished clinicaltrialevaluatingapsychedelicdrugforeatingdisorders.Fromhere thehopeistocontinuetocontributetothestudyandevaluationofnew formsofdrugtherapyandnovelmodelsofpsychotherapyforeatingdisorders.Iwasinvolvedindeliveringcareandadaptingatreatmentmodel forCompass’sPhase2btrialforAN.Ihopetocontinuethatpathwayto learnwhetherthesetreatmentsmaymakeamarkeddifferenceinasubsetofpeopleindesperateneed.Inthemeantime,Ialsocontinuetotrain anddeliverTemperament-basedTreatmentwithSupports(TBT-S),which isabehavioraltreatmentthatIco-developedforthosewithAN.Itsnovel featuresincludedeliveringamoreintensiveoutpatientmodelofcare (40hoursoftreatmentoverfivedaysversusstandardweeklyoutpatient therapy),includingsupportpersonsacrosstheagespectrum,andworking withthespecifictemperamentprofileofthosewithAN.Iamproudtosay thatthistreatmenthasbeendisseminatedthroughoutmanycountriesin theworldandisbeingusedinhospitalandoutpatientsettingsinvarious countries.MycolleagueandpartnerKristinStedaliscurrentlyengaged inarandomizedcontrolledtrialtoevaluateTBT-Sforadultswithsevere anorexiaasastep-downfrominpatienthospitalsettings.
Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?
IamsoluckytohavehadexceptionalmentorshipinWalterKaye.Mymentoralwayssaid,“Perfectionistheenemyofthegood"and“Itdoesnot needtobeperfect;itneedstobedone.”Mybiggestproductivityhack islettinggoofperfectionismandengaginginnon-evaluativeflow.Ido bestatthisveryearlyinthemorningbeforemyday-to-dayresponsibilitiescompeteformyattention.
Iamfortunatethatmymentoralsolivedbyfoundationalprinciples ofscience.Whilelearningmorespecificskillsforsciencethroughexperience,Ialsoabsorbedfoundationalprinciplesofsciencemodeled bymymentor,particularlylogos.Therewasmuchun-boundariesopenmindednesstonewideasondisplay,alongwithacommitmenttoletting sciencedetermineyouropinion,notviceversa.
AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethat deeplystirsyourpassions?
Pertheabove,inourcurrentsocioculturalcontext,thereneedstobea greateremphasisonexplicitteachingandmentorshiponfoundational principlesofempiricismandsciencealongsidethemorespecificandmaterialexperiencesinscientificresearchthatmostgettrainedandlearn through.Questionsthatfeelcurrenttomeare:Howdoyourecognizeyour ownbias,whichnoneofusareimmuneto?Howcanyouengageincivil discourseandunderstandthatscientificpluralismgetsusclosertothe truth?Howdoyouengageintopicswithlogosversusethosandensure thatinterestsdon’tconverttozealousness?Scientificthinkingisadisciplinethatrequireseffort.
Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?
Ireallyenjoymentorshipandleadingbyexample.Again,becauseIwas luckytohaveexcellentmentors,itfeelsessentialformetomakeacontributionbysettingagoodexampleandleadingthroughtheprinciples describedabove.Ialsoenjoyhavingmyexpectationsandbeliefsconsistentlyviolatedandbeingprovedwrongbecause,forme,thisissimplyan indicationthatIamlearningandgrowing.
Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?
Icontinuetolovedancinginthecommunity,andIlovebeingoutside,especiallyatthebeachsurfingandswimming.Iamluckytohaveaccessto allofthesethingsinSanDiego.IfIamnotinteractingwithpeople,Iam definitelylisteningtomusicalongsidealmosteveryotheractivityIam engagedwith!
Part2:StephanieKnatzPeck–SelectedquestionsfromtheProust Questionnaire1
Whatisyourideaofperfecthappiness?
Knowingandlovingmyselffully,andtrustingothers.
Whatisyourgreatestfear?
Deathofmylovedones.Ihaveneverreallylostanyoneveryclosetome, andIhavebothfearandfascinationabouthowIwillexperiencethat.
Whichlivingpersondoyoumostadmire?
Mydaughterismygreatestteacher(see Figure2).Seeingtheworld throughachild’seyesfeelslikeanotherstepclosertoseeingthetruth outsideofourconditioning.Thatismyclichéanswer.Myotheransweris certaincurrentfemalemusicalartists—ChappellRoanandQveenHerby,
1 Inthelatenineteenthcentury,variousquestionnaireswereapopulardiversion designedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.In2003Proust’shandwrittenanswerswereauctioned offfor$130,000.Multipleotherhistoricalandcontemporaryfigureshaveanswered theProustQuestionnaire,includingamongothersKarlMarx,OscarWilde,ArthurConanDoyle,FernandoPessoa,StéphaneMallarmé,PaulCézanne,VladimirNabokov, KazuoIshiguro,CatherineDeneuve,SophiaLoren,GinaLollobrigida,GloriaSteinem, Pelé,Valentino,YokoOno,EltonJohn,MartinScorsese,PedroAlmodóvar,Richard Branson,JimmyCarter,DavidChang,SpikeLee,HughJackman,andZendaya.The ProustQuestionnaireisoftenusedtointerviewcelebrities:theideaisthatbyansweringthesequestions,anindividualwillrevealhisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthenumberofquestionsandslightly rewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinner world,rangingfromnotionsofhappinessandfeartoaspirationsandinspirations.
Figure2. StephanieKnatzPeckandherdaughterlookingforseacreaturesat thetidepoolsneartheirhomeinsouthernCalifornia.
tonameafew—whoaresoboldandunapologeticabouttheirfemininity,almosttothepointofaudacity.Ireallylovetoseeatrulyembodied femalewhoisn’tabidingbyinhibition.
Whatisyourgreatestextravagance?
Clothing,costume,andfashion.Choosingclothingdeliberatelyisalsoan expressionofself-careandself-love.Asahobby,Isubtlymanipulatemy identitythroughclothes,andIamalwaysintouchwiththesenseofbeing inadailycostume.Ialsoloveanychancetodesignandwearacostume. Rightnow,Iamworkingonthreeofthem,oneofwhichishighlyconceptualandcomesalongsideavisionboardandawrittencommentarybecauseIamsonerdy!LastyearforHalloween,Ispentabout25hoursgluingthousandsofdotsindistinctivepatternsonapieceofclothingsoI couldbetheartistYayoiKusamabecause,inherwords,"Dotsaretheway toinfinity.”
Whatareyoumostproudof?
IamproudthatImaintainafulfillinglifewithmanyotherinterestsand activitiesoutsideofmyprofessionalidentity.
Whatisyourgreatestregret?
Iamhighlyagreeablebynatureandliketogoalongwiththings.ButI alsorecognizethatIadvocatedformyselfandwentoutofmywaytoget somethinginmanyofthepivotalmoments.Sometimes,Iwonderifthere weremissedopportunitiesformoreofthissinceitisonlysometimesin mynaturetograbatthingsthatdonotcomenaturally,thoughIamdeeply gratefulforthisability.ThistensionissomethingIoftenthinkabout.
Whatisthequalityyoumostadmireinpeople? Currently,Iamappreciatingstoicism.
Whatisthetraityoumostdislikeinpeople? Loquaciousness.
Whatdoyouconsiderthemostoverratedvirtue? Modesty.
Whatisyourfavoriteoccupation(oractivity)?
Myfriendsknowthisaboutme,butmyretirementplanistowaitressat averyhigh-endrestaurant.OthercareersthatcometomindthatIthinkI wouldhaveenjoyedandthrivedinarejournalismandpublicrelations.
Wherewouldyoumostliketolive?
InSanDiego,whereIcurrentlydo!Basedonmychildhood,Ihavethought aboutthisalotassomeonewithaningrainedfeelingofneedingtomove. Iamreallyrelishingfeelingaculturalidentity,beingdeeplyembedded inthecommunity,andmarvelingatmydaughtergrowingupwiththese thingsthatIdidnot!
Whatisyourmosttreasuredpossession? Mypassport.
Whenandwherewereyouhappiest?Andwhyweresohappythen? IamnowthehappiestIhaveeverbeen.Ihopethisforwardtrajectory continuesasIgetolderandwiser.
Whatisyourcurrentstateofmind? Atouchofhypomania.
Whatisyourmostmarkedcharacteristic? Flexibility:mygreatestassetandgreatestweakness.
Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Creativity.
Whatdoyouconsideryourgreatestachievement?
Maintainingafulllifeandidentityoutsideofmyprofessionalonewhile stillbeinginvestedandsuccessfulinmycareer.
Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Iwouldlovetohavegreatersustainedattention.
Whatdoyoumostvalueinyourfriends? Genuineness.
Whoareyourfavoritewriters? RoaldDahlandGeorgeSaunders. Whoareyourheroesoffiction? WinniethePooh,thoughImostidentifywithTigger.
Whoareyourheroesinreallife?
Alltheintellectualswhoarecurrentlyfreelysharingdiverseperspectives andopinions,withlogosandrespect,evenwhentheyareunpopularand againstthecurrentzeitgeist.
Whataphorismormottobestencapsulatesyourlifephilosophy? Donothing,andallwillbewell.Thisgoesbacktomyintuitivenature, whichallowsmetomovethroughlifewithmoreflowthanforce.
StephanieKnatzPeck,PhD1 1 UniversityofCalifornia,SanDiego,SchoolofMedicine,SanDiego,CA92121 e-mail: sknatz@health.ucsd.edu
Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.
OpenAccess. The“GenomicPressInterview”frameworkiscopyrightedtoGenomicPress.Theinterviewee’sresponsesarelicensedtoGenomicPressundertheCreativeCommonsAttribution-NonCommercialNoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates: (1)Attribution:Creditmustbegiventotheoriginalwork,withalinktothelicense andnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3)NoDerivatives:Modifiedversionsoftheworkcannotbedistributed.(4) Noadditionallegalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthelicense.Publicdomainmaterialsorthosecoveredbystatutoryexceptionsareexemptfromtheseterms.Thislicensedoesnotcoverallpotential rights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Thirdpartycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunless otherwisestated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmustbeobtainedfromthecopyrightholder.Forcompletelicensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithoutwarranties.
Psychedelics
INNOVATORS&IDEAS:RESEARCHLEADER
BernardLerer:Pre-clinical,translationalandclinicalresearchfocusedontheuseof psychedelicdrugsandtheirderivativestotreatpsychiatricdisorders
©TheAuthor(s),underexclusivelicencetoGenomicPress2024
Psychedelics January2025;1(1):10–12;doi: https://doi.org/10.61373/pp024k.0004
Keywords: psychedelics,psilocybin,obsessive-compulsivedisorder, psychiatricdisorders,brain
ProfessorBernardLererisintheFacultyofMedicine,Hebrew University,Jerusalem,Israel,whereheisDirectortheCenterfor PsychedelicResearch(https://cfpr.brainlabs.org.il/)atHadassah MedicalCenter,inJerusalem.TheCenterhasagrowingstaffthat includesseniorscientists,post-docs,Ph.D.andgraduatestudents, technicians,andpsychiatristsundergoingresearchtraining.Their researchispreclinical,translational,andclinicalandfocusesonthe useofpsychedelicdrugsandtheirderivativestotreatpsychiatric disorders.Previously,hewasHeadoftheBiologicalPsychiatryUnitat HadassahMedicalCenterfor30years,withresearchandclinical responsibilities.AconversationwithProfessorLerercoveredtopics onhislifeandcareer.
TheGenomicPressInterviewPart1:BernardLerer:Lifeandcareer Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?
IwasborninSouthAfricaduringtheapartheideraandgrewupina middle-class,JewishfamilynearthebeautifulcityofCapeTown.Atschool Iexcelledinlanguages,literature,andsportsratherthanscience.Iwent tomedicalschoolstraightfromhighschoolandwasadoctorat23years ofage.AftermovingtoIsraelwithmywife,Ziona,Istartedaresidency ininternalmedicineandthenmovedtopsychiatry.Thepivotalmoment thatkindledmypassionforsciencewaswhen,asadisillusioned,psychoanalysttobe,Idiscoveredbiologicalpsychiatryinthelate1970s.This wasduringaremarkableseriesofseminarsgiventothepsychiatryresidentsatHadassahMedicalCenterbytherenownedHermanVanPraag, thenonsabbaticalinourdepartment.Ihadneverbeencompletelysure thatIwantedtobeadoctor,aninternistorapsychiatrist;VanPraag’s seminarsopenedanentirelynewdirectionforme—understandingthe workingsofthemind,anditsmaladies,throughbiology.IknewimmediatelythatthiswasthedirectionIwantedtogo.Itwasnotanepiphany, moreanintellectualrealizationthattherewasanentireworldwaiting forme.
Wearewouldliketoknowmoreaboutyourcareertrajectoryleading uptoyourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?
Myleadershiproleinbiologicalpsychiatrybeganin1985whenItook overasHeadoftheResearchLaboratoryatHerzog(thenEzrathNashim) HospitalinJerusalem.EzrathNashimwasthefirstfullyfledgedresearch facilityinIsraeldevotedtobiologicalpsychiatryandpsychopharmacology.ItwasapioneeringeffortfoundedbyElliotGershonandexpanded anddevelopedundertheleadershipofmyresearchmentor,Robert(Haim) Belmaker.In1985,Ihadjustreturnedfromapost-doctoralfellowship withmyotheresteemedmentor,SamuelGershon,atLafayetteClinicin Detroit.HaimBelmakerleftforanextendedsabbaticalandItookover asHeadoftheLaboratorywhichInurturedanddevelopedfor5years.In
Received:11January2024.Accepted:12January2024. Publishedonline:25January2024.
1990,IacceptedaninvitationfromHadassahMedicalCentertorejointhe DepartmentofPsychiatryasDirectorofanewlyfoundedBiologicalPsychiatryUnit.Inthe30yearsthatfollowed,IledtheBiologicalPsychiatry LaboratoryatHadassahMedicalCenteruntilIhandedthereinsovertomy protégé,DrAmitLotan,in2021.Ithenfoundedaresearchgroupdevoted topsychedelicresearchwhichhassinceexpandedintotheHadassah BrainLabsCenterforPsychedelicResearch(https://cfpr.brainlabs.org.il/)
Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteareaofresearchorprofessionalfocus ImentionedHermanVanPraag’sseminarsatHadassahinthelate1970s. Theywerehighlysystematic,focusingontheroleofserotonininaffective disorders,definingabiologicalsubtypeofdepressionwhichVanPraag called“VitalDepression”andoutliningthecareful,systematicresearch performedbyhisgroupandothersindepressedpatientstoassemble proofoftheserotonergichypothesis.IthenwentontoworkwithBelmakerandtheremarkablegroupheassembledatEzrathNashimand learnedhowtoconductbothpreclinicalandclinicalresearchandmost important,howtocombinethetwomodalities.Theapproachwastranslational,longbeforethetermwasinvented.Duringmytwoyearswith SamGershoninDetroitIexpandedanddevelopedthisapproachunder
Figure1. BernardLerer,MD,HadassahMedicalCenter–HebrewUniversityof Jerusalem,Israel.
hisguidance.AffectivedisordershavealwaysbeenacentralfocusbutI havebeenintriguedbyschizophreniasincemyresidencywithOCDnotfar behind.InthelastfewyearsIhavedevotedmyeffortstotheapplication ofpsychedeliccompoundstothetreatmentofthesedisorders.
Whatkindofimpactdoyouhopetoachieveinyourfieldthroughyour focusonyourspecificresearchtopics?
ItmaysoundsimplisticbutwhatIhavealwayswantedtodoistounderstandthebiologyofthedisordersIstudy(affectivedisordersand schizophreniainparticular)inordertousethisunderstandingasaplatformfordevelopingnewandmoreeffectivetreatments.Forseveralyears, IthoughtthatECTcouldholdthekeytothisunderstandingandthiswas theimpetusforagreatdealofpreclinicalandclinicalresearch.Ithen shiftedmyfocustogeneticsinthehopeofuncoveringdruggablemechanismsbyidentifyinggenesimplicatedintheetiologyofthedisordersI wasstudying.Inrecentyears,myapproachhasbecomemuchmoredirect; IworkonpsychedelicdrugsthatareknowntohaveimportanttherapeuticpotentialandIlookfornovelvariantsandtreatmentcombinations. Changingfocus,asIhavedonemorethanonce,meanslearningalotof newinformationandskills.It’sbeenachallengebutitkeepsupmyhopes thateventuallyIwillfindwhatIamlookingfor.
Couldyoutellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?
Myfocalpointsarecurrentlymuchmoreclearlydefinedthantheyhave everbeen.Withmycolleagues,Istudythepharmacologyofclassical psychedeliccompoundsandtrytounderstandkeytherapeuticmechanisms.Iamveryinterestedinnaturallyderivedpsychedelics,specifically mushroomextracts,andtheroleofadditionalcomponentsbesidespsilocybinintheirtherapeuticeffects.Wedothisworkprimarilyinmousemodelsbutarereadytomovetohumanstudieswhenthisisindicated.Iwork withmedicinalchemiststosynthesizenewchemicalentitiesthatembody ourfindingsandalsoconsidernoveldrugcombinationsthatcanbetested inpatientsinproof-of-conceptstudies.
Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiences,thatyouupholdwithinyour ownresearchenvironment?
IlearnedsystematicthinkingfromHermanVanPraag.Ilearnedtoconnect ideasfromdifferentdomainsfromHaimBelmaker.SamGershontaught metodaretodomorethanseemsfeasibleordoable.Ihavetriedtocombinealltheseapproachesandstampthemwithmyownpersonalbrand. MystudentsaretheoneswhocansaywhetherIhavesucceededornot.
AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatyouthinkwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?
Irealizethatpsychiatricdisordersarestronglycoloredbytheculturalmilieuinwhichtheymanifest.Delusionsdifferbetweencountriesandsocietiesandthemostprominentfeaturesofdepressive,manicandpsychotic episodesmayvarygreatly.YetIamalwaysstruckbythesimilarities.Ihave seenpatientsonseveralcontinentsandthecoreclinicalmanifestations aretomyeyesastonishinglysimilar.Thisdoesnotsurprisemebecauseof theapproachthatunderliesmyresearch,thatthebasicbiologyhasvery muchincommon.
Whatdoyoumostenjoyinyourcapacityasanacademicand researchleader?
WhatIenjoymostisworkingwithstudents.Iamastonishedathowsmart manyofthemare,howinsightful,howmanynewideastheyhaveandhow muchtheyareabletoaccomplishinashortspaceoftime.Iamastep aheadofthembecauseoftheknowledgeIhaveacquiredandthevastexperienceIhavegathered,butthatisonlytemporary.Iviewtheknowledge andexperienceIhaveacquiredasadepositthatIneedtotransfertomy studentssothattheycanbringtofruitionideasthatneverfailtoamaze
me.It’swhyIhavenotretiredandwillnotretireaslongasIcanimpart somethingofvaluetomystudents.
Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?
Myabsolutelypreferredleisureactivityisspendingtimewithmyfamily. ZionaandIhavethreechildren,twochildren-in-law,andsevengrandchildren.Weliveclosetothemandspendagreatdealoftimetogetheron weekendsandontripsandvacations.Itrytotakeofftimefromworkto exerciseseveraltimesaweekwhethercycling,walking,orinourhome gym.Iquitrunningmarathonsbutstillparticipatefromtimetotimein offroadcyclingevents.IenjoyreadingandacontrolleddietofpopularTV serieswhenIwanttorelaxintheevening.
TheGenomicPressInterviewPart2:BernardLerer:Selectedquestions fromtheProustQuestionnaire1
Whatisyourideaofperfecthappiness?
Knowingthatmywife,children,andgrandchildrenarehealthy,happy,and fulfilled.
Whatisyourgreatestfear?
Severeimpairment—cognitive,physical,orboth.
Whichlivingpersondoyoumostadmire? Iadmiredifferentpeoplefordifferentreasons.
Whatisyourgreatestextravagance? Travel.Fortunately,it’sapassionIsharewithmywife.
Whatareyoumostproudof? Myfamily.
Whatisyourgreatestregret? Ihavemanybuttheydon’tkeepmeupatnight.
Whatisthequalityyoumostadmireinpeople? Kindnessandconsiderationofothers.
Whatdoyouconsiderthemostoverratedvirtue? Idon’tthinkavirtuecanbeoverrated.
Whatisyourfavoriteoccupation? Doingresearch.
Wherewouldyoumostliketolive? Temporarily—nexttoabeautifulbeachwithperfectweather. Permanently—whereIlivenow—nearJerusalem,Israel.
Whatisyourmosttreasuredpossession?
Myhousecouldburndownandifmyfamilyemergesafely,Iwouldbe happy.ThereisnopossessionthatIwouldspecificallymourn.
1 Inthelate19thcenturyvariousquestionnaireswereapopulardiversiondesigned todiscovernewthingsaboutoldfriends.Whatisnowknownasthe35-question ProustQuestionnairebecamefamousafterMarcelProust’sanswerstothesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice, atages14and20.MultipleotherhistoricalandcontemporaryfigureshaveansweredtheProustQuestionnaire,suchasOscarWilde,KarlMarx,ArthurConanDoyle, StéphaneMallarmé,PaulCézanne,MartinBoucher,HughJackman,DavidBowie,and Zendaya.TheProustQuestionnaireisoftenusedtointerviewcelebrities:theideais thatbyansweringthesequestionsanindividualwillrevealhisorhertruenature. WehavecondensedtheProustQuestionnairebyreducingthenumberofquestions andslightlyrewordingsome.Thesecuratedquestionsprovideinsightsintotheindividual’sinnerworld,rangingfromnotionsofhappinessandfeartoaspirationsand inspirations.
Whenandwherewereyouhappiest?Andwhyweresohappythen? Iwasveryhappyinhighschoolbecauseofthenever-endingcombination ofsocialactivities,sport,andstudiesthatIreallyenjoyed;buttherehave beenmanyotherveryhappyperiodsincludingrightnow(inspiteofthe challengesofgrowingolder).
Whatisyourmostmarkedcharacteristic? Notformetosay.
Amongyourtalents,whichonedoyouthinkgivesyoua competitiveedge?
Ihavelearnedtomakeconnectionswhereothersdonotseethemandto makebolddecisionsquickly.Mylanguageskills,datingfromhighschool, havebeenaverygreatadvantage.
Whatisapersonality/characteristictraityouwishyouhad? Beingabletounderstandwhatpeopleactuallywant.
Whatdoyouconsideryourgreatestachievement?
Bringingupafamilywiththekindofvaluesmychildrenhave,whichIsee themactivelyimpartingtotheirchildren.
Whatdoyoumostvalueinyourfriends? Commitment.
Whoareyourfavoritewriters?
JohnLeCarreandPatConroy.
Whoareyourheroesoffiction?
GeorgeSmiley,JohnLeCarre’santihero.
Whoareyourheroesinreallife? Peoplewhoselflesslystriveforthesafetyandhappinessofotherseven attheirownrisk.
Whataphorismormottobestencapsulatesyourlifephilosophy? Neverstopdoing.
BernardLerer1 1 HadassahMedicalCenter,HebrewUniversity,Jerusalem91120,Israel
e-mail: lerer@mail.huji.ac.il
Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.
OpenAccess. ThisarticleislicensedundertheCreativeCommons Attribution-NonCommercial-NoDerivatives4.0InternationalLicense (CCBY-NC-ND4.0).Thelicensemandates:(1)Attribution:Creditmustbegiventothe originalwork,withalinktothelicenseandnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerial cannotbeusedforcommercialpurposes.(3)NoDerivatives:Modifiedversionsofthe workcannotbedistributed.(4)Noadditionallegalortechnologicalrestrictionsmay beappliedbeyondthosestipulatedinthelicense.Publicdomainmaterialsorthose coveredbystatutoryexceptionsareexemptfromtheseterms.Thislicensedoesnot coverallpotentialrights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Third-partycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunlessotherwisestated.Ifuseexceedsthelicensescopeorstatutory regulation,permissionmustbeobtainedfromthecopyrightholder.Forcomplete licensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.The licenseisprovidedwithoutwarranties.
COMMENTARY
Peripheralsignals,centralquestions:Examiningtherelationshipbetween psychedelicsandbrain-derivedneurotrophicfactor(BDNF)
©TheAuthor(s),underexclusivelicencetoGenomicPress2024
Psychedelics January2025;1(1):13–14;doi: https://doi.org/10.61373/pp024c.0013
Keywords: brain-derivedneurotrophicfactor(BDNF),psychedelics, depression,dimethyltryptamine(DMT),meta-analysis
Whatarethemechanismsthroughwhichpsychedelicsmayexert therapeuticeffectsinpsychiatricdisorders?Therearetwo approachestoansweringthisquestion:firstistheidentificationof novelpathways.Additionally,itwouldbeofinteresttodeterminethe effectsofpsychedelicsonmechanismsthatalreadyappearto underlietheneurobiologyandtherapeuticsofpsychiatricdisorders. ThiscommentaryhighlightsarecentarticlebyShafieeetal.(1)that reportedameta-analysisoftheeffectofpsychedelicsonthe peripherallevelsofbrain-derivedneurotrophicfactor(BDNF).
Certainbreakthroughshavesucceededinsparkingseismicshiftsinour understandingandapproachtotherapy.Fromthediscoveryofantibiotics totheadventofanesthesia,eachmilestonehasreshapedtheboundaries ofmedicineandwhatwearecapableof.Theresurgenceofpsychedelics intreatingandpreventingpsychiatricdisordersmayrepresentanother suchtransformativemoment.
Althoughthecounterculturemovementsofthe1960screateda shadowofstigmaandprohibitionaroundpsychedelicsthathaslasted fordecades,researchinrecentyearshasrevealedtheirtruetherapeuticpotential,changingpublicopiniononthesesubstances.Indeed,ifthe firstantibioticcamefromafungus(genus Penicillium),whycannotother medicinesalsocomefromfungi?
Psilocybin,foundprimarilyinthemushroomgenus Psilocybe,isjust oneofthemanypsychedelicdrugsbeingresearchedtoday.Othersincludelysergicaciddiethylamide(LSD),dimethyltryptamine(DMT),3,4methylenedioxymethamphetamine(MDMA),mescaline,andayahuasca. Allthesesubstanceshavebeenshowntoalterconsciousnessbyinteractingwithserotoninreceptorsinthebrain.Nevertheless,themolecularmechanismsunderlyingtheirtherapeuticefficacyremaintobefully understood.Sincealterationsinbrain-derivedneurotrophicfactorhave beenobservedinvariousneuropsychiatricdisordersaswellasinantidepressanttreatment,therelationshipbetweenpsychedelicsandBDNFhas becomeapromisingtopicofresearch.
BDNFisthemostabundantproteinwithinthenervegrowthfactor (NGF)family,whichencompassesNGFitself,alongwithneurotrophin-3 andneurotrophin-4(2).Initiallyrecognizedfortheirindispensableroles inregulatingtheproliferation,movement,development,andsurvivalof cells,neurotrophinscontinuetobeexpressedinthematurebrain,playing acrucialpartinmaintainingsynapticflexibilityandtheoverallfunctionalityandlongevityofneurons(3).
Depressionisassociatedwithstructuralchangesinthebrain,includingneuronshrinkageandreducedconnectivityincriticalareaslikethe hippocampus.Thisdisruptionisacrucialfactorindepressivesymptoms, andantidepressanttreatmentscancounteracttheseeffects.BDNF,apeptidevitalformaintainingandformingsynapticconnections,iscentral tothisrecoveryprocess.Studiesindicatethatstressanddepressioncan lowerBDNFlevelsinthebrain,exacerbatingthecondition.However,antidepressanttreatments,especiallyrapid-actingoneslikeketamine,can
Received:8April2024.Accepted:9April2024. Publishedonline:10April2024.
quicklyelevateBDNFlevels,facilitatingrapidimprovementsinmood andcognitivefunction.Thiscontrastswithtraditionalantidepressants, whichgraduallyincreaseBDNFoverweeksormonths.Thesignificance ofBDNFinthebrain’sresponsetoantidepressantsunderscoresitspotentiallypivotalroleindepression.ByboostingBDNF,treatmentscanreversethedetrimentaleffectsofstressanddepressiononthebrain,offeringapathtorecovery.Additionally,theinterplaybetweenBDNFandother growthfactors,likeVEGF,highlightsthecomplexbuthopefullandscape ofdepressiontreatment,whereunderstandingandenhancingBDNF’s rolecouldbekeytomoreeffectivetherapies(4).
InFebruary2024,anarticletitled“Theeffectofpsychedelicson thelevelofbrain-derivedneurotrophicfactor:Asystematicreviewand meta-analysis”waspublishedinthe JournalofPsychopharmacology by Shafieeandcolleagues(1).Thisteamofresearcherswasabletometiculouslysynthesizeallthecurrentinformationontherelationshipbetween psychedelicsandBDNF.
ToexaminetherelationshipbetweenpsychedelicsandBDNF,Shafiee etal.usedthePreferredReportingItemsforSystematicReviewsand Meta-Analyses(PRISMA)guidelines.Thisinvolvedperformingasystematicsearchininternationaldatabases(Embase,Scopus,WebofScience, andPubMed)toidentifyeverypublishedpaperandpeer-reviewedrandomizedclinicaltrialthatevaluatedthecorrelationbetweenpsychedelic consumptionandBDNFlevels.Afterscreeningtheresultsandperforming aqualityassessmentofthedatausingtheCochraneRiskofBias2tool, theywereultimatelyleftwith37fulltextsandninestudies.Thecaseand non-casegroupswerecomparedusingastandardizedmeandifference (SMD)and95%confidenceinterval.Afixedeffectmodelwasusedincase oflowheterogeneity(I2 valuebelow25%).Otherwise,arandomeffect meta-analysiswasused.
Themeta-analysis,thefirstofitskind,revealedthatthelevelsofperipheralBDNFinpsychedelicusersweresignificantlyhigherthaninnonexposedcontrols.However,itisessentialtonotethatonlyDMTwasassociatedwithastatisticallysignificantincreaseinperipheralBDNFlevels. TherewerenosignificantalterationsinperipheralBDNFwiththeother psychedelicsubgroups,suchasLSD,psilocybin,andothers;also,mostof thesestudies(sevenoutofnine)reportedlevelsofBDNFintheplasma, whileonlytwostudiesreportedlevelsofBDNFintheserum.
PeripheralBDNFis99%storedinplatelets,withonlyatinyamountof freeBDNFintheplasma(5).Asaresult,serumBDNFlevelsmaybeaffectedbyBDNFreleasefromplatelets.SerumBDNFalsoshowsgreater stabilitythanplasmaBDNF,sostoragetimeandtemperatureconditions afterbloodsamplingmustalsobeconsidered(6, 7).Indeed,Tsuchimine etal.foundnocorrelationbetweenserumandplasmaBDNF,suggesting thattheymaybeindependentmeasuresofrelevance(6).Inaddition,sex steroidsandmenstrualperiodshavethepotentialtoinfluencethefunctionandexpressionofBDNF(8–10).Consequently,levelsofBDNFinmen andwomenshouldbereportedseparately.
Noneofthestudiesinthemeta-analysismeasuredBDNFlevelsdirectlyinthecentralnervoussystem(CNS),representingachallenge inclinicalstudies.Consequently,themeasurementofBDNFinthe
peripheryisoftenusedasaproxy.Kleinandcolleaguesexaminedblood, serum,plasma,andbrain-tissueBDNFlevelsinthreemammalianspecies: rat,pig,andmouse(11).Theirdatasupporttheviewthatmeasuresof bloodandplasmaBDNFlevelsreflectbrain-tissueBDNFlevels.Additionally,Pillaietal.demonstratedthatthereareparallelchangesinBDNFlevelsofboththeplasmaandcerebrospinalfluid(CSF)inpatientswhohad psychosis(12).ThisindicatesthatplasmaBDNFlevelsmayreflectbrain changesinBDNF.Furthermore,ithasbeendemonstratedthatBDNFcan crosstheblood-brainbarrier,furtherestablishingbloodandplasmaasa proxyforCNSBDNFlevels(5).
Thoughdecreasedinpatientswithdepression,levelsofBDNFareincreasedinpatientswithpost-traumaticstressdisorder.Thissuggests acompensatoryroleforBDNFinstressresponse(13).Moreover,the roleofBDNFinneuropsychiatricillnessesismorecomplexthanwe thought.ThisrequiresfurtherinvestigationtoconfirmBDNF’spotential roleinelucidatingtheenigmaticneurobiologicalmechanismswithwhich psychedelicsexerttheireffects.AnothercriticalpieceitemtobeconsideredisthefactthatBDNFappearstobeavitalmediatorofthetherapeutic responsetoantidepressants(14, 15).WouldBDNF,therefore,beapotentialmediatoroftheantidepressanteffectsofpsychedelics?
Tosumitup,thiscarefullyconductedmeta-analysisrevealedthatthe levelsofperipheralBDNF(mainlysampledfromtheplasma)weresignificantlyincreasedinpatientswhoreceivedDMT.Duetothelimitednumber ofstudiesintheothersubgroupsofpsychedelicsandfactorsrelatedto BDNFvariability,includingserumvsplasmaandmalevsfemale,definitiveconclusionscannotbedrawnyet.
Understandingtheneuroprotectivemechanismsofpsychedelicscould haveimplicationsfornotonlypsychiatricdisordersbutalsothetreatmentofneurodegenerativediseasesandage-relatedcognitivedecline. Researchersmaybeabletodesignmoretargetedandeffectivetreatmentswithfewersideeffects.FuturestudiesshouldalsoobserveBDNF levelslongitudinallytoseehowlongtheeffectsofpsychedelicsremain. BDNFlevelsshouldalsobecomparedwithnotesfrompsychotherapysessionswhenavailable.Astandardizedclassificationforpsychedelicexperiencescouldassistinconfirmingthedefinitiveclinicalefficacyandsafety ofpsychedelics.Thisisparticularlyrelevantasvariouscountriesbeginto approvethesesubstancesforthetreatmentofvariouspsychiatricdisorders.Asanexample,Australia’sTherapeuticGoodsAdministration(TGA) nowallowsthedrugspsilocybinandMDMAtobeprescribedbydoctors totreatpsychiatricconditions,includingdepressionandpost-traumatic stressdisorder(16).
Therevivalofpsychedelicsinpsychiatry,theso-calledpsychedelicrenaissance,hascometoreflectabroadershiftinmedicinethatismovingawayfromareductionistmodeloftreatingsymptomsandtowards amoreholisticapproachthataddressestherootcauseofillness.Further researchisneededtotesttheexcitinghypothesisthatbycatalyzingtransformativeexperiencesthattranscendtheconfinesofegoandidentity, psychedelicsmayofferauniqueopportunitytoaccessthedeeperlayers ofthepsycheandfacilitatehealingandthepreventionoffurtherdistress.
VivekSeelamneni1
1 UniversitàVita-SaluteSanRaffaele,20132MilanoMI,Italy e-mail: vivek.seelamneni@gmail.com
2.CastrenE,KojimaM.Brain-derivedneurotrophicfactorinmooddisordersandantidepressanttreatments.NeurobiolDis.2017;97(PtB):119-126.DOI: 10.1016/j.nbd.2016. 07.010
3.MartinowichK,ManjiH,LuB.NewinsightsintoBDNFfunctionindepressionandanxiety.NatNeurosci.2007;10(9):1089-93.DOI: 10.1038/nn1971
4.DumanRS,DeyamaS,FogacaMV.RoleofBDNFinthepathophysiologyandtreatment ofdepression:Activity-dependenteffectsdistinguishrapid-actingantidepressants. EurJNeurosci.2021;53(1):126-39.DOI: 10.1111/ejn.14630 PMC7274898
5.FujimuraH,AltarCA,ChenR,NakamuraT,NakahashiT,KambayashiJ,etal.Brainderivedneurotrophicfactorisstoredinhumanplateletsandreleasedbyagonist stimulation.ThrombHaemost.2002;87(4):728-34.DOI: 10.1055/s-0037-1613072
6.TsuchimineS,SugawaraN,IshiokaM,Yasui-FurukoriN.Preanalysisstorageconditions influencethemeasurementofbrain-derivedneurotrophicfactorlevelsinperipheral blood.Neuropsychobiology.2014;69(2):83-8.DOI: 10.1159/000358061
7.PolyakovaM,SchloglH,SacherJ,Schmidt-KassowM,KaiserJ,StumvollM,etal.StabilityofBDNFinHumanSamplesStoredUpto6MonthsandCorrelationsofSerumand EDTA-PlasmaConcentrations.IntJMolSci.2017;18(6).DOI: 10.3390/ijms18061189 PMC5486012
8.PluchinoN,RussoM,SantoroAN,LittaP,CelaV,GenazzaniAR.Steroidhormonesand BDNF.Neuroscience.2013;239:271-79.DOI: 10.1016/j.neuroscience.2013.01.025
9.ChanCB,YeK.Sexdifferencesinbrain-derivedneurotrophicfactorsignalingandfunctions.JNeurosciRes.2017;95(1-2):328-35.DOI: 10.1002/jnr.23863 PMC5271179
10.BegliuominiS,CasarosaE,PluchinoN,LenziE,CentofantiM,FreschiL,etal.Influence ofendogenousandexogenoussexhormonesonplasmabrain-derivedneurotrophic factor.HumReprod.2007;22(4):995-1002.DOI: 10.1093/humrep/del479
11.KleinAB,WilliamsonR,SantiniMA,ClemmensenC,EttrupA,RiosM,etal.Blood BDNFconcentrationsreflectbrain-tissueBDNFlevelsacrossspecies.Theinternationaljournalofneuropsychopharmacology/officialscientificjournaloftheCollegiumInternationaleNeuropsychopharmacologicum.2011;14(3):347-53.DOI: 10. 1017/S1461145710000738
12.PillaiA,KaleA,JoshiS,NaphadeN,RajuMS,NasrallahH,etal.DecreasedBDNFlevels inCSFofdrug-naivefirst-episodepsychoticsubjects:correlationwithplasmaBDNF andpsychopathology.Theinternationaljournalofneuropsychopharmacology/officialscientificjournaloftheCollegiumInternationaleNeuropsychopharmacologicum. 2010;13(4):535-9.DOI: 10.1017/S1461145709991015
13.ZhangL,LiXX,HuXZ.Post-traumaticstressdisorderriskandbrain-derivedneurotrophicfactorVal66Met.WorldJPsychiatry.2016;6(1):1-6.DOI: 10.5498/wjp.v6.i1. 1 PMC4804258
14.MusazziL,CattaneoA,TarditoD,BarbonA,GennarelliM,BarlatiS,etal.Early raiseofBDNFinhippocampussuggestsinductionofposttranscriptionalmechanismsbyantidepressants.BMCNeurosci.2009;10:48.DOI: 10.1186/1471-2202-1048 PMC2689227
15.D’SaC,DumanRS.Antidepressantsandneuroplasticity.BipolarDisord.2002;4(3):183194.DOI: 10.1034/j.1399-5618.2002.01203.x
16.HaridyR.AustraliatoprescribeMDMAandpsilocybinforPTSDanddepressioninworld first.Nature.2023;619(7969):227-8.DOI: 10.1038/d41586-023-02093-8
Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutrality regardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliations ofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors, withouteditingthem.Suchusesimplyreflectswhattheauthorssubmittedtousand itdoesnotindicatethatGenomicPresssupportsanytypeofterritorialassertions.
References
1.ShafieeA,ArabzadehBahriR,RafieiMA,EsmaeilpurAbianehF,RazmaraP,Jafarabady K,etal.Theeffectofpsychedelicsonthelevelofbrain-derivedneurotrophicfactor:A systematicreviewandmeta-analysis.JPsychopharmacol.2024:2698811241234247. DOI: 10.1177/02698811241234247
OpenAccess. ThisarticleislicensedundertheCreativeCommons Attribution-NonCommercial-NoDerivatives4.0InternationalLicense (CCBY-NC-ND4.0).Thelicensemandates:(1)Attribution:Creditmustbegiventothe originalwork,withalinktothelicenseandnotificationofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.(2)NonCommercial:Thematerial cannotbeusedforcommercialpurposes.(3)NoDerivatives:Modifiedversionsofthe workcannotbedistributed.(4)Noadditionallegalortechnologicalrestrictionsmay beappliedbeyondthosestipulatedinthelicense.Publicdomainmaterialsorthose coveredbystatutoryexceptionsareexemptfromtheseterms.Thislicensedoesnot coverallpotentialrights,suchaspublicityorprivacyrights,whichmayrestrictmaterialuse.Third-partycontentinthisarticlefallsunderthearticle’sCreativeCommonslicenseunlessotherwisestated.Ifuseexceedsthelicensescopeorstatutory regulation,permissionmustbeobtainedfromthecopyrightholder.Forcomplete licensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4.0/.The licenseisprovidedwithoutwarranties.
Psychedelics
OPEN
EMERGINGTOPIC
Psychedelictreatmentforanorexianervosa:Afirst-handviewofhowpsilocybin treatmentdidanddidnothelp
StephanieKnatzPeck1 ,HannahFisher1 ,JessieKim1 ,SamanthaShao1 ,JulieTrim1 ,andWalterH.Kaye1
Anorexianervosa(AN)isapsychiatricillnesswithhighmortalityratesandlimitedtreatmentoutcomes.Psilocybintreatment(PT)hasshown promiseforvariousmentalhealthindicationsandthereissignificantinterestinexploringitspotentialforAN;however,studiestodateare preliminary.GiventheprobablesurgeinpsychedelicstudiesforAN,moreinformationisneededtounderstandhowtosuccessfullyapplyand optimizethesetreatmentsforthisvulnerablepopulation.InthisEmergingTopicsarticle,wepresentanuancedexplorationofthepotential benefitsandconstraintsofPTforAN,contextualizedwithintheframeworkofourclinicalfindingsfromamodestphase1pilotstudy.Weoffer hereasynthesisoffirst-handexperiencesandcomprehensivethematicinsightsgleanedfrom10individualswithlivedexperience,providinga richtapestryofperspectivesonthisnoveltherapeuticapproach.
Psychedelics January2025;1(1):15–18;doi: https://doi.org/10.61373/pp024e.0034
Keywords: Psilocybin,anorexianervosa,eatingdisorders,psychedelictreatment,psilocybintherapy,psychedelictherapy
Psilocybintreatment(PT)isbeingevaluatedforabroadrangeofmental healthindicationsandthereissignificantinterestinexploringitspotentialforanorexianervosa(AN)(1).AdultANisanotoriouslytreatmentresistantpsychiatricillnesswithhighmortalityrates(2)andnotreatmentsdemonstratingclearsuperiorityorstrongoutcomes,particularly forperceptionsregardingbodyimageandeating,orothermentalpsychopathology(3).Considerableevidenceimplicatesalteredserotonin functioninAN(4, 5).Psilocybinactsontheserotoninsystemandmay beabletoalterperception(6).AlthoughtheroleoftheserotoninalterationsinANisnotwellunderstoodandfindingsaresomewhatmixed (7, 8),thedocumentedroleof5-HTdysfunctionraisesthepossibility thatPTmayhavethepotentialtoimprovecorepsychopathologyand perceptionsnotsuccessfullytargetedbyexistingbehavioralandpharmacologicaltreatments.Therearefewclinicaltrialstodateandpreliminaryresultsareinconclusive.Morestudiesareneededtoexploreits potential.
WepublishedthefirstclinicaltrialevaluatingPTforANinasmall, phase1pilotstudyofsafety,tolerability,andpreliminaryoutcomesfor participantswithANandANinpartialremission(9).Resultsofthisstudy werepublishedbyourgroupin2023(9).Thiswasaverysmallfeasibilitystudyandthereforeresultsmustbeinterpretedwithcaution.However,inthiscommentary,weprovideagranularviewoffindingsbasedon qualitativedatafromsemistructuredinterviews,extensivefeedbackand interviewsfromparticipants,andoursubjectiveinterpretationsofdata patterns.Providinganintegratedperspectivebasedonthesefindingsand accruedexperienceensuresthatweareutilizingfeedbackfromkeystakeholderstoiteratetreatment,andtoensuretreatmentacceptabilityand facevalidityinfuturestudiesforatreatmentpopulationthatisnotoriouslydifficulttotreat.
Resultsfromourstudyarehighlypreliminary;however,theysuggest thatPTissafe,tolerable,andhighlyacceptable.PTincludedasingle 25mgdoseofpsilocybinadministeredwithspecializedpsychological supportbefore(twosessions),during,andafter(twosessions)thedrug administrationbytrainedpsychologists(foradditionaldetailsaboutthe psychologicalsupport,seeref. 9).Atotalof60%(6/10)ofparticipantsreportedareductionintheimportanceofphysicalappearance,70%(7/10) reportedfeelingaquality-of-lifeimprovementandshiftinpersonalidentity,and90%endorsedthepsilocybindosingasoneoftheirtopfivemost
meaningfullifeexperiences.Withinthecontextoftheexistingtreatment landscapewheretreatmentutilizationratesarelowanddropoutratesare high(10),thesepersonalreportsareclinicallysignificantandwarrantfurtherinvestigation.Theseendorsementssuggestthepotentialforshifts inidentity,therelativevalueofphysicalappearance,andquality-of-life improvements,allofwhicharebehavioralmarkersofentrenchmentand dysfunctionwithintheillness.
Quantitatively,preliminaryoutcomesdemonstratedasubset(4/10) ofparticipantswhoexperiencedclinicallysignificantreductionsineatingdisorder(ED)psychopathologytowithincommunitynormativelevelsat3-monthfollow-upafterasingletherapeuticdoseofpsilocybin offeredinconjunctionwithpsychologicalsupportbyaspecializedtherapist.ThesescorechangessuggestremissionfromEDpsychopathology, whichweinterprettobenoteworthy,asdidtheparticipantswhoexperiencedtheseeffects.Importantly,manyquestionsemergefromthisstudy thatcaninformfutureresearchpathways.Whatwasdifferentaboutthe 4/10responders?WhatoccurredthatresultedinreductionsinEDpsychopathologyscores?Thesequestionsspeaktotheimportanceofelucidatingmechanismsofactionandchange(11).Otherquestionsemergingpertaintothelackofeffectoncertainrecoverymarkerstraditionally definingfullrecovery(i.e.,weight),andalackofresponsebyasubset ofparticipants.Whatexplainsthediscrepancybetweenparticipantsendorsingthetreatmentashighlytherapeuticallymeaningful,andyetnot demonstratingchangesinmeasuredEDpsychopathology?Last,inthose whoexperiencedsignificantandprecipitousreductionsinpsychopathology,whydidweightrestorationnotfollow?
Wecannotdrawanysystematicconclusionsbasedonourlimiteddata andsample.However,herewediscussimportantquestionsandraisehypothesesaroundpsychologicalmechanismsthatwereengagedbasedon thematicresponsesfromparticipantsinthecontextofeffectsobserved.
WhatDifferentiatedResponders?
Amongthosewhodemonstratedsignificantimprovementsineatingdisordersymptoms,reductionswereprecipitousandsudden.Eatingdisorder examination(EDE)scoresgenerallydecreasedsharplyatDay1followup,withcontinuousdecreasesreportedatthe1-monthfollow-upperiodandsustainedat3-monthfollow-up.Shapeconcernsandweight concernswerethemostsensitivetochangewithsignificanteffectsat
1 EatingDisorderTreatment&ResearchCenter,UniversityofCalifornia,SanDiego,DepartmentofPsychiatry
CorrespondingAuthor: StephanieKnatzPeck,PhD,UCSDEatingDisordersTreatmentCenter,4510ExecutiveDriveSuite315,SanDiego,CA92121,USA.Phone: 1-619-573-5073.E-mail: sknatz@health.ucsd.edu
Received:24May2024.Revised:13September2024and16October2024.Accepted:16October2024. Publishedonline:7November2024.
1-monthfollow-up,andsustainedeffectsat3-monthfollow-upfor weightconcerns.Theseconstructscapturedissatisfactionandpreoccupationandtherelativeimportanceofthesefeaturesinrelationtoselfesteem/self-evaluation,whichisaprimarycriterionofANbasedonthe DSM5(12).Theseeffectsalignwithparticipant-responderdescriptions ofhowthetreatmentdecreasedeatingdisordersymptomsbyresulting inashiftintheirsubjectiveimportance.
ItkindofjustmademerealizethatIhadwastedmostofmylifetrying tomanipulatemybodywhenthat’stheleastimportantthingaboutme. Inreality,theleastimportantthingaboutmylifeismyphysicalbody.
IfeellikeIdisconnectedfrommyphysicalbody,whichwasveryliberatinginalotofwaystoo.IfeltthewholesouldeaththingwhereIjustfelt likeIwasasoul,justkindoftravelingthroughtheuniverseandthatmade mesadtothinkthatIhadwastedsomanyyearsofmylifejustbeingso hyperfixatedonthisbigchunkofmethatjustholdsmybeing.
Thissuggeststhat,forresponders,thetreatmentresultedinareorganizationinperception,values,anddiminishedsignificanceofweight/ shapeindefiningself-worth;thatis,areductionintheprimarydiagnosticcriterionnotedabove.Theseparticipantstendedtoreportdiminished internalpreoccupationandmorementalcapacityforrenewingfocuson othervaluesandlifeexperiences,whichtranslatedintolessanguishand obsessionaboutbehavioralchoicesaroundfood.
BeforeIparticipated,myanorexiawasthemostimportantrelationshipinmylifethatcamebeforefriends,familyorpartnersandeverything.Iwasvaluingweightasthenumberonefocusinmylife.Butduringthepsilocybinexperience,Iwasabletoseesortoftheinsignificance anditseemedsotrivialaftertheexperience.Itjustseemedtrivialforme tofocusmylifearoundweightwhenthereweresomanyotherimportant factors.
Whatdifferentiatedtheseparticipantsfromnonresponderparticipants?Thesmallsamplelimitedquantitativeanalyses;however,wedid notfindanysignificantcorrelationsbetweendemographicvariables, psychedelicsubscalescoresand/orpretreatmentscoreswithoutcomes. Insemistructuredqualitativeinterviews,thisgroupofparticipantsreportedexperiencingadissociationfromtheireatingdisorderasacore partoftheiridentityalongwithadeeperconnectiontoself.Inthesecases, thistransformationinperspectiveappearedtomotivateadecentralizing ofweightandshape,whichinsomecasesresultedinchangesineating behaviors.
Onaneuropharmacologicallevel,psilocybin’spsychedeliceffectsare believedtoemergebecauseofstimulationoftheserotonin2Areceptor (13)astheintensityofpsychedeliceffectshavebeenshowntoberelatedtopsilocybin’soccupancyoftheserotonin2Areceptorinthehumanbrain.BrainimagingstudiesshowthatsomeindividualswithAN havereducedactivityoftheserotonin2Areceptor(14).Studiesshowthat somewithANhavepolymorphismsoftheserotonin2Areceptorgene andthispolymorphismcouldalterexpressionofthisreceptor(15).Two linesofevidencesupportthiscontention.First,PETbrainimaging(5) showssomeindividualswithANhavereducedbindingofthe5HT2Areceptor.Second,anumberofinvestigators(16)reportedpolymorphisms ofthe5HT2AreceptorinAN.Schmitz(17)reportedthatsequencevariationsof5HT2Aaffecttheefficacyandpotencyofpsychedelics,includingpsilocybin.Thus,itispossiblethatalteredfunctionofthe5HT2A receptormayplayaroleinwhysomewithANfailtorespondtopsilocybin.Toourknowledge,thishypothesishasnotbeentestedinterms ofpsilocybinresponseinAN.Wementionthispotentialconfoundasan issuethatshouldbeinvestigatedinfuturestudiesusingpsilocybinto treatAN.
Futurestudiesshouldfocusonmechanismsofactionandchange(11) toelucidatepsychological,demographic,andneurochemicalfeatures thatmayaffecttreatmentresponse.Itispossible,andindeedlikely,that notallparticipantswillrespond,whichmirrorsthecourseofotherpharmacology.Despitevariableresults,moreevaluationiswarrantedgiven thestrikingresponsefromasubsetthatincludedahighlytreatmentresistantcase,afemalewhorefusedtraditionaltreatment,andtwoother treatment-refractorycaseswithillnessdurationsof >5yearsandsignificantdistressconferredfromEDpsychopathology.
HowandWhyDidParticipantsExperienceThisTreatmentas TherapeuticallyMeaningful?
Onlyasubsetofparticipantswasresponders;however,themajority endorsedthetreatmentastherapeuticallymeaningfulandsignificant. Understandingthesubjectivevalueofthetreatmentisimportantforfuturetreatmentiterationandtoensurefeasibilityandacceptability.Furthermore,itisalsoimportanttounderstandwhysubjectiveperceptions ofbenefitdidnotinallcasesresultinmeaningfulreductionsinEDpsychopathology.Itispossiblethatassessmentdeviceslackedsensitivityto capturegranularbehavioralchangesthatrequiremoreextendedperiods oftimetotranslateintoassessmentmarkerssuchasweight.Thissuggeststheneedforalongerfollow-upperiodandconsiderationsformore sensitiveassessmentdevicestotrackrelevantbehavioralchanges,such asdietaryrecalls.Inqualitativereports,whichinmostcaseswereatleast 1yearoutfromstudyparticipation,participantsnotedsomechangesthat theyperceivedtobepersonallysignificantforrecoverybutcouldbedefinedassubtlebecausetheywouldbedifficultorrequireprolongedsustainedenactmenttotranslateintomeaningfulsymptomreduction.
Ithelpsmetofocusmoreonthejoyfulaspectsoffood.Justtaste,textures,smells.Justkindoffinding,rediscoveringthiskindofjoywithfood.
IwouldsayI’mkindofgenerallymoreintuitiveandkindofjustlooking tofindmorejoyfulexperienceswithfoodasopposedtojusteatingthings outofobligationor,youknow,followingrules.
Itmademelikemoreappreciatemybody.ThathasimpactedwhatI choosetoeatandwhenandhowandnotobsessingoverit,butmyhabits havebeenthesame.
Somealsonotedlesspreoccupationsurroundingfoodandincreased engagementinotherlifeareas,evenintheabsenceofsignificantorprogrammaticshiftsinfoodintake.
It’sjustmoreoflikesomethingthatwasinmylifeorcomesandgoes, youknow,Idon’tfeellikeit’smywholeidentity,whichforalongtimewas reallyhardtoseparate.Andthenmovingforward,I’mlike,howdoIbeme withoutit?So,it’slikeIfeellikeI’mabletokindofcreateawholelifenot havingthatasmyidentity,butstilllikevalidatingit.
Idothinkthatithashelpedmetojustcontinuetrying,Ithink,and continuetryingtokeeponwhereI’mnotgoingbackwards,whereIkeep oneithermaintainingortryingtopushforwardbecauseofthatinsightI gainedintothebiggerpicture.Andithelpsmetokindofzoomoutwhen I’mreallystuckinmythoughtsorbehaviors.
It’simpactedmyabilitytobelievewhatI’mcapableofandithasshown methatIdon’thavetoliveinthecycleofanorexiaandhowmuchanorexia hastakenfrom,frommeandmylife.Icantrulybeatotallydifferentperson.Anditgavemesomuchmorebrainspaceandbraincapacitytoeither haveahobbyorworkinadifferentcapacity,it’sgivenmesomuchspace todootherthings.
Thisimpliesthatthesetreatmentsmayintheshortterm,improve qualityoflifeandclinicalimpairment(1).Evenintheabsenceofchanges intheprimaryoutcome,webelievethatqualitativeperceptionssurroundingquality-of-lifeimprovementsareimportanttohighlightandclinically meaningful.PatientswithEDshavesignificantmorbidityandmortality relatedtosuicide,andthustheseimprovementsshouldbeapriorityin treatmentapproaches.
WhatAboutWeight?
Itisequallyimportanttonotethattreatmenteffectsdidnotgenerally translateintoimprovementsinunderweightstatus—aprimarydiagnostic markerandimportantphysiologicalrecoverymetric.OfthefourrespondersontheprimaryoutcomeofmentalEDpsychopathology,threegained weightat3-monthfollow-up(0.4–1.2bodymassindex[BMI]points)and onereporteda1.5decreaseinBMI,notingillnessastheprimaryreason. Whenaskedaboutthisdisparity,participantsnoted:
IthoughtthatifInolongerworriedaboutgainingweightitwouldbe easy,butIamnowrealizingthatrestoringweightrequireseffort.
Whenyouaskmequestionsaboutmyweightandwhyithasn’t changed,itfeelslikeyouareonlybasingmyrecoveryonweightandthat feelsbadsinceIfeellikeInolongerhaveanED.
TheironyisthatnowthatIwanttorecover,Icaneatintuitively,but thatisnotenoughtosupportphysicalrecovery.
Thingsmightnotlookthatdifferentfromtheoutside,buttheyfeel completelydifferentfromtheinside.
Furthermore,changesinBMIintheoverallsamplewerehighlyvariable.WecannotassumethatanyBMIchangeswererelatedtotreatment effects;however,theresultspresentacompellinghypothesisthatbehavioralchangesnecessaryforfullphysicalrecovery(versusinternalphenomenologicalbeliefsystemsrelatedtoAN)werenotinitiatedfrom treatment,atleastinitscurrentdesign.Theresponder-participantwith themostnoteworthyweightrestoration(1.2BMIpointsat3-month follow-upwithaBMIshiftfrom16.9to18.1)statedthatthenecessary changesineatingwere“notwithouteffort”andrequiredoversightfrom adieticianandaprogrammaticeatingstructure(versusintuitiveeating). Shenotedthatthesechangeswereoftendifficultandrequiredhertodeliberatelyrevisittheinsightsfromthedosingexperience.
Youareabletoactinawaythatmaybehadfeltunachievablebeforeifyousettherightintentionandsoyoustillhavetoyourselfimplementit.
Itgavemethepushtobeabletorecover.Imean,it’sstillbeenachallengeandit’sstillbeensomethingthatIactivelyhavetoworkat.
ANischaracterizedbyrigidandrepetitivebehaviorssurroundingeatingandexercisewhicharehighlyresistanttodisruptionandnewlearning. SomeparticipantsreportednochangeinEDbehaviorspostdosing,while othersreportedanimproveddesiretodoso,butnosignificantstructuralchanges.OneparticipantappearedonDay1highlydistraughtthat shehadengagedinacompulsiveexerciseroutineimmediatelyupondischargefromherdosingexperience.Thatis,evenwheninsightswereconferredandbeliefsshifted,itmaycontinuetobedifficulttobreakrigidand repetitiveEDbehaviors.Participantsmayemergewithincreasedwillingness,andyetstillnotknowhowtoproceedwithrecoverysystematically. Adjunctivebehavioraltreatmentsmaybenecessarytoleveragepotentialneuroplasticityandprovidemorestructuredguidanceforachieving meaningfulbehaviorchanges.ThosewithANusuallypreferhighstructureandcertainty(18),andmoredirectivemodelsofbehavioraltreatmentmaybenecessarytosupportthisparticulartemperamentsignature.
Idon’twantittogotowaste.SoIkeepontryingtobelike,no,Iknow betterthanthisbecauseIknowit’snotnecessary.AndsoIusethattofuel myrecovery.Itdidn’treallyfeellikeitchangedmyrelationshipwithfood, butitdidmakemefeellikeIdon’tneedtheanorexia.
Actionisdefinitelytheharderpart.ButmentallyI’mabletoseebeyond thatandknowthat’swhatIwant.SoIkeepatiteveryday.
Thelackofbehavioralresponseoverallmayalsoberelatedtogenetic variations.IfsomeindividualswithANinourpsilocybintrialhad5HT2A polymorphisms,aswasdiscussedpreviously,thiscouldaltertheirbehavioralresponsetopsilocybinandcontributetohighvariabilityandalack ofchangeinphysicaloutcomes,includingweight.Toourknowledge,no studieshaveinvestigatedtherelationshipof5HT2AreceptorpolymorphismsinregardtopsilocybinresponseinAN.
Nevertheless,theresultssuggestthatpsilocybintreatmentmayhold potentialtooccasionimportantattitudinalshiftsthatdefineAN.Thelack ofaclearsignalinimprovingweightandbehaviorshouldnotunderminetheimportanceofthispotentialeffect.Indeed,moretreatments areneededtoimprovecorepsychopathology,asmanyexistingtreatment paradigmsemphasizetheinverse—behavioralshiftswithnochangeinattitudeorcognitivepathology.
Findingsfromthisstudybasedonquantitativeandqualitativedata suggestthatpsilocybinmaybehelpfulinsupportingmeaningfulpsychologicalchangeinasubsetofpeoplewithAN,andinsomecasesreductions indifficult-to-treat,coreANpsychopathologysuchasshapeandweight concerns.Ourfindingsalsosuggestthatpsilocybintreatmentmaynotbe effectiveforallwithAN,andmaynotserveasastand-alonetreatment initscurrentbriefformduetoapossiblelackofeffectonthefullsymptomsprofile,andspecificallyimportantphysicalmetricssuchasweight restoration.However,theseresultsandrelatedhypothesesarehighly preliminaryandmustbeinterpretedwithcautionduetothesmall,uncontrollednatureofthisstudy.Ultimately,itwillbeimportanttobetterpredictwhoislikelytobenefitfromthistreatmentandunderstand
thepossiblebenefitsofthisparadigmacrossthedevelopmentalspectrumgiventheprevalenceratesofANinyouth.Basedonourexperience, larger,well-controlledfuturestudiesshouldincludemorethoroughbaselineassessmentstounderstandtheuniquefeaturespredictingresponse includingbrainimagingstudiesandcollectionofgeneticmaterialtoidentifyanybiologicalfactorsassociatedwithoutcome.Giventhediscrepancy betweenqualitativeself-reportsofexperienceandquantifiedchange,it isalsopossiblethatalternativemeasurementsourcesandassessments shouldbeconsidered.Additionally,robust,specializedpsychologicalsupportand/orbehavioraltreatmentmaybenecessaryforthispopulation toleveragesubtleshiftsinattitudesduetoAN’sstrongbehavioralsignature.Othervariablesthatmayimpactoutcomeandwarrantfurtherinvestigationincludedosageandnumberandfrequencyofadministrations. Last,futurestudiesshouldassessforandplaceseriousvalueonqualityof-lifeimprovements,includingreductionsinimpairmentnecessaryfor reducingmorbidity.Researchersshouldalsobeawareoftheuniquerisks associatedwiththosewithAN(19).Inconclusion,wehopethesequalitativefindingsprovideopportunitiesforotherresearchteamstodesign studieswherefeaturescanbeevaluated,andtreatmentscanbeoptimizedbasedontheseimportantclinicalimpressionsfromourteamand participantswithlivedexperience.
DataAvailability
Clinicaldatareferencedinthismanuscriptarepubliclyavailablein DryadDataRepository(https://datadryad.org/stash/landing/show?id= doi%3A10.5061%2Fdryad.47d7wm3hq).
Acknowledgments
AspecialthankyoutoCompassPathwaysandtheirteamforfundingthis studyandprovidingsupport(WHK).
AuthorContributions
SKP,PHDactedassubinvestigatorofthestudy.Shewasprimaryauthorof themanuscriptandorchestratedandcontributedtointellectualconceptualizationoftheperspectivepaper.Shealsoparticipatedinqualitative datacollection.HannahFisheractedasresearchcoordinator,conducted semistructuredinterviewsonparticipantsandeditedthemanuscript. JessieKim,BSactedasresearchcoordinator.Shecollatedrelevantdata andeditedthemanuscript.SamanthaShao,BAactedasresearchcoordinator.Sheconductedallprimaryassessmentsandscreening,oversawclinicalresearchcoordination,organizedandmanagedthedatabase ofresults,andeditedthemanuscript.JulieTrim,PHDcontributedto theintellectualconceptualizationofthemanuscriptandandeditedthe manuscript.WalterH.Kaye,MDwasinvestigatorofthisstudyandcontributedtothewritingandeditingofthismanuscript.
FundingSources
TheoriginalstudywasfundedbyCompassPathways.
AuthorDisclosures
Someoftheresultsrestatedinthiscommentaryforinterpretationand contextwerepreviouslypublishedinourprimaryevaluationpaperpublishedinNatureMedicine[KnatzPeck etal.,2023,reference(9)].
Thecontributorshaveconfirmedthatnoconflictofinterestexists.The studyfunder,CompassPathways,hadnoroleinthedatacollection,analysis,interpretation,orwritingofthereport.Thecorrespondingauthor hadfullaccesstoallthedatainthestudyandhadfinalresponsibilityfor thedecisiontosubmitforpublication.Themanuscripthasbeenreadand approvedbyallauthors.
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Psychedelics
BENCHTOBEDSIDE
Exploringthetherapeuticpotentialofpsychedelics:Fearextinctionmechanismsand amygdalamodulation
ThomasJ.Kelly1 ,andQing-songLiu1
Classicalpsychedelicsareincreasinglyreceivingattentionaspotentialtherapeuticagentsfortreatingpost-traumaticstressdisorder(PTSD). Researchhasexploredvariousclassicalpsychedelicsinthecontextoffearlearning,recall,andextinctioninrodents.Weprovideanoverviewof thereportedeffectsofthesesubstancesonbehavioralresponsestolearnedfear.Theamygdalacomplex,akeybrainregioninvolvedinfear learningandextinction,playsacentralroleintheseprocesses.Wediscusshowpsychedelicsinteractwithvariouscelltypesintheamygdala andproposewhichneuralcircuitsmaybeessentialfortheobservedfear-suppressingeffectsfollowingpsychedelicadministrationinrodents. Therodentamygdalahasfunctionalhomologywiththehumanamygdala.Thus,insightsgainedfrompreclinicalstudiescaninformthedesign andimplementationofclinicaltrialsforpsychedelic-assistedpsychotherapyforPTSD.Finally,westresstheimportanceofconsidering compound-specificpharmacologyandtheacutedurationofactionaskeyfactorsinguidingthefuturedirectionofthisfield.
Psychedelics January2025;1(1):19–24;doi: https://doi.org/10.61373/pp024b.0019
Keywords: Psychedelics,psychedelic,psilocybin,psilocin,fear,amygdala,PTSD,tryptamine,serotonin
Introduction
Fearandanxiety-relateddisorders,suchasposttraumaticstressdisorder(PTSD),specificphobias,andgeneralizedanxietydisorder,present significantchallengesforbothpatientsandclinicians.Despiteadvancementsintraditionaltherapeuticapproaches,suchascognitive-behavioral therapyandexposuretherapy,asubstantialproportionofindividuals withthesedisorderscontinuetoexperiencepersistentsymptomsand impairedqualityoflife(1, 2).Themechanismsunderlyingthetherapeuticeffectsofexposuretherapyhavebeenexploredinrodentmodelsutilizingclassicalfearconditioningandextinctionparadigms(3).The neuralsubstratesimplicatedinfearextinctioninrodentsarecomparabletothoserecruitedduringexposuretherapyinhumans(4).Inrecent years,therehasbeenaresurgenceofinterestinthetherapeuticpotentialofpsychedelicsubstances,suchaspsilocybinand3,4-methylenedioxy methamphetamine(MDMA),forthetreatmentoffearandanxiety-based disorders(5).ClinicaltrialsassessingtheefficacyofMDMA-assistedpsychotherapyforthetreatmentofPTSDhaveshownpromisingresults(6, 7), andtrialsforpsilocybin-assistedtherapyforthesameindicationareongoing.Aprevailingviewisthatpsychedelicsinduceenduringtherapeutic effectsbyenhancingstructuralplasticityofcorticalneurons(8–10).This viewpointstemsfromobservationsthatasingledoseofapsychedelic inducesbothsustainedchangesincorticaldendriticspinedensityand sustainedantidepressant-likeeffectsinrodentmodelsofdespair.Inthis perspectivearticle,weproposethatthefear-associatedenvironmental cuesmayactivateexcitatoryprincipalneuronsintheamygdala,while psychedelicsacutelysuppressfearresponsesbyenhancingGABAergicinhibitionoftheseprincipalneurons.Theopposingeffectsonneuronalactivityintheamygdalamayprovideabasisforunderstandingpsychedelicassistedtreatmentforfear-baseddisorders.
ClassicalPsychedelicsAcutelySuppressLearnedFearResponses
Classicalpsychedelicsinduceacharacteristic5-HT2A receptor–dependent headtwitchresponseinrodents(11, 12)thatcorrelateswithhallucinogenicpotencyinhumans(13).Indeed,the5-HT2A receptorantagonistketanserindose-dependentlyblockssubjectivepsychedeliceffects inhumans(14).Ithasbeenpostulatedthatthetherapeuticeffectsof classicalpsychedelicsrelyonprolongedneuroplasticchangesinthe
cortexaftertheacutedrugeffectshavewornoff(8, 9, 15–17).Inthe caseoffearextinctionlearning,thepreclinicaldatahavenotdirectlysupportedthismodelofaction.Studiesinmicehavedemonstratedthatclassicalpsychedelicsreducefreezingresponsestoconditionedauditoryfear cues(18–24).However,fearsuppressiontoconditionedcueswanesasthe acuteeffectsofclassicalpsychedelicssubside(20).Incontrast,theheight ofpsychedelic-inducedstructuralplasticityinthecortexisapparentlong afterthedrughaswornoff(1–3days)(9).Thus,psychedelicsinducean acutesuppressionoflearnedfearthatisunlikelytodependonstructural neuronalplasticity.
Themagnitudeofpsychedelic-inducedfearsuppressionappearsto relyondrugdosage,andtimingofthedose,whilesustainedeffects appeartorelyonthespecificfearextinctionparadigmpsychedelictreatmentispairedwith(See Table1 forsummary).Notably,studiesthat pairedpsychedelictreatmentwithfewerconditionedfearcuepresentations(≤12),orasingle3-mintoneshowedenhancedextinctionretention thefollowingday(21, 22),whilestudiesthatpairedahighernumberof fearcues(20–40tones)withpsychedelictreatmentshowednodifference inextinctionretentionbetweentreatmentandcontrolgroups24hlater (19, 20).Alargernumberofcuepresentationsstrengthensfearextinctionwithinthesessionbutalsonormalizesfreezinglevelsbetweendrug treatmentgroupsbytheendoftheextinctionsession.Thus,thetiming, dose,andnumberofcuepresentationsduringpsychedelic-pairedfearextinctionlikelydeterminewhetherreductionsincue-inducedfreezingare observedatlatertimepoints.
Regardlessofthefearextinctionprotocolthatisused,theacute fear-suppressingeffectofclassicalpsychedelicslikelydependson 5-HT2A receptoragonismasfullknockoutofthereceptorprevented theacutefear-suppressingeffectofthefull5-HT2A/2C agonist2,5dimethoxy-4-iodoamphetamine(DOI)(19),andsystemicinjectionofthe selective5-HT2A antagonistvolinanserin(alsoknownasMDL100907or M100907)preventedtheacutefear-suppressingeffectsofpsilocybinand 4-(2-((2-hydroxybenzyl)amino)ethyl)-2,5-dimethoxybenzonitrile(25CNNBOH)(18).Overall,thesedatasuggestthat5-HT2A receptoragonismis requiredfortheacutefear-suppressingeffectsofclassicalpsychedelic drugs,buttheenduringeffectsonfearbehaviorarehighlydependenton thespecificextinctionparadigmpsychedelictreatmentispairedwith.
1 DepartmentofPharmacologyandToxicology,MedicalCollegeofWisconsin,Milwaukee,Wisconsin53226,USA
CorrespondingAuthor: ThomasJ.Kelly,DepartmentofPharmacologyandToxicology,MedicalCollegeofWisconsin,8701WatertownPlankRoad,Milwaukee,Wisconsin 53226,USA.Phone:1-920-427-6177.E-mail: tjkelly@mcw.edu
Received:4November2024.Revised:6April2024.Accepted:7November2024. Publishedonline:9August2024.
Table1. Overviewofthedoses,timing,andfear-suppressingeffectsofvariousclassicalpsychedelics
CompoundMechanismDoseandTimingEffectonConditionedFear
Psilocybin/PsilocinNon-selective5-HTreceptoragonist, low5-HT2B receptoraffinity(25)
N,N-DMTNon-selective5-HTreceptoragonist (25)
2mg/kg,30minbeforecontextualtestSuppressionoffreezingtocontext(18) 0.1,0.5,and2.5mg/kg;30minbefore cuepresentation 0.5and2.5mg/kgcausedsuppression ofcuedfreezing(23)
10mg/kg,1hbeforecuepresentationSuppressionofcuedfreezing(22)
DOISelective5-HT2 agonist(26)2mg/kg,30minbeforecue presentation
2mg/kg,2hafterconditioning, 24hoursbeforecuepresentation
2mg/kg,24hbeforefearconditioning, 48hbeforecuepresentation
Suppressionofcuedfreezing
Weaksuppressionofcontextual freezing(27)
Weaksuppressionofcontextual freezing(27)
TCB-2Highaffinity5-HT2A agonist,offtarget bindingsitesunknown(28)
1mg/kg,Immediatelyaftertracefear conditioning
Enhancedcuedfreezingduringrecall 24hlater(24)
1mg/kg,30minbeforecue presentation Suppressedcuedfreezing(24)
1mg/kg,30minbeforecontexttestSuppressedcontextualfreezing(18)
4-OH-DiPTModestlyselectivefor5-HT2 A/B receptorsover5-HT2C and5-HT1 receptorfamily(20)
25CN-NBOHHigh-affinity5-HT2A receptoragonist, moderateselectivityover5-HT2B/C receptors(29)
TheAmygdalaPlaysaCrucialRoleintheFear-SuppressingEffect ofPsychedelics
3mg/kg,30minbeforeextinctionNosuppressionofcuedfree(20) 3mg/kg,5minbeforeextinctionSuppressionofcuedfreezing(20)
3mg/kg,30minbeforecontextualtestSuppressionoffreezingtocontext(18)
Thelocuswhereby5-HT2A agonismsuppressesconditionedfearisanarea ofongoinginvestigation.Fearextinctionisacomplexbehaviorwhich involvesprocessingsalientstimuli,respondingtoexpectedstimulioutcomes,andadjustingresponsestotheseoutcomesovertime(30).The hippocampus,amygdalacomplex,andprefrontalcortex(PFC)playdistinctrolesintheextinctionoffear(31);in-depthreviewscanbefound elsewhere(32–34).The5-HT2A receptorisexpressedinalltheseregions(35–37),anditscollectiveactivationateachregioninvivolikely contributestotheacutefear-suppressingeffectofsystemicallyadministeredclassicalpsychedelics.However,localinfusionofDOIintothe amygdalacomplex,andnotthemedialPFCmostcloselyresemblesits fear-suppressingeffectaftersystemicinjection(19).Thissuggeststhat activationofthe5-HT2A receptorinoneormoreamygdalanucleiisnecessaryfortheacutefear-suppressingeffectsofclassicalpsychedelicdrugs inrodents.
Theamygdalacomplexiscommonlybrokenintothecentral(CeA) andbasolateralcomplex.Thebasolateralcomplexisfurtherdividedinto thelateralamygdala(LA),basolateralamygdala(BLA),andbasomedial amygdala(BMA)(38).CeA,LA,BMA,andBLAhaveanterior-posteriorheterogeneityandcontainsubregionswithdistinctfunctions(38).TheLA ispositionedimmediatelydorsaltotheBLAandhashighexpressionof Htr2a mRNA(20).Duringauditoryfearconditioning,synapticinputsfrom auditoryandsomatosensorycortexconvergeontoLAneuronsandinduce synapticstrengthening(39).ThedepolarizationofLAneuronsinduced byglutamatereleasefromcorticalinputneurons(40–42)causescalcium influxthroughNMDAreceptors,AMPAreceptorsurfacetrafficking,and sustainedsynapticpotentiation(43, 44).LocalinfusionoftheNMDAantagonistAPVintotheamygdaladuringfearconditioningimpairscueoutcomeassociation(45).Thus,simultaneousexcitationfromauditory andsomatosensoryinputstolateralamygdalaprincipalneuronsledto NMDA-dependentsynapticstrengtheningandfearlearning.Activationof the5-HT2A receptorinLAneuronsduringfearconditioningcouldinduce depolarizationandcalciuminfluxthroughGq-proteindissociation(46). Itisplausiblethatdepolarizationvia5-HT2A receptoractivationcould lowerthethresholdforHebbian-basedformsofplasticitythatoccurbetweenLAneuronsandtheirsomatosensoryandauditoryinputsduring fearlearning.StrengthenedinputstoLAneuronscouldpotentiallyre-
sultinheightedfearresponsesduringarecalleventthefollowingday. Thisideahasnotbeendirectlytestedyet,butmaybedifficulttodistinguishfrom5-HT2A –mediatedenhancementofmemoryconsolidationafterfearconditioningprocedures.Forexample,theadministrationofTCB2shortlyafterfearconditioningledtoenhancementoffearlearningthe followingday(24).Ontheotherhand,administrationofDOIpriortocued fearrecallsuppressesfreezing,yet,increasesexpressionoftheimmediateearlygenec-FosintheLA(19).Thus,psychedelic-inducedactivation ofLAneurons,mightenhanceordisruptconditionedfearresponsesdependingontheadministrationtimepoint.
TheBLAisdirectlybelowtheLAandiscomprisedof ∼80%excitatoryneuronsand ∼20%inhibitoryGABAergicneurons(20).WhiletheBLA containsslightlymoreGABAneuronsthantheLA(47),theexpression of5-HT2A receptormRNAissubstantiallylowerintheBLAcomparedto theLA,andhashigherlocalizationtoinhibitoryneurons(20).Notably, notallGABAneuronsexpressed Htr2a mRNAintheabovestudy.However,RNA-sequencinghascharacterizedtheexpressionof Htr2a mRNA acrossthemousebrainingreatdetailincludingBLAinhibitoryneuronal subtypes(48).TheBLAcontainsfourmajorpopulationsofinterneurons whichexpresseitherparvalbumin(PV+ ),somatostatin(SST+ ),vasoactive intestinalpolypeptide(VIP+ ),orcholecystokinin(CCK+ )andhavedifferentialrolesinfearencodingandexpression(49).ThespecificsubpopulationofinhibitoryBLAneuronswhichexpress5-HT2A receptorprotein isunclear.Studiesshowconflictingresults,5-HT2A receptorexpression hasbeenshowntoberestrictedtoonlyPV+ (50),bothPV+ andSST+ (37),orwidespreadexpressionincludingexcitatoryneurons,although mostaccountsshowexpressionlocalizedtopostsynapticsomaanddendriticsites(51).Exvivosliceelectrophysiologyexperimentsprovidesome cluesastowhichBLAinterneuronpopulationexpressesthe5HT2A receptor.Bathapplicationofserotoninenhancesthefrequencyandamplitude ofspontaneousinhibitorypostsynapticcurrents(sIPSCs)inBLAneurons, aneffectwhichcanbeblockedbytheselective5-HT2A receptorantagonistvolinanserin(50, 52).TheincreaseinsIPSCfrequencyandamplitudeislikelyduetoenhancedactionpotentialfiringfromoneofthelocalinterneuronpopulationsasfocalapplicationofthe5-HT2A receptor agonists4-OH-DIPTor α -methyl-5-hydroxytryptamineleadstointerneurondepolarizationandactionpotentialfiring(20, 53).Psychedelicslikely exertcomparableinterneuron-mediatedinhibitioninvivoasthenumberofBLAneuronsexpressingtheimmediateearlygenec-Foswere
Figure1. Schematicofatheoreticalmechanismforpsychedelic-inducedfear suppression.ActivationofexcitatoryinputstoBLAprincipalneuronsdrives fearresponsesduringcuepresentation.5-HT2A receptoragonistsactivatePV neuronswhichreleaseGABAtoinhibitprincipalneuronactivityandreducefear responsestocues.CreatedwithBioRender.
decreasedinpsilocybin-treatedmicecomparedtosaline-treatedcontrols (54).Moreover,exvivoactivationofGq-DREADDsexpressedonBLAPV+ neuronsmimicsthe5-HT2A receptor–mediatedenhancementofsIPSCsin BLAneurons(52).Thus,5-HT2A receptor–mediatedactivationofPVneuronslikelycausesinhibitionofBLAprincipalneurons.
ModulationofPV+ neuronactivityintheBLAduringfearconditioning orextinctionleadstodistinctoutcomesinfearexpression.Gq-mediated activationofBLAPV+ interneuronsduringfearconditioningenhances fearexpressiononedaylater(52).WhileoptogeneticactivationofPV+ neuronsduringfearextinctionsuppressesfreezing(55)andchemogeneticinhibitionofBLAparvalbuminneuronsenhancesfreezinginmice thathaveundergoneextinction(56).Agonismorantagonismofthe 5-HT2A receptoratsimilartimepointsinducesacomparablepatternof behaviorasBLAPV+ neuronactivationorinhibition,respectively(Fig.1). Administrationofthepotent5-HT2A receptoragonistTCB-2shortly afterfearconditioningledtoenhancedfearexpressiononedaylater,yet administrationofTCB-2priortofearextinctionsuppressedcue-induced freezing(24).Systemicadministrationoftheselective5-HT2A receptor antagonistvolinanserinatthesametimepointsintheabovestudyshowed oppositeeffectsonfearexpression,suggestingthebehavioraleffectsof TCB-2inthisparadigmweredependenton5-HT2A receptoractivation (24).OnecaveatisthatwhileTCB-2isahighlypotent5-HT2A receptoragonist,itsselectivityhasnotbeenestablished(57).Takentogether, thesestudiesindicatethattheacuteeffectof5-HT2A receptoractivation leadstoPVinterneuron-mediatedinhibitionofexcitatoryBLAneurons andmaydifferentiallyaugmentfearfulresponsesdependingontheadministrationtimepoint.Futureexperimentsshoulddirectlytestthispotentialmechanisminvivo.
TheCeAhasalsobeenreportedtoexpressthe5-HT2A receptoron SST+ interneurons(58).Chemogeneticinhibitionof5-HT2A + CeAneurons reducesfreezingtolearnedfearcues,whilechemogeneticactivationhad
noeffectonfreezingtolearnedfearcues(58).However,thesamestudy foundthatactivationof5-HT2A + CeAneuronsreducedfreezingtoinnate fear(58),whichmightcontributetotheacuteanxiolytic-likeeffectofthe potent5-HT2A receptoragonistDOIintheelevatedzeromazeandelevatedplusmaze(19).Interestingly,systemicadministrationofpsilocin, theactivemetaboliteofpsilocybin,ledtoanacuteincreaseinCeAactivityinbothmaleandfemalerats,whileitenhancedstimulus-specificCeA reactivitysolelyinfemales,ratherthanmales(59).ThisraisesthepossibilitythattheCeAmaycontributetosomeofthesexdifferencesinfear andavoidancebehaviorsobservedafteradministrationofpsychedelicsin rodents(20, 60, 61).
FearInducesAmygdalaActivationinRodentsandHumans Fearextinctionrequiresalteringtheperceivedthreatofastimulus,aconceptnotdirectlymeasurableinrodents.Humantrialsareultimatelyrequiredtounderstandhowpsychedelicsaltertheperceptionofthreat. Theneurobiologicalmechanismsunderlyingfearresponsesarerelatively wellconservedacrossmammalianspecies.RNA-sequencingexperiments showthathumansandmicecontainsimilarproportionsofexcitatoryand inhibitoryneuronsintheamygdala(62).Functionalstudiesinrodents andhumanshavedemonstratedthecriticalroleoftheamygdalainfear processingandfear-relatedbehaviors.Forexample,lesionstudiesinrats haveshownthatdamagetotheamygdalaimpairstheacquisitionofconditionedfear(63).ExcitatoryBLAneuronsareactivatedbyfearcuepresentationinrats,andoptogeneticinhibitionofthesameneuronsimpairs cue-inducedfreezingduringextinction(55).Moreover,functionalimaginginhumansrevealedincreasedamygdalaactivityinresponsetofear conditioning(64).Whileinvivofieldpotentialrecordingsoftheamygdala inawakehumansdemonstratedincreasedactivityuponthepresentation offearfulfaces(65).Incontrast,reductionsinamygdalaactivityareassociatedwiththeearlyphaseoffearextinctioninhumans(66),andhumans withbilateralamygdalalesionsdonotdisplaytypicalfearresponses(67). Thus,fearlearning,andexpressionrequireexcitatoryamygdalaactivityin bothrodentsandhumans.
ImplicationsfortheTreatmentofPTSD
Functionalmagneticresonanceimaginghasshownthatacutepsilocybin administrationtohumansubjectsreducedamygdalareactivitytoboth negativeandneutralstimulicomparedtoplaceboadministration(68). Inthesamestudy,thereductioninbloodoxygenlevel-dependentsignalintherightamygdalawascorrelatedwithelevatedmood210min afterpsilocybinadministration(68).Hyperactivityoftheamygdalais implicatedinPTSD(69, 70).Thus,classicalpsychedelicsandexposure therapymayworksynergisticallytodampenamygdalaactivityandreducePTSDsymptoms.ClinicaltrialsinvestigatingtheefficacyofpsilocybinfortreatingPTSDareongoing(NCT05243329,NCT05312151, NCT05554094)andsomeclinicaltrialsintegrateexposuretherapyinto theirdesign(71).Itiscriticalthatfutureclinicaltrialsinvestigatehow modulatingthenumberoftraumaexposuresortypeofpsychotherapy accompaniedbypsychedelicadministrationinfluenceslong-termoutcomesinpatientswithPTSD.Ithasbeensuggestedthatthepsychologicalinsightgainedfromthepsychedelic-assistedtreatmentcanimprove anindividual’sabilitytorespondtosubsequentstressorsmoreadaptively(72),whichisconsistentwiththefindingsthattheintensityof theacutepsychedelicexperienceisassociatedwithimprovedmetricsof mentalhealth(73).Thus,thetypeoftherapyadministered,andintensityofpsychedeliceffectswillultimatelyinformthelong-termbehavioral changesinducedbypsychedelicassistedpsychotherapyforfear-based disorders.
PharmacologicalConsiderations
Agonismofthe5-HT2A receptorisresponsiblefortheacuteillusory andsensoryeffectsofpsychedelicdrugs,However,nearlyallpsychedelic drugshaveactivityatotherreceptorswhichaugmentstheiractivityatthe levelofneuralcircuitsandsystems.Thedifferentialeffectsofserotonin receptorsonanxietyandfeararereviewedelsewhere(74).Itwasrecently shownthatseveralcommonlystudiedclassicalpsychedelicssuchasN,NDMT,5-MeO-DMT,psilocin,andlysergicaciddiethylamidehavehigher efficacyattheGi/o-coupled5-HT1A receptorcomparedtothe5HT2A
Funding
ThisworkwassupportedbyNationalInstitutesofHealthGrants R01DA035217(toQ.S.L.)andR01DA047269(toQ.S.L.).T.J.K.isamemberoftheMedicalScientistTrainingProgramatMCW,whichispartially supportedbyatraininggrantfromNIGMST32-GM080202.
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Conclusion
Despiteadvancementsintraditionaltherapeuticapproachesfearand anxiety-baseddisordersremainchallengingtotreat.WhileexposuretherapyhasbeeneffectiveinmanycasesofPTSD,theresurgenceofinterest inpsychedelicsubstancesofferspromisingavenuesfortreatment.Classicalpsychedelicshavebeenshowntoacutelysuppressfearresponses inrodentmodelsoffear,suggestingpotentialtherapeuticapplications forfear-relateddisorders.Understandingtheneuralmechanismsunderlyingtheseeffects,particularlyinregionssuchastheamygdala,iscrucial fordevelopingeffectivepsychedelic-assistedpsychotherapytreatments. Additionalconsiderationforthepharmacologicalprofileofpsychedelics, theirdurationofaction,andthetherapeuticcontextinwhichtheyareadministeredisessentialforoptimizingtreatmentstrategies.Short-acting psychedelicsmaybepromisingalternativestreatmentsforPTSD.Further researchintotheirsafetyandefficacyisneededtoaddressthepersistent challengesposedbyfear-baseddisorders.
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Psychedelics
OPEN RESEARCHREPORT
Single-dosepsilocybinaltersresting statefunctionalnetworksinpatients withbodydysmorphicdisorder
XiZhu1 , 2 ,ChenZhang2 ,DavidHellerstein1 ,JamieD.Feusner3 , 4 , 5 , MichaelG.Wheaton2 , 6 ,GloriaJ.Gomez2 ,andFranklinSchneier1 , 2
1 DepartmentofPsychiatry,ColumbiaUniversityIrvingMedicalCenter, NewYork,NY,USA
2 AnxietyDisordersClinic,NewYorkStatePsychiatricInstitute,NewYork, NY,USA
3 DivisionofNeurosciencesandClinicalTranslation,Universityof Toronto,Toronto,Ontario,Canada
4 CentreforAddictionandMentalHealth,Toronto,Ontario,Canada
5 DepartmentofWomen’sandChildren’sHealth,KarolinskaInstitutet, Stockholm,Sweden
6 BarnardCollege,ColumbiaUniversity,NewYork,NewYork,USA
CorrespondingAuthor: XiZhu,Ph.D.AssistantProfessorofClinical Neurobiology,DepartmentofPsychiatry,ColumbiaUniversityIrving MedicalCenter,NewYork,NY10032,USA.
E-mail: xi.zhu@nyspi.columbia.edu
Psychedelics January2025;1(1):25–31; doi: https://doi.org/10.61373/pp024r.0028
Bodydysmorphicdisorder(BDD)isaseverepsychiatricconditioncharacterizedbypreoccupationwithperceivedflawsinone’sappearance, whichtheindividualviewsasdefectiveorugly.Psilocybin,aserotonin2Areceptoragonistwithpsychedelicproperties,hasemerged asapotentialtherapeuticagentfordepressionandotherpsychiatric disorders.Thisstudyaimedtoidentifysubacuteneuralchangespredictingsymptomaticresponsetopsilocybintreatmentinadultswith BDD.Eightadultswithmoderate-to-severenondelusionalBDDwere administeredasingleoral25mgdoseofpsilocybin,accompaniedby psychologicalsupport,andunderwentrestingstatefunctionalmagneticresonanceimagingassessments1daybeforeand1dayafterthe dosing.Botharegionofinterest(ROI)-to-ROIanalysisandmultivariatepatternanalysis(MVPA)wereusedtoidentifychangesinresting statefunctionalconnectivity(rsFC)atday1afterdosingthat predictedtreatmentresponseatweek1,measuredbychangeinYaleBrownObsessiveCompulsiveDisorderScaleModifiedforBDD(BDDYBOCS)score.Allparticipantscompletedthedosingandfollow-upassessmentsover12weeks.BDD-YBOCSscoresdecreasedatweek1and week12afterdosing(p<0.001forboth).MVPArevealedasignificant increaseinrsFCwithintheExecutiveControlNetwork(ECN)atday1. IncreasedrsFCwithintheECN(dlPFC–SuperiorParietalLobule[FPL]), betweentheECNandDefaultModeNetwork(dlPFC–Precuneus),and betweentheECNandtheSalienceNetwork(dlPFC–insula)werepredictiveofimprovementinBDDsymptomsatweek1.Thesefindingsare thefirstreportofsubacutebraineffectsofpsilocybininpatientswith BDD.Giventhesmallsamplesizeanduncontrolleddesignofthestudy, largercontrolledstudiesarenecessarytovalidatetheseobservations. ClinicalTrialsRegistration: Clinicaltrials.gov ID:NCT04656301
Keywords: Bodydysmorphicdisorder,psilocybin,restingstatefMRI, functionalconnectivity,treatmentresponse.
Introduction
Bodydysmorphicdisorder(BDD)isachronicpsychiatricdisordercharacterizedbyanobsessivefixationonperceivedflawsordefectsinphysical
appearance,whichappearslightornonexistenttoothers(1).ThepopulationpointprevalenceofBDDisestimatedtobefrom0.7%to2.4% (2, 3).BDDisadebilitatingandpersistentdisorder,andisoftencomorbid witheatingdisorders,obsessive-compulsivedisorder(OCD),depression, andanxietydisorders(4),complicatingdiagnosisandtreatment.Studies usingrestingstatefunctionalmagneticresonanceimage(rs-fMRI)have revealedthatpatientswithBDDexhibitalteredbrainrestingstatefunctionalconnectivity(rsFC)withinandbetweenbrainregionsinvolvedin visualprocessing(5),emotionalregulation,andattention(6–8).These alterationsmayunderliethedistortedperceptionofbodilyappearance withintheBDDpopulation.
Bothcognitivebehavioraltherapy(CBT)andselectiveserotoninreuptakeinhibitors(SSRIs)haveappearedefficaciousfortreatingBDD;however,manyindividualseithercannottolerateordonotbenefitfromthese treatments,suggestingagreatneedfornoveltreatments(9).Psilocybin, aserotonin2Areceptor(5-HT2A)agonistwithpsychedelicproperties, hasrecentlyshownpromiseinrandomizedcontrolledtrialsfortreating depression(10, 11)andOCD(12).Psilocybinhasdemonstratedpromisingresultsinalleviatingsymptomssuchasthoughtrumination(13–15), whichmayalsobeaprominentsymptominBDD(16, 17).Theneural mechanismsthroughwhichpsilocybinachievestherapeuticeffectsremainpoorlyunderstood.Imagingstudieshaveexaminedpsilocybineffectsacutely(duringthepsychedelicexperiencethatoccursforupto 8hoursafterdosing),subacutely(at1dayto1weekpost-dosing),orlongterm(atgreaterthan1weekpost-dosing)inhealthycontrols(HC)and depressedindividuals.
ThisstudyfocusedonthesubacuteeffectsofpsilocybinonrsFCat 1daypost-dosing,lessthan24hoursafterthepsychedelicexperience hadended.Previousrs-fMRIstudieshavefoundrsFCtobealteredsubacutelywithintheExecutiveControlNetwork(ECN)andbetweenthe ECNandothernetworksandbrainregionsfollowingpsilocybinadministrationinHCandindividualswithdepression.Specifically,inHC,reductionofrsFCintheECNwasobserved1weekafterpsilocybinadministration.GreaterreductioninECNrsFCpredictedincreasedmindfulness 3monthslater(18).Anotherstudyofsubacuteeffects,however,found thatpsilocybinincreasedwhole-brainrsFCconnectivityat1weekand 1monthpost-psilocybin(19).Inindividualswithdepression,at1day post-administrationofpsilocybin,rsFCwasincreasedinventromedial prefrontalcortexandbilateralinferiorlateralparietalcortex(10).This changeinrsFCwaspredictiveofthetreatmentresponseindepressedpatientsafter5weeks(10).AnotherstudyindepressionreportedrsFC1day afterpsilocybintobesignificantlyincreasedbetweentheECNandthe DefaultModeNetwork(DMN),andbetweentheDMNandtheSalience Network(SN),butreducedwithintheDMN(20).Furthermore,increased dynamicrsFCinthecingulatecortexwasobserved1weekafterpsilocybin treatmentinindividualswithdepression(21).
Therehavebeennopreviousreportsoftheeffectsofpsilocybinon brainrsFCinindividualsofBDD.InthefirststudyofpsilocybinforBDD, werecentlyreportedsignificantlydecreasedBDDsymptomsafterasingleopen-label25mgdoseofpsilocybin(22).Thisstudyreportsonthe subsetofthoseparticipantswhoalsocompletedrs-fMRI,aimingtoinvestigatesubacuteeffectsonrsFCandtheircorrelationwithsymptom changeinadultswithBDD.WehypothesizedthatinBDD,similarlyto whatwasobservedinindividualswithdepression1daypost-treatment, psilocybinwouldincreasefunctionalconnectivityofthefollowingnetworks:ECN,DMN,andSN,andthatthesechangeswouldpredicttreatment outcomes.
Methods Participants
Twelveadultswithmoderate-to-severenondelusionalBDDreceived asingleoraldoseofpsilocybin25mgwithpsychologicalsupport (demographicinformationfoundin Table1).Eightparticipantscompletedbothpre-andpost-dosing(day1)MRIassessments,andthese
Received:3July2024.Revised:16August2024and29August2024.Accepted:30August2024. Publishedonline:24September2024.
Table1. Demographicandclinicalcharacteristicsofthesample
Gender, n
Male3
Female5
Race/Ethnicity, n
White,non-Hispanic6
White,Hispanic0
Black,non-Hispanic0
Black,Hispanic0
Asian/PacificIslander2
Other0
Education, n Collegegraduate4
Graduateorprofessionalschool4
Age,mean(SD)years36.75(8.82)
DurationofBDD,mean(SD)years23.91(11.83)
Comorbidity, n Majordepressivedisorder3
Attentiondeficithyperactivitydisorder1
Generalizedanxietydisorder1
Posttraumaticstressdisorder0
NumberofSSRI/SNRItrials,mean(SD,range)2.75(3.37,1–11)
TimefromlastdoseofSSRI/SNRItostudy treatment,mean(SD,range),weeks
Totalnumberofpsychotherapytrials,mean (SD,range)
320(219.53,6–572)
1.38(1.77,0–5)
Exposurebasedtherapytrials,mean(SD, range) 0.63(1.41,0–5)
comprisethesampleanalyzedforthisreport.Fourparticipantsdidnot completeMRIassessmentsduetohavingacontraindicationtoMRI orduetoschedulingdifficulties.Thestudydesignwasreviewedand approvedbytheNewYorkStatePsychiatricInstituteInstitutionalReview Board,andparticipants’informedconsentwasobtainedafterstudyprocedureshadbeenfullyexplained.
Inclusioncriteriawere:1)age18–55years;2)principaldiagnosisof nondelusionalDSM-5BDDfor >6months;3)atleastmoderateseverity [totalscore ≥24ontheYaleBrownObsessiveCompulsiveScaleModified forBDD(BDD-YBOCS)(23)andscore ≥4ontheClinicalGlobalImpressionSeverityScale)(24)],and4)historyofnonresponseto(orintoleranceof)apriortrialofanSSRI,serotonin-norepinephrinereuptakeinhibitor,orclomipramine,atdoseequivalentto ≥20mg/dayfluoxetine for ≥2months.Absenceofdelusionalitywasoperationalizedbya6-item totalscoreof ≤18ontheBrownAssessmentofBeliefsScale(25).
Exclusioncriteriaincludedcurrentmajordepressivedisorderof greaterthanmoderateseverity(17-itemHamiltonRatingScaleforDepressionscore >20)(26);currentsignificantsuicidalityorattemptinthe pastyear;currentorpastbipolardisorder,psychoticdisorder,borderlinepersonalitydisorder,ordissociativedisorder;alcoholorsubstance usedisorderinthepast3months,orpositiveurinedrugscreenforillicit substancesofabuse;significantcognitiveimpairment;useofinvestigationalmedicationwithin3months,depotantipsychoticwithin6months, orserotonergicmedicationwithin2weeks(6weeksforfluoxetine);presenceofsignificantmedicalillness;historyofseizuredisorder;andfemaleswhowerepregnant,breastfeeding,orsexuallyactiveandnotusing adequatecontraception.CurrentCBTforBDDwasexclusionary,butparticipantswererequiredtobeseeingapsychotherapistwithwhomthey couldcontinuenon-CBTpsychotherapyafterdosing,tofurthersupport integrationoftheirpsilocybinexperience(beyondthepsychologicalsupportprovidedwithinthestudy).
TreatmentProcedures
ThesearedetailedinSchneier etal. (22).Briefly,studydrugwasadministeredorallyat9AMasfive5mgcapsulesofCOMP360psilocybin,COMPASSPathways’proprietarysyntheticformulation,inconjunctionwith
psychologicalsupport.The25mgdosewasselectedbaseduponprior findingsofefficacyandtolerabilityfordepression(27).
Assessments
Clinicalassessmentswerecarriedoutatbaseline(1daybeforedosing), theendofthedosingday(day0),day1,andweeks1,2,3,6,9,and12 post-dosing.MRIscanswerecollectedatbaselineandday1.Theprimary efficacymeasurewasBDDsymptomseverityinthepriorweek,asmeasuredbytheBDD-YBOCS,aclinician-ratedscale(totalscorerange:0–48, withhigherscoresindicatinggreaterseverity).
NeuroimagingProcedures
NeuroimagingDataAcquisition. MRIdatawereacquired1daypriorto thefirsttreatmentsession,andagain1dayaftertreatmentusinga3T GeneralElectricPREMIER(GEMedicalSystems,Waukesha,WI,USA)witha 32-channelreceive-onlyheadcoil.Ahigh-resolutionT1-weightedthreedimensionalBRAVOsequencewasacquiredusingthefollowingparameters:T1 = 1060ms,Flipangle = 8°,fieldofview = 25.6cm,256 × 256matrix,slicethickness = 1mm.Ten-minuteeyes-openrestingstate scanswereacquiredwithTR = 900ms,TE = 26ms,FA = 52°,FOV = 21.6cm,slicethickness = 2.4mm,numberofslices = 60,numberof volumes = 300.
ImagingPreprocessing. rs-fMRIimageswerepreprocessedusingMATLABversionR2020b(TheMathWorks,Inc.,Natick,Massachusetts)and statisticalparametricmappingsoftware(SPM12;WelcomeTrustCentre forNeuroimaging,UCL,London,UnitedKingdom).Preprocessingstepsincludedslice-timecorrectionandmotioncorrectionusingasix-parameter rigidbodytransformation,thenco-registrationtoeachparticipant’sT1weightedstructuralimage.Co-registeredimageswerenormalizedtothe MontrealNeurologicalInstitute(MNI)canonicaltemplate,andsmoothed withan8mmfull-width-at-half-maximumGaussiankernel.Functional connectivityanalyseswereperformedonthesmoothedimages.
FunctionalConnectivityAnalysis
Denoising. Resting-statefunctionalconnectivityanalyseswerecarriedoutusingCONN-fMRIFunctionalConnectivitytoolboxv13(28). Beforecorrelationanalysis,band-passfilteringwithafrequencywindow of0.01to0.09Hzwasperformed.Outlierdetectionwascarriedoutwith artifactdetectiontools(ART)implementedinCONN.Outliervolumesin eachparticipantwereidentifiedashavinglargespikingartifacts(i.e.,volumes >3standarddeviationsfromthemeanimageintensity),orlarge motion(i.e.,0.5mmforscan-to-scanhead-motioncompositechangesin the x, y,or z direction).Anatomicalimagesweresegmentedintogreymatter,whitematter,andcerebrospinalfluid(CSF)regions.Covariatescorrespondingtoheadmotion(sixrealignmentparametersandtheirderivatives),outliers(onecovariateperoutlierconsistingofan1sforthe outliertimepointand0sforallothertimepoints),andtheBOLDtimeseriesfromthesubject-specificwhitematterandCSFmaskswereusedin theconnectivityanalysisascovariatesofnoninterest,andwereremoved fromtheBOLDfunctionaltimeseriesusinglinearregression.
Wecarriedoutthreeanalyses:Thefirstanalysiswastoidentifybrain regionswherechangeinrsFCfrompre-topost-dosing(day1)waspredictiveoftreatmentoutcomesmeasuredbyreductionofBDD-YBOCSscore frombaselinetoweek1.ThechangeinBDD-YBOCSscoreatweek1was usedastheprimaryclinicaloutcomeinthisstudybecauseitwastheearliesttimepointatwhichsymptomseveritycouldbeassessedoveraweek, theusualtimeframeforassessmentwiththisinstrument.Thesecond analysiswastoexplorebrainregionswherechangeinrsFCfrompre-to post-dosing(day1)waspredictiveoftreatmentoutcomesmeasuredby reductionofBDD-YBOCSfrombaselinetoweek12.Thethirdanalysiswas toidentifychangeinrsFCfrompre-topost-dosing(day1).
rsFCanalyseswerecarriedoutintwoways,using1)regionofinterest (ROI)-to-ROIcorrelationanalysisbasedonpriornetworksofinterest,and 2)wholebrainmulti-variatepatternanalysis(MVPA).
1)ROI-to-ROIconnectivityanalysiswasperformedusing19network ROIsselectedfromclassicalnetworksdefinedfromdefaultCONNtoolbox networkatlas:DMN(4ROIs),SN(3ROIs),ECN(4ROIs),dorsalattention network(DAN)(4ROIs),andlanguagenetwork(4ROIs)(29).AllROIswere definedbasedonCONN’sindependentcomponentanalysis(ICAs)ofthe
Figure1. ROI-to-ROIanalysisshowedthattheincreasedFPN–SNrsFC(lateralPFCright[lPFCr]–anteriorinsulaleftandright,andposteriorparietalcortex left[PPCl]–anteriorinsulaleftandright)predictedreductionofclinicalsymptoms(BDD-YBOCS)frombaselinetoweek1, p < 0.05cluster-levelp-FDRcorrected.LPFCr–leftanteriorinsula,andLPFCr–rightanteriorinsulahavebeenaveragedandgeneratedlPFCr–anteriorinsula(AInsula).Atotalof19ROIsfrom 5networkswereincludedintheanalysis:defaultmode(DMN),salience(SN),dorsalattention(DAN),executivecontrol(ECN),andlanguagenetwork(LAN).
HumanConnectomeProject(HCP)datasetof497participants(28).Weincluded171ROI-to-ROIconnectivitypathwaysfromthe19ROIs[19 × 1919)/2].ThemeanBOLDtimeserieswascomputedacrossallvoxelswithin eachROI.Bivariateregressionanalyseswereusedtodeterminethelinear associationoftheBOLDtimeseriesbetweeneachpairofregionsforeach subject.Bothpositiveandnegativecorrelationswereexamined.Eachconnectivityistestedindependentlyagainstanullhypothesisandconsideredassignificantifitmeetstheprespecified p-valuethreshold.The significantROIsaresubsequentlygroupedintoclusters;theseclusters suggesttheobservedeffectsareconsistentlysignificantasitisabovethe threshold.Theresultantcorrelationcoefficientsweretransformedinto z-scoresusingFisher’stransformationtosatisfynormalityassumptions. Survivingtheheightthresholdof p<.05,theseROI-to-ROIpathwaysare adjustedformultiplecomparisonusingtheFDRmethod,andFDRclusterlevelthresholdof p < .05wereconsideredsignificant.Ageandsexwere regressedoutascovariatesofnointerestinallsubjects.
2)WealsoappliedMVPAformodel-freevoxel-wisersFCanalysisusingtheCONNtoolbox.Thefirststepofthisapproachistoidentifyregions/seedswherechangeinrsFCwasassociatedwithchangeinthemain clinicaloutcomeinallthreeanalyses.Thisstepallowsnarrowingdown ofseedbrainROIsfromthevastnumberofpossibleregions.Foreach subjectandMRIsession,wecomputedpair-wisecorrelationsbetween eachvoxelandallothervoxels,whichrepresentshowsimilarthevoxelsrespondthroughoutthersfMRIdataacquisition.Tomanagethelarge amountofdata,principalcomponentsanalysiswasperformedtoreduce datadimensionality(defaultnumberof64components)byprojectingthe datafromhighdimensionalspacetolowerdimensionalsubspace(principalsubspace)suchthatthevarianceoftheprojecteddatawasmaximized;thiscapturesthevariancesofthedatausingreducedamount ofdata.Thefourstrongestspatialprincipalcomponentswereselected (30).Inotherwords,eachvoxelhadafour-dimensionalrepresentation ofthespatialpatternofitsconnectivitytoallothervoxelsforeachsubject.Then,toassesstheassociationofchangesinrsFCfrombaselineto day1withchangesinBDDsymptomsfrombaselinetoweek1(analysis1)andtoweek12(analysis2),andtoassesschangesinrsFCfrom pre-topost-dosing(analysis3),anomnibus F testwascarriedoutcomparingthebetween-subjectvarianceacrossallvoxels’connectivitypatternsinfour-dimensionalspace.Thistestyieldedseedsthatdisplayed asimilarbetween-subjectvarianceoftheirspatialconnectivity.Thus, theseclustersdefineareasofsimilarchangeinthersFCpatternsassociatedwithchangesinclinicaloutcome.Theseseedswereextractedas
ROImasksandwereappliedforseed-to-voxelwhole-brainanalysisto determinewhole-brainconnectivitypatternsthatwereassociatedwith theclinicaloutcome(changeinBDD-YBOCS).Clusterssurvivingaheight thresholdof p < .05andFDRcluster-levelthresholdof p < .05wereconsideredsignificant.
Results
Alleightparticipantscompleteddosingandfollow-upclinicalassessmentsover12weeks.BDD-YBOCSscoresdecreasedsignificantlyfrom pretreatmenttoweek1andtoweek12(p < 0.001foreach),aspreviouslyreportedforthefullsample(22).
1. Changesinfunctionalconnectivitypredictingsymptomimprovementatweek1withpsylocibin
ROI-to-ROIanalysisrevealedthatchangesinrsFCofeachoftworegions oftheECN(rightlateralPFC[lPFCr]andleftposteriorparietalcortex [PPCl])withtheSN(insula)predictedsymptomaticimprovement.Greater increasesinthesersFCswerepredictiveofgreaterresponsetotreatment measuredbyreductionofYBOCSscorefrombaselinetoweek1(p < 0.05 cluster-level p-FDRcorrected)(Figure1).
TheMVPAreplicatedfindingsoftheROI-to-ROIanalysisthatincreasedECNrsFCpredictedclinicaloutcome,andidentifiedoneseed regionintheECN,specificallyinthedlPFC[483822](Figure2).Usingthiscluster,aseed-basedwhole-braincorrelationanalysisofrs-fMRI data,correctedformultiplecomparisonsatclusterlevel(peaklevel: p < 0.05,uncorrected;clusterlevel: p < 0.05,FDR-corrected),indicatedthat greaterrsFCwithinECN(dlPFC-superiorparietallobe[SPL]),between ECNandSN(dlPFC-anteriorcingulatecortex[ACC]),andbetweenECN andDMN(dlPFC-precuneus)predictedgreaterresponsetotreatmentat week1(Figure2).
2. Changesinfunctionalconnectivitypredictingsymptomimprovementatweek12withpsylocibin
ROI-to-ROIanalysisdidnotrevealanysignificantchangesinrsFCthat predictedsymptomaticimprovementatweek12.However,atrend-level resultsuggestedthatchangeinECN-SN(lPFCr-Insula)waspredictiveof agreaterresponsetotreatmentmeasuredbyreductionofYBOCSscore frombaselinetoweek12(p < 0.008uncorrected).
TheMVPAofchangeinrsFCpredictingchangeinsymptomsfrom baselinetoweek12revealedsignificantclustersincludingthethalamus [8–68],theinsula[–428–6],theinferiorparietallobe(IPL)[–54–38
Figure2. WholebrainMVPArevealedthatoneseedregiondlPFClPFC[483822]predictedsymptomaticimprovementatweek1.Usingthisclusterasaseed region,aseed-basedwhole-braincorrelationanalysisrevealedthatincreasedwithin-ECN,ECN-SN,andECN-DMNconnectivitypredictedsymptomaticimprovement(BDDYBOCS)atday1,peaklevel: p < 0.05,uncorrected;clusterlevel: p < 0.05,FDR-corrected.
38],andtheACC[163424].Usingtheseclustersasseeds,separateseedbasedwhole-braincorrelationanalyseswereconductedforeachseedregion,andthesedidnotrevealanyotherregionsassociatedwithsymptomaticimprovementatweek12(Figure3).
3. Changesinfunctionalconnectivityfrombaselinetoday1
ROI-to-ROIanalysisdidnotrevealanysignificantchangesinrsFCfrom baselinetoday1.
TheMVPAofchangeinrsFCfrombaselinetoday1revealedonesignificantclusterinthedlPFC[–364602].Usingthiscluster,aseed-based whole-braincorrelationanalysisofrs-fMRIdata,correctedformultiple comparisonsatclusterlevel(peaklevel: p < 0.05,uncorrected;cluster level: p < 0.05,FDR-corrected),showedsignificantincreasewithinthe ECNconnectivity(dlPFC-SPL)(Figure4).
Discussion
Thesefindingsarethefirstreportofbrainchangesafterpsilocybin administrationinpatientswithBDD.Findingsindicatethatwithin-ECN connectivityincreased.Moreover,increasedwithin-ECN,ECN-DMN,and
ECN-SNconnectivitiesatday1predictedgreaterreductioninsymptoms atweek1,asmeasuredbythedecreaseinBDD-YBOCSscores.
ToassesstheclinicalrelevanceoftheseearlychangesinrsFC,beyond anybroad,nonspecificeffectsofpsilocybinonbrainnetworks,weconductedregressionanalysestoidentifyanyspecificchangesinconnectivitythatwerepredictiveofpositivetreatmentoutcomes.Theseanalysessuggestthatthetherapeuticeffectsofpsilocybinarepredictedby changesinmore-specificconnectivitypatterns,includingthosewithinthe ECN,betweentheECNandtheSN,andbetweentheECNandtheDMN. Thesefindingssuggestthatpsilocybin’sclinicalbenefitsmayderivefrom itscapacitytofostermorefunctionallyintegratedbrainnetworkactivity, particularlyinvolvingthesekeynetworks.
Within-ECN
TheECN,characterizedbyitsextensiveconnectivitywithotherbrain networks,playsaroleinadaptingandrespondingtotheexternal environmentthroughcommunicationbetweenneuralnetworks(31, 32). TheECNisparticularlyinvolvedinset-shifting,thecognitiveabilityto switchattentionbetweendifferenttasks.Thisfunctioniscrucialfor
Figure3. Whole-brainMVPArevealedthatseedregionsincludingthethalamus[8–68](yellow),insula[–428–6](green),IPL[–54–3838](red),andACC [163424](blue)predictedsymptomaticimprovementatweek1.Usingtheseclustersasseedregions,nofurtherregionswereidentified. ResearchReport Zhuetal.
Figure4. UsingMVPA,rsFCwassignificantlyincreasedwithintheECN(dorsolateralprefrontalcortex[dlPFC])frombaselinetoday1.UsingdlPFCasa seed,seed-to-wholebrainanalysisrevealedincreaseddlPFC-SPLr[28–5264] andSPLl[–34–5052]frombaselinetoday1.Peaklevel: p < 0.05,uncorrected; clusterlevel: p < 0.05,FDR-corrected.
mentalflexibilityandisoftendisruptedinneuropsychiatricdisorders.Impairedset-shiftingisacharacteristicfeatureofBDD(33, 34),andmay manifestclinicallyasdifficultymovingthoughtsorattentionawayfrom appearance-focusedobsessionalthinking.Emergingevidencesuggests thatpsilocybinmayenhancecognitiveflexibilityandset-shifting.One studyreportedneurochemicalchangesinACC1weekafteracutepsilocybinadministration,andincreasedcognitiveflexibilityassessedbysetshiftingtask4weekspost-psilocybin(21, 35).Ourfindingsofincreased subacutewithin-ECNconnectivity,specificallybetweendlPFCandSPL, andofgreaterrsFCwithintheECN(dlPFC-SPL)predictinggreaterresponsetotreatmentatweek1,alignwithobservationsinHCimmediatelyafterpsilocybinadministration(36).Incontrast,McCulloch etal. (18)reporteddecreasedrsFCwithin-ECNinHC1weekafterpsilocybinadministration.Inconsistencyinthedirectionofconnectivitychange mayberelatedtodifferencesinthetimeofscanninginrelationship topsilocybinadministration,orbaselinedifferencesbetweensamples. Insummary,subacuters-fMRIstudiessuggestthatpsilocybinleadsto changesinconnectivitywithintheECN.Moreover,ourfindingthatincreasedwithin-ECNconnectivityafterpsilocybinadministrationpredicts clinicalimprovementinpatientswithBDDisconsistentwiththeprevious reportofECN(rightSPL)involvementinthepsychopathologyunderlying BDD(18)andsuggeststhatthisincreasemaypromoteclinically-relevant enhancedmentalflexibilityanddecreasedrigidityofthoughtpatterns (21, 37).
ECN-SN
ConnectivitybetweentheECNandtheSNisimportantforthedetectionof salientcues,leadingtoefficientallocationofcognitiveresources.DifferentialactivationwithintheSNandtheECNinresponsetothestop-signal tasksuggeststhatwhiletheSNidentifiessalientevents,theECNisinvolvedininhibitorycontrolandset-shifting(38).TheSNmaybeapotentialabiomarkerinBDDparticipants,assuggestedbystructuralandtaskbasedfMRIfindingsofSNregions(8, 36, 39, 40).InHC,onestudyrevealed increasedrsFCconnectivitybetweentheECNandSNacutely,at70minutesfollowingpsilocybinadministration(36).OurstudyassessedECN-SN rsFCsubacutely,1daypost-psilocybin.Specifically,wenotedthatgreater rsFCbetweentheECNandinsulapredictedclinicalimprovementatweek 1(41).EnhancedECN-insularsFCmightfacilitateexecutivecontrolover emotionalandsalientstimuli,byshiftingattentionawayfromemotionallysalientcuesandsupportingemotionalregulation(38, 42, 43).Consequently,thismayrepresentamechanismthroughwhichpsilocybincontributestoareductionintheobsessive,negativeemotionally-valenced preoccupationwithperceivedflawscharacteristicofBDD.
ECN-DMN
TheDMNisinvolvedinself-referentialthoughts,mind-wandering,and internallyfocusedtasks.rsFCbetweentheECNandtheDMNplaysan importantroleinswitchingbetweentask-focusedstatesandintrospectiveorself-referentialstates.DecreasedECN-DMNconnectivityhasbeen identifiedasabiomarkerunderlyingdepression,implyingexecutivedysfunctioninregulatingtheDMNthroughinhibitorycontrolandemotional regulation(44).IncreasedECN-DMNrsFChasbeenobservedsubacutely afterpsilocybininadepressedsample(20).Alonger-termfollow-upMRI studyalsoobservedincreasedECN-DMN3weeksafterpsilocybinadministration(21).Lastly,increasedECN-DMN1dayafterpsilocybintreatmenthasbeenfoundtopredictalleviationofdepressivesymptoms(10). OurfindingsofincreasedECN-DMNrsFCpredictingsymptomreduction atweek1inpatientswithBDDisconsistentwiththisliterature.Reduced rsFCbetweentheECN(SPL)andtheDMN(posteriorcingulatecortex)has beenassociatedwithseverityofself-focusedattentioninBDD(16, 45). Theobservedpost-psilocybinincreaseinrsFCbetweentheECN(LPFC) andtheDMN(precuneus)isconsistentwithafunctionalenhancementof emotionregulationcapacityinBDDthroughfacilitatingtheswitchaway fromself-focusedattention(46, 47).
WeusedbothROI-to-ROIandMVPAsinthisstudy.TheMVPAnotonly replicatedthefindingsfromROI-to-ROIanalysis,butalsoextendedthem byidentifyingadditionalsignificanttargetclusters.MVPAiscapableof findingpatternsofneuralimagingdataatvoxel-level.Unliketraditional univariateapproaches(e.g.,ROI-to-ROI)thatevaluateeachregionorconnectioninisolation,MVPAconsidersthefullspatiotemporalpatternof brainactivity.Thisallowscaptureofsubtleinteractionsbetweenregions, whichmightbemissedwhenlookingateachregionseparately,asiscommoninROI-to-ROIanalyses.OurresultssuggestthatMVPAheredetected nuancedpatternsofrsFCinvolvingtheDMNthatwerenotprespecifiedin theROI-to-ROIanalysis.Furthermore,MVPAidentifiedspecificincreased connectivitiesofdlPFCwiththeSPL,ACC,andprecuneus,whichindicatea broaderintegrativeroleofthedlPFCacrossmultiplenetworks(ECN,SN, andDMN)predictiveoftreatmentresponseatweek1.
Week12:Consistentwiththefindingspredictingweek1outcome, theROI-to-ROIanalysisrevealedatrendresultsuggestingthatincreased connectivitybetweenECN-SN(lPFCr-Insular)waspredictiveofagreater responsetotreatmentatweek12.However,thisresultdidnotsurvive correctionformultiplecomparisons.Incontrast,theMVPAfoundnosignificantrsFCoftheseidentifiedseedregionstobepredictiveofclinical outcomeatweek12.Thelossofsignificancesuggests,perhapsunsurprisingly,thatlong-termoutcomesmaybelessdirectlytiedtotheearly changesinnetworkconnectivitythatcoulddiminishovertime.McCulloch etal. (16)reportedimpermanenceofneuroplasticityinHCs,notingasignificantreductioninwithin-ECNrs-FCatweek1thatwasnolongerevidentatthe3-monthtimepoint.Thelong-termmaintenanceoftheearly clinicalresponseobservedfollowingpsilocybinadministrationcouldbe affectedbymanyfactors,includingpreexistingpsychopathology,brain
function,andinteractionwithenvironmentalinfluences,suchastheongoingpsychotherapyreceivedbymostparticipantsinthisstudy.
Limitationsofthisstudyincludeitssmallsamplewithlimiteddiversity,whichincludedsixCaucasiansandtwoofAsian/Pacificdescent,all withacollegedegreeandhigher.Thesmallsamplesizeandtheabsence ofacontrolgroupsuggeststhattheobservationsmustbeconsideredtentative,butnonethelessprovidethefoundationofpsilocybin’stherapeuticpotentialinBDDwarrantingfutureinvestigations.Futurestudiesof morediverseandlargersamplesareneededtoverifytheseobservations andevaluatetheirgeneralizability.Second,theabsenceofacontrolgroup raisesconcernsaboutnonspecificconfoundscontributingtotheobserved neurobiologicalchanges.Theseconfoundscouldincludeexpectancyeffectsandtheeffectsofpsychologicalsupportandpsychotherapyreceived byallparticipants.Futurestudiesshouldincludeacontrolgrouptoclearly differentiatethespecificeffectsofpsilocybinfrompotentialplaceboeffectsandtoestablishacausalrelationshipbetweenpsilocybinadministrationandobservedchangesinneuralconnectivityandsymptomatology.Third,thestudy’ssingle-dosedesign,withMRIrepeated1day afterdosing,waschosentominimizeparticipantburdenandtofocuson thesubacuteclinicalandneuraleffectsofpsilocybin.Obtainingamore comprehensiveunderstandingofpsilocybin’smechanismsanddurability oftreatmenteffectswillrequirestudyofmultiple-dosingregimenswith longerfollow-upperiods,andwithimagingrepeatedatacute,subacute, andlonger-termtimepoints.
ThecurrentstudyprotocolalsoexaminedrsFCchangesonlyat 1dayafteradministrationofpsilocybin.Futurestudiesshouldincorporatescanningacrossacute,subacute,andlong-termtimepointstofacilitateamorecomprehensiveunderstandingofthelongitudinalimpact ofpsilocybin.Imagingattheacutetimepointmayreflectneuralcorrelatesofthepsychedelicexperience,atthesubacutetimepointearly changesinclinicalsymptoms,andatlonger-termtimepointspersistent changesinclinicalsymptoms.Futurestudiesshouldalsoexplorewhether acutesubjectiveeffectsofpsilocybinareassociatedwithneuralconnectivitychangesatthesetimepoints.Lastly,previoustask-basedresearch inBDDparticipantshasidentifiedabnormalitieswithinvisual,perceptual,andattention-relatednetworks(7, 45),alteredconnectivitybetweenfusiformfacialareaandhubswithinDMNandSNwhileviewingimagesofotherfaces(39, 40).TheECNalterationthatwasobservedinthis preliminarystudymayberelatedtocognitivecontroloverSNandDMN hubs,thusachievingalteredconnectivitybetweenSNand/orDMNand othervisual,perceptual,andattention-relatednetworks.Futurestudies shouldexploretheECN’sroleininterventionaluseofpsilocybininBDD.
Insummary,ourstudyprovidesapreliminaryexplorationofneurobiologicalmechanismsunderlyingpsilocybintreatmentforBDD.Wefound increasedwithin-ECNconnectivity,andfoundthattheincreasedwithinECN,ECN-SN,andECN-DMNconnectivitypredictedclinicalimprovement frombaselinetoweek1.OurfindingsareconsistentwithviewingtheECN asacentralhuboftheneurobiologicalunderpinningsofBDDandsuggestthatpsilocybinmayexertitstherapeuticeffectthroughmodulation ofthesenetworks.Thisindicatespotentialneuraltargetsforenhancing theeffectivenessoftreatmentsforBDDandmayguidefuturetherapeutic strategies.
AuthorDisclosures
F.S.hasreceivedresearchsupportfromCompassPathways,Otsuka,Vistagen,andNIMH,royaltiesfromUptoDate,CambridgeUniversityPress,and GuilfordPress,andservedasconsultanttoReceptorLifeandPureTech. D.H.hasreceivedresearchsupportfromCompassPathways,Relmada, IntracellularTherapies,BeckleyFoundation,servesonthescientificadvisoryboardforResetPharmaceuticalsandhasreceivedroyaltiesfrom JohnsHopkinsUniversityPressandColumbiaUniversityPress.J.D.F.receivesresearchsupportfromtheNIMH,NIBIB,andtheKlarmanFamily FoundationandservesasaconsultanttoNOCD,Inc.M.G.W.,X.Z.,andC.Z. andG.G.havenofinancialrelationshipstoreport.
FundingSources
ThisresearchwassupportedbyagrantfromCompassPathwaysPLC, UnitedKingdom.Compasssuppliedmaterialsandparticipatedinformu-
latingtheoutlineofthestudybuthadnoroleinstudyselectionorinterpretationoftheevidence.
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OPEN RESEARCHREPORT
Readingthecrowd:attitudestoward psychedelicsandpsychedelictherapies amongattendeesataconference
ZacharyBosshardt1 , 2 ,JessicaL.Maples-Keller1 , 2 , DeannaM.Kaplan2 , 3 , 4 ,BarbaraRothbaum1 , 2 ,SarahEisenacher1 , 2 , KimDupreeJones2 , 5 , 6 ,TanjaMletzko1 , 2 ,GeorgeH.Grant2 , 3 , 5 , BoadieW.Dunlop1 , 2 ,AliJohnZarrabi2 , 3 , 7 ,andRomanPalitsky1 , 2 , 3
1 DepartmentofPsychiatryandBehavioralSciences,EmoryUniversity SchoolofMedicine,Atlanta30329,Georgia
2 EmoryCenterforPsychedelicsandSpirituality,EmoryUniversity, Atlanta30322,Georgia
3 EmorySpiritualHealth,WoodruffHealthSciencesCenter,Emory University,Atlanta30322,Georgia
4 DepartmentofFamilyandPreventiveMedicine,EmoryUniversity SchoolofMedicine,Atlanta30322,Georgia
5 NellHodgsonWoodruffSchoolofNursing,EmoryUniversity,Atlanta 30322,Georgia
6 DivisionofNeurology,OregonHealth&ScienceUniversity,Portland 97239,Oregon
7 DivisionofPalliativeMedicine,DepartmentofFamilyandPreventive Medicine,EmoryUniversitySchoolofMedicine,Atlanta30322,Georgia
CorrespondingAuthors: RomanPalitsky,MDiv,PhD,WoodruffHealth SciencesCenter,PsychiatryandBehavioralSciences,1440CliftonRd, Room102,Atlanta,GA30303.E-mail: roman.palitsky@emory.edu;and ZacharyBosshardt,MD,12ExecutiveParkDrive,Suite142,Atlanta,GA 30329.E-mail: zbossha@emory.edu
Psychedelics January2025;1(1):32–38; doi: https://doi.org/10.61373/pp024r.0040
Socialattitudes,policy,andperceptionsofpsychedelicsarecurrentlyundergoingconsiderablechange.Growingpublicsalienceof psychedelicshasbeenaccompaniedbytheemergenceofconferences focusedonpsychedeliceducationanddialogue.Attendeesatsuch eventscomposeanimportantgroupofstakeholdersinpsychedelicscienceandpractice;theirviewsofpsychedelicscanbevaluableforunderstandingthecurrentstatusofthisemergingfield.Forthisstudy,a surveywasadministeredtoattendees(N = 178)atanacademicconferencefocusedontwotopics:psychedelicsandspiritualcare.Thesurvey queriedattitudestowardpsychedelicsinemergingresearchdomains: 1)thepotentialbenefitsofmicrodosingand2)potentialforharm withpsychedelicsuse.Asubsetofattendeeswhowerefacilitators ofpsychedeliccare(n = 32)werealsoaskedabouttheirfacilitation practicesandtheirbeliefsconcerningaspectsofpsychedelicfacilitation.Participantsgenerallyagreedthatmicrodosingmayhavebenefits (M = 3.90,where4 = Probably,SD = 0.95)andmodestconcern(40.2% (n = 72)agreedorstronglyagreedand30.7%(n = 55)respondents“not sure”)thatpsychedelicscouldbeharmfulwhenusedtherapeutically. Descriptiveanalysesofasubsetofpsychedeliccarefacilitatorsalso characterizedharmsobservedduringpsychedeliccare.Psychedelic carefacilitatorsreportedthattheyusedpsychedelicstotreata widerangeofdiagnoses,employingdiversepsychotherapymodalities,andendorsedaneedforculturaladaptationsamongpsychedelic treatments.
Keywords: Attitudes,microdosing,adverseeffects,psychedelics conference,psychedelicfacilitation.
Introduction
Psychedelicsareagroupofcompoundsknowntohavepotenteffectson subjectiveexperience,cognition,andemotion,oftenwithprofoundimpacts,evenafterasingledose.Theyinclude“classicpsychedelics”suchas 5HT2AreceptoragonistspsilocybinandLSD,aswellasothercompounds suchasMDMA,Ibogaine,andKetamine.Manypsychedelicshaveextensive historiesofceremonialuseinIndigenoussettings,aswellasinextralegal settingswith“underground”practitionerswhoprovidepsychedeliccare. Theiruseinhealthcaresettingsisnowemergent,includingasanexperimentaltherapywithpromisetotreatarangeofpsychiatricconditions.Althoughclinicaltrialsreflectpossiblebenefit,ongoingconcernsregarding studymethodologyandtherisksofadverseeventsrelatedtopsychedelic treatmentremain(1).
Attitudestowardpsychedelicsaredevelopingamidstincreasingscientificevidenceofpotentialefficacyfordifficulttotreatconditions(2, 3),as wellas“hype”inpopularmedia(4).Theseattitudescanvaryasafunction ofprofession,demographics,andothercharacteristics(2, 5).Astudyof attitudestowardpsychedelicsamongthegeneralpopulationinCroatia foundthatyounger,male,andlesseducatedrespondentshadmorefavorableattitudestowardpsychedelics(6).Otherstudiesfoundthatinthe UnitedStates,47.9%ofpsychologistswereconcernedaboutpsychiatric riskswithpsychedelictreatment(7)and80.39%ofpsychiatristsagreed thatpsychedelicsshowpromise(8).Asurveyofwideraudiencesofmental healthcareprovidersfoundthatwhile“amajorityofparticipants(91%) believedpsychedelicsaresafeundermedicalsupervision,asubstantial minority(33%)ofparticipantsbelievedrecreationalpsychedelicuseto beunsafe”(2).
Theperspectivesofpsychedelicfacilitators,whoincludepractitioners inlegal“aboveground”andnonlegal“underground”settings,areespeciallyimportantbecauseoftheirroleindisseminatingpsychedelictreatments(9).Qualitativestudiesofpsychedelicfacilitatorshavehighlighted therisksofpsychedelictreatment(10, 11),aswellastheutilityofdifferentprofessionalbackgroundsandrolesinpsychedelictherapy(12).However,thevarietyofmodalities,perceptionofappropriatetherapygoals, andpracticesamongfacilitatorsarenotwellunderstoodwithin(13)or outsideofclinicaltrials.
Shiftingopinionstowardpsychedelicshavebeenaccompaniedbya growthindustryofacademicandpara-academicconferencesandsymposia,focusedoneducation,dissemination,networking,anddialogue aroundpsychedelics.Sucheventscanplayaroleinshapingacademic(14) andsocial(15)impact.Attendeesatsucheventsconstituteakeygroupin thelandscapeofpsychedelicstudies,representingthosewhoarelikelyto beinvestedinunderstandingpsychedelics,learningaboutthem,andconnectingpsychedelicresearchersandproponentswiththeir“publics”(16). Althoughitisimperativetounderstandtheviewsandpracticesofthis groupofstakeholdersgiventheirinfluence,theymayalsobeahighlymotivatedsubgroupandpotentiallysubjecttobiasestowardpsychedelics (17).Forthisreason,identifyingaconferencewithmixedattendance— includingindividualsinterestedinpsychedelicsandthoseinterestedin anothertopic—providesanoptimalopportunitytostudyattitudestoward psychedelicsamongconference-goerswithvariedinterests.Thepresent researchsurveyedattendeesatanacademicconferencefocusedontwo themes:1)spiritualhealth(i.e.,chaplaincy),and2)psychedeliccare,and thusmayhavedrawnamoremixedcohortofattendeesthanexclusively psychedelics-focusedconferences.Thissurveyqueriedpsychedelicattitudes,beliefs,priorities,and(forpsychedelicfacilitatorsamongattendees)thepracticestheyfavoredandbeliefsaroundthosepractices.This studyaimedto1)investigateconferenceattendees’attitudestowardthe benefitsandrisksofpsychedelics,andgraspcurrenttrendsintheseattitudesacrossparticipants’backgroundcharacteristics,and2)evaluate beliefsaboutpsychedelicassistedtherapyamongpsychedelicfacilitators whoattended.
Received:11May2024.Revised:9November2024and28November2024.Accepted:28November2024. Publishedonline:17December2024.
MaterialsandMethods
Recruitment
Aninternational,hybrid(onlineandonsite)single-daysymposiumwas heldbyEmoryUniversityintheSpringof2023.Attendeesoftheconferencewereinvitedtoparticipateinanonlinesurveyadministeredthrough REDCapthroughalinktheyreceivedbyemail.All1144registrantstothe conferenceweresentalinktotheonlinesurvey.Thisstudywasapproved bytheInstitutionalReviewBoardatEmoryUniversityandparticipants providedinformedconsent.
Materials
Anexploratorysurveycomprising134itemswasdevelopedbyaninterdisciplinarygroupofauthorstoassessthecharacteristicsofattendees (seeSupplementalDocumentsS1andS2).The134totalitemswereinclusiveofbranchingsurveylogic.Thus,participantstypicallyanswered fewerquestions,withspecificitemsdependingontheitemsparticipants endorsed.Forexample,psychedeliccarefacilitatorshadmorequestions thannonfacilitators,duetospecificquestionsabouttheirpracticethat wouldbeirrelevanttootherrespondents.Thesubsetofsurveyitemsexaminedinthisarticle(detailedbelow)wasanimatedbyinterestsin:1)potentialharmofpsychedelics,evenintherapeuticcontexts;2)perspectives onthebenefitsofmicrodosing,and3)practicesandperspectivesamong psychedelictherapyfacilitators.Participantsalsowereaskedquestions about:personalbackgroundanddemographicinformationincluding age,gender,educationalattainment,perceivedsocioeconomicstatus, parenthood,militaryservicebackground,rurality,race,ethnicity,religiousaffiliations,frequencyofreligiousserviceattendance,andwhether participantscurrentlyworkedinahealthcareenvironment(seeSupplementalDocumentS1forfurtherdetail).Anattentioncheckaskingparticipantstoselectaspecifiedresponsewasutilized,andparticipantswere excludedfromanalysisiftheydidnotrespondcorrectly:“Ifyouarereadingthisquestion,pleaseselect“probablyno”—thisquestionisjustto checkwhetheryouarepayingattention.”Participantswereasked,intwo separatequestions,abouttheextenttowhichtheirmotivationforattendingtheconferencewasduetoaninterestin1)psychedelics,or2)orspirituality(1 = notatall,5 = extremely,foreachtopic).Attendeeswereasked aboutpriorpersonalpsychedelicuse(yes/no),personalpsychedelicuse inatherapeuticcontext(yes/no),orwhethertheyever“facilitatedthe therapeutic,healing,ormedicaluseofpsychedelics”(yes/no).Thosewho endorsedthefinalitemwerepresentedwithitemsspecifictopsychedelic facilitators.
OneLikert-typeitemqueriedbeliefsaboutpotentialharmsassociatedwithpsychedelics:“Ifusedtherapeutically,psychedelicscouldstill beharmful”(1 = stronglydisagree,5 = stronglyagree,or“Notsure”).One itemattemptedtoevaluateperceivedbenefitsofpsychedelicsbyasking aboutatopicthathasbeenlessresearched,andthereforedeemedmore susceptibletogeneralattitudestowardpsychedelics:microdosing.“Do youbelievethatmicrodosingofapsychedelichasbeneficialeffects?”with responseoptions(1 = definitelyno,5 = definitelyyes,or“Notsure”).
Participantswhoendorsedfacilitatingtherapeutic,healing,ormedicaluseofpsychedelicswerepresentedwithadditionalitems(seeSupplementalDocumentS2).Facilitatorswereaskedtoselectfromalist ofconditionsthattheyhavepersonallytreatedwithpsychedelics.Anotheritemaskedthemtoratetheimportanceofdifferentpsychotherapeuticelementsinpsychedelictherapy(psychologicalinsight,experience ofconnectionwithothers,traumaprocessing,experienceofconnecting withnature,moodimprovement,spiritualormysticalexperiences,ego dissolutionexperience)(1 = notimportant,5 = extremelyimportant). Participantswereaskedtoselectfromalistof“longterm(occurring >1monthafterdosing)challenging,difficult,ordistressingexperiences inindividualstreatedwithpsychedelicassistedtherapythatyouwould attributetothetreatment.”Theywerespecificallyaskedwhetherthey hadeverobserveda“spiritualharmtohappentoindividualstreated withpsychedelicassistedtherapy,”(1 = never,5 = allthetime).Three itemsqueriedperspectivesonindigenousandbiomedicalapproachesto psychedelichealingbyasking(1 = notatall,5 = entirely)whether1) useofpsychedelicsshouldprimarilybebasedinindigenoushealingcontexts,2)scientific/medicalhealingcontexts,and3)thenecessityofcul-
turaladaptationsinpsychedeliccare.Facilitatorswereaskedtheirmental healthprofessionalroles,andwhichapproachesormodalitiestheyused whenworkingwithclients.
Analyses
StatisticalanalyseswerecompletedwithSPSS29.Descriptivestatisticsweregeneratedforalldemographicvariables.Averageratingsof potentialharmsofpsychedelicsandpotentialbenefitsofmicrodosing weregeneratedfortheoverallsampleandforpsychedeliccarefacilitatorsspecifically.Becausethesurveyallowedparticipantstoendorse morethanonereligiousaffiliation,theassociationsbetweenanyreligiousaffiliation,spiritualbutnotreligious,agnostic,ornoreligiousaffiliationandattitudestowardpsychedelicswereexaminedinseparatemultivariatelogisticregressions.Exploratorybivariatecorrelationsexamined associationsamongcontinuousvariablesincludingage,frequencyofreligiousserviceattendance,socioeconomicstatus,andreasonsforattendingtheconference(compassion-centeredspiritualhealthorinterestintheintersectionofpsychedelicsandspirituality),withKendall’s tauusedforlevelofeducation.Beliefsaboutpsychedelics(harms,microdosing)wereseparatelycomparedbetweensubgroupswithinrace, ethnicity,urban/suburban/ruralresidence,andgender,usingone-way ANOVAs.Independentsample t testscomparedbeliefsaboutpsychedelics basedondichotomous(yes/no)differencesinparentalstatus,military service,recreationalpsychedelicuse,therapeuticpsychedelicuse,work asapsychedelicassistedtherapyfacilitator,andwhetherparticipants currentlyworkedinhealthcare.Significancethresholdwas p = .05(twotailed),butbecauseofthedescriptiveandexploratorynatureofthese analyses(and,correspondingly,nocorrectionformultiplecomparisons), significancevaluesarereportedprimarilyfordescriptivepurposes.Descriptivestatisticsweregeneratedforitemsspecifictofacilitators.
Results
Atotalof243participantscompletedconsentandrespondedtothe survey.Atotalof65wereexcludedfromanalysisduetofailedattentionchecks.Amongtheremaining178respondents,32endorsedprior psychedelicfacilitation.Sampledemographicsandfacilitators’professionalrolesandcaretypesaredisplayedin Table1.Amongpsychedelic carefacilitators,56%(18)reportedpriorpersonaltherapeuticuseand 87%(28)reportedpriorrecreationaluse.
Beliefsaboutpotentialharmfrompsychedelicsvaried,withacentraltendencytowardthemiddleofthescaleamongallparticipants n = 178(M = 3.44,SD= 0.982)andamongfacilitators n = 32(M = 3.26, SD = 0.984),withnodifferencebetweenfacilitatorsandnonfacilitators n = 146(t = 1.074, p = 0.285)(Figure1A).Atotalof40.2%(72)ofall participantsagreedorstronglyagreedthatpsychedelicscouldstillbe harmfulevenwithintherapeuticcontexts,and30.7%(55)respondents answered“notsure.”Endorsementofpotentialforharmwasonlyassociatedwithspiritualbutnotreligiousidentity(B = 0.548,SE = 0.253, F = 1.566,OR = 1.73, p = 0.032).
Participants(M = 3.90,SD = 0.95)andfacilitators(M = 4.04,SD = 0.82)demonstratedsomeagreementthatmicrodosinghasbenefits(responseof4 = Probably),withnodifferencebetweenfacilitatorsandnonfacilitators(t =−0.889, p = 0.376),see Figure1B.Atotalof23.5%(42)of allrespondentsresponded“notsure”tothisquestion.Onlyweakassociationswithparticipantcharacteristicswereobserved,witholderparticipants(r = 0.19, p = 0.032)andthosemotivatedtoattendtheconference becauseofinterestinpsychedelics(r = 0.19, p = 0.036)morelikelyto agree.Greaterbeliefinbenefitsofmicrodosingwasendorsedbyurban n = 83(vs.urban n = 76)respondents(F = 3.945,meandifference = 0.492,SE = 0.175, p=0.006),andbywomen n = 126(vs.men n = 45) (F = 2.648,meandifference = 0.459,SE = 0.200, p = 0.024).
Allofthelong-term(occurring > 1monthafterdosing)postpsychedelicchallengesthatwerequeriedwereobservedbyatleastsome facilitators,exceptfordissociativeorsomaticproblems(see Figure2A). Themostfrequentlyendorsedlong-termchallengewas“problemswith mood”(n = 5,15.6%).Amongfacilitators,9.4%(3)endorsedhavingobservedaspiritualharminindividualstreatedwithpsychedelic-assisted therapy.
Table1. Thecolumnsrepresentrespondentswhowerepsychedeliccarefacilitatorsontheright,versustherestofthesampleontheleft. Therowsaredemographicfactors.Thebottomofthetableshowsadditionalmentalhealthcarepsychedelicfacilitatorsprovide Facilitatedthetherapeutic,healing,ormedicaluseofpsychedelics
No(n = 146)Yes(n = 32) MeanCount%MeanCount%
Age50.6854.19 SocioeconomicStatus(1–10)7.197.62 ParentNo5940.7%721.9% Yes8659.3%2578.1% CommunitysettingUrban6343.2%1340.6% Suburban6947.3%1443.8% Rural149.6%515.6% MilitaryNoservice13794.5%3196.9% MilitaryService85.5%13.1% “NoReligion”Didnotchoose“No Religion”
Choseareligiousaffiliation11679.5%2165.6% GenderFemale10673.1%2064.5% Male3524.1%1032.3% Transgender42.8%13.2% RaceBlack/AfricanAmerican149.6%13.1% Multiracial96.2%00.0% White10874.0%2578.1% NativeAmerican00.0%00.0% Asian53.4%26.3% Other/PreferredNotToSay106.8%412.5% EthnicityHispanic85.9%13.3% Non-Hispanic12794.1%2996.7% CurrentlyprovidehealthcareNo6042.0%1237.5% Yes8358.0%2062.5% HighesteducationalMiddleSchoolorless00.0%00.0% experienceSomehighschool00.0%00.0% Highschooldiploma00.0%13.3% Somecollege32.1%00.0% Technical/vocational certification 00.0%00.0%
4-yearcollegedegree2114.4%310.0% Mastersdegree7853.4%1446.7% Doctorateorequivalent4430.1%1240.0%
PersonalpsychedelicuseNo8861.1%412.5% Yes5638.9%2887.5% PersonalpsychedelicuseforaNo12686.3%1137.9% therapeuticpurposeYes2013.7%1862.1%
Mentalhealthcare,otherthanpsychedelicassistedtherapyCount%
Electromagneticstimulationtreatment(e.g.,rTMS,ECT,tCDS)00.0%
Figure1. Displaysresponsesfromallparticipants(n = 178)ontheleftandpsychedeliccarefacilitators(n = 32)ontherightregardingharms(A)andmicrodosing (B).Responsesarefromstronglydisagree1tostronglyagree5.(A)Ifusedtherapeutically,psychedelicscouldstillbeharmful.(B)Doyoubelievethatmicrodosing ofapsychedelichasbeneficialeffects?
Themostfrequentlyreportedconditionfacilitatorsendorsedtreating withpsychedelicswasanxiety(43.8%, n = 14).Nofacilitatorsendorsed treatingdementia,sociopathy,oreatingdisorders(see Figure2B).Atotalof21.9%(7)respondentsselected“Idon’tthinkaboutmyworkwith psychedelicsintermsofmentalhealthproblemsinthisway.”Facilitatorsidentifiedmultipletherapeuticapproacheswiththeirclients,with 65.6%(21)selectingsupportiveorRogerianpsychotherapy,although thisquestiondidnotspecifywhetherthesemodalitieswereusedduringpsychedeliccareormorebroadly(summarizedin Figure2C).Facilitatorsacknowledgedthefollowingfactorsasimportantforefficacy intreatment,withmeanimportanceindescendingorder:psychologi-
calinsight(M = 4.30SD = 0.669),experienceofconnectionwithothers (M = 4.12SD = 0.653),traumaprocessing(M = 4.08SD = 0.812),experienceofconnectingwithnature(M = 4.07SD = 0.675),moodimprovement(M = 3.85SD = 0.834),spiritualormysticalexperiences(M = 3.70 SD = 0.993),egodissolutionexperience(M = 3.63SD = 0.824).Facilitators’responseswereconsistentwithneutral(neitheragreenordisagree) viewsthatpsychedelicsshouldbeprimarilybasedinindigenoushealing contexts(M = 2.65,SD = 0.988),oronscientific/medicalhealingcontexts (M = 2.92,SD = 1.018).Averagescoreswereconsistentwithslightagreement(M = 3.53,SD = 0.772)thatculturaladaptationswereneededin psychedeliccare.
Figure2. (A)Long-termchallengingexperiencesinindividualstreatedwithpsychedelic-assistedtherapy(n = 32).(B)Conditionsfacilitatorstreatwith psychedelics(n = 32).(C)Psychotherapymodalitiespsychedelicfacilitatorsuse(n = 32).
Discussion
Thissurveycontributestotheunderstandingofbeliefsabout psychedelicsheldbyindividualswhoareinterestedinpsychedelics andspiritualcare,includingasubgroupofpsychedeliccarefacilitators. Notably,theconferencefromwhichparticipantswererecruitedincluded attendeeswhoweredrawntotheeventbasedontheirinterestineither spiritualhealth,psychedelics,orboth,giventheoverlapbetweenthese
fields.Historically,spiritualhealthcliniciansworkinginmedicalandother organizationalsettingshavebeenchaplains,andwereoftenassociated withtraditionalreligiousperspectivesalthoughthisislikelyshifting(12, 18).Thus,thesamplemayhaveincludedindividualswithvaryinginterest inpsychedelicsacrossarangeofprofessionalbackgrounds. Harmswithinpsychedelictreatmentsmaybedistinctandmorechallengingtomonitorthanotherclinicalinterventions,giventheircombined
treatmentwithpsychotherapyandpotentialforprofoundexperiences thatmayshiftsocioculturalorpsychospiritualperspectives(19).Beliefs aboutpotentialharmsofpsychedelicsendorsedbyconferenceattendees maybeindicativeofconcernsheldbyanimportantsubsetofthepublic. Atotalof40.2%ofallparticipantsagreedthatpsychedelicscouldstillbe harmfulevenwithintherapeuticcontexts,andanother30.7%chose“not sure”forthisquestion.Thesubsetoffacilitatorsinthissurveywerealso queriedregardingspecificharmstheyhaveobservedlastinglongerthan amonthandhighlightedseveralproblemsresultingfrompsychedelic treatment.Thismirrorsconcernsofpsychedeliccarefacilitatorsregardingacuteandpersistingeffectsofpsychedelicsthathavebeenreported inqualitativestudies(10, 11).Thesefindingshighlightandaffirmongoingconcernsforsafetyinpsychedelictreatmentinrecentmediaandscientificpublications,aswellascallsforenhancedmonitoringofadverse eventsinpsychedelictreatment(20).Emergingframeworksformonitoringadverseeventsarebeingdevelopedtowardthisaim(19–21).
Beliefsaboutthebenefitsofmicrodosinghadgreatervariation,includingmoredifferencesbetweensubgroups,withtheoverallsample selectingthatmicrodosing“probably”hasbenefits.Somedifferencein communitiesmaybeexpectedgiventheongoingdebateofmicrodosing’s risksorbenefitsintreatmentandlimitedscientificexaminationofthis approach(22).Becausethebenefitsofmicrodosinghavenotbeenempiricallyestablished,beliefsabouttheirbenefitsmayextendfrommoregeneralizedpositiveviewsofpsychedelics.Notably,participantsweremore likelytoendorsebenefitstomicrodosingiftheyweremotivatedtoattendtheconferencebecauseofinterestinpsychedelics,providingsome supportforthisinterpretation.
Psychedelicfacilitatorshighlightedutilizinganumberofstructured andunstructuredpsychotherapeuticapproachesintheirpsychedelicand generalpractice.Manualsinclinicaltrialsofpsychedelictherapiesoften emphasizearelativelyunstructured,client-directedapproach,although manytrialshavenotspecifiedthepsychotherapeuticapproachused(13). FacilitatorsinthisstudyidentifiedtheirapproachaspredominantlysupportiveorRogerian(65.6%).However,facilitatorsidentifiedspecificmanualizedtherapeuticapproachesaswell,includingCognitiveBehavioral Therapy(CBT),AcceptanceandCommitmentTherapy(ACT),andDialecticalBehavioralTherapy(DBT),withtheirclients.Thissuggeststhatdespite atendencytousenondirectivetherapyinresearchsettings,psychedelic facilitatorsexhibitarangeofapproaches,includingoneswithactiveand directivecontent(23).Morestructuredandmanualizedapproachesare beingdevelopedtotestinpsychedelictreatments(24, 25).
Psychedelicfacilitatorsendorsedtreatingabroadrangeofconditions, includingdiagnosesthathavepreviouslyconstitutedexclusioncriteriafor randomizedcontrolledtrials(26),suchasbipolardisorder,personality disorders,orautismspectrum,orforconditionswhereclinicalresearch onpsychedelicsdoesnotyetexist,suchasphysicalinjury(27).Thisindicatessomedegreeofdiscrepancybetweenthereportedscopeofpractice amongfacilitatorsandtheempiricalresearch.Itsuggests,ononehand, thepotentialforinformationfromfacilitatorstoinformclinicalunderstandingsofpsychedelictreatment,aswellasimplementation(or,for caseswhereevidenceisnotsupportive,de-implementation)ofsafeand effectivepsychedeliccare.
Debatesaboutemergingnormsinpsychedelicusehaverevealedculturalborrowing,appropriation,andbiomedicalizationastensionpoints. Ethicalandpragmaticargumentshavesupportedauseofpsychedelics thatisconsistentwith,orhasreciprocalrelationshipwith,Indigenous practices,values,andcultures(28).Ontheotherhand,movementstolegalizepsychedelicsanddeveloptheirsafeandeffectiveuseforthetreatmentofdisordershavereliedonbiomedicalmodelsofpsychedeliccare (29, 30).Alongsidetheseperspectives,culturaladaptationofmedical treatmentsisincreasinglyrecognizedasapublichealthneed,including inpsychedeliccare(31).Culturaladaptationsofempiricallysupported treatmentsarenoninferior,andoftensuperior,totheirnonadaptedcounterparts(32).Advancingculturaladaptationsinthefieldofpsychedelics willrequireculturallyresponsiveeffortstorecruitdiverseparticipants, researchers,andclinicians(33).Facilitatorsinthepresentstudyendorsed moderatebeliefsthatpsychedelicsshouldbegroundedinscientificmedicalaswellasIndigenoushealingcontexts,withmoreconsistent
endorsementofaneedforculturaladaptationsamongpsychedelictreatments.
Typically,mentalhealthprofessionalsarenotexpectedorrequiredto havepersonalexperiencewiththeremediesusedbytheirpatients(althoughlivedexperienceofmentalhealthchallengesamongclinicians maybeanasset)(34).Forpsychedelicfacilitators,however,personalexperiencewithapsychedelicmaybeatacitorexplicitexpectation.Most psychedelicfacilitatorsinthissurveyhadusedpsychedelicsthemselves, eithertherapeutically(56%)orrecreationally(87%).Thisisconsistent withfindingsinothersurveys(35),aswellasqualitativeinterviewsof psychedeliccarefacilitatorsalsostatingtheimportanceoftheirown psychedelicexperiencesforfacilitatingpsychedelicexperiencesfortheir clients(11).
Limitations
Severallimitationsconstraintheinterpretationofthisresearch.The cross-sectionaldesignprecludescausalinferencesfromstudydata.Measurementreliedonself-report,includingtheuseofsingle-itemnovel measures,suggestingthatthetruerelationshipbetweenresponsesand behaviorsoropinionsmaydifferfromobservedrelationships.Becauseof this,interpretationofthesefindingsshouldbetakenwithreserveandbe regardedasinitialandimpressionistic,butworthyoffuturestudy.Only 21.2%ofallconferenceattendeesrespondedtothesurvey,suggesting thatgeneralizationofstudyfindingsmayberestrictedanddependenton characteristicsthatledattendeestoparticipateinthestudyinthefirst place.Forexample,thosemoreinvestedinpsychedelicsmayhavebeen morelikelytocompletethesurvey.ThesamplewaspredominantlycomposedofwomenandindividualswhoidentifyasWhite.Wealsocaution againstinferencesbasedonstudystatisticaltests,whichwereprimarily conductedfordescriptivepurposesduetothenovelnatureofthesedata.
Conclusion
Socialattitudes,policy,andperceptionsofpsychedelicsareundergoingconsiderablechangeamidstclinicalstudiespurportingthebenefitsofpsychedelictreatment,andconcernsregardingsafetyandrisks ofexpandeduse.Thissurvey’sfindingsaccompanythepresentdialogue aroundpsychedelics,illustratingmodestconcernregardingtheharmsof psychedelicsevenintherapeuticsettings,whilealsodisplayinghopein theirpotential.Psychedeliccarefacilitatorsinthisstudydescribedtreatmentofconditionswithpsychedelicsthathavepreviouslybeenexcluded fromclinicaltrials,alongwithusingbothsupportiveandstructuredpsychologicalinterventionsduringtreatment,whileendorsingtheneedfor culturaladaptionintheirwork.
DataAvailabilityStatement
Nooriginaldatawasgeneratedinthisworkthatrequirespublicdissemination.
AuthorContributions
ZBperformeddataanalysis,manuscriptwritingandrevisions.RPand DKperformeddataanalysis,surveydevelopment,manuscriptwritingand revisions.JLM-K,BR,SE,KJ,TM,GG,andBDcontributedtosurveydevelopment,manuscriptwritingandrevisions.AJZcontributedtosurvey development.
FundingSources
Therewasnoexternalsupportforthiswork.
AuthorDisclosures
JLM-KhasreceivedresearchsupportfromWoundedWarriorProjectand CompassPathwaysandhasservedasaconsultantofCompassPathways. BRreceivesroyaltiesfromOxfordUniversityPress,Guilford,APPI,Psych Campus,andEmoryUniversityandreceivedadvisoryboardpayments fromJazzPharmaceuticals,Bioserenity,CerebralTherapeutics,Otsuka, Psychwire,andSenseye.BRownsequityinVirtuallyBetter,Inc.thatcreatesvirtualenvironments.Thetermsofthesearrangementshavebeen reviewedandapprovedbyEmoryUniversityinaccordancewithitsconflict ofinterestpolicies.BWDhasreceivedresearchsupportfromBoehringer Ingelheim,CompassPathways,NIMH,UsonaInstitute,andhasservedas aconsultantforBiohaven,CerebralTherapeutics,MyriadNeuroscience, NRxPharmaceuticals,andOtsuka.RPhasreceivedresearchsupportfrom
theJimJosephFoundationviaShefaJewishPsychedelicSupportandthe VailHealthFoundation.ZB,DK,JZ,GHG,KDJ,andSEreportnodisclosures. TMreportsnodisclosures.Thecorrespondingauthorhadfullaccesstoall thedatainthestudyandhadfinalresponsibilityforthedecisiontosubmitforpublication.Themanuscripthasbeenreadandapprovedbyall authors.
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