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Recent publications cover topics such as the economic and public health implications of psychedelic therapies, the e ects of ayahuasca on fear and anxiety, psychedelic treatment for anorexia nervosa and body dysmorphic disorder, and advancements, challenges, and future directions for treating resistant depression with psilocybin-assisted psychotherapy.
EDITORIAL
Countingtheuncountable:Thecriticalquesttoquantifypsychedelicmedicine’sreach
©TheAuthor(s),2025.ThisarticleisunderexclusiveandpermanentlicensetoGenomicPress
Psychedelics March2025;1(2):1–2;doi: https://doi.org/10.61373/pp025d.0005
Inthissecondissueof Psychedelics (1),wefeatureonourcover thethought-provokingstudybyRab,Raison&Marseille(2).Thatpaperpresentsthefirstrigorousestimateofthepotentialdemandfor psilocybin-assistedtherapy(PSIL-AT)intheUnitedStates.Aspsychedelic medicinemovesfromtheperipheryofpsychiatricresearchtowardthe possibility,andnowthereality,ofapprovalbynationaldrugregulatory agencies,1 thisanalysiscouldnotbemoretimely(3, 4).Understandingthe sizeofthepotentialpatientpopulationeligibleforPSIL-ATinformspharmaceuticaldevelopmentandthebroaderhealthcareecosystem,preparingtoaccommodatethisemergingclassoftherapy.
Byestablishingarangeofestimates,theauthorsbringwelcomenuancetotheirmethodology,steeringclearofhyperboleandunduepessimism.Theyavoidoverlybroadassumptionsthatwouldbeimpossible tomeetandexclusioncriteriasoimplausiblynarrowtheyareunlikelyto occurinactualclinicalpopulations.Theirapproachprovidesacredible frameworkforestimatingincidenceinarelativelynarrowyetclinically relevantsetting.Rabandcolleagues’finding—thatbetween24%(using stringentcriteria)and62%(afteradjustmentforcomorbidities)ofindividualswithmajordepressivedisorder(MDD)ortreatment-resistantdepression(TRD)maybeeligibleforPSIL-AT—offersacrucialstartingpoint forhealthcareplanning,onethathasbeensorelyneeded(2).
Thisstudyadvancestheconversationonpsychedelicmedicineinseveralways.First,itacknowledgesthatnoteveryindividualwithadepressiondiagnosisisautomaticallyacandidateforPSIL-AT,pushingback againstoverlyenthusiasticclaimsofpsychedelicsasuniversalremedies. Second,itillustrateshowexclusioncriteriacanactasbarrierstoaccess, highlightingthatdecisionsaboutwhoreceivestreatmentarenotmerely clinical—theyarepublichealthdecisions.Third,itdrawsaclearlinebetweentheoreticalbenefitandpracticalimplementation:thepotentialof atreatmentcannotbeseparatedfromthereal-worldconstraintsonits delivery.
Rabetal.identifyalcoholandsubstanceusedisordersaskeyfactorslimitingeligibilityinclinicaltrials.Theiranalysisisparticularly sharponthispoint.Byshowingthatremovingtheseexclusioncriteriawouldsignificantlyexpandtheeligiblepopulation,theyraiseacriticalquestion:Shouldtheseconditionsautomaticallydisqualifypatients— especiallygivenemergingevidencethatpsychedelicsmayhelpthosewith substanceusedisorders?
Whilemethodologicallystrong,thestudydoeshavelimitationsworth noting.TheassumptionthatdemandwillariseprimarilyfromthosealreadyreceivingcaremayunderrepresentbroaderinterestoncePSIL-AT becomeswidelyaccessible.Additionally,theanalysistreatsexclusioncriteriaasbinary—presentorabsent—whereas,inclinicalpractice,theseare oftensubjecttomorenuancedjudgment.
Theauthorsarecarefultoemphasizethattheyareestimatingpotentialdemand.Butbetweenpotentialandaccessliesacomplexlandscape:
1 TheAustralianTherapeuticGoodsAdministration(TGA)approvedtheuseofpsilocybinfortreatment-resistantdepressionandMDMAforPTSD,effectiveon1July 2023.
Received:7April2025.Accepted:9April2025. Publishedonline:15April2025.
insurancecoverage,providertraining,geography,andculturalattitudes. AsOregonandColoradoleadthewaywithstate-levelframeworksfor psilocybintherapy(5),theseestimatesarenolongerjuststatistics.They areplanningtools,policytriggers,andmoralsignposts.
OregonbecamethefirstU.S.statetolegalizepsilocybinfortherapeuticusethroughMeasure109,whichwaspassedinNovember2020. Thelawestablishedaregulatedsystemforpsilocybinservices,includinglicensedservicecenterswhereindividualsaged21andoldercan accesspsilocybinunderthesupervisionoftrainedfacilitators.Colorado followedin2022bypassingProposition122,whichdecriminalizedthe personaluse,cultivation,possession,andsharingofpsilocybinmushroomsforadults21andover.Italsolegalizedpsilocybin-assistedtherapiesatlicensedhealingcenters.
Yet,historyoffersacautionarynoteasthefieldedgestowardmainstreamlegitimacy.Newtherapies—especiallythoseimbuedwiththeallureofinnovation—tendtoreachtheprivilegedfirst.Inequitiesarenot incidental;theyaresystemic.Equitymustbeengineered,notmerely hopedfor.FutureresearchmustexplorewhoqualifiesforPSIL-ATandwho receivesit.
Thereareurgentnextsteps.Longitudinaltrackingofreal-worldimplementationinOregonandColoradocanhelpvalidateorrefinethese projections.Cost-effectivenessanalysesstratifiedbypatientsubgroups cansupportrationalpolicyandreimbursementdecisions.Clinicaltrials mustevolvetoincludepopulationshistoricallyexcluded—notrecklessly, butwithcarefuloversight—sothat“evidence-based”doesnotbecomea euphemismforexclusion.
Rabetal.havedonemorethanquantifypotentialdemand.Theyhave mappedoutaterrainthatpsychiatrymustnownavigate—notonlywith databutwithconscience.Aswefaceanepidemicofdepressionandacrisisinpsychiatricinnovation,wecannotaffordtomiscalculateeitherour reachorourresolve.
What’satstakeisnotmerelyregulatoryapprovalbutareimagining ofwhatpsychiatriccarecouldbecome—wheninformedbyinnovativescience,shapedbysociety,andgovernedbyethics.
1
Editor-in-Chief,
References
JulioLicinio1
Psychedelics,GenomicPress,NewYork,NewYork10036,USA e-mail: julio.licinio@genomicpress.com
1.LicinioJ.Psychedelics:TheJournalofPsychedelicPharmacology–Chartinganewcourse inpsychedelicscience.Psychedelics.2024:1–2.DOI: 10.61373/pp024d.0007
2.RabSF,RaisonCL,MarseilleE.Anestimateofthenumberofpeoplewithclinicaldepressioneligibleforpsilocybin-assistedtherapyintheUnitedStates.Psychedelics.2024: 1–5.DOI: 10.61373/pp024r.0025
3.NogradyB.Australia’sapprovalofMDMAandpsilocybinforPTSDanddepressionispremature,saycritics.BMJ.2023;382:1599.DOI: 10.1136/bmj.p1599.PMID:37433614
4.NuttDJ,HuntP,SchlagAK,FitzgeraldP.TheAustraliastory:currentstatusandfuturechallengesfortheclinicalapplicationsofpsychedelics.BrJPharmacol.2024.DOI: 10.1111/bph.17398.PMID:39701143
5.XenakisSN,ShannonSM.Whatisneededfortheroll-outofpsychedelictreatments? CurrOpinPsychiatry.2024;37(4):277–81.DOI: 10.1097/YCO.0000000000000946 PMID:38726805
Publisher’snote: GenomicPressmaintainsapositionofimpartialityandneutralityregardingterritorialassertionsrepresentedinpublishedmaterialsandaffiliationsofinstitutionalnature.Assuch,wewillusetheaffiliationsprovidedbytheauthors,withouteditingthem.Suchusesimplyreflectswhattheauthorssubmitted tousanditdoesnotindicatethatGenomicPresssupportsanytypeofterritorial assertions.
OpenAccess. ThisarticleislicensedtoGenomicPressundertheCreativeCommonsAttribution-NonCommercial-NoDerivatives4.0InternationalLicense(CCBY-NC-ND4.0).Thelicensemandates:(1)Attribution:Credit mustbegiventotheoriginalwork,withalinktothelicenseandnotification ofanychanges.Theacknowledgmentshouldnotimplylicensorendorsement.
(2)NonCommercial:Thematerialcannotbeusedforcommercialpurposes.(3) NoDerivatives:Modifiedversionsoftheworkcannotbedistributed.(4)Noadditional legalortechnologicalrestrictionsmaybeappliedbeyondthosestipulatedinthe license.Publicdomainmaterialsorthosecoveredbystatutoryexceptionsareexemptfromtheseterms.Thislicensedoesnotcoverallpotentialrights,suchas publicityorprivacyrights,whichmayrestrictmaterialuse.Third-partycontent inthisarticlefallsunderthearticle’sCreativeCommonslicenseunlessotherwise stated.Ifuseexceedsthelicensescopeorstatutoryregulation,permissionmust beobtainedfromthecopyrightholder.Forcompletelicensedetails,visit https:// creativecommons.org/licenses/by-nc-nd/4.0/.Thelicenseisprovidedwithout warranties.
Psychedelics
INNOVATORS&IDEAS:RISINGSTAR
AlainaM.Jaster:Bridgingthegapacrosspreclinicalandclinicaldisciplinesinthe psychedelicsciences
©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.
Psychedelics March2025;1(2):3–5;doi: https://doi.org/10.61373/pp024k.0043
Keywords: Psychedelics,serotonin2Areceptor,neuroplasticity, biomarkers,depression,substanceusedisorder,pharmacology, endocannabinoids,fearextinction,endocannabinoids,adolescence
Dr.AlainaM.JasterisapostdoctoralscholarintheDepartmentof PsychiatryandBehavioralNeurosciencesatWayneStateUniversity. Shecurrentlyservesonthetraineeeditorialboardof Psychedelic Medicine,thejournalfortheInternationalSocietyforResearchon Psychedelics(ISRP),andispartoftheSociety’sDiversityEquity InclusionandAccessibilitycommittee.Jasterisalsopartofthe SciencePolicyCommitteeofStudentsforSensibleDrugPolicy(SSDP) andco-foundedascientificcommunicationwebsiteandpodcast, PsychedelicBrainScience. Herresearchaimstounderstandthe underlyingmoleculartargetsandmechanismsofneuropsychiatric disordersandsubstanceusedisorders.HerPhDdissertationfocused ontheserotonin2Areceptor’smodulatoryroleinrewardingaspects ofopioidsandneuroplasticityacrosssexes.Mostofherworkuses translationalmethodologyrelatedtoPavlovianconditioning combinedwithtechniquestomeasureandmanipulate pharmacologicalfactorsinvolvedinthesediseases.Hercurrentwork focusesontheinvolvementofendocannabinoidsinfearextinction, biomarkersoffamilialriskofdepression,andpsychedelicuseamong adolescentpopulations.Dr.JasterisexcitedtoengageintheGenomic PressInterview,lookingdeeperintoherlifeinsideandoutside thelab.
Part1:AlainaM.Jaster–LifeandCareer
Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience?
ThisquestionisalwaystrickytoanswerbecauseIdidnotrealizethepivotalmomentsuntilIwasalreadydoingscience.Ididnotlinkmypersonal historytomydriveuntilIwaswellintocollege,butitmakessensenow. Ihaveafamilyhistoryofaddictionandhavefirsthandexperiencewith druguse,includingwhatitdoestofamiliesandtopeopleIcareabout. So,whenIwenttocollegeanddecidedtostudyneuroscienceandsubstanceuse,Ididitbecausethat’swhatIknewabout,andIwantedtounderstandwhysomepeoplechoosedrugsoverothervaluesandwhysome peopledon’thaveanyissueswithrecreationaluse.Ilearneditisalotmore complexthanthat,butmyentirelifeledmetothispassionforlearning aboutthemindandprovingthatyourcircumstancesdonothavetobethe end-all-be-all.
Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?
MytrajectoryisalittleinterestingbecauseIdidnotreallyknowIwanted tobeascientist,asIwasneverreallyexposedtothatoption.Iknewabout medicinebecausemymotherwasanurse,butIwantedtobeanartistin highschool.Ihadlittleinterestinsciencesatschool,exceptformyAP
Received:30November2024.Accepted:3December2024. Publishedonline:17December2024.
psychologyclass.So,inmysenioryear,IendeduptouringCentralMichiganUniversity,wheretheyshowedapresentationontheirneuroscience programandtalkedaboutthebrain,whichIthoughtwasinteresting.I toldmyselfIcoulddoitandwantedtoproveIwasnotmyfamilyhistory.Attheendofmyundergraduateexperience,Iwastryingtodecide onbeingacounselororgoingforaPhDinclinicalpsychology.Eventually, IdecidedthroughexperiencesworkingataninpatientpsychiatricfacilitythatIwasnotreadyfordirectpatientcare.However,Istillwantedto helppeoplewhoweresufferingfromthesehorriblepsychiatricillnesses. IendedupwitharesearchassistantjobatWayneStateUniversity,whereI workedwithhumanpostmortemtissueandgeneticsofopioiduse,along withtoxicologyandpharmacologyprojects.Thissolidifiedmyinterestin drugsandhowtheychangethebrain.
Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.
Honestly,eversinceIwasinhighschool,Ithoughtpsychedelicdrugs werefascinating.Theclinicaltrialswithsmokingcessationanddecreased drinkingfollowingpsilocybincameoutwhenIwasinmyundergraduate degree,andIwasjustsoexcitedtoseepsychedelicsbeingusedfortreatingsubstanceusedisordersthatIknewIhadtofindawaytostudythis
Figure1. AlainaM.Jaster,PhD,WayneStateUniversity,USA.
Figure2. AlainaJasterexplores“HilltopTrine,”oneofThomasDambo’s“6ForgottenGiants”sculpturesinHvidovre,Denmark(2017).Thephotowastaken duringdowntimefromhersummerneurosciencecourseinCopenhagenwhensheparticipatedinanartistictreasurehunttodiscovertheselarge-scalepublic artinstallationsthroughoutthecity’swesternmunicipalities.ThisimagecapturesoneofAlaina’smanyexplorationsbeyondthelaboratory.
myself.Now,mystudiesarebroader,focusingonthecannabinoidsystem aswell,butitisjustasinterestingbecausecannabishasbeenshownto helpalotoffolkswithneuropsychiatricillnesseslikedepression.
Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?
Ihopetoexpandourcurrentknowledgeofwhyandhowdrugslikepsilocybinorcannabishaveprofoundeffectsonpeople.Itisessentialtodig intothosewhorespondandthosewhodonotrespondandfigureoutif somespecificbiomarkersorpathwaysareinvolvedintheseclinicaloutcomes.Withthisknowledge,wecanbetterinformtreatmentstrategies anddrugpoliciesthatmakesense.
Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?
Theuseofmultidisciplinaryapproachestounderstandingdiseasehas onlyrecentlytakenoff,wheremanystudieswithinthefieldofneurosciencefocusedsolelyonbehaviorormolecularpharmacology.However, withmorepeopleinthefieldandnoveltechniques,wecanprobefor thingslikebiomarkers,theinfluenceofspecificcelltypesandtheirprojections,andalterationsinbrainconnectivity—allatonce.Mycurrent focusisonusingtranslationaltechniquesandbridgingthegapbetween preclinicalandclinicalresearchonneuropsychiatricandsubstanceuse disorders.
Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?
Iamcurrentlyinmypostdoctoralposition,whereIamlearningsomuch aboutcoordinatingandleadingclinicaltrials,teamwork,andpositive workenvironments.AcrossmyPhDandnowmycurrentposition,one thingthatIhavefoundmostimportantisallowingmyselftoenjoythe thingsIloveoutsideofscience.AnotherthingIhavefoundacrosspositionsisthatkeepingagreatlabnotebookisaninvaluablehabit.
AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?
Ithinkthereisashiftinthecommunitywherepeoplearebecomingmore tolerantandacceptingofallwalksoflife,butthereisstillmuchwork todo.Alotoffolksgointosciencebecausetheyhaveapersonalconnectiontotheirresearchquestions,butalotofpeoplewithlivedexperience(specificallywithsubstanceuseandneuropsychiatricdisorders) areturnedawayfromthefieldordonothaveproperaccesstothetools andhelptheymayneedtothrivewithinthescientificcommunity.Ithink insteadofhidingourpersonalexperiences,weshouldfosteracommunitythatapplaudsopennessandnotrefusestudentsortraineesbecause theywouldbe“difficult”toworkwithbecauseoftheirmentalhealthor disabilities.
Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?
Thebestpartisalltheopportunitiestomakeadifference.Thereareso manyunansweredquestionsandsomanyopportunitiestocollaborate withothersinsideandoutsidemyspecificexpertisetoanswerthesequestions.Inaddition,theabilitytoinspireothersisalwaysgreat.Itisveryexcitingtohearthatsomeonereadmywork,listenedtomypodcast,orsaw meonapanel,anditgotthemexcitedaboutscience.
Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?
Ontheday-to-day,afterwork,Ilovecominghometomycatsandputting onsomemusicwhileIcookwithmyfiancé.Ialsolovesittingdownwitha goodbookandacozyblankettospendmyleisuretime.Ialsoreallyenjoy travelingandgoingtoseelivemusic,sowhenIamabletodothesethings, Ialwaystakeuptheopportunityasshownin Figure2
Part2:AlainaM.Jaster–SelectedquestionsfromtheProust Questionnaire1
Whatisyourideaofperfecthappiness? Perfecthappinessdoesnotexist.Lifeisallaboutembracingthingsasthey comeandfindingjoyinthesmallthings.
Whatisyourgreatestfear? Theworldendingduetoclimatedisaster.
Whichlivingpersondoyoumostadmire?
Notasinglepersonbutallthepeoplewhohavebeendealtacrappyhand andkeepongoingdespiteallthethingsmovingagainstthem.
Whatisyourgreatestextravagance?
Idonotfeelquiteextravagant,butIdoenjoyafunstatementpiece fromtimetotime,likeabig,colorfulfuzzycoatorafunhatandgiant sunglasses.
Whatareyoumostproudof? IammostproudofmyselfovercomingalottogetwhereIamtoday.
Whatisyourgreatestregret? IdonotthinkIhaveone.
Whatisthequalityyoumostadmireinpeople? Senseofhumor.
Whatisthetraityoumostdislikeinpeople? Dishonestyandarrogancearetied.
Whatdoyouconsiderthemostoverratedvirtue? Theyallhavevalueandrequirebalanceineveryindividual.
Whatisyourfavoriteoccupation(oractivity)? Myfavoriteactivityisdancingataconcert.
Wherewouldyoumostliketolive?
Iwouldlovetolivesomewherewarmwithmountains.Iwouldalsoenjoy movingaroundEuropeandlivinginanewplaceeveryfewmonths.
Whatisyourmosttreasuredpossession? Mycats.
Whenandwherewereyouhappiest?Andwhyweresohappythen? IamhappiestwheneverIseetheworldandaminnature.Exploringand lettingourcuriosityrunwildiswhatwearemeanttodo.
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.
Whatisyourcurrentstateofmind?
Iamgratefulformyexperiencesandopportunitiesandforthehealthof mylovedones.
Whatisyourmostmarkedcharacteristic? Mydetermination.
Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Iamreallygoodattimemanagement,andthatmakesiteasierformeto getalotdoneinashorttimeframe.
Whatdoyouconsideryourgreatestachievement?
Todate,probablytakingtheUSDrugEnforcementAgencytocourtchallengingtheschedulingofpsychedelicresearchchemicalsDOI/DOC.
Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Nothing.Peoplearechangingallthetime,everyday.
Whatdoyoumostvalueinyourfriends? Comfortability,knowingyoucanbeyourwholeselfaroundthem.
Whoareyourfavoritewriters?
IamabigfanofCharlesDickens,J.R.RTolkien,Ta-NehisiCoates,andCarl Hart.
Whoareyourheroesoffiction? IdonotthinkIhaveany.
Whoareyourheroesinreallife? Mymomcomestomindfirst;shereallyisa“super-mom.”
Whataphorismormottobestencapsulatesyourlifephilosophy? Inomniaparatus, aLatinphrasethatmeans“preparedforallthings”or “readyforanything.”
Detroit,Michigan,USA 30November2024
AlainaM.Jaster1 1 WayneStateUniversity,Detroit,Michigan48201,USA e-mail: jasteralaina@wayne.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.
INNOVATORS&IDEAS:RISINGSTAR
FayzanRab:Whataretheeconomicandpublichealthimplicationsof psychedelictherapies?
©GenomicPress,2024.The“GenomicPressInterview”frameworkisprotectedundercopyright.Individualresponsesarepublishedunderexclusive andpermanentlicensetoGenomicPress.
Psychedelics March2025;1(2):6–9;doi: https://doi.org/10.61373/pp024k.0046
Keywords: Psilocybin,FDA,economicdemand,publichealthestimate, exclusioncriteria
Attheintersectionofmedicine,psychedelics,andsocialimpact standsFayzanRab,anMDCandidateatEmoryUniversitySchoolof Medicinewhobringsafascinatingblendofexperiencestohiscurrent roleasaclinicalresearcherattheEmoryCenterforPsychedelicsand Spirituality.Hisresearchexplorescrucialquestionssurroundingthe emergingpsychedelictherapylandscape,fromunderstanding minoritycommunities’perspectivestoexaminingthebroaderpublic healthandeconomicimplicationsofthesegroundbreaking treatments.Beforepursuingmedicine,Fayzancarvedoutadistinctive paththatincludedleadingproductdevelopmentattechgiants GoogleandMindstrongHealth,followedbygrassrootspolitical organizingintheBayArea.Today,alongsidehisresearch,hechannels hisleadershipexperienceintoexecutivecoaching,helping entrepreneursrefinetheircommunicationskillsandpresence.When heisnotexploringthefrontiersofpsychedelicmedicine,Fayzan enjoyslifeinAtlantawithhisfiancéeShuaandtheircatBella,where youmightfindthemhuntingforfreshproduceattheirneighborhood farmer’smarketorhostingspiritedgamenightswithfriends.Inthis GenomicPressInterview,heshareshisinsightsonthetransformative potentialofpsychedelictherapyinmodernhealthcare.
Part1:FayzanRab–LifeandCareer
Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience? Bothmyparentsarephysiciansandwhileweneverexplicitlydebatedthe meritsofthescientificmethod,itwasbakedintotheDNAofmyupbringing.Afewclassesincollegethatlookedatepistemologyandthehistoryof sciencereinforcedinmethevalueofscienceasaneutralarbiterindecipheringreality.InmyfirstcareerasaproductmanageratGoogle,weused principlesfromscience(breakingproblemsintofirstprinciples,validatingresults,seeingwhatwasreproducible)tobuildtechnologyproducts forusers.BythetimeIstartedmedicalschool,Ihadablendedphilosophyaroundscience.Iwantedtousethescientificmethodtorigorously testandexaminequestionsthatwerepertinentintherealworld.Ihave beensurroundedbymentorswhohaveencouragedthatinquiryindevelopingmyrelationshipwithscienceandusingitasapowerfulinstrument tobringclaritytotopicsthatIfeelareimportanttoanswer.
Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourcurrentrole.Whatdefiningmomentschanneledyoutowardthis opportunity?
Myinterestinpsychedelicsciencebeganduringaseriesofmini-lectures atUCSFdesignedforthepublic.Iwascontemplatingacareerswitchfrom SiliconValleytomedicine,andIwasblownawaybysomeoftheclinical researchonpsychedelictherapiesforhard-to-treatconditionslikePTSD
Received:5December2024.Accepted:9December2024. Publishedonline:24December2024.
anddepression.Thestatisticswerecompelling,butthetransformative, qualitativeaccountsfromparticipantscaptivatedme.
EmoryestablishedaCenterforPsychedelicsandSpiritualityduringmy thirdyearofmedicalschool,whichprovidedanaturalplaygroundtoexploresomeofthequestionsarisingintheburgeoningpsychedelicecosystem.Whilemanyresearchersfocusedonclinicaltrialoutcomes,Isawan unmetneedtoexplorequestionsaroundimplementation—suchaspublic healthneedsandreal-worldoperatingmodels.Thisrealizationledmeto createaresearchteamtoaddressthesecriticalissues.
Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.
Sooften,Iwoulddrivehomeattheendofapsychiatricclinicalserviceand besaddenedbythewaythehealthcaresystemtreatssomeofthemost
Figure1. FayzanRab,MDCandidate,EmoryUniversity,USA.
vulnerableandmentallyillinoursociety.Thesearethepatientsthatmany generalprovidersoftenfeelsomeaversiontowantingtotreat.Thecurrenttreatmentswehavedonotseemtoreachthepatientswiththeworst mentalillnessorprovideasustainedimpactthatchangesthetrajectory oftheiroutcomes.
Itwouldbeafool’serrandtosaythatpsychedelictherapies alonewouldchangethat.Treatingmentalillnesswillrequirechanges withinclinicalpracticebutalsoinvestmentsintosocialsafetynets,reemploymentopportunities,andaffordablehousing.
Psychedelictherapiesareoneofmanyingredientsthatcouldmakea significantdifference.Iamfortunatetoseeawholenewfieldofmedicine emergeatthisstageofmyclinicaltraining.Someofthequestionswe gettoaskaboutpsychedelics,suchasreimbursementmodels,diversityandinclusion,andpublichealth,provideentrypointstore-examine manyfundamentalaspectsofthewaymentalhealthcareoccursinthe UnitedStates.
Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?
Manyquestionsarewell-intentionedinacademicresearchformentalillness:howdoweincorporatemoreminorities,whatwouldimproveaccesstoallgroupsofpeople,andhowdowemeasureormakeadentin growingratesofmentalillnessintheUnitedStates?However,manyexistinghealthcaresystemsarestructuredinawaythatmakesithard—if notimpossible—tochangetheseinequities.Myhopeinpsychedelicscienceisthatwegettointegratethosequestionsearlyonwhilepsychedelic therapiesareintheirinfancy.Byaddressingandplanningforthemnow,I believethesetherapiescouldreachandbecomemoreaccessibletothose generallyexcludedfromtreatmentinnovations.
Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience?
Myresearchwithinpsychedelicscienceencompassesseveralinterconnectedareasoffocus.Iexaminethepublichealthandeconomicimplicationsofpsychedelictherapyapproval,particularlyregardingpatienteligibilityandbroaderhealthoutcomes.Anothercrucialaspectofmywork investigateshowculturalandreligiousminorities,withaspecificfocuson Muslimcommunities,relatetoandmightbenefitfrompsychedelictherapies–thisresearchaimstocreatemoreinclusivetherapeuticframeworks.Iamalsodeeplyinterestedinexpandingtheclinicalapplications ofpsychedelicsbeyondtraditionalmentalhealthconditions.Whilecurrenttrialspredominantlyfocusontreatment-resistantmentalillnesses,I amexploringpotentialapplicationsfordiversepopulations,suchascancerpatientsandthosewithpostpartumconditions,aswellasdifferent therapeutictargets,includingOCDandchronicpain.
Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?
Inleadingmyresearchgroup,Iamguidedbytwofundamentalprinciplesthatshapeourapproach.Thefirstcentersonmaintaininganarrow focuswhileseekingbroaderapplications–eachresearchquestionwe pursuemustconnectspecificinquiriestolargerimplicationswithinthe field.Aprimeexampleisourstudythatestimatedpotentialpatientdemandforpsilocybintherapyindepressiontreatment.Whilewefocusedon determiningeligiblepatientnumbers,thisresearchilluminatedbroader aspectsofmedicaleligibilitycriteria,FDAapprovalprocesses,andpublichealthoutcomes.1 Thesecondprincipleemphasizesvaluingprogress overthepursuitofperfection.Academicworkcanoftenstallwhenresearchersbecomeoverlyfocusedonachievingperfection.Instead,Iencouragemyteamtoviewpeerreviewnotasatestdemandingperfectionbutasacollaborativeopportunitytorefineandenhanceourideas. Asdemonstratedinourrecentpublication(Rab,Raison&Marseille,2024,
1 RabSF,RaisonCL,MarseilleE.Anestimateofthenumberofpeoplewithclinicaldepressioneligibleforpsilocybin-assistedtherapyintheUnitedStates. Psychedelics PublishedonlineSeptember13,2024.doi: 10.61373/pp024r.0025 –inthisissue.
doi: 10.61373/pp024r.0025 –inthisissue),thisapproachhasenabledus tocontributemeaningfulinsightstothefieldwhilemaintainingscientific rigor.
AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?
Thescientificmethodholdsimmensepotentialtoaddresssociety’smost pressingchallenges,yetscienceisoftenconductedinisolationfromcommunityproviders.Iwouldlovetoseemoredirectcollaborationswith organizationsandproviderstoidentifythemostpertinentreal-world questions.Inoneofmyresearchareas—Muslimsandpsychedelics—the majorityofhypothesesaredevelopedincoordinationwithlocalproviders. Bygroundingresearchquestionsinpartnershipswithon-the-groundorganizations,wecanensurethattheresultsanddiscoveriesarerelevant andmeaningfultothoseinthefield.
Whatdoyoumostenjoyinyourcapacityasanacademicorresearch risingstar?
Atafundamentallevel,itisvalidating.Sometimes,venturingoutsidethe comfortzoneoftheconventionalquestionsbeingstudiedcanfeelrisky. Already,manyclinicalpeersraiseeyebrowswhenImentionIamstudyingpsychedelictherapies.Inaddition,mostresearchersinthepsychedelic spacearenotdivingintothequestionsIamstudying;itcanbealottobe withattimes.Tohaveourpublicationacceptedandthenwidelypublicizedcanbeaffirmingforthatinitialinstinctthathadmeventureinthis direction.
Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?
Ibelievethatleisureisanimportantpartofanycreativeresearchprocess. Askingunconventionalquestions,gettinginspired,andplayingwithideas wereallmadepossiblebecauseIcreateddedicated,uninterruptedleisure time.Leisure’snon-utilitariannaturetakesthepressureoffforitallto feelusefulandparadoxicallymakestheinquiriesIaskfeelmoreorganic andnatural.
Forme,leisureconsistsofsomestructuredstream-of-consciousness writing(checkoutthemorningpagesconceptfrom TheArtistWay),playingpickleballwithfriendsinmylocalcommunity,andspendingquality timewithmyfiancéeandcat.
Part2:FayzanRab–SelectedquestionsfromtheProust Questionnaire2
Whatisyourideaofperfecthappiness?
Celebratingthemomentsinmylifethatarealreadyjoyfulsuchasmy morningwalk,watchingamoviewithmyfiancée,andrelishingthatIget
2 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.
toaskthequestionsandworkontheproblemsIorganicallylovetothink about.
Whatisyourgreatestfear?
TolivealifethatisnotauthentictowhoIam.
Whichlivingpersondoyoumostadmire?
BernieSanders.Heiswillingtobemisunderstoodtoservewhathebelieveswillbenefithumanity.
Whatisyourgreatestextravagance?
Iloveagoodspaday.OneofmygoodfriendsandIwillmakeitahabitto visitalocalKoreanspaforawholeevening.
Whatareyoumostproudof?
Imetagreatlifepartnerandhadthecouragetoproposetoher.
Whatisyourgreatestregret?
StayingtoolonginajobwhereIfeltlikemymanagerwaspersonally puttingmedown.
Whatisthequalityyoumostadmireinpeople?
Pioneerswhoareinvestedinbridgingdisparateworlds.
Whatisthetraityoumostdislikeinpeople?
Self-righteousness.
Whatdoyouconsiderthemostoverratedvirtue?
Peoplewhotakemuchprideinsayingtheyarebusy.Busynessdoesnot equatetoprogressorvalue.
Whatisyourfavoriteoccupation(oractivity)?
Ilovecoachingpeoplewhoarefacingpersonallymeaningfulchallenges intheirlife.
Wherewouldyoumostliketolive?
Ahomethatisbasedaroundalotofwildlifeandnaturebutstillclose enoughtoalargeurbancenter.
Whatisyourmosttreasuredpossession? Mygrandfather’sstethoscope.
Whenandwherewereyouhappiest?Andwhyweresohappythen? TheweekendIproposedtomyfiancée:atotalsurprisetoher.Ourclose friendsandfamilycameintotownthefollowingdayandsurprisedus againwithafull-blowncelebration.
Whatisyourcurrentstateofmind?
Iamabitsadaboutcurrenteventsintheworld,butIamalsocalm, present,andgratefulforwhat’snext.
Whatisyourmostmarkedcharacteristic?
Deeplisteningandnotbeingafraidtotaketheconversationonelevel deeper.
Amongyourtalents,whichone(s)give(s)youacompetitiveedge?
Myabilitytodistillmultiple,diverseperspectivesandsynthesizethem intoapathforward.
Whatdoyouconsideryourgreatestachievement?
Cultivatingaclosesetoffriendshipsandmentorswhoserelationships havenotsuccumbedtothebusynessoflife.
Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? IwouldhavemorefaithduringtimesofuncertaintyinthepathIamchartingformyself.
Whatdoyoumostvalueinyourfriends?
Iamluckytohaveanempoweredandaccomplishedsetoffriends.However,noneofthemconflatetheirresumesforwhatismostimportant:relationships.
Whoareyourfavoritewriters?
JohnSteinbeck,HarukiMurakami,andJhumpaLahiri.
Whoareyourheroesoffiction?
IlovethecharacterYusukeUrameshifromthe1990sJapaneseanime Yu YuHakusho.Heisahighschoolstudentwhodiesinacarcrashonlyto beresurrectedtofightinvisiblebattleswithspirits,demons,andvillains. Theshowissurprisinglydeepaboutredemption,rememberingthedayto-dayjoys,andbeingwillingtoputeverythingonthelineforsomething youbelievein.Iregularlywatchclipsfromthatshowforinspirationwhen Iencountersetbacksoruncertainty.
Whoareyourheroesinreallife?
Dr.TomInselforhiswillingnesstoreinvent;BernieSandersforhiscommitmenttoservingthecommonperson,andmygrandfatherforhisability toconnectdeeplywithothersandamazingstorytellingabilities.
Whataphorismormottobestencapsulatesyourlifephilosophy? “AmorFati.”3
Atlanta,Georgia,USA 4December2024
FayzanRab1 1 EmoryUniversitySchoolofMedicine,Atlanta,Georgia30329,USA e-mail: syed.f.rab@emory.edu
3 “AmorFati”isaLatinphrasemeaning“loveoffate”or“loveofone’sfate”thatwas particularlyembracedandpopularizedbyGermanphilosopherFriedrichNietzsche inthe19th century.However,theconcepthasearlierrootsinStoicphilosophy,especiallyinthewritingsofMarcusAureliusandEpictetus.
Figure2. FayzanRabwithhiscat,BellaDonna.
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
CharlesL.Raison:Elucidatingtheroleofconsciousexperienceinthetherapeutic effectsofpsychedelicsasameanstooptimizeclinicaloutcomes
©TheAuthor(s),underexclusivelicencetoGenomicPress2024
Psychedelics March2025;1(2):10–12;doi: https://doi.org/10.61373/pp024k.0010
Keywords: psilocybin,psychedelics,consciousness,depression, inflammation
CharlesRaison,MD,isaProfessorofHumanEcologyandPsychiatryin theDepartmentofPsychiatry,SchoolofMedicineandPublicHealth, UniversityofWisconsin-Madison.Dr.RaisonalsoservesasDirectorof ClinicalandTranslationalResearchforUsonaInstitute,asDirectorof theVailHealthBehavioralHealthInnovationCenter,Directorof ResearchonSpiritualHealthforEmoryHealthcare,andasVisiting ProfessorintheCenterfortheStudyofHumanHealthatEmory UniversityinAtlanta,GA.Dr.Raison’sresearchfocusesonthe examinationofnovelmechanismsinvolvedinthedevelopmentand treatmentofmajordepressionandotherstress-relatedemotional andphysicalconditions,aswellashisworkexaminingthephysical andbehavioraleffectsofcompassiontraining.Morerecently, Dr.Raisonhastakenaleadershiproleinthedevelopmentof psychedelicmedicinesaspotentialtreatmentsformajordepression. Hewasnamedoneoftheworld’smostinfluentialresearchersbythe WebofScienceforthedecade2010–2019.WithVladimirMaletic,heis authorof TheNewMind-BodyScienceofDepression publishedby W.W.Nortonin2017.WearehappytoshareDr.Raison’sperspectives onhislifeandcareerwithourreaders.
Part1:CharlesL.Raison–LifeandCareer
Couldyougiveusaglimpseintoyourpersonalhistory,emphasizing thepivotalmomentsthatfirstkindledyourpassionforscience? Mychildhoodwasdominatedbyaloveofscience,especiallyastronomy. Insixthgrade,Istartedmyownstargazingmagazine(withtheprinting helpofmyparents,whoownedasmall-townnewspaper).Myinterestin sciencelapsedinmyteenageyearsandwasreplacedbyasearchforspiritualanswerstolife’smysteries.Myjourneybacktowardsciencebegan notwithsciencebutinthehumanitieswhenIdiscoveredpsychoanalysis notinaclinicalcontextbutwhileworkingonaPh.D.inEnglish.Spurred onbythisandafirstencounterwiththepowerofpsychotherapyinmy ownlife,onChristmasEve1984,Ihada“roadtoDamascus”typeexperienceonaforlornhighwayinSouthTexaswhenIsuddenlydecidedthatI shouldchangemylife’sdirectionandbecomeapsychiatrist.Thisrequired thatIreturntoschooltocompleteallthepre-med-typeclassesIhadstudiouslyavoidedasanundergraduate.Thebeautyofphysicsravishedme, andImighthavesteppedawayfrommymedicalplanshadIthetalent; however,lackingtherequisitemathematicalgifts,Ididbecomeadoctor andapsychiatrist.ButIwasstillawaysawayfromspendingalifeinscienceasmyearlyyearsafterresidencywerespentasafull-timeclinician. Itisinterestinghowlifebringsthingsbackaround.Mylong-terminterestinspiritualtraditionslaunchedmylifeinscience.Inthemid-90s, IhadthegoodfortunetobefriendtheDalaiLama’ssister,who,inturn, introducedmetoseveralbrilliantTibetanBuddhistmonks.Thesegentlementaughtmemuchaboutesotericmeditationpractices,whichfascinatedme.Ibecameobsessedwithunderstandingwhatthesepractices didtothebrainandbodyfromaWesternscientificperspective.Iwas
Received:5March2024.Accepted:6March2024. Publishedonline:8March2024.
CharlesL.Raison,MD,UniversityofWisconsin-Madison,USA. especiallyinterestedintheeffectofthesepracticesonbodytemperature, asraisingbodytemperatureiscentraltothesetechniques,asoddasthat soundsfromourWesternperspective.
Aswonkyastheseconsiderationssound,theymotivatedmetoleavea clinicalfacultypositionatUCLA,throwcautiontothewind,andmoveto EmoryUniversityinAtlantainhopesthatIcouldleveragetheuniversity’s strengthsinTibetanBuddhiststudiesandmind-bodymedicinetopursue thestudiesIwantedtocommence.
Justaslifebringsthingsbackaround,sodoesitmoveforwardin paradoxicalways.IbecamearesearcheratEmoryunderthetutelage ofmyfriendandmentor,AndrewMiller.However,IcouldneverconductthestudiesofadvancedTibetanBuddhistmeditationpracticesthat hadbeenmyinitialimpetusforretoolingmycareertowardresearch. ApivotalmomentcameearlyonatEmorywhenIwasstilltrying—but strugglingtodotheworkIwantedtodo—whenAndysaid,“Whileyou arefiddlingwiththismeditationstuff,howaboutdoingsomerealscienceinthemeantime?”Thiswashisoffertojoinhiminstudyinghow inflammationaffectsthebrainandbodytoproducedepression.Iwas interestedinthermoregulationandbodytemperaturebecauseofmy
Figure1.
Figure2. CharlesL.Raisonvolunteeringto“betatest”anEEGprotocol. interestinameditationtechniquecalledtummo(madesomewhatfamousrecentlybyWimHof).Inflammationincreasesbodytemperature,so Ithought,"Whynot?"andjoinedAndy’sresearchteam.HadIsaid“no”and insistedonmymorenarrowfocus,Iwouldneverhavebeengiftedwitha lifeinscientificresearch.Thisisanimportantpointandaprofoundchallengeforyoungscientists.Ontheonehand,youdonotwanttogosofar awayfromyourintereststhattheworkistedious;however,ifyouaretoo rigid,tremendousopportunitieswillsailpast.
Myexperiencehasbeenthatresearchislikefollowingafascinating trailofbreadcrumbsthroughtheforest.Ifonemaintainsafeltsenseof whatoneislookingfor,thingsoftencircleback.AlthoughIneverdidthe studiesIhadinitiallyhopedtodo,overtheyears,Ihavebeenfortunateto conductmeditationstudiesand,inthelastdecade,studiesthatharken backtomylong-terminterestinbodytemperature/thermoregulation andmood.
Wewouldliketoknowmoreaboutyourcareertrajectoryleadingupto yourmostrelevantleadershiprole.Whatdefiningmoments channeledyoutowardthatleadershipresponsibility?
Myleadershiproles,suchastheyare,weresomethingotherthanwhatI activelypursued.IrealizedmanyyearsagothatIprefertooccupya“vice president”typerole,beingsecondincommandinaresearchgroup.Iwas nevermoreproductivethanwhenIexistedinthistypeofrelationshipat EmoryUniversitywithAndyMiller.Iamanexcellent“wingman”.Butyears pass,oneages,andovertime,oneisfacedwithachoice:toeitherstep intoleadershiporstepaside.Ihavegenerallysteppedin.Ihavehadseveralleadershippositionsoverthelastdecade,butIwillfocusontwohere. In2017,GeorgeGrant,MDiv,PhD,askedmetobecometheDirectorofResearchonSpiritualHealthfortheWoodruffSciencesCenteratEmoryUniversity.Becausemyprimaryacademicpositionis—andwasthen—atthe UniversityofWisconsin-Madison,IrealizedearlyonthatthebestwayI couldleadfromabitofadistancewastobringinasmuchresearchtalentaspossibleandthendisperseleadershipamongsttheseresearchers. IconsiderthisoneofmyprimaryleadershipaccomplishmentsbecauseI havebeenremarkablysuccessful(ifIcanbrag)atbringingremarkable youngerscientiststoEmoryasfacultyworkinginSpiritualHealth.More recently,adefiningmomentinthelastseveralyearsoccurredwhenIwas invitedtotakeontheroleofDirectorofthenewVailHealthBehavioral HealthInnovationCenter,anewinstitutesituatedwithinalargerconsortiumthathasbeenestablishedbetweenUW-MadisonandVailHealth.
Itookthispositionbecauseitpromisestobringmanyofmyresearch interestsandcolleaguestogetherintooneplacetoexploretheimplementationofnoveltreatmentsfordepression,anxiety,andsubstanceuse disorders.
Pleasesharewithuswhatinitiallypiquedyourinterestinyour favoriteresearchorprofessionalfocusarea.
Ihavealwayshadtwodeepintereststhathaveformedanundercurrent inallmywork.Oneoftheseistheabilityofthebodytoinfluencemental states.Theotheristhepotentialofparticularmentalstatestopromote profoundandsustainedwellbeing.Thesetwoare—ofcourse—related: thebodycanbeusedtodrivethemindintocertainmentalstates,and certainmentalstatescanprofoundlyaffectbodilyfunction.AsIdescribed above,IcameintoresearchbecauseIwasfascinatedbythepossibility thatcertainesotericBuddhistmeditationpracticesmightbeequivalent todeepbrainstimulatorstoinduceprofoundlypositivemental/emotional states.Morelately,myworkwithpsychedelicshasinducedinmeaprofoundinterestinthequestionofwhetherconsciousnesshasactualcausal powerintheworld(asopposedtobeingepiphenomenaltomorebasic non-consciousbrainprocesses).
Whatimpactdoyouhopetoachieveinyourfieldbyfocusingon specificresearchtopics?
Onamorefundamentalsciencelevel,Iwouldliketousepsychedelicsto explorethequestionofwhetherconsciousnesshascausalpower.Ona clinicallevel,Ihopetoconductstudiesthatidentifyandoptimizenovel treatmentsfordepressionandanxiety,especiallythosethatbuildupon ancientpracticesthatareoftenalsoadaptivestressors.
Pleasetellusmoreaboutyourcurrentscholarlyfocalpointswithin yourchosenfieldofscience.
IamcurrentlyuptomyeyeballsinfivemajorstudiesforwhichIhave primaryresponsibility.Fourofthesestudiesfocusontryingtounderstandbettertheroleofconsciousexperienceinthetherapeuticeffects ofpsychedelicsand,viathisunderstanding,tooptimizeoutcomes.One ofthestudiesfocusesonwhole-bodyhyperthermia.Thisstudyseeksto understandwhetherthetherapeuticeffectofheatcanbeexpandedby combiningheatwithcoldexposure.Thisstudyalsoseekstofollowupon priorworkthathasidentifiedapotentialimmune-basedantidepressant mechanismofactionofwhole-bodyhyperthermia.
Whathabitsandvaluesdidyoudevelopduringyouracademicstudies orsubsequentpostdoctoralexperiencesthatyouupholdwithinyour researchenvironment?
AprimaryvalueisnevertosetouttoprovewhatIalreadyknowtobe true—atraitthatistoooftenpresentinpeoplewhostudymind-bodytype interventionslikemeditationornoveltreatmentslikepsychedelics.Years ago,Iwastoldbyawiseperson,“Ifyouarescaredofthetruth,getoutof science,”andIhavetakenthattoheart.Istartstudieswithhypothesesbut amalwaysreadytoabandontheseandlistentowhattheworldistrying totellmethroughtheactualresultsofastudy.Themostexcitingstudies Ihavedonehavebeenthosethatdisprovenmyinitialhypotheses.
AtGenomicPress,weprioritizefosteringresearchendeavorsbased solelyontheirinherentmerit,uninfluencedbygeographyorthe researchers’personalordemographictraits.Arethereparticular culturalfacetswithinthescientificcommunitythatwarrant transformativescrutiny,oristhereacausewithinsciencethatdeeply stirsyourpassions?
Ihavebecomeincreasinglyconcernedaboutdatafalsificationwithinscience,asithasbecomesadlyandincreasinglyclearthatthisisarealissue.Asmuchasanyone,Iunderstandtheterriblepressureresearchersare undertoproducepositive“catchy”results.Nevertheless,theentireedificeofscienceisbuiltuponourabilitytotrustresults.Failedstudiesdo notaddmuchtoone’scareerinanystraightforwardsense.However,my bestideasgenerallycomefromresultsthatcontradictedmyeasyinitial hypotheses.
Whatdoyoumostenjoyinyourcapacityasanacademicorresearch leader?
Ienjoytheopportunitytodeviseandimplementstudiesthatattempt toaddressquestionsthatmostinterestmeandareessentialforhuman wellbeing.
Outsideprofessionalconfines,howdoyouprefertoallocateyour leisuremoments,orconversely,inwhatmannerwouldyouenvision spendingthesemomentsgivenachoice?
Itakea“SwissCheese”approachtoworkandleisure.Becauseofmymany responsibilities,Iworkallthetime,meaningIstartthedaywithwork,and lateintotheevening,itisusuallythelastthingIdo.Nevertheless,like SwissCheese,Ileaveholesintheconstantworkstreamtodofunthings withfamilyandfriends.SoIwork,offandonfrom7a.m.to10p.m.,but duringthatperiod,Iwillalsotakeacoupleofwalkswithmypartneror kids.WhenItravelforwork,Ioftentrytoleaveafewextrahoursopenfor whatIhavecalled“targetedtravel,"abriefexcursionthattransformsa worktripintosomethingfunandmemorable.IfIhadmoreofachoicein mytime,Iwouldeliminateemail.Fartoomuchofmytimeisspentjust cullingthroughallthedetailsthatemailingmakesitsoeasytobecome boggeddown.
Part2:CharlesL.Raison–SelectedquestionsfromtheProust Questionnaire1
Whatisyourideaofperfecthappiness?
Iwanttoexploresomewherenewandfascinatingonaperfectsummer’s daywiththepeopleIlove.
Whatisyourgreatestfear? DyingafterthepeopleIlove.
Whichlivingpersondoyoumostadmire? Igreatlyadmiremanypeople.ButIknowmypartnerChristineWhelan bestandadmirehermost.
Whatisyourgreatestextravagance? GreenChartreuse.
Whatareyoumostproudof?
ThewidevarietyofamazingpeopleIhavebeenhonoredtoknowas friends,colleaguesandfamily.
Whatisyourgreatestregret? Notmeetingmypartnersoonerinmylife.
Whatisthequalityyoumostadmireinpeople? Highlycompetent/talentedpeoplewhodon’ttoottheirownhorns.
Whatdoyouconsiderthemostoverratedvirtue?
Overtheyears,peoplehavecomplimentedmeonbeingarisk-taker,which Iappreciatebecause,infact,Iamrathercautiousandconservativeat heart.
1 Inthelatenineteenthcenturyvariousquestionnaireswereapopulardiversiondesignedtodiscovernewthingsaboutoldfriends.Whatisnowknownasthe35questionProustQuestionnairebecamefamousafterMarcelProust’sanswersto thesequestionswerefoundandpublishedposthumously.Proustansweredthequestionstwice,atages14and20.Multipleotherhistoricalandcontemporaryfigures haveansweredtheProustQuestionnaire,suchasOscarWilde,KarlMarx,Arthur ConanDoyle,StéphaneMallarmé,PaulCézanne,MartinBoucher,HughJackman, DavidBowie,andZendaya.TheProustQuestionnaireisoftenusedtointerview celebrities:theideaisthatbyansweringthesequestionsanindividualwillreveal hisorhertruenature.WehavecondensedtheProustQuestionnairebyreducingthe numberofquestionsandslightlyrewordingsome.Thesecuratedquestionsprovide insightsintotheindividual’sinnerworld,rangingfromnotionsofhappinessandfear toaspirationsandinspirations.
Whatisyourfavoriteoccupation(oractivity)?
Walkinginanewandexcitingplacewithmypartner.
Wherewouldyoumostliketolive?
WalnutCreek,CA
Whatisyourmosttreasuredpossession? Mycopyof“TheHandbookoftheYokuts.”
Whenandwherewereyouhappiest?Andwhyweresohappythen? IamthehappiestIhaveeverbeenrightnow.Laterinlife,Imetthelove ofmylife,andwehavefivechildrentogetherwhoarethelightofmylife. Myworkisstressfulbutfascinatingandmeaningful.
Whatisyourmostmarkedcharacteristic?
Wide-rangingcuriosityaboutlifeandtheworldwefindourselvesin.
Amongyourtalents,whichone(s)give(s)youacompetitiveedge? Abilitytopublicspeakandwrite.
Whatdoyouconsideryourgreatestachievement? Raisingmytwoteenageboys.
Ifyoucouldchangeonethingaboutyourself,whatwoulditbe? Iwouldbemoreorganized.
Whatdoyoumostvalueinyourfriends? Kindness,intelligence,passion,andvision.
Whoareyourfavoritewriters?
JohnSpivey(TheCryingDance,TheGreatWesternDivide),Rilke,Whitman, TSEliot(FourQuartets).
Whoareyourheroesinreallife?
FranklinDelanoRoosevelt,EleanorRoosevelt,Buddha,SamuelJohnson.
Whataphorismormottobestencapsulatesyourlifephilosophy?
“Oldmenoughttobeexplorers Hereortheredoesnotmatter Wemustbestillandstillmovingintoanotherintensity Forafurtherunion,adeepercommunion.”
CharlesL.Raison,MD1 1 SchoolofMedicineandPublicHealth,UniversityofWisconsin-Madison, Madison,Wisconsin53719;VailHealthBehavioralHealthInnovationCenter, Edwards,Colorado,UsonaInstitute,Fitchburg,Wisconsin,andWoodruffHealth SciencesCenter,EmoryUniversity,Atlanta,Georgia,USA e-mail: raison@wisc.edu
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.Thislicensedoes notcoverallpotentialrights,suchaspublicityorprivacyrights,whichmayrestrict materialuse.Third-partycontentinthisarticlefallsunderthearticle’sCreative Commonslicenseunlessotherwisestated.Ifuseexceedsthelicensescopeor statutoryregulation,permissionmustbeobtainedfromthecopyrightholder.For completelicensedetails,visit https://creativecommons.org/licenses/by-nc-nd/4. 0/.Thelicenseisprovidedwithoutwarranties.
Psychedelics
COMMENTARY
Psilocybin-assistedpsychotherapy:Advancements,challenges,andfuturedirections fortreatingresistantdepression
©TheAuthor(s),2024.ThisarticleisunderexclusiveandpermanentlicensetoGenomicPress
Psychedelics March2025;1(2):13–14;doi: https://doi.org/10.61373/pp024c.0022
Keywords: Psilocybin-assistedpsychotherapy(PAP), treatment-resistantdepression(TRD),psychedelics,psilocybin Depressionisaglobalpublichealthchallengethatrepresentsthe world’slargestcauseofdisability,especiallyinthecontextof traditionaltreatments.Onepotentialsolutionbeingexploredis psilocybinassistedpsychotherapy(PAP)whichshowspromisefor treatingdepression.ArecentstudybyRosenblatetal.exploresthe useofpsilocybininclinicalmentalcarewithpromisingresults(1).
Theincreaseinmajordepressivedisorder(MDD)casesparticularlysince 2005andworsenedbyCOVID-19isalarming(2).Whilemonoaminergic antidepressantshavebeenusedasatreatmentsincethe1980’s,theyoftentaketwotofourweekstoshoweffectsandmaynotworkforuptoonethirdofpatients(2).Additionally,sideeffectsleadupto50%ofpatients tostoptreatment(2, 3).Therefore,thereisagrowingfocusonfinding betterwaystoaddressdepression.
Respondingtotheneedforantidepressantoptions,psychedeliccompoundshavegarneredattentioninrecenttimes.Despitepastdisapproval duetorecreationaldruguse,thereisnowrenewedinterestinexploring psychedelicslikepsilocybinfortheirtherapeuticpotential(2, 4).
Psilocybin,anaturallyoccurringpsychedeliccompoundfoundincertainmushroomspecies,hasbeenfoundtohaveaprofoundimpacton consciousnessbyinteractingwithserotonin5HT2Areceptors(2, 3).Researchonanimalssuggeststhatpsilocybinisassociatedwithanincrease inbrainderivedfactor(BDNF)whichinfluencesplasticity,neurogenesis anddendriticgrowth(5).Interestingly,lowerlevelsofBDNFhavebeen linkedtodepressioninseveralstudies(6).Whiletheexactpathways throughwhichpsilocybinbenefitsconditionsisstillupfordebate,there ispromiseinusingittohelptreattreatment-resistantdepression(TRD) whencombinedwithpsychologicalsupport(3, 7).
TheideaofPAPhasbeengainingtractionasasupportedmethodfor addressingdepressionsymptomsinindividualswithbipolarIIdisorderas notedbyAaronsonandcolleagues(8).However,determiningthecombinationoftherapysessionsanddosagelevelsforeffectivenessremainsan areaofconcern.
Oneimportantareaofconcernisthecriticalissueofadversereactions, whichareparticularlyimportantinthelightofreportsofpsychedelicsinducedmaniathatcouldparadoxicallyindicatetheireffectivenessasantidepressants(9).Averygermanepointisthateffectivenessandsafety mustbewellascertainedinordertoavoidinvestingintherapiesthat maynotwork.Thisisparticularlyrelevantforlong-termpsychotherapyin combinationwithpsychedelics(10).Oneofthefrustrationsexperienced bycliniciansisthatmostoftheevidencesupportingtheuseofpsilocybinfordepressioncomesfromstudieswithverystricteligibilitycriteria, whichmakesitunclearifthefindingsfromthoserigoroustrialsareapplicableinreal-worldsettings,whereconditionslikepersonalitydisorders andsuicidality(whichtendtobeclinicaltrialexclusioncriteria)arehighly prevalent(11).
InaMarch2024articletitled“Psilocybinassistedpsychotherapyfor treatmentdepression:Arandomizedclinicaltrial(RCT)evaluatingrepeateddosesofpsilocybin,”Rosenblatandcolleaguesshedlightonthese issuesinthefieldofPAPresearch(1).ThisnewRCTprovidesevidencesupportingtheuseofpsilocybindosinginapopulationdealingwithcomplex psychiatricissuessuch,asTRDbipolarIIdisorder(BPII)orothercomorbid conditions.
InthestudyconductedbyRosenblatandcolleagues,participantshad anaverageMontgomery-AsbergDepressionRatingScale(MADRS)score of30.5,experiencingdepressionfor18.3years,andhavinggonethrough approximately11.27failedmedicationtrials.Interestingly40%ofthem hadexperiencewithelectroconvulsivetherapyorketamineinfusions.This trialinvolved31individualswithTRD;mostwereinitiallydiagnosedwith MDD(26participants),whileonlyfourwerediagnosedwithBPII.Eachparticipantalsohadatleastanotherco-morbidpsychiatricdiagnosis.One participantwithdrewbeforethestudybegan.Thetrialaimedtoevaluate thefeasibilityofusingpsilocybinincombinationwiththerapytoaddress TRD.Participantsweresplitintotwogroups:onereceivingtreatment (n = 16)andtheotheronawaitlistcontrol(n = 14).Oversixmonthsall treatedparticipantsreceivedonetothreedosesofpsilocybinat25mg eachalongwithpreparatoryandintegrationpsychotherapysessionsover asix-monthperiod.
Resultsshowedsignificantreductionsindepressionseverityinthefull sample,withfurtherMADRSscorereductionsfromrepeateddoses.The resultsshowedareductionindepressionseverityacrossallparticipants afterreceivingrepeateddosesofpsilocybin.Thetreatmentwaswelltoleratedwithoutanyreportedevents.Thehighretentionratesandmanageablesideeffectsemphasizedtheeffectivenessofthisapproachfor individualsstrugglingwithTRD.
TheuniqueaspectoftheresearchstudyconductedbyRosenblatand teamwastheirmethodofdosing,whichinvolvedadministeringpsilocybin basedonrelapseindicators.Thissetsitapartfromstudiesthattypically followedafixedsingledoseprotocol(4, 7, 9, 11, 12).Asacomparison,in astudybyGoodwinetal.,asingledoseapproachwasusedtoevaluatethe effectivenessofpsilocybindosesalongwithsupportforTRD(12).Inthis study,a1mgdoseservedasareferencepointcomparedtodoses.The findingsrevealedthatthe25mgdoseimprovedparticipantssymptoms afterthreeweekswhereasthemedium10mgdosedidnotshowsymptomreduction.Interestinglythecontroldoseof1mgdidnotyieldbenefits.Whilethisresearchemphasizedtheimportanceofdosingstrategies itonlyobservedpatientsfor12weeksindicatingtheneedforlongertrials tofullyunderstandthelastingeffectsofpsilocybintreatment.
Followingtheexaminationofdosingfrequency,theRosenblatetal. studybrokenewgroundbyextendingthefollow-upperiodtosixmonths andallowingforaschedulewithdosesgivenasneeded(1).Evaluating outcomestwoweeksposteachdose,thestudyfoundthattheprimary depressionmeasure,theMADRS,wassignificantlyloweratthelastpostdosefollow-upcomparedwithbaseline.Theauthorsconcludethattheir
Received:1June2024.Revised:16July2024and5August2024.Accepted:7August2024. Publishedonline:12August2024.
resultsindicatethatwhendepressionisrecurrent,asitoftenis,treatingit asonewouldtreattherecurrenceofotherepisodicdisordersmakesmore sensethanstickingwithamorerigidfixed-doseschedulethatmaynotbe personalizedtotheneedsofthepatient.
IfoundthattheapproachtakenintheRosenblatetal.studytodosingwasbetterthanwhatotherstudieshaveshown.However,whilethe researchbyRosenblatandcolleaguesshowspromise,therearesomelimitationstoconsider.Thefactthatitwasanopenlabelstudyhadasamplesize.Usingwaitlistcontrolsinsteadofaplacebogrouparesignificant issuesthatcouldmaketheantidepressanteffectsseemstrongerthan theyactuallyare.Additionally,thisstudydifferedfromonesbyproviding preparatoryandintegrationpsychotherapy,whichmightexplainwhythe antidepressanteffectwasnotasstrongasseeninstudieslikeGoodwin etal.,wheretherewasagreaterreductioninMADRSscores(1, 12).
Instudiesinvolvingpsilocybin,includingtheoneledbyRosenblat etal.,participantsreceivesupportthroughthreephases:preparation, dosingsessionandintegration(1, 13).ForpatientswithTRD,therapyis believedtoenhancetheeffectsofpsilocybinandhelpindividualsprocess theirdosingexperiences(5).Thisdynamicrelationshipmakesitdifficult todeterminewhetherimprovementsinsymptomsareduetopsilocybin itselforthepsychologicalsupportprovidedalongsideit.
TheeffectofpsychotherapiesusedinPAPtrialsontheeffectiveness oftreatingdepressionhasyettobedeterminedbyresearchers.Clinical trialsvaryinthenumberandtypeofpreparationandintegrationsessions provided(14).Aswenotedpreviously,therangeofbackgroundtraining forthetherapistsisequallydiverse(13).ThesePAPtrialshavenottried tostandardizeeitherthepsychotherapiesorthetherapists.
Aswemoveforward,theintegrationofPAPintopracticemaypresent somerealchallenges.Whiletherearethosewhobelievethatpsilocybin therapycouldwellprovidesomelastingbenefitswhencomparedtoketamine,thepotentialcostofthesetherapieshassomeprofessionalsconcerned.Ifthecostofthesetherapiesrises,itbecomesanevenbiggerbarriertoaccess.Rightnow,acoupleofdifferenteffortsareexploringgroup therapyandvirtualtherapyaspotentialalternativesthatcouldsavepeoplemoney,butthesafetyandefficacyofthosetherapiesarenotyetestablished.Anotherthingthatisperhapslessfrequentlydiscussedisthe hugeimportanceofsettinginenhancingtheeffectsofthesetherapies.In short,placesmatter;andyouneedtohaveanaccessiblespaceifyouare goingtohaveapositiveeffect(15).
Tosumup,animportantstepwastakenbyRosenblatandassociates whentheyrecentlyilluminatedthesubjectofpsilocybinanditspossible useasatreatmentfordepression.Whattheydidwasquitedifferentfrom whathasbeendonebeforeinthisarea.Theytookagroupofpeoplewho hadseriousmentalhealthissues(inthisinstance,depression),inreallifesettingsthatincludedmultiplecomorbidities.Futurestudieswillbe requiredtoaddressconstraintslikeanopenlabeldesignsamplesizesand controls.
Onecouldmakethecasethatfutureresearchmustincludelarger, placebo-controlledtrialsoverextendedtimesothatwecanclearlyascertainthelong-termsafetyaspectsofpsilocybinandgeneratetheevidenceneededtooptimizethecombinationofdosingwithpsychotherapy sessions.AddressingvariationsinpsychotherapytechniquesandtherapisttrainingwillplayaroleinenhancingtheeffectivenessandconsistencyofPAP.Moreover,logisticalandfinancialobstaclesneedtobeaddressedsincePAPdemandstherapistengagement,specializedtraining andsuitableclinicalenvironments.Continuousresearchisvitaltorealize thepotentialofpsilocybinasatreatmentfordepressionofferingrenewed optimismforthosestrugglingwithTRD.
RodolfoMyronndeMeloRodrigues1
1 InternalMedicineDepartment,TexasTechUniversityHealthSciencesCenter, ElPaso,Texas79911,USA
e-mail: rdemelor@ttuhsc.edu
References
1.RosenblatJD,MeshkatS,DoyleZ,KaczmarekE,BrudnerRM,KratiukK,etal.Psilocybinassistedpsychotherapyfortreatmentresistantdepression:Arandomizedclinicaltrial evaluatingrepeateddosesofpsilocybin.Med.2024;5(3):190–200.e5.DOI: 10.1016/j. medj.2024.01.005.PMID:3835938
2.PearsonC,SiegelJ,GoldJA.Psilocybin-assistedpsychotherapyfordepression: Emergingresearchonapsychedeliccompoundwitharichhistory.JNeurolSci. 2022;434:120096.DOI: 10.1016/j.jns.2021.120096.PMID:34942586
3.CopaD,ErritzoeD,GiribaldiB,NuttD,Carhart-HarrisR,TagliazucchiE.Predicting theoutcomeofpsilocybintreatmentfordepressionfrombaselinefMRIfunctional connectivity.JAffectDisord.2024;353:60-9.DOI: 10.1016/j.jad.2024.02.089.PMID: 38423367
4.TabaacBJ,ShinozukaK,ArenasA,BeutlerBD,CherianK,EvansVD,etal.Psychedelic therapy:Aprimerforprimarycareclinicians-psilocybin.AmJTher.2024;31(2):e121–32.DOI: 10.1097/MJT.0000000000001724.PMID:38518269
5.ChisamoreN,KaczmarekE,LeGH,WongS,OrsiniDK,MansurR,etal.Neurobiologyof theantidepressanteffectsofserotonergicpsychedelics:Anarrativereview.CurrTreat OptionsPsych.2024;11:90–105.DOI: 10.1007/s40501-024-00319-8
6.SeelamneniV.Peripheralsignals,centralquestions:Examiningtherelationship betweenpsychedelicsandbrain-derivedneurotrophicfactor(BDNF).Psychedelics. 2024;1(1):1-2.DOI: 10.61373/pp024c.0013
7.PerezN,LanglestF,MalletL,DePieriM,SentissiO,ThorensG,etal.Psilocybin-assisted therapyfordepression:Asystematicreviewanddose-responsemeta-analysisofhumanstudies.EurNeuropsychopharmacol.2023;76:61–76.DOI: 10.1016/j.euroneuro. 2023.07.011.PMID:37557019
8.AaronsonST,vanderVaartA,MillerT,LaPrattJ,SwartzK,ShoultzA,etal. Single-dosesyntheticpsilocybinwithpsychotherapyfortreatment-resistantbipolar typeIImajordepressiveepisodes:anonrandomizedcontrolledtrial.JAMAPsychiatry.2024;81(6):555–62.DOI: 10.1001/jamapsychiatry.2023.4685.PMID:38055270; PMCID: PMC10701666
9.BoschOG,HalmS,SeifritzE.Psychedelicsinthetreatmentofunipolarandbipolar depression.IntJBipolarDisord.2022;10(1):18.DOI: 10.1186/s40345-022-00265-5 PMID:35788817;PMCID: PMC9256889
10.AdayJS,HortonD,Fernandes-OsterholdG,O’DonovanA,BradleyER,RosenRC, etal.Psychedelic-assistedpsychotherapy:whereisthepsychotherapyresearch?Psychopharmacology(Berl).2024;241(8):1517–26.DOI: 10.1007/s00213-024-06620-x PMID:38782821
11.GoodwinGM,CroalM,FeifelD,KellyJR,MarwoodL,MistryS,etal.Psilocybinfor treatmentresistantdepressioninpatientstakingaconcomitantSSRImedication. Neuropsychopharmacology.2023;48(10):1492–9.DOI: 10.1038/s41386-023-016487.PMID:37443386;PMCID: PMC10425429
12.GoodwinGM,AaronsonST,AlvarezO,ArdenPC,BakerA,BennettJC,etal.Singledosepsilocybinforatreatment-resistantepisodeofmajordepression.NEnglJMed. 2022;387(18):1637–48.DOI: 10.1056/NEJMoa2206443.PMID:36322843
13.HaikazianS,Chen-LiDCJ,JohnsonDE,FancyF,LevintaA,HusainMI,etal.Psilocybinassistedtherapyfordepression:Asystematicreviewandmeta-analysis.Psychiatry Res.2023;329:115531.DOI: 10.1016/j.psychres.2023.115531.PMID:37844352
14.CroweM,ManuelJ,CarlyleD,LaceyC.Psilocybin-assistedpsychotherapyfor treatment-resistantdepression:Whichpsychotherapy?IntJMentHealthNurs. 2023;32(6):1766–72.DOI: 10.1111/inm.13214.PMID:37589380
15.VargasMV,MeyerR,AvanesAA,RusM,OlsonDE.Psychedelicsandotherpsychoplastogensfortreatingmentalillness.FrontPsychiatry.2021;12:727117.DOI: 10.3389/ fpsyt.2021.727117.PMID:34671279;PMCID: PMC8520991
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Psychedelics
THOUGHTLEADERSINVITEDREVIEW
Effectsofayahuascaonfearandanxiety:cross-talkbetween5HT1Aand 5HT2Areceptors
LorenaTereneLopesGuerra1 ,RafaelGuimarãesdosSantos1 , 2 ,andJaimeEduardoCecilioHallak1 , 2
Ayahuascaisahallucinogenicsubstancecurrentlybeinginvestigatedforthetreatmentofmood,anxiety,andtrauma-relateddisorders. Evidencefromanimalandhumanstudiessuggestthattheeffectsofayahuascainvolvemodulationofneuralsubstratesrelevantforemotional processing,especiallyinregionsrichinserotonergicreceptors.Moreover,preclinicalstudiesalsoshowthatayahuascahasspecificeffectson fear-relatedmemories.Theserotonergicsystemhasbeenclassicallyassociatedtoanxietyandfearresponses,withselectiveserotonin reuptakeinhibitorsbeingfirst-classmedicationtotreatmood,anxiety,andstress-relateddisorders.Herewereviewcurrentlyavailabledata regardingayahuasca(anditsmaincomponents)behavioralandfunctionaleffectsonanxietyandfear-relatedresponsesthroughits modulationofserotoninergicsignaling.
Psychedelics March2025;1(2):15–25;doi: https://doi.org/10.61373/pp024i.0037
Keywords: Ayahuasca,fear,anxiety,serotonin
Introduction
Ayahuasca(AYA)isahallucinogenicbeveragetraditionallyconsumedby indigenousgroupsfromNorthwesternAmazonand,morerecently,bysyncreticreligiousgroupspresentworldwide.ThemainpsychoactivecompoundinAYAisN,N-dimethyltryptamine(DMT),presentintheleavesof Psychotriaviridis,butthepreparationofAYAalsoinvolvesthe Banisteriopsiscaapi vine,richin β -carbolines(1).The β -carbolinesactasantagonistsondigestivesystemmonoamineoxidaseenzymesthat,otherwise,woulddegradeDMTbeforeitcouldreachthecentralnervous system(2).Harmine,tetrahydroharmine,andharmalinearethemostrelevant β -carbolinesinAYA,whichhavetheirownpharmacologicalproperties,addinganotherlayerofcomplexitytothemechanismsofactionof AYA(3).
AYAcanbedefinedasaclassichallucinogen,sinceithasagonisticeffectsindifferentserotonergicreceptors,especiallythe2Asubtype (5HT2Areceptor)(4).ThesubjectiveandhallucinogeniceffectsofAYA seemtoresultfromitsagonismat5HT2Areceptors;however,itcanalso actondifferentreceptorsubtypes,withthe1Areceptor(5HT1A)being ofspecialinterestforthediscussionproposedbythisreview(5, 6).The effectsofAYAonserotonergicpathwaysmostlyrelyonDMTaction,since β -carbolinespresentlittletonoaffinityformostserotoninergicreceptors,exceptforamodestaffinityforthe5HT2Areceptor(3, 5).
Similarlytowhathavebeenhappeningtootherpsychedelicsubstances,AYApropertieshavebeeninvestigatedastreatmentfornumerouspsychiatricdisorders,suchasdepression,anxiety,andsubstanceuse disorder(7–11).Additionally,preclinicalstudieshavesuggestedapossibleactionofAYAonfearprocessingcircuits,whichcouldsupportpossiblemechanismfortherapeuticeffectsonanxietyandposttraumatic stressdisorder(PTSD)(12, 13).Afewobservationalstudiesandcase reportshavealreadybeenpublishedabouttherapeuticeffectsofAYA ontraumaprocessingandtreatmentofPTSD(14, 15),withpromising results.Nonetheless,untilnow,clinicaltrialsperformedincontrolledsettingsarelacking.
Apartfromserotoninreceptors,AYAalsohaseffectsonglutamatergic, dopaminergic,andendocannabinoidsystems(16–18).Itispossiblethat DMTactsasanagonistof sigma-1 receptors(19),whichwasalreadysuggestedasapossiblemechanismforAYAeffectsonfearprocessing(20).
Moreover,AYAintakecanalterneuroendocrineresponsesaswell(21). Thesecomplexinteractions,however,arebeyondthescopeofthisreview. Here,weaimedtoconcatenateanddiscussdataregardingAYAeffectson fearandanxietyandhowitcanbeassociatedwithitsactionsonserotonin (5HT)receptors.
FearBehaviorandAnxiety
Fearisanevolutivepreservedbehaviorthatactsasadefensemechanism andisusuallytriggeredbythreateninganddangerousstimuli.Somestimulicannaturallyelicitadefensivebehavior,whileotherscanbelearned andassociatedtolifelongresponses.Thisbehavioralplasticityiscrucial foradaptationtoanenvironmentthatcontinuouslychallengesindividualswithnewcontexts(22).Anxiety,ontheotherhand,representsastate ofincreasedarousalandvigilanceevenintheabsenceofanimminent threat,anditcanalsoelicitbehavioraldefensiveresponses(23).
Impairmentsonappropriatefearandanxietyresponsesarethecause ofavarietyofpsychiatricdisorders,suchasPTSD,generalizedanxietyand panicdisorders(24).Effortstodevelopbettertreatmentoptionsforpatientssufferingfromthesedisordersdemandthedevelopmentoftests andparadigmsthatcanassessthebehavioralandneuralalterationsunderlyingthesymptoms.
ParadigmsforAssessingFearandAnxietyResponses
Themorefrequentlyemployedparadigmstoassessfearandanxietyresponsesinpreclinicalstudiesusuallyarerootedoninherentbehavioral characteristicsoftheanimalsoronassociativelearningofconditioned responsestonaturallyaversivestimuli.
Inthefirstcategory,theanimalbehaviorisaffectedbyanapproachavoidanceconflictbetweentheinherenttendencyfortheanimaltoexplorethenewenvironmentversusfear-drivenbehaviors.Theelevated plus-maze(EPM)andtheopenfieldtest(OFT)aretwoofthemostfamoustasksbasedonthispremise.Animalsexpressingincreasedanxietylikebehaviorspendmoretimeontheclosedarms(EPM)orintheedges ofthefield(OFT),respectively.Treatmentwithanxiolyticdrugsincrease entrancesandtimespendontheopenarmsfortheEPM,aswellastime spentinthecenterofthearenafortheOFT(25, 26).
Onthesecondcategory,theclassicalorPavlovianconditioningisthe mostwidelyemployedprotocoltostudyfearbehaviorandmemories.
1 DepartamentodeNeurociênciaseCiênciasdoComportamento,UniversidadedeSãoPaulo,RibeirãoPreto14015-010,Brazil; 2 NationalInstituteofScienceandTechnology TranslationalMedicine(INCT-TM)14015-010,Brazil
CorrespondingAuthor: Prof.RafaelGuimarãesdosSantos,DepartamentodeNeurociênciaseCiênciasdoComportamento,FaculdadedeMedicinadeRibeirãoPreto,UniversidadedeSãoPaulo,HospitaldasClínicas,TerceiroAndar,Av.Bandeirantes,3900,RibeirãoPreto,SãoPaulo,Brazil.Phone: +551636350713.E-mail: banisteria@gmail.com Received:9September2024.Revised:28October2024and12November2024.Accepted:14November2024. Publishedonline:10December2024.
Throughthisparadigm,astimulusonceneutral,thatis,thatdoesnot elicitabehavioralresponse,ispairedtoastimulusthatnaturallyevokes afearresponse.Oncetheanimalistrainedthroughsimultaneouspresentationsofthelatter(thatiscalledtheunconditionedstimulusorUS)togetherwiththeformer(whichwillbecalledtheconditionedstimulusor CS),anassociativememoryisacquiredandtheCSaloneisabletoevoke thebehavioralresponse(27, 28).AlterationsinUSintensityandCScharacteristicscanresultinmemorieswithdifferentcharacteristics,likeduration,intensityofevokedbehavioralresponseandgeneralization(22). Thetwomorefrequentlyemployedfearconditioningparadigmsarethe contextualfearconditioning(CFC)andthetonefearconditioning(TFC). Bothapplyelectricshocksattheanimal’spawastheUS,butthefirstuses thewholecontextwheretheanimalistrainedastheCS,andthelatter usesaspecificsoundastheCS,andtheanimalistestedbeingexposedto thesamesoundbutinadifferentcontextfromtraining(29).
Fearconditioningprotocolshavebeenwidelyemployedbypreclinical researchersasatooltounderstandmemoryformationaswellashowthey canbealteredorforgotten.Repeatedre-exposuretotheCSisthebase forreconsolidationandextinctionprotocols(30).Ifelucidatingthefear memoryformationisrelevant,understandinghowalreadyestablishedresponsescanbealteredcanbeevenmorevaluabletocontributefortreatingdisorderslikePTSD(31).
Inhumans,thebehavioralandsubjectiveconsequencesoffearand anxietyarefrequentlyassessedusingspecificallydevelopedpsychometricinstruments.However,therearemanytasksaswellthatcanbeemployed,beingespeciallyusefulwhenaccessingneuralalterationsunderlyingthebehavioralresponsesthroughneuroimagingtechniques.
Socialcognitiontasksfrequentlyemployemotionalrelevantstimuli. Duringtasksinvolvingtherecognitionofemotionsinfacialexpressions (REFE),subjectsarepresentedtostaticordynamicimagesoffacialexpressionsandaskedtorecognizepicturedemotion.Therearemanyvariationsinthesetasks,butseveralarebasedonEkman’stheoryofbasic universalemotions(32).Performanceinthesetasksseemstobealtered bynumerousconditions,especiallywhenrespondingtonegativevalence emotions,likefear(33–35).AnothertaskexampleistheSimulationof PublicSpeakingTest(SPST),ananxiety-inducedtaskwhereindividuals areaskedtoelaborateaspeechonarandommatterandpresentitinfront ofcamera,mimickingapublicspeaksituation(36).
NeuralSubstratesUnderlyingFearandAnxietyResponses
Multiplebrainregionsareinvolvedonprocessingofemotionallyrelevant stimuli,butasignificantpartoftheavailabledataproducedinthelast decadesfocusesonunderstandingcortical-limbiccircuitsdynamics.In thissection,wewillfocusonprefrontalcortex(PFC),amygdala(AMY), andhippocampus(HPP)influenceonfearandanxietyprocessing.Later (Section2.3),raphenucleiinnervationstothesestructureswillalsobe discussed.
PrefrontalCortex. ThePFCisinvolvedinnumerousexecutiveprocesses. Itreceivesandprojectstostructuresrelevanttoemotional,cognitive, sensory,andmotorfunctioning,resultinginacentralintegrativerolefor behavioralcontrolandflexibility,highlyinfluencedbyexternalcuesand internalcontingencies(37).AlthoughthereisanongoingdebateregardingthehomologiesbetweenrodentandprimatecompositionofthePFC, themedialPFC(mPFC)fromrodentsholdssimilaritiesinthemodulation exertedbyhumandorsolateral,medialandcingulatecorticesovermemory,emotionalregulationandresponsecontrol,amongotherfunctions (38).
TherodentmPFCincludestwomainsubdivisions,theprelimbiccortex(PL),thattogetherwiththeanteriorcingulatecortexconstitutes thedorsalmPFC,andtheinfralimbiccortex(IL),moreventrallylocated. Despitebeingcloselylocatedandintimatelyinterconnected,thesetwo regionshavedifferentprojectingprofiles(37, 39).ThePLhavemore efferentconnectionswiththebasolateralnucleusoftheAMY(BLA),and dorsalandmedianraphenuclei,whiletheILinnervatesnumerousAMY nuclei,butespeciallythecentralAMYnucleus(CeA),andthelateral septum(39).
ThePLprojections,althoughnotnecessaryforfearconditioningacquisition,areneededfortheconsolidationoftheassociativefearmemory
(40).ThePLisalsorelevantforfreezingexpressionafterTFC,sinceCSmodulateddisinhibitionofPLprincipalneurons(PNs)projectionstothe BLAisrelevantforfearexpressionduringtest(41).TheILactivitydoes notinfluencefearacquisitionorconsolidation;however,itisessentialfor fearextinctionretention,suggestingaroleonbehavioralflexibility(42). OptogeneticallysilencingILPNsduringextinctionlearningdoesnotinterferewithfreezingreductionwithinsession,butimpairedextinctionrecall. However,silencingthePNsduringextinctiontestdoesnotimpairextinctionrecall,indicatingthatproperILactivationisnecessaryforconsolidationoftheextinctionmemory(43).
ThemPFCactivityexertsatop-downmodulationofsubcorticalstructuresrelevantforemotionalregulation(37).Consistentwiththat,data fromclinicalandpreclinicalstudiessuggestthatincreasedanxietyresponsesarelinkedtoahypoactivationofthisregion,whichcanalsoresultinimpairedcognitiveflexibility(44–46).Inmice,synchronybetween mPFCandBLAactivityisrelatedtodiscriminationofsafetycontextsduringfearlearningandanxietyprotocols(47).Similarly,whencompared withhealthycontrols,patientswithgeneralizedanxietydisorderhadreducedventromedialPFCactivationwhenprocessingsafetysignals(48).
RegardingPLandIL,theirpreciseroleonmodulationofanxietyresponsesislesswelldefined,withcontrastingresultsontheliterature, thatmayresultfromprojections’functionalheterogeneity(49).
Amygdala. TheAMYisasubcorticalstructurecomprisingdifferentnucleiandlocatedinthemedialtemporallobe.Itreceivesprojections fromcorticalandsubcorticalstructures,essentiallyactingasaninformationprocessinghubthattranslatesensoryinputstootherareasrelevanttobehavioralcontrolandemotionalprocessing,suchasthePFCand HPP(50, 51).
Duringfearconditioning,theCSandUSassociationdependsonanintricatetemporalbalanceofthedifferentAMYnucleiactivation(22).The lateralportionoftheAMYistheinputregionforsensoryinformation,and itisalsowheretheCSandUSstimulirepresentationsareassociated.However,thecommunicationwithotherAMYnucleidependsonglutamatergic projectionsleavingfromthebasalAMY.Sincebothregionsareintimately interconnected,theyareoftenreferredasthebasolateralAMY(BLA)(52). IftheBLAisthemaininputcenter,thecentralAMY(CeA)istheoutput, projectingtostructuresrelevantforfearexpression,suchasthehypothalamusandtheperiaqueductalgray(53).TheBLAPNsinnervatedeCeAdirectly,butalsoregulateitsactivityindirectlythroughprojectionstothe intercalatedcells(ITC),aGABAergiccellmass,thatalsoinnervatesthe CeA(54).AMYactivityisnecessaryforbothCFCandTFC,butontheformer,thecontextrepresentationreliesondorsalHPPactivitywhichthen indirectlycommunicateswiththeAMYthroughventralHPPprojections (29, 55).
AlteredactivityindifferentAMYnucleiisassociatedtoanxietyresponses.InsidetheAMY,activationofprojectionsfromtheBLAtoCeA haveananxiolyticeffect,whileselectiveoptogeneticinhibitionofthese neuronsresultinanincreaseofanxiety-likebehaviorinmice(56).Functionalconnectivitybetweenthesetwosubregionsisalsoimpairedinpatientswithgeneralizedanxietydisorder(57).Whenexposedtoemotional relevantstimuli,patientswithanxietyandtrauma-relateddisorderstend topresentincreasedAMYresponse(58).
Hippocampus. TheHPPislocatedinthetemporallobeandimplicated inmultiplecognitive,memoryandemotionalprocessingfunctions.This structurecanbefunctionallydifferentiatedintotwodistinctareas,the ventralHPPandthedorsalHPP(59).
ThedorsalHPPfunctioningisassociatedtocognitiveperformanceand isresponsibleforencodingtherepresentationofthecontextduringCFC, hencewhythistaskisdescribedasHPP-dependent.Lesionsonthedorsal HPPimpairCFCexpressionwithoutalteringTFC(60).
Additionally,HPPisoneofthefewstructureswherenewneuronscan beborninadultbrains(61),althoughthereisanongoingdebatewhether thispropertyispresentinhumans(61, 62).Impairedneurogenesisseems toberelatedtosymptomatologyofmultiplepsychiatricdisorders,like depressionandPTSD(63).
However,thishippocampalregiondoesnotdirectlyprojecttotheAMY andtheintegrationsofcontextrepresentationtosensoryinputstoAMY
dependsonventralHPPprojections(64).AddedtoitsroleonCFCacquisition,dorsalHPPalsoisrelevantforfearmemoryrecallandextinction (65, 66).
TheventralHPP,ontheotherhand,ismoreassociatedtoemotional processing,beingtheonlyHPPregionprojectingdirectlytoAMY(64). Additionally,theventralHPPalsoseemtoberelevantforexpressionof anxietyresponses.Anxiogenicenvironmentsincreasesynchronizationof mPFCandventralHPP,thesamenotbeingreportedforthedorsalHPP (67).Additionally,lesionsontheventralHPPleadtodecreaseinanxietylikeresponsesintheEPM(68).
Inhumans,PTSDisassociatedwithdecreasedHPPvolumeandimpairedHPPactivationinwomenperformingaverbaldeclarativememory task(69),anditisalsoassociatedwithreducedHPPactivationtotraumarelatedstimuli(70).Inpatientswithgeneralizedanxietydisorder,the anteriorHPP(analogtotheventralHPPinrodents)haddecreasedactivationtorepeatedexposuretothreatcueswhencomparedwithhealthy controls(71).
SerotoninEffectsonFearandAnxietyResponses Studiesonhumanserotoninreceptorsareintimatelylinkedtohallucinogeniccompounds.In1953,Gaddumreportedlysergicaciddiethylamide (LSD)antagonisticeffectover5-HTresponseselicitedinvitro(72, 73) and,sincethen,sevenserotoninreceptorclasseshavebeendescribed, mostlyrepresentedbyG-proteincoupledreceptors(74).Althoughhallucinogeniccompoundscaninteractwithdifferent5HTreceptorclasses, mostoftheavailabledatafocusonthe5HT2and5HT1subtypes,specificallythe2Aand1Asubtypes(75).
The5HT2AsubtypeisGq/11 -coupledandabundantlyexpressedincorticalareas,especiallyonlayerVdendritesofPNs,whicharedenselyinnervatedby5HTaxons(76).Theiractivationmostlyproducesincreased membraneexcitabilitythroughaslowmembranedepolarizationandinhibitionofcalciumactivatedafter-hyperpolarizationcurrents(77).
The5HT1Areceptors,ontheotherhand,arepresynapticallyexpressed on5HTneuronsoftheraphenucleiwheretheyactasautoreceptors andregulate5HTrelease(78).However,theyarealsowidelydistributed throughsubstratesrelevanttomemoryandemotionalprocessing,suchas theHPP,cingulateandentorhinalcorticesandAMY,wheretheyarepostsynapticallyexpressed(79, 80).ThesereceptorsarecoupledtotheGi protein,andtheiractivationinducesmembranehyperpolarizationthrough increaseinrectifyingpotassiumcurrentsandinactivationofcalcium channels(74, 77).
Theseeminglyopposingeffectsof5HT2Aand1Areceptorsonmembranepotentialmayappearcontradictoryastheyareoftenco-expressed oncorticalPNs(81),butthesedifferencesarerelevantforstimuliprocessing.Thehyperpolarizingactionof5HT1Aaltersthesensibilityto input-generatedexcitability,restrainingfiringfrequency,whiletheinhibitionofafter-hyperpolarizationinducedby5HT2Aactivationincreases excitability,modulatingneuronalgain(77).ApartfromPNs,thesereceptorscanbeexpressedoncorticalGABAergicinterneurons(INs)aswell, addinganotherlayerofcomplexitytoserotonergiccontrolovercortical excitatory/inhibitorybalance(76, 81).
Throughthe70sand80smanystudiesexploredhow5HTaffectedpunishmentconditionedbehaviors.Atthetime,5HTsignalingpathwayswere thoughttoregulatethesebehaviorsandpromotepunishment-induced responsesuppression.Althoughfurtherevidenceelucidatedthatthisrelationshipisnotasstraightforwardasinitiallythought,5HTroleonfear andanxietyneurobiologyisstillundeniable,withselective5HTreuptake inhibitors(SSRIs)beingthefirstlineoftreatmentformanystressand anxietydisorders(24).
ThetheoryformulatedbyDeakinsandGraeffproposesthatdistinct fearandanxietybehavioralresponsesarecontrolledbyspecific5HTpathwaysarisingfromtheraphenuclei.Thedorsalraphe(DRN)periventriculartractisresponsibletoreacttoacuteUSexposure,controllingflightor fightresponses,andmostlymodulatingtheperiaqueductalgrayactivity. TheDRNforebrainbundletract(DRD/DRC)isactivatedbyacuteexposure toCSandcontrolsavoidancebehaviorsthroughprojectionstostructures suchastheAMY,ventralHPPandPFC.Andthemedianrapheforebrain bundletract(DRI/MnR)respondstochronicUSand/orCSexposure,being
responsibletopromoteresilienceortolerancetochronicstress,projectingtothedorsalHPPandPLandILcortices,actingmostlythoughpostsynaptic5HT1Aactivation(82, 83).
Knock-outmiceforthe5HT2Areceptorpresentdecreasedanxietylikebehaviors,buthavenormalCFCandTFC,andthereestablishment of5HT2Asignalingincorticalneuronsnormalizedtheanxiety-likeresponses(84).IntheBLA,activationof5HTprojectionsofDRNincreases anxiety-likeresponsesthrough5HT2Aactivation(85).
Pretreatmentwiththe5HT2AagonistTCB-2orantagonistMDL11,939 beforeacquisitionandretrievalofconditionedfearmemorydidnotinterferewithfreezingexpressionofmalemice,whileTCB-2administration posttrainingenhancedfreezingonCFCandTFCtests.Asfortheextinctionlearning,5HT2Aactivationisnotessential,butfacilitatestheprocess (86).Altogether,thesedatasuggestaroleforthe5HT2Areceptoronplasticitymechanismsalteringmemorytracesandbehavioralresponses,but thatroleislimitedtoalreadyacquiredmemoriesanddoesnotseemto influencetheestablishmentofnewassociations.
Activationofpostsynaptic5HT1Areceptors,ontheotherhand,seems todecreaseanxietyandstressresponses.Systemicorintrahippocampal treatmentwith5HT1Aagonist8-OH-DPATbeforeCFCimpairsfearmemoryretrieval,withoutsignificantlyalteringTFCmemoryretrieval.Theimpairmentswerenotobservedwhentreatmentwasadministeredafter training.Additionally,WAY100635,a5HT1Aantagonist,wasnotableto producememoryalterationswhenadministeredalone,butpreventedretrievalimpairmentswhencombinedwith8-OH-DPAT.Opposedtotheoutcomesobservedafter5HT2Amanipulation,5HT1Areceptorsseemtobe relevantformemoryacquisition,especiallyofHPP-dependentmemories, liketheCFC(87).
SerotoninReceptors’RoleonPsychedelicEffects
Thebehavioralandmentalalterationsresultingfrompsychedelicadministrationarefrequentlyassociatedtoitsagonismat5HT2Areceptors.In humans,ketanserin,a5HT2A/2Cantagonist,canbeusedtoreducesubjectiveeffectsinducedbyLSD(100or200 μg)(88, 89).Pretreatmentwith ketanserinalsopreventsthepsilocybin-induced(215 μg/kg)increasein positiveaffectandthedecreaseonrecognitionofnegativefacialexpressions(90).ForDMT(0.7mg/kg,i.m.),pretreatmentwithcyproheptadine,another5HT2A/2Cantagonist,didnotinterferewithsubjective effects(91).Ontheotherhand,pretreatmentwithpindolol,a5HT1A/βadrenergicreceptorsantagonist,intensifiedDMT(0.1mg/kg,i.v.)subjectivereactions,suggestinganattenuationresponseof5HT1Areceptors activationonDMTeffects.Theenhancementofsubjectiveeffectscaused bypindololcouldbearesultofincreased5HT2Asignalingafter5HT1A blockade(5).
RegardingAYA,pretreatmentwithketanserinalteredtheneurophysiologicaloscillatorypatternsinducedbyAYA(doseadjustedtocontain 0.75mg/kgofDMT)intakeandblockedvisualeffectsthroughblocking AYA-induceddecreaseinalphaoscillations(6).
Althoughtheavailableliteraturemostlyattributesthesubjectiveeffectsofpsychedelicstoagonismatthe5HT2Areceptor,someevidence pointsoutthatnoteverythingcanbeexplainedbyit.Inhealthyvolunteers,pretreatmentwithketanserindidnotpreventthereductioninattentionaltrackingabilitycausedbypsilocybin(215 μg/kg),suggesting arolefor5HT1Areceptors(92).Combinedadministrationofbuspirone, 5HT1Aagonist,andpsilocybin(170 μg/kg)reducedtheacutesubjective effectsofpsilocybin(93).Inchronicallystressedmice,treatmentwithketanserindidnotpreventtheantidepressanteffectsofasingledoseof psilocybin(1mg/kg,i.p.)(94).
PreclinicalEvidenceforAyahuasca’EffectsonFearandAnxiety-like Responses
AnimalstudiesevaluatingtheeffectsofAYAadministrationaretryingto decodehowthissubstancecaninterferewithbehavioral,functionaland structuralparametersoffearandanxiety-likeresponses,andhowthis couldbelinkedtothepossibletherapeuticeffects(Table1).
AsingleoraladministrationofAYA(containing9mg/kgofDMT)to femaleratsdecreasedlocomotionontheOFTandEPM,whichcouldbe anindicationofananxiogeniceffect,whilstitalsodecreasedimmobilityonforcedswimtest(FST),anindicationofantidepressanteffect.The
Table1. Fearandanxiety-likeresponsesfrompreclinicalstudies
TrainingTestingReconsolidationExtinction
Fearmemorytests
AYA–ChronicpretreatmentwithAYA(120 mg/kg)increasedfreezingatCFC andTFC(99).
AYAtreatment(60mg/kg) pretreatmentbeforeor afterreconsolidation sessiondecreasesfear expressiononCFCtest(12).
SingleAYA(0.3mg/kg ofDMT)dosereduces freezingduringCFC extinctiontraining, butnottest. However,two treatmentpaired extinctionsessions decreasefreezing duringtest(13).
SingleAYAdose(60 mg/kg)before retrieval,facilitates CFCextinction learningoneday after(12).
DMTAcutetreatmentwithDMT (10mg/kg)increased freezingduringTFC(96).
ChronictreatmentwithDMT (1mg/kg)didnotaffect behaviorduringCFCand TFCtraining(100).
β -carbolinesPre-trainingharmine(10 mg/kg)treatmentdidnot alteredaversiveavoidance learningduringPMDAT training(102).
AcutetreatmentwithDMT (10mg/kg)beforetrainingdid notalterfearresponseduring TFCtest(96).
ChronictreatmentwithDMT(1 mg/kg)didnotaffectbehavior duringCFCandTFCtest(100).
Pre-trainingtreatmentwith harmaline(1mg/kg)impaired fearresponseatthestep-down passiveavoidancetask(101).
Pre-trainingharmine(10mg/kg) treatmentimpairedfearresponse atCFC,butnotTFC(102).
Pre-trainingharmine(10mg/kg) treatmentimpaired aversive-avoidanceduringPMDAT test(102).
–DMTacute(10mg/kg) orchronic(1mg/kg) treatmentfacilitated TFC,butnotCFC, extinction(96, 100).
Anxietytest
AYAAcuteoralAYAdose(9mg/kgofDMT)decreasedlocomotiononOFTandEPM(95).
AcuteoralAYAtreatment(0.1,0.3ofDMT)hadnoeffectontimeintheopenarmsandclosedarmentries,butthehigherAYA dose(1.0mg/kgofDMT)increasedclosedarmentriesandgeneralexploratorybehavior(13).
OralsingledoseofAYA(60mg/kg)didnotalteropenarmandclosedarmentries,anddidnotalterlocomotion(12).
DMTOneDMTdose(10mg/kg,i.p.)reducedexplorationintheOFTandopenarmstimeandentriesonEPM(96). β -carbolinesAcuteharmine(5,10,15mg/kg,i.p.)treatmentdidnotalterbehavioralexpressionontheOFT(98).
AYA:Ayahuasca;CFC:Contextualfearconditioning;DMT:N,N-dimethyltryptamine;EPM:Elevatedplus-maze;OFT:Openfieldtest;PMDAT:Plus-maze discriminativeavoidancetask;TFC:Tonefearconditioning;–:Unavailabledata.
treatmentalsoinducedanincreasein c-fos expressingneuronsinthe DRN,posteriorBLAandHPP(95).Maleratstreatedwithonedoseof DMT(10mg/kg,i.p.)alsopresentedreducedexploratoryandincreased anxiety-likebehaviors,whilethreedoseswereabletoinduceantidepressanteffectsontheFST(96).Psylocibin,another5HT2Apsychedelicagonist,alsoincreasesanxiety-likeresponseswhenadministered15min priortotheOFT,butpromotesanxiolyticeffectswhenanimalsaretested 4haftertheadministration(3mg/kg,i.p.)(97).
Interestingly,acutetreatmentwithharmine(10or15mg/kg,i.p.)also inducedthedecreaseindepressive-likeresponsesonFST,withoutalteringexploratorybehaviors.Additionally,animalstreatedwiththehigher doseofharminealsopresentedincreasedhippocampalbrain-derived neurotrophicfactor(BDNF)expression(98).
FurthercomprehendinghowAYAcanaffectfearmemoryprocessing mighthelpelucidatehowthissubstancecouldbeusefulfortreatingdisorderssuchasPTSD.Mostpreclinicalstudiesonthisthemefocusonhow
AYAtreatmentcouldalteranalreadyestablishedfearmemory,which makessensewhenconsideredfromatranslationalpointofview.Nevertheless,theresultselicitedbytreatmentwithAYAanditsconstituent compoundspriortofearmemoryformationorduringreconsolidationand extinctionofalreadyestablishedmemoriesseemtodifferentlyaffectbehavioralresponses.
RatschronicallytreatedwithAYA(120mg/kg,oral)for30daysand latersubmittedtoCFCandTFCpresentedenhancedfreezingbehavior duringthetest.OnTFCtest,freezingwasincreasedevenbeforetheCS presentation.Treatmentwithhigherdoses(240and480mg/kg)didnot alterbehavioralexpression(99).DMT(10mg/kg,i.p.)alsoseemstoinfluencefreezingbehaviorwhenadministered1hpriortoTFC,increasing thisbehaviorduringtraining,butnotduringtest(96).Chronictreatment withsmallerdosesofDMT(1mg/kg,i.p.)beforetheconditioningprotocol,ontheotherhand,doesnotincreasefreezingbehavioronCFCandTFC tests(100).
β -carbolines,ontheotherhand,seemtopresentanamnesiceffect whenadministeredtoanimalspriortofearmemorytasks.Harmaline (1mg/kg,i.p.)injectedtomice5minbeforeastep-downpassiveavoidancetasktrainingpreventedincreasedlatencytostepdown24hlater duringtheretentiontest(101).Harmineadministered(10mg/kg,i.p.) torats1hbeforeCFCandTFCconditioningdecreasedfreezingbehavior whenanimalsweretestedforCFC24hlaterbutdidnotaffectfreezing ontheTFCtest48hlater.Ratssubmittedtoaplus-mazediscriminative avoidancetask(PMDAT)alsoweretreatedwithharmine(5,10,15mg/kg, i.p.)beforethetraining.Inthistask,aregularelevatedplusmazeisused, butoneoftheclosedarmswillbeequippedwithvisualandsoundaversivestimuli.Everytimetheanimalenterstheaversivearmduringtraining,thestimuliiscontinuouslypresenteduntiltheanimalleftsthearm. Althoughduringtrainingallanimalslearnedtoavoidtheaversivearm,indicatingmemoryacquisition,24hlaterallharmine-treatedgroupswere notsignificantlyavoidingtheaversivearmwhencomparedwiththeother nonaversivearms(102).
RatstrainedinaCFCprotocolthatreceivedasingledoseofayahuasca (60mg/kg)20minbeforeor3hafterare-exposuresessiontothe conditionedcontextpresentlessfreezingbehaviorwhentestedinthe samecontextonedaylater.Thisdecreaseisnotobservedduringthereexposuresessionitselfnorduringthetestwhentheanimalsaretreated withoutbeingre-exposedtoconditionedcontextpreviouslytotesting.Interestingly,thesameresultsarereproducedevenforremotememories, whentheanimalsaretested22daysafterthere-exposure.Theseresults suggestthatayahuascacouldbeactingonmemoryreconsolidation,reshapingthefearresponseasaconsequenceofthememorytracebecomingmorelabile(12).
Regardingextinctionprotocols,theresultsareconflicting.ThetreatmentwithasingledoseofDMT(10mg/kg,i.p.)1hpriorextinctiontrainingonTFC,aswellaschronictreatmentwithsmallerDMTdoses(1mg/kg, i.p.),seemtofacilitatefearextinction(96, 100).However,intheCFCprotocol,evenmultipletreatment-pairedextinctionsessionswerenotable toextinguishthefearresponse(96).OnmousesubmittedtoTFC,psilocybinadministration(2.5mg/kg,i.p.)priortoextinctiontrainingdecreased fearexpressionduringtrainingandduringextinctiontests1and6days aftertraining(103).
AYA(adjustedtocontain0.3mg/kgofDMT)administrationtorats 1hbeforeaCFCextinctionsessiondecreasesfreezingbehaviorduringthe sessions,butthereductionisnotsustainedonedaylaterontheextinction test.However,whentheanimalissubmittedtotwotreatment-pairedextinctionsessions,theextinctionmemoryisrecalledwhentestedoneday later(13).WhentheAYA(60mg/kg)treatmentwasadministered20min beforeor3hafteraretrievalsession,onedaypriortoextinctiontraining,asingledosewassufficienttofacilitatetheacquisitionofextinction memory(12).ChronicAYAtreatment(120mg/kg,oral)beforeCFCaltered freezingexpression,butdidnotaffectextinctionlearning(99).
Evenafterextinction,re-exposinganimalstotheUScanpromote thereinstatementofthefearresponse.TreatmentwithAYA(60mg/kg) 20minbeforeor3hafteraretrievalsessioncanpreventreinstatement aftertheacquisitionoftheextinctionmemory(12).However,whenthe treatment(adjustedtocontain0.3mg/kgofDMT)iscarriedoutduring theextinctionsession,althoughtheextinctionmemoryisacquired,the reinstatementisnotprevented(13).
ThedifferencesbetweentheresultsobservedfortreatmentwithisolatedcompoundsofAYAsuggestthe β -carbolinescouldbemoreeffectivetargetingHPP-dependentmemories,asisthecaseofCFC,step-down passiveavoidanceandPMDATtasks.Theseamnesiceffectscanbeanindicationthat β -carbolinesarepromotingincreasedneurogenesis,once increasingHPPneurogenesisonHPP-dependenttaskscanpromoteforgetting(104).However,allavailabledatatestthesesubstancesonmemoryacquisitionandearlyconsolidation,whiledataregardingitseffects onalreadyestablishedmemorytracesarestilllacking(101, 102).
DMT,ontheotherhand,doesnotaffectmemoryacquisitionandearly consolidation,althoughitsadministrationbeforeTFCenhancesfreezing responseduringthetraining.However,duringextinctionprotocolsfor TFC,treatingtheanimalwithasingledose1hbeforetheextinctionsessionorachronictreatmentwithsmallerDMTdosescanfacilitatefearex-
tinction,butthesameresultdoesnotoccuronCFCtrainedanimals(96, 100).Theseresultssuggestthat,althoughDMTcaninterferewithfear processing,itisnoteffectivefortargetingHPP-dependentmemories.
WhenAYAitselfisbeingtested,theextinctionandreconsolidation efficacywaslinkedtodurationandfrequencyofexposuretotheconditionedcontext.Extinctionretentionwasdependentonanimalsbeingreexposedtotheconditionedcontextatleasttwotimes(12, 13).Thecurrentmostwidelyacceptedviewonconsolidationofrecentintolong-term memoriespositsthatduringthisprocessthememorytracewillincreasinglyrelymoreoncorticalthanonHPPactivation(105).However,prolongedre-exposuretotheconditioningcontextcanleadtoHPPactivation,whichthencanmakethealreadyestablishedmemoryonceagain susceptibletoneurogenesisinducedforgetting(104, 106).Thesedata arereminiscentofexposuretherapyprotocolscurrentlybeingemployed totreatPTSD(31, 107).TheeffectofAYAonTFCreconsolidationand/or extinctionprotocolsstillneedstobetested.
AlthoughthesestudiessuggestthatAYAanditscomponentsmodulatefearmemoryprocessing,theconditioningprotocolstestedresponses inducedbynonpathologicalfearmemories,sincenoprotocolinduced generalizedfearbehaviorandmosttreatmentsdidnotincreaseanxietylikeresponseswhentestedusingtheEPM(12, 13).Thequestionremains whethertheoutcomeswouldbedifferentwhentestedforpathologicallikememories.
TraumafocusedtherapeuticinterventionsarecurrentlywidelyemployedandadvisedfortreatmentofPTSD(108).Theseinterventions arebasedonthepreviouslydiscussedpremisethatmemoryrecallcan facilitatethealterationofemotionalandbehavioralresponsesassociatedtothememorytrace.However,eventhoughdatasupporting trauma-focusedtherapiesarethemostrobustforallcurrentlyemployedtherapeuticstrategies,theyarenotalwayseffectiveand,inmany cases,theimprovementisnotsufficienttoabolishPTSDdiagnosis(109). Additionally,thereisalsoreportedvariabilityinpharmacologicaltreatmentefficacywhencomparingdifferenttraumaticevents.Forexample,cannabidiol(300mg)iseffectiveinreducinganxietyandcognitiveimpairmenttriggeredbytraumaticmemoryrecallonlyfornonsexual trauma(110).
Amongotherthings,thisvariabilitycanbeaconsequenceofdifferentsymptomatology.ThefiftheditionoftheDiagnosticandStatistical ManualforMentalDisorders(DSM-5)recognizedadissociativePTSDsubtype,characterizedbythepresenceofdepersonalizationandderealizationsymptoms(111).ComparedwithnondissociativePTSD,thissubtype seemstobelinkedtoincreasedcorticalinhibitionoflimbicstructures (112).Inpatientswithborderlinepersonalitydisorder,higherprevalence ofdissociativeexperienceswasapredictorforimpairedacquisitionand extinctionofanAMY-dependentclassicconditioningtask(113).
Althoughanimalmodelscanbeusefultounderstanddifferentinterventionsoutcomesonspecificcircuits,theylackprecisiontoevaluatespecificsymptoms.BroadeningtheunderstandingofhowPTSDcanalterpatients’brainfunctioningisessentialtothedevelopmentofbettermodels.
EvidenceforAyahuasca’EffectsonFearandAnxietyResponsesin Humans
NeuroimagingtechniquesusedtoinvestigatehowAYAintakealtersneuralsubstratessuggestthatitmodulatesstructuresandnetworksrelevant toemotionalprocessing.
Inonestudy,healthymalesubjectswererandomizedtoreceiveAYA (adjustedtocontain1mg/kgofDMT)orplaceboand100–110minafterintakeparticipantsweresubmittedtosinglephotonemissiontomography(SPECT)toassesshowAYAalteredregionalcerebralbloodflow (rCBF).Comparedwithplacebo,AYAbilaterallyincreasedrCBFonanterior insulaandinferiorfrontalgyrus,increasedrCBFontherightanteriorcingulateandfrontomedialcortex,andontheleftAMYandparahippocampalgyrus(114).AnotherSPECTstudy,thistimeevaluatingdepressivepatients,comparedrCBFpriortoand8hafterAYAintake(2.2mL/kg).The treatmentincreasedrCBFonleftnucleusaccumbens,rightinsulaandleft subgenualanteriorcingulatecortex(11).
Functionalmagneticresonanceimaging(fMRI)wasusedtoassess AYAeffectsonthedefaultmodenetwork(DMN)inhealthyvolunteers.
Subjectswereevaluatedbeforeand40minafterAYAintake(2.2mL/kg) whenperformingaverbalfluencytaskorduringrestingstate.Results contrastedDMNsignalduringrestingstateandduringtaskperforming, andadecreaseinsignalwasreportedfortheanteriorandposteriorcingulatecortices,mPFC,precuneusandinferiorparietallobules(115).
Hallucinogenseffectsevaluatedthroughsocialcognitiontaskscan alsobeusefultobettercomprehendhowthesesubstancescanalteremotionalprocessing.Studieswithhealthyandclinicalsampleshavebeen performedtoevaluatehowtheycaninterferewithREFE.
AstudywithhealthyvolunteerscomparedhowdifferentLSDdoses (100or200 μg)couldalterREFEperformancewhencomparedwith placebo.Subjectsweretested5hafterintakeofthelowerdoseand 7hafterintakeofthehigherone,andbothdosesdecreasedaccuracyfor recognitionoffearfulexpressions(116).Anotherstudybythesamegroup usedfMRItocomparehowhealthyindividualsrespondwhenpresented tofearfulorneutralexpressions.Eachsubjectreceived100 μgofLSDor placebo2.5hbeforethescan.Comparedwithplacebo,LSDreducedneuralresponsetofearfulversusneutralfacesonleftAMYandrightmedial frontalgyrus.TheAMYactivationtofearfulfaceswasalsonegativelycorrelatedtoreportedsubjectivedrugeffects(117).Also,administrationof psilocybin(215 μg/kg)tohealthysubjectsdecreasedtherecognitionof negativefacialexpressionswhencomparedwithplacebo(90).
RegardingAYA,healthyvolunteersweresubmittedtofMRIbeforeand afterdrugintake(25–35mL,0.333 ± 0.056mg/kgDMT),andaskedto performataskwithimplicitemotionalstimuli(neutral,disgustedorfearfulfacialexpressions).BeforeAYAintake,reactiontimewaslongerwhen aversivestimuliwerepresented,butduringtheAYAeffects,thereaction timewasnolongerdifferentforneutralandaversivestimuli.Together withthebehavioralalterations,AMYresponsivenesstoaversivestimuli wasattenuatedbyAYA,whiletheanteriorinsulaandthedorsolateral PFCresponsivenessincreased(118).Similarly,increasesinreactiontime inaREFEtaskwereobservedinhealthyvolunteersafterasingleAYA dose(1mL/kg; ±0.72mg/mLDMT)(119).Ontheotherhand,apreviousstudyevaluatingtheeffectsofasingledoseofayahuasca(1mL/kg; ±1.58mg/mLDMT)inhealthyvolunteersdidnotidentifybehavioraldifferencesonREFEperformancewhencomparedwiththeplacebogroup (120).However,thesestudiesdidnotassessparametersregardingneuralactivity,whichcouldbealteredevenintheabsenceofbehavioral outcomes.
AlthoughtheclinicalevidenceassessingtheeffectsofAYAonfear andanxietydisordersisstillscarce,afewobservationalandexperimentalstudieswithhealthysubjectsexploreditseffectsontrauma,memory, anxietyandphobiameasurements.
Long-termmembersofayahuascachurchesinBrazil(over15years), whencomparedwithactivelypracticingreligiousindividualsfrom catholicandprotestantchurches,showedlowerscoresonphobicanxiety availedthroughtheSymptomChecklist90–Revised(SCL-30-R),aselfreportinventorytoassesspsychopathologies(121).Anobservational, naturalisticstudyconductedwithhealthyparticipantstakingpartona AYAtraditionalindigenousretreatinPeruusedtheSentenceCompletionforEventsfromthePastTest(SCEPT)toevaluatehowthehallucinogenicexperiencecouldaltertheirperceptionofautobiographicalmemories,andasignificantreductiononscoresfornegativevalencememories wasobservedwhencomparingthebaselinewithpostretreatmentatthe6 monthsfollow-up.However,itisimportanttopointoutthattheseparticipantsdidnotpresentahighleveloftraumaticchildhoodexperiences,as assessedthroughtheChildhoodTraumaQuestionnairescorescollected onbaseline(14).
Anexperimentaldouble-blindedstudywithexperiencedmembersof anAYAchurchassessedpanicandanxietyoutcomesduringthesubstance peakeffects(1hafteringestion).AYA(3mL)andplaceboscoreswere comparedwithbaseline,andonlyAYAwaseffectiveinreducingpanicrelatedsignsassessedthroughtheAnxietySensitivityIndex.Anxietywas assessedusingtheState-TraitAnxietyInventory(STAI),buttheplacebo andAYAscoresdidnotdifferfrombaseline(122).
AnotherstudyinvestigatedthesubjectiveeffectsofAYA(1mL/kg; ±0.72mg/mLDMT)combinedwithplaceboorcannabidiol(600mg)on healthysubjectsusingtheVisualAnalogueMoodScale(VAMS).During
AYAeffectsparticipantsreportedadecreaseinanxiety,independently fromthepretreatmentgroup(119).
Regardingclinicalpopulations,arecentcaseseriesreportedtheuse ofAYAtotreatPTSDinwarveteranstakingpartinaretreat.ThePosttraumaticStressChecklist(PCL-5)wasusedtoassessPTSDsymptoms andtoevaluateclinicalchangesthroughtheprotocol.Mostparticipants (7outof8)loweredPCL-5scoresaftertheintervention,and5ofthemstill hadlowerscores3monthsaftertheinterventionwhencomparedwith baseline.Morethanhalfoftheparticipantsreportedintenselyexperiencingintrusivememoriesofthetraumaticevent.Aftertheintervention,the largestimprovementswereobservedinClusterEsymptoms,concerning sleepdisturbances,hypervigilance,andconcentrationdifficulties,andalthoughsomeparticipantsreportedareductiononintrusivememories,it wasnotstatisticallysignificant(15).
AYAwasalsotestedinarandomized,placebo-controlledtrialwith subjectsdiagnosedwithsocialanxietydisorder.Participantsreceiveda singledoseofayahuasca(2mL/kg, ±0.68mg/mLDMT)orplaceboand, aftertheacuteeffects(300minafterintake),theyweresubmittedto theSPST.Duringtheprotocol,anxietyandself-perceptionofperformance wereassessedusingtheVAMS,theBeckAnxietyInventoryandtheState VersionoftheSelf-statementsDuringPublicSpeakingScale.Nosignificantdifferenceswerefoundbetweengroupsontheanxietymeasures,but theAYAgroupshowedimprovedperceptionofperformancewhencomparedwithplacebo(7).
Theobservationalandexperimentaldataavailableimplythat ayahuascamightbeapotentialtreatmentforanxietyandstressdisorders;however,thereisalackofstudieswithclinicalpopulationsconductedoncontrolledsettings.SinceAYAisanelementoftraditionalcultures,thereisaninherentchallengeonvariabilitycontrolofAYAstudies. Itcannotbemanufacturedwithcommercialpurposes,andtheabsence ofstandardizedproceduresleadtobrewbatcheswithhighlydiversealkaloidcompositionandconcentration,whichreflectsonthedosagevariabilitypresentinnaturalisticandexperimentalsettings.
Syntheticformulationsarealreadybeingtestedasapossiblealternativetotryimprovingthisvariability,andtotrytodealwithethicalproblemsattachedtotheuseoftraditionalformulations(123).
AyahuascaEffectsonFearandAnxietyResponsesThrough5HT Signaling
ThecurrentlyavailabledatasuggestthatAYAanditsconstituentsubstances,thatis,DMTand β -carbolines,canmodulatefearandanxietyresponses.However,molecularandfunctionaldatasupportingthebehavioralandclinicalobservationsarestillscarce.
Neuronalandsynapticplasticitymechanismsareafundamentalaspectsupportingbehavioralflexibility.Increasingefforthasbeenmade intoelucidatingpsychedelicinducedplasticity,anditispossiblethatthey holdtheanswerforthefast-actingtherapeuticpropertiesthesesubstancesapparentlyhave.
Similarlytootherpsychedelicsubstances,DMTcanpromoteincreased neuritogenesisandsynaptogenesisoncorticalneurons.ThiseffectispossiblymediatedbyBDNFinteractionwithTrkBreceptorsandsubsequent activationofmTORintracellularsignalingpathways(18).Micechronically treatedwithharmine(20mg/kg,i.p.for10days)alsopresentincreased BDNFexpressiononthePFC(124)(Figure1A).Inhumans,healthyanddepressiveparticipantsreceivingasingleAYAdose(1mL/kg)expressedincreasedBDNFserumlevels48hafterintakewhencomparedwithplacebo groups(125).
Oncorticalneurons,DMTplasticityincreasingpropertiesaredependenton5HT2Areceptorsactivation(18).However,injectionofa5HT2A antagonistintotheILdidnotpreventAYAfacilitationofextinctionlearningandrecallonratspreviouslysubmittedtoCFC,eventhoughitincreasedfreezinglevelsduringextinctionsessions(13).Theincreased freezingexpressionmightbeduetoadecreaseintheinhibitorycontrol overcentralAMYprojections,sincetheILPNsinnervatetheITCwhichthen inhibitscentralAMY(126)andthePNsactivationmightberegulatedby the5HT2Areceptor.
IncreasedplasticityattheILisnecessaryforextinctionmemoryretention(127);however,5HT2Aantagonismdidnotimpairextinction
Figure1. Plasticity-promotingmechanismstriggeredbyDMTandBC.(A)DMTandBC-inducedincreaseincorticalplasticityarelinkedtoenhancedBDNFlevels, althoughthismightresultfromactivationofdifferentreceptors.(B)IncreasedhippocampalplasticityandneurogenesisinducedbyDMTandBCrelyondifferent molecularpathways.5HT2A:serotonergicreceptor2Asubtype;BC: β -carboline;BDNF:brain-derivedneurotrophicfactor;DMT:N,N-dimethyltryptamine;SIGMA1: sigmareceptorsubtype1.
learning.Apossibleexplanationisthefactthatextinctionlearningrelies onBDNFincreaseonHPPinputstotheIL(128),soeventhough5HT2A antagonismcouldpreventDMTinducedplasticityattheIL,theextinction memorywasnotaffected.
Ontheotherhand,thesameprotocoltestinga5HT1AantagonistpreventedAYAeffectsonextinctionretentionorrecall,althoughitdidnot alterthedecreaseinfearexpressionduringextinctionlearning(13).IL projectionstoBLAarenecessaryforextinctionretention(129),andthese datasuggestthatthiseffectmightbemediatedby5HT1Aactivity.TheIL projectstoBLAPNsandINs,andduringfearextinctionsynapticefficacy ofPNsinnervationisreducedthroughaprocessthatmightresemblesa long-termdepression(126).Since5HT1Areceptorsarerelevanttomodulateinput-generatedexcitabilityoncorticalPNs,itispossiblethatthey areinvolvedinthesynapticefficacydecrease.AYAandDMTacutetreatmentsinrodentscanleadtoanincreaseinanxiety-likeresponsesonEPM andFST,despitealsoinducinganantidepressanteffectontheFST(95, 96).Thisincreaseinconflictanxietyresponsescouldbeaconsequence of5HT2Areceptoractivationbythesecompounds.Interestingly,different fromwhatisobservedafterAYAandDMTadministration, β -carbolinesdo notinduceanincreaseinanxiety-likeresponsedespitetheirmildaffinity for5HT2Areceptors(98)
Harminechronicadministration(20mg/kg,i.p.for10days)canincreaseHPPneurogenesisinmice(124),whichcouldalsoexplainthe behavioraloutcomesof β -carbolinesadministrationonHPP-dependent tasks(Figure1B).Opposinglytotheeffectsof5HT2Aactivationoncorticalneurons,ontheHPPthisreceptorisnotlinkedtoplasticityincrease. RatstreatedwithDOI,anotherpsychedeliccompound,presentdecreased HPPBDNFmRNAexpression,whilststillhavingincreasedBDNFlevelson corticalareas.Thismodulationwascompletelyblockedbya5HT2Aantagonistadministration.Interestingly,immobilizationstressalsoresults inadecreaseinBDNFmRNAsontheHPPthrough5HT2Aactivation(130). Hence,5HT2AactivationontheHPPpossiblydoesnotcontributeto theantidepressiveandmightberesponsiblefortheanxiogenicDMTef-
fects.Nevertheless,DMTtreatmentcaninduceneurogenesisonHPP,but themechanismseemstoresultfromsigma-1receptorsactivationinstead (131)(Figure1B).
Itispossiblethatthe β -carbolineseffectondepressive-likebehaviorsaswellasinHPP-dependentmemoriescouldrelyonitsantagonism ofmonoamineoxidaseenzymes,thatcouldincreasecirculatinglevelsof 5HT.Additionally,sincetheydonotpresentaffinityfor5HT1Areceptors, theywouldnotactivatetheraphenucleiautoreceptors,preventingthe decreasein5HTreleaseobservedafteracuteadministrationof5HT1A agonists(79, 132).
Possibly, β -carbolinesadministrationcouldsomehowpredominantly activatespecificraphenucleipathways,sincethebehavioralresponses observedafteritsadministrationresemblethemedianrapheforebrain bundletractmediatedresponses.ThispathwaydirectlycontrolsHPPactivity,andincreasedactivityinthiscircuitislinkedtoantidepressantbehavioralresponses(133).Also,thispathwaystimulationcandesynchronizeHPPthetaoscillations,whicharerelevantforassociativememory processing(134).Thiscouldexplainwhy β -carbolinestreatmentseems tobemoreeffectiveoninterferingwithHPP-dependentmemoryprocessing.Theanxiety-likeresponsesevokedbyacutetreatmentwithDMT suggeststhissubstancemightbeactingonsubstratesinnervatedbythe DRD/DRCprojectionsandwouldexplainthelackofeffectsofDMTtreatmentonCFCextinction,sincethistaskisHPP-dependent.Ontheother hand, β -carbolinespreferentialeffectonDRI/MnRpathwaycouldexplain thelackoftreatment-inducedanxiety-likebehaviors,despitetheirmild 5HT2Aaffinity,besidestheantidepressantpropertiesandamnesiceffects onHPP-dependentmemoriesprocessing.
FuturePerspectives
AlthoughAYAhasbeenemployedintherapeuticandreligiouscontextsfor centuries,thereisstillalottobedissectedonitsbiologicalandpsychologicaleffects.Thecomplexnatureofthisbrew,thatcombinesdifferent alkaloids,addsanotherlayerofintricacytoanalreadychallengingtask.
Incurrentlyavailableliterature,DMTisfrequentlymentionedasthe mainpsychoactiveconstituentofAYA,howevermanystudiesdiscussed throughoutthisreviewhighlightrelevantdifferencesonisolatedDMTeffectswhencomparedwithAYAor β -carbolines.Although β -carbolines lackthemind-alteringpropertiesofAYAandDMT,theyseemtohave therapeuticpropertiesaswell.Morestudiesinvestigatingthemolecularpathwayssupportingantidepressantandmemoryeffectselicitedby themcouldimprovecomprehensiononAYA,aswellasindicatecontexts whereisolated β -carbolinescouldbeemployedastreatment.Hereof, differencesonHPPplasticityandneurogenesismolecularpathwaysactivatedbyDMTand β -carbolinescouldclarifythedistinctbehavioral outcomespromotedbythesesubstances.
Regardinghumanstudies,thereisstillalongwaytogo.Theobservationalandexperimentalstudiesinvestigatinghealthypopulationssupporttherelevanceoffurtherinvestigations;however,clinicalstudiesare stilllacking,especiallyincontrolledsettings.Theunknownrisksthat psychedelicintakecanrepresenttospecificclinicalpopulationstogether withtheprejudiceaccumulatedfromyearsofcriminalizationaresome ofthechallengesfacedbytheresearchers.Ontopofthat,theincreasing hypearoundpsychedelictherapeuticeffectscanresultinapositivebias. Controllingthisbiasisalsoadifficulttask,sinceblindingisstillachallengeforthefield.
FinalRemarks
Inanattempttoassociatetheemergingdataonhallucinogenstherapeuticpropertiesfortreatmentofmentaldisordersandtheclassical Deakin/Graefftheorylinkingfearandanxietyresponsesto5HTsignaling,Carhart-HarrisandNutt(2017)proposethathallucinogen-induced 5HT2Aagonism,andthesubsequentactivation-inducedplasticity,mediateactivecopinginasimilarideatotheDRD/DRCprojections.Inthe samereview,theyalsoproposethatpassivecopingwouldbethemechanismsupportingconventionalantidepressantsefficacy,suchasSSRIs, andwouldbemediatedby5HT1Aactivity,similarlytotheDRI/MnR pathway(135).
Throughthatperspective,AYAtherapeuticpropertiescouldbeacombinationofactiveandpassivecopingmechanisms.The β -CarbolinesapparentcapacitytomodulateHPPactivity,inwhattheycallpassivecoping, couldbearelevantfactorbehindAYAeffectsonCFCextinctionthatcould notbereproducedbyDMTtreatment.DMT,ontheotherhand,seemto behavesimilarlytowhatisproposedforotherclassichallucinogens,favoringactivecopingstrategiesandmechanisms.
AuthorContributions
LTLG,MScpreparedtheoriginaldraft.RGDS,PhDintellectualconceptualization,reviewandeditingthemanuscript.JECH,MD,PhDintellectual conceptualization,reviewandeditingthemanuscript.
FundingSources
LTLGreceivedfundingfromCoordenaçãodeAperfeiçoamentodePessoal deNívelSuperior(CAPES,Brazil).JECHisrecipientofCNPq1Aproductivityfellowship.
AuthorDisclosures
Theauthorsdeclarenoconflictsofinterest.Thecorrespondingauthorhad fullaccesstoallthedatainthestudyandhadfinalresponsibilityforthe decisiontosubmitforpublication.Themanuscripthasbeenreadandapprovedbyallauthors.
References
1.Domínguez-ClavéE,SolerJ,ElicesM,PascualJC,ÁlvarezE,delaFuente RevengaM,etal.Ayahuasca:Pharmacology,neuroscienceandtherapeuticpotential.BrainResBull.2016;126:89–101.DOI: 10.1016/j.brainresbull.2016.03. 002.PMID:26976063
2.KimH,SablinSO,RamsayRR.Inhibitionofmonoamineoxidaseabyb-carboline derivatives.ArchBiochemBiophys.1997;337(1):137–42.DOI: 10.1006/abbi. 1996.9771.PMID:8990278
3.GlennonRA,DukatM,GrellaB,HongSS,CostantinoL,TeitlerM,etal.Bindingof β -carbolinesandrelatedagentsatserotonin(5-HT2and5-HT1A),dopamine (D2)andbenzodiazepinereceptors.DrugAlcoholDepend.2000;60(2):121–32. DOI: 10.1016/s0376-8716(99)00148-9.PMID:10940s539
4.VollenweiderFX,SmallridgeJW.Classicpsychedelicdrugs:updateonbiologicalmechanisms.Pharmacopsychiatry.2022;55(03):121–38.DOI: 10.1055/a1721-2914.PMID:35079988;PMCID: PMC9110100
5.StrassmanRJ.HumanpsychopharmacologyofN,N-dimethyltryptamine. BehavBrainRes.1995;73(1):121–4.DOI: 10.1016/0166-4328(96)00081-2 PMID:8788488
6.ValleM,MaquedaAE,RabellaM,Rodríguez-PujadasA,AntonijoanRM,Romero S,etal.Inhibitionofalphaoscillationsthroughserotonin-2Areceptoractivationunderliesthevisualeffectsofayahuascainhumans.EurNeuropsychopharmacol.2016;26(7):1161–75.DOI: 10.1016/j.euroneuro.2016.03.012. PMID:27039035
7.DosSantosRG,OsórioFDL,RochaJM,RossiGN,BousoJC,RodriguesLS, etal.Ayahuascaimprovesself-perceptionofspeechperformanceinsubjects withsocialanxietydisorder:apilot,proof-of-concept,randomized,placebocontrolledtrial.JClinPsychopharmacol.2021;41(5):540–50.DOI: 10.1097/ JCP.0000000000001428.PMID:34166299
8.OsórioFL,SanchesRF,MacedoLR,dosSantosRG,Maia-de-OliveiraJP, Wichert-AnaL,etal.Antidepressanteffectsofasingledoseofayahuascain patientswithrecurrentdepression:apreliminaryreport.BrazJPsychiatry. 2015;37:13–20.DOI: 10.1590/1516-4446-2014-1496.PMID:25806551
9.Palhano-FontesF,BarretoD,OniasH,AndradeKC,NovaesMM,PessoaJA, etal.Rapidantidepressanteffectsofthepsychedelicayahuascaintreatmentresistantdepression:arandomizedplacebo-controlledtrial.PsycholMed. 2019;49(4):655–63.DOI: 10.1017/S0033291718001356.PMID:29903051; PMCID: PMC6378413
10.RodriguesLS,ReisJAS,RossiGN,GuerraLTL,MaekawaRM,DeLima OsórioF,etal.Effectsofasingledoseofayahuascaincollegestudentswith harmfulalcoholuse:asingle-blind,feasibility,proof-of-concepttrial.JClin Psychopharmacol.2024;44(4):402–6.DOI: 10.1097/JCP.0000000000001872 PMID:38820373
11.SanchesRF,deLimaOsórioF,dosSantosRG,MacedoLRH,Maia-de-Oliveira JP,Wichert-AnaL,etal.Antidepressanteffectsofasingledoseofayahuasca inpatientswithrecurrentdepression:aSPECTstudy.JClinPsychopharmacol.2016;36(1):77–81.DOI: 10.1097/JCP.0000000000000436.PMID: 26650973
12.DaneluzDM,SohnJMB,SilveiraGO,YonamineM,SternCA.Evidenceonthe impairingeffectsofAyahuascaonfearmemoryreconsolidation.Psychopharmacology(Berl).2022;239(10):3325–36.DOI: 10.1007/s00213-022-062172.PMID:36069952
13.WerleI,NascimentoLMM,dosSantosALA,SoaresLA,dosSantosRG,Hallak JEC,etal.Ayahuasca-enhancedextinctionoffearbehaviour:Roleofinfralimbic cortex5-HT2Aand5-HT1Areceptors.BrJPharmacol.2024;181(11):1671–89. DOI: 10.1111/bph.16315.PMID:38320596
14.RuffellSGD,NetzbandN,TsangW,DaviesM,InserraA,ButlerM,etal.Ceremonialayahuascainamazonianretreats—mentalhealthandepigeneticoutcomesfromasix-monthnaturalisticstudy.FrontPsychiatry.2021;12:687615. DOI: 10.3389/fpsyt.2021.687615.PMID:34177670;PMCID: PMC8221532
15.WeissB,Dinh-WilliamsLAL,BellerN,RaughIM,StraussGP,CampbellWK. Ayahuascainthetreatmentofposttraumaticstressdisorder:mixed-methods caseseriesevaluationinmilitarycombatveterans.PsycholTrauma.2023.DOI: 10.1037/tra0001625.PMID:38059941
16.BrierleyDI,DavidsonC.Harmineaugmentselectricallyevokeddopamineefflux inthenucleusaccumbensshell.JPsychopharmacol.2013;27(1):98–108.DOI: 10.1177/0269881112463125.PMID:23076833
17.DosSantosRG,RochaJM,RossiGN,OsórioFL,OnaG,BousoJC,etal.Effectsofayahuascaontheendocannabinoidsystemofhealthyvolunteers andinvolunteerswithsocialanxietydisorder:Resultsfromtwopilot,proofof-concept,randomized,placebo-controlledtrials.HumPsychopharmacol. 2022;37(4):e2834.DOI: 10.1002/hup.2834.PMID:35107855
18.LyC,GrebAC,CameronLP,WongJM,BarraganEV,WilsonPC,etal. Psychedelicspromotestructuralandfunctionalneuralplasticity.CellRep. 2018;23(11):3170–82.DOI: 10.1016/j.celrep.2018.05.022.PMID:29898390; PMCID: PMC6082376
19.FontanillaD,JohannessenM,HajipourAR,CozziNV,JacksonMB,RuohoAE. ThehallucinogenN,N-dimethyltryptamine(DMT)isanendogenousSigma1receptorregulator.Science.2009;323(5916):934–7.DOI: 10.1126/science. 1166127.PMID:19213917;PMCID: PMC2947205
20.InserraA.Hypothesis:thepsychedelicayahuascahealstraumaticmemories viaasigma1receptor-mediatedepigenetic-mnemonicprocess.FrontPharmacol.2018;9:330.DOI: 10.3389/fphar.2018.00330.PMID:29674970;PMCID: PMC5895707
21.dosSantosRG,ValleM,BousoJC,NomdedéuJF,Rodríguez-EspinosaJ,McIlhennyEH,etal.Autonomic,neuroendocrine,andimmunologicaleffectsof ayahuasca:acomparativestudywithd-amphetamine.JClinPsychopharmacol. 2011;31(6):717–26.DOI: 10.1097/JCP.0b013e31823607f6.PMID:22005052
22.KimJJ,JungMW.NeuralcircuitsandmechanismsinvolvedinPavlovianfear conditioning:acriticalreview.NeurosciBiobehavRev.2006;30(2):188–202.DOI: 10.1016/j.neubiorev.2005.06.005.PMID:16120461;PMCID: PMC4342048
23.GrillonC.Modelsandmechanismsofanxiety:evidencefromstartlestudies. Psychopharmacology(Berl).2008;199(3):421–37.DOI: 10.1007/s00213-0071019-1.PMID:18058089;PMCID: PMC2711770
24.ZangrossiH,DelBenCM,GraeffFG,GuimarãesFS.Serotonininpanicandanxietydisorders.HandbookofBehavioralNeuroscience.London,UnitedKingdom: Elsevier;2020.p.611–33.
25.PellowS,ChopinP,FileSE,BrileyM.Validationofopen:closedarmentriesinanelevatedplus-mazeasameasureofanxietyintherat.JNeurosci Methods.1985;14(3):149–67.DOI: 10.1016/0165-0270(85)90031-7.PMID: 2864480
26.PrutL,BelzungC.Theopenfieldasaparadigmtomeasuretheeffectsofdrugs onanxiety-likebehaviors:areview.EurJPharmacol.2003;463(1):3–33.DOI: 10.1016/s0014-2999(03)01272-x.PMID:12600700
27.BlanchardRJ,FukunagaKK,BlanchardDC.Environmentalcontrolofdefensive reactionstofootshock.BullPsychonSoc.1976;8(2):129–30.
28.FanselowMS.Conditionalandunconditionalcomponentsofpost-shockfreezing.PavlovJBiolSci.1980;15(4):177–82.DOI: 10.1007/BF03001163.PMID: 7208128
29.CurzonP,RustayNR,BrowmanKE.Cuedandcontextualfearconditioningfor rodents.MethodsofBehaviorAnalysisinNeuroscience.2nded.BocaRaton (FL):CRCPress/Taylor&Francis;2009.
30.KidaS.Interactionbetweenreconsolidationandextinctionoffearmemory.BrainResBull.2023;195:141–4.DOI: 10.1016/j.brainresbull.2023.02.009 PMID:36801360
31.KidaS.Reconsolidation/destabilization,extinctionandforgettingoffear memoryastherapeutictargetsforPTSD.Psychopharmacology(Berl). 2019;236(1):49–57.DOI: 10.1007/s00213-018-5086-2.PMID:30374892; PMCID: PMC6373183
32.EkmanP.Anargumentforbasicemotions.CognEmot.1992;6(3–4):169–200.
33.BottinelliF,DelvecchioG,MoltrasioC,FerroA,DiwadkarVA,BrambillaP. Facialemotionrecognitioninpanicdisorder:amini-reviewofbehavioural studies.JAffectDisord.2021;282:173–8.DOI: 10.1016/j.jad.2020.12.064 PMID:33418364
34.ReisJAS,RossiGN,OsórioFL,BousoJC,HallakJEC,DosSantosRG.Interventionsfordeficitsinrecognitionofemotionsinfacialexpressionsin majordepressivedisorder:Anupdatedsystematicreviewofclinicaltrials. NeurosciBiobehavRev.2023;153:105367.DOI: 10.1016/j.neubiorev.2023. 105367.PMID:37619644
35.WilliamsCL,MilanakME,JudahMR,BerenbaumH.Theassociationbetween PTSDandfacialaffectrecognition.PsychiatryRes.2018;265:298–302.DOI: 10.1016/j.psychres.2018.04.055.PMID:29778050
36.McNairDM,FrankenthalerLM,CzerlinskyT,WhiteTW,SassonS,FisherS.Simulatedpublicspeakingasamodelofclinicalanxiety.Psychopharmacology (Berl).1982;77(1):7–10.DOI: 10.1007/BF00436092.PMID:6126900
37.JacobsDS,MoghaddamB.Medialprefrontalcortexencodingofstressand anxiety.IntRevNeurobiol.2021;158:29–55.DOI: 10.1016/bs.irn.2020.11.014 PMID:33785149
38.LaubachM,AmaranteLM,SwansonK,WhiteSR.What,ifanything,isrodent prefrontalcortex?eNeuro.2018;5(5):ENEURO.0315-18.2018.DOI: 10.1523/ ENEURO.0315-18.2018.PMID:30406193;PMCID: PMC6220587
39.VertesRP.Differentialprojectionsoftheinfralimbicandprelimbiccortexinthe rat.Synapse.2004;51(1):32–58.DOI: 10.1002/syn.10279.PMID:14579424
40.StevensonCW.Roleofamygdala–prefrontalcortexcircuitryinregulatingthe expressionofcontextualfearmemory.NeurobiolLearnMem.2011;96(2):315–23.DOI: 10.1016/j.nlm.2011.06.005.PMID:21689772
41.CourtinJ,ChaudunF,RozeskeRR,KaralisN,Gonzalez-CampoC,WurtzH,etal. Prefrontalparvalbumininterneuronsshapeneuronalactivitytodrivefear expression.Nature.2014;505(7481):92–6.DOI: 10.1038/nature12755.PMID: 24256726
42.QuirkGJ,RussoGK,BarronJL,LebronK.Theroleofventromedialprefrontal cortexintherecoveryofextinguishedfear.JNeurosci.2000;20(16):6225–31.DOI: 10.1523/JNEUROSCI.20-16-06225.2000.PMID:10934272;PMCID: PMC6772571
43.Do-MonteFH,Manzano-NievesG,Quiñones-LaracuenteK,Ramos-MedinaL, QuirkGJ.Revisitingtheroleofinfralimbiccortexinfearextinctionwithoptogenetics.JNeurosci.2015;35(8):3607–15.DOI: 10.1523/JNEUROSCI.313714.2015.PMID:25716859;PMCID: PMC4339362
44.BishopSJ.Traitanxietyandimpoverishedprefrontalcontrolofattention.Nat Neurosci.2009;12(1):92–8.DOI: 10.1038/nn.2242.PMID:19079249
45.ParkJ,WoodJ,BondiC,DelArcoA,MoghaddamB.Anxietyevokeshypofrontalityanddisruptsrule-relevantencodingbydorsomedialprefrontalcortexneu-
rons.JNeurosci2016;36(11):3322–35.DOI: 10.1523/JNEUROSCI.4250-15. 2016.PMID:26985040;PMCID: PMC4792942
46.ParkJ,MoghaddamB.Impactofanxietyonprefrontalcortexencoding ofcognitiveflexibility.Neuroscience.2017;345:193–202.DOI: 10.1016/j. neuroscience.2016.06.013.PMID:27316551;PMCID: PMC5159328
47.LikhtikE,StujenskeJM,TopiwalaMA,HarrisAZ,GordonJA.Prefrontalentrainmentofamygdalaactivitysignalssafetyinlearnedfearandinnateanxiety.Nat Neurosci.2014;17(1):106–13.DOI: 10.1038/nn.3582.PMID:24241397;PMCID: PMC4035371
48.ViaE,FullanaMA,GoldbergX,Tinoco-GonzálezD,Martínez-ZalacaínI,SorianoMasC,etal.Ventromedialprefrontalcortexactivityandpathologicalworry ingeneralisedanxietydisorder.BrJPsychiatry.2018;213(1):437–43.DOI: 10.1192/bjp.2018.65.PMID:29739481
49.ChenY,HuN,YangJ,GaoT.Prefrontalcorticalcircuitsinanxietyandfear:an overview.FrontMed.2022;16(4):518–39.DOI: 10.1007/s11684-022-0941-2 PMID:35943704
50.JanakPH,TyeKM.Fromcircuitstobehaviourintheamygdala.Nature. 2015;517(7534):284–92.DOI: 10.1038/nature14188.PMID:25592533;PMCID: PMC4565157
51.LeDouxJ.Theamygdala.CurrBiol.2007;17(20):R868–74.DOI: 10.1016/j.cub. 2007.08.005.PMID:17956742
52.GoosensKA,MarenS.NMDAreceptorsareessentialfortheacquisition,but notexpression,ofconditionalfearandassociativespikefiringinthelateralamygdala.EurJNeurosci.2004;20(2):537–48.DOI: 10.1111/j.1460-9568. 2004.03513.x.PMID:15233763
53.VivianiD,CharletA,vandenBurgE,RobinetC,HurniN,AbatisM,etal.Oxytocin selectivelygatesfearresponsesthroughdistinctoutputsfromthecentral amygdala.Science.2011;333(6038):104–7.DOI: 10.1126/science.1201043 PMID:21719680
54.JünglingK,SeidenbecherT,SosulinaL,LestingJ,SanghaS,ClarkSD,etal. NeuropeptideS-mediatedcontroloffearexpressionandextinction:roleofintercalatedGABAergicneuronsintheamygdala.Neuron.2008;59(2):298–310. DOI: 10.1016/j.neuron.2008.07.002.PMID:18667157;PMCID: PMC2610688
55.GoosensKA,MarenS.Contextualandauditoryfearconditioningaremediated bythelateral,basal,andcentralamygdaloidnucleiinrats.LearnMem.2001; 8(3):148–55.DOI: 10.1101/lm.37601.PMID:11390634;PMCID: PMC311374
56.TyeKM,PrakashR,KimSY,FennoLE,GrosenickL,ZarabiH,etal.Amygdalacircuitrymediatingreversibleandbidirectionalcontrolofanxiety.Nature.2011;471(7338):358–62.DOI: 10.1038/nature09820.PMID:21389985; PMCID: PMC3154022
57.EtkinA,PraterKE,SchatzbergAF,MenonV,GreiciusMD.Disruptedamygdalar subregionfunctionalconnectivityandevidenceofacompensatorynetworkin generalizedanxietydisorder.ArchGenPsychiatry.2009;66(12):1361–72.DOI: 10.1001/archgenpsychiatry.2009.104.PMID:19996041
58.ShinLM,LiberzonI.Theneurocircuitryoffear,stress,andanxietydisorders. Neuropsychopharmacology.2010;35(1):169–91.DOI: 10.1038/npp.2009.83 PMID:19625997;PMCID: PMC3055419
59.MoserMB,MoserEI.Functionaldifferentiationinthehippocampus.Hippocampus.1998;8(6):608–19.DOI: 10.1002/(SICI)1098-1063(1998)8:6 608::AIDHIPO3 3.0.CO;2-7.PMID:9882018
60.KimJJ,FanselowMS.Modality-specificretrogradeamnesiaoffear.Science. 1992;256(5057):675–7.DOI: 10.1126/science.1585183.PMID:1585183
61.Terreros-RoncalJ,Flor-GarcíaM,Moreno-JiménezEP,Rodríguez-MorenoCB, Márquez-ValadezB,Gallardo-CaballeroM,etal.Methodstostudyadulthippocampalneurogenesisinhumansandacrossthephylogeny.Hippocampus.2022;33(4):271.DOI: 10.1002/hipo.23474.PMID:36259116;PMCID: PMC7614361
62.GandhiS,GuptaJ,TripathiPP.Thecuriouscaseofhumanhippocampalneurogenesis.ACSChemNeurosci.2019;10(3):1131–2.DOI: 10.1021/acschemneuro. 9b00063.PMID:30724553
63.Tunc-OzcanE,PengCY,ZhuY,DunlopSR,ContractorA,KesslerJA.Activatingnewbornneuronssuppressesdepressionandanxiety-likebehaviors. NatCommun.2019;10(1):3768.DOI: 10.1038/s41467-019-11641-8.PMID: 31434877;PMCID: PMC6704083
64.FanselowMS,DongHW.Arethedorsalandventralhippocampusfunctionally distinctstructures?Neuron.2010;65(1):7–19.DOI: 10.1016/j.neuron.2009.11. 031.PMID:20152109;PMCID: PMC2822727
65.CorcoranKA,MarenS.Hippocampalinactivationdisruptscontextualretrieval offearmemoryafterextinction.JNeurosci.2001;21(5):1720–6.DOI: 10.1523/ JNEUROSCI.21-05-01720.2001.PMID:11222661;PMCID: PMC6762930
66.PereiraLM,deCastroCM,GuerraLTL,QueirozTM,MarquesJT,PereiraGS. Hippocampusandprefrontalcortexmodulationofcontextualfearmemoryisdissociatedbyinhibitingdenovotranscriptionduringlateconsolidation.MolNeurobiol.2019;56(8):5507–19.DOI: 10.1007/s12035-018-1463-4 PMID:30623374
67.AdhikariA,TopiwalaMA,GordonJA.Synchronizedactivitybetweentheventralhippocampusandthemedialprefrontalcortexduringanxiety.Neuron. 2010;65(2):257–69.DOI: 10.1016/j.neuron.2009.12.002.PMID:20152131; PMCID: PMC2822726
68.KjelstrupKG,TuvnesFA,SteffenachHA,MurisonR,MoserEI,MoserMB.Reducedfearexpressionafterlesionsoftheventralhippocampus.ProcNatl AcadSciUSA.2002;99(16):10825–30.DOI: 10.1073/pnas.152112399.PMID: 12149439;PMCID: PMC125057
69.BremnerJD,VythilingamM,VermettenE,SouthwickSM,McGlashanT,Nazeer A,etal.MRIandPETstudyofdeficitsinhippocampalstructureandfunctioninwomenwithchildhoodsexualabuseandposttraumaticstressdisorder. AmJPsychiatry.2003;160(5):924–32.DOI: 10.1176/appi.ajp.160.5.924.PMID: 12727697
70.BremnerJD,OrtegoRV,CampanellaC,NyeJA,DavisLL,FaniN,etal.NeuralcorrelatesofPTSDinwomenwithchildhoodsexualabusewithandwithoutPTSD andresponsetoparoxetinetreatment:aplacebo-controlled,double-blind trial.JAffectDisordRep.2023;14:100615.DOI: 10.1016/j.jadr.2023.100615 PMID:38088987;PMCID: PMC10715797
71.ChaJ,GreenbergT,SongI,SimpsonHB,PosnerJ,Mujica-ParodiLR.Abnormalhippocampalstructureandfunctioninclinicalanxietyandcomorbiddepression.Hippocampus.2016;26(5):545–53.DOI: 10.1002/hipo.22566.PMID: 26743454;PMCID: PMC4837065
72.GaddumJH.Tryptaminereceptors.JPhysiol.1953;119(2–3):363–8.DOI: 10.1113/jphysiol.1953.sp004851.PMID:13035757;PMCID: PMC1392807
73.GaddumJH,PicarelliZP.Twokindsoftryptaminereceptor.BrJPharmacolChemother.1957;12(3):323–8.DOI: 10.1111/j.1476-5381.1957.tb00142. x.PMID:13460238;PMCID: PMC1509685
74.MarinP,BécamelC,Chaumont-DubelS,VandermoereF,BockaertJ,Claeysen S.Classificationandsignalingcharacteristicsof5-HTreceptors:towardthe conceptof5-HTreceptosomes.HandbookofBehavioralNeuroscience.London, UnitedKingdom:Elsevier;2020.p.91–120.
75.HalberstadtAL,NicholsDE.Serotoninandserotoninreceptorsinhallucinogen action.HandbookofBehavioralNeuroscience.London,UnitedKingdom:Elsevier;2020.p.843–63.
76.WeberET,AndradeR.Htr2ageneand5-HT(2A)receptorexpressioninthecerebralcortexstudiedusinggeneticallymodifiedmice.FrontNeurosci.2010;4:36. DOI: 10.3389/fnins.2010.00036.PMID:20802802;PMCID: PMC2928707
77.AndradeR.Serotonergicregulationofneuronalexcitabilityintheprefrontal cortex.Neuropharmacology.2011;61(3):382–6.DOI: 10.1016/j.neuropharm. 2011.01.015.PMID:21251917;PMCID: PMC3110517
78.BlierP,deMontignyC.Electrophysiologicalinvestigationoftheadaptiveresponseofthe5-HTsystemtotheadministrationof5-HT1Areceptoragonists. JCardiovascPharmacol.1990;(15Suppl7):S42–48.PMID:1702486
79.DiGiovanniG,ChagraouiA,BharatiyaR,DeDeurwaerdèreP.Serotonergiccontrolofexcitability:fromneurontonetworks.HandbookofBehavioralNeuroscience.London,UnitedKingdom:Elsevier;2020.p.197–215.
80.KiaHK,MiquelMC,BrisorgueilMJ,DavalG,RiadM,ElMestikawyS,etal.Immunocytochemicallocalizationofserotonin1Areceptorsintheratcentralnervoussystem.JCompNeurol.1996;365(2):289–305.DOI: 10.1002/(SICI)10969861(19960205)365:2 289::AID-CNE7 3.0.CO;2-1.PMID:8822171
81.SantanaN.Expressionofserotonin1aandserotonin2areceptorsinpyramidalandGABAergicneuronsoftheratprefrontalcortex.CerebCortex. 2004;14(10):1100–9.DOI: 10.1093/cercor/bhh070.PMID:15115744
82.DeakinJF,GraeffFG.5-HTandmechanismsofdefence.JPsychopharmacol.1991;5(4):305–15.DOI: 10.1177/026988119100500414.PMID: 22282829
83.PaulED,LowryCA.FunctionaltopographyofserotonergicsystemssupportstheDeakin/Graeffhypothesisofanxietyandaffectivedisorders.JPsychopharmacol.2013;27(12):1090–106.DOI: 10.1177/0269881113490328 PMID:23704363
84.WeisstaubNV,ZhouM,LiraA,LambeE,González-MaesoJ,HornungJP, etal.Cortical5-HT2Areceptorsignalingmodulatesanxiety-likebehaviorsin mice.Science.2006;313(5786):536–40.DOI: 10.1126/science.1123432.PMID: 16873667
85.ChristiansonJP,RagoleT,AmatJ,GreenwoodBN,StrongPV,PaulED,etal. 5-Hydroxytryptamine2Creceptorsinthebasolateralamygdalaareinvolvedin theexpressionofanxietyafteruncontrollabletraumaticstress.BiolPsychiatry. 2010;67(4):339–45.DOI: 10.1016/j.biopsych.2009.09.011.PMID:19914601; PMCID: PMC3278236
86.ZhangG,ÁsgeirsdóttirHN,CohenSJ,MunchowAH,BarreraMP,StackmanRW. Stimulationofserotonin2Areceptorsfacilitatesconsolidationandextinction offearmemoryinC57BL/6Jmice.Neuropharmacology.2013;64:403–13.DOI: 10.1016/j.neuropharm.2012.06.007.PMID:22722027;PMCID: PMC3477617
87.StiedlO,MisaneI,SpiessJ,ÖgrenSO.Involvementofthe5-HT1AreceptorsinclassicalfearconditioninginC57BL/6Jmice.JNeurosci.2000;20(22):
8515–27.DOI: 10.1523/JNEUROSCI.20-22-08515.2000.PMID:11069959; PMCID: PMC6773161
88.HolzeF,VizeliP,LeyL,MüllerF,DolderP,StockerM,etal.Acute dose-dependenteffectsoflysergicaciddiethylamideinadouble-blind placebo-controlledstudyinhealthysubjects.Neuropsychopharmacology. 2021;46(3):537–44.DOI: 10.1038/s41386-020-00883-6.PMID:33059356; PMCID: PMC8027607
89.PrellerKH,BurtJB,JiJL,SchleiferCH,AdkinsonBD,StämpfliP,etal.Changes inglobalandthalamicbrainconnectivityinLSD-inducedalteredstatesofconsciousnessareattributabletothe5-HT2Areceptor.Elife.2018;7:e35082.DOI: 10.7554/eLife.35082.PMID:30355445;PMCID: PMC6202055
90.KometerM,SchmidtA,BachmannR,StuderusE,SeifritzE,VollenweiderFX. Psilocybinbiasesfacialrecognition,goal-directedbehavior,andmoodstate towardpositiverelativetonegativeemotionsthroughdifferentserotonergic subreceptors.BiolPsychiatry.2012;72(11):898–906.DOI: 10.1016/j.biopsych. 2012.04.005.PMID:22578254
91.TuetingPA,MetzJ,RhoadesBK,BoutrosNN.PharmacologicchallengeinERP research.AnnNYAcadSci.1992;658(1):223–55.DOI: 10.1111/j.1749-6632. 1992.tb22847.x.PMID:1497260
92.CarterOL,BurrDC,PettigrewJD,WallisGM,HaslerF,VollenweiderFX.Using psilocybintoinvestigatetherelationshipbetweenattention,workingmemory, andtheserotonin1Aand2Areceptors.JCognNeurosci2005;17(10):1497–508.DOI: 10.1162/089892905774597191.PMID:16269092
93.PokornyT,PrellerKH,KraehenmannR,VollenweiderFX.Modulatoryeffectof the5-HT1Aagonistbuspironeandthemixednon-hallucinogenic5-HT1A/2A agonistergotamineonpsilocybin-inducedpsychedelicexperience.EurNeuropsychopharmacol.2016;26(4):756–66.DOI: 10.1016/j.euroneuro.2016.01. 005.PMID:26875114
94.HesselgraveN,TroppoliTA,WulffAB,ColeAB,ThompsonSM.Harnessingpsilocybin:antidepressant-likebehavioralandsynapticactionsofpsilocybinareindependentof5-HT2Ractivationinmice.ProcNatlAcadSci USA.2021;118(17):e2022489118.DOI: 10.1073/pnas.2022489118.PMID: 33850049;PMCID: PMC8092378
95.Pic-TaylorA,daMottaLG,deMoraisJA,JuniorWM,deFátimaAndrade SantosA,CamposLA,etal.Behaviouralandneurotoxiceffectsofayahuasca infusion(BanisteriopsiscaapiandPsychotriaviridis)infemaleWistarrat.BehavProcesses.2015;118:102–10.DOI: 10.1016/j.beproc.2015.05.004.PMID: 26049017
96.CameronLP,BensonCJ,DunlapLE,OlsonDE.EffectsofN,Ndimethyltryptamineonratbehaviorsrelevanttoanxietyanddepression.ACS ChemNeurosci.2018;9(7):1582–90.DOI: 10.1021/acschemneuro.8b00134 PMID:29664276;PMCID: PMC7196340
97.JonesNT,ZahidZ,GradySM,SultanZW,ZhengZ,RazidloJ,etal.Transient elevationofplasmaglucocorticoidssupportspsilocybin-inducedanxiolysisin mice.ACSPharmacolTranslSci.2023;6(8):1221–31.DOI: 10.1021/acsptsci. 3c00123.PMID:37588757;PMCID: PMC10425994
98.FortunatoJJ,RéusGZ,KirschTR,StringariRB,StertzL,KapczinskiF,etal.Acute harmineadministrationinducesantidepressive-likeeffectsandincreases BDNFlevelsintherathippocampus.ProgNeuropsychopharmacolBiolPsychiatry.2009;33(8):1425–30.DOI: 10.1016/j.pnpbp.2009.07.021.PMID:19632287
99.FavaroVM,YonamineM,SoaresJCK,OliveiraMGM.Effectsoflong-term ayahuascaadministrationonmemoryandanxietyinrats.PLoSOne.2015; 10(12):e0145840.DOI: 10.1371/journal.pone.0145840.PMID:26716991;PMCID: PMC4696664
100.CameronLP,BensonCJ,DeFeliceBC,FiehnO,OlsonDE.Chronic,intermittentmicrodosesofthepsychedelicN,N-Dimethyltryptamine(DMT) producepositiveeffectsonmoodandanxietyinrodents.ACSChem Neurosci.2019;10(7):3261–70.DOI: 10.1021/acschemneuro.8b00692.PMID: 30829033;PMCID: PMC6639775
101.NasehiM,Jamshidi-MehrM,KhakpaiF,ZarrindastMR.Possibleinvolvementof CA15-HT1B/1Dand5-HT2A/2B/2Creceptorsinharmaline-inducedamnesia. PharmacolBiochemBehav.2014;125:70–7.DOI: 10.1016/j.pbb.2014.08.007 PMID:25181578
102.LibânioTC,EufrásioRA,NiigakiSS,PeresFF,SilvaRH,ZuardiAW,etal.Harmine impairsmemoryperformanceoftreatedratsandnontreatedcagemates.Exp ClinPsychopharmacol.2022;30(6):751–9.DOI: 10.1037/pha0000525.PMID: 34735205
103.DuY,LiY,ZhaoX,YaoY,WangB,ZhangL,etal.Psilocybinfacilitates fearextinctioninmicebypromotinghippocampalneuroplasticity.ChinMed J(Engl).2023;136(24):2983.DOI: 10.1097/CM9.0000000000002647.PMID: 37000971;PMCID: PMC10752473
104.IshikawaR,FukushimaH,FranklandPW,KidaS.Hippocampalneurogenesisenhancerspromoteforgettingofremotefearmemoryafterhippocampalreactivationbyretrieval.Elife.2016;5:e17464.DOI: 10.7554/eLife.17464.PMID: 27669409;PMCID: PMC5036964
105.SekeresMJ,WinocurG,MoscovitchM,AndersonJAE,PishdadianS,Wojtowicz JM,etal.Changesinpatternsofneuralactivityunderlieatime-dependent transformationofmemoryinratsandhumans.Hippocampus.2018; 28(10):745–64.DOI: 10.1002/hipo.23009.PMID:29989271
106.SuzukiA,FukushimaH,MukawaT,ToyodaH,WuLJ,ZhaoMG,etal.UpregulationofCREB-mediatedtranscriptionenhancesbothshort-andlong-term memory.JNeurosci.2011;31(24):8786–802.DOI: 10.1523/JNEUROSCI.325710.2011.PMID:21677163;PMCID: PMC6622960
107.McLeanCP,LevyHC,MillerML,TolinDF.ExposuretherapyforPTSD:ametaanalysis.ClinPsycholRev.2022;91:102115.DOI: 10.1016/j.cpr.2021.102115. PMID:34954460
108.BurbackL,Brémault-PhillipsS,NijdamMJ,McFarlaneA,VermettenE.Treatmentofposttraumaticstressdisorder:astate-of-the-artreview.CurrNeuropharmacol.2023;22(4):557.DOI: 10.2174/1570159X21666230428091433 PMID:37132142;PMCID: PMC10845104
109.SmidGE,vanderMeerCAI,OlffM,NijdamMJ.Predictorsofoutcomeand residualsymptomsfollowingtrauma-focusedpsychotherapyinpoliceofficers withposttraumaticstressdisorder.JTraumaStress.2018;31(5):764–74.DOI: 10.1002/jts.22328.PMID:30338583
110.BolsoniLM,CrippaJAS,HallakJEC,GuimarãesFS,ZuardiAW.Theanxiolytic effectofcannabidioldependsonthenatureofthetraumawhenpatients withpost-traumaticstressdisorderrecalltheirtriggerevent.BrazJPsychiatry.2022;44(3):298.DOI: 10.1590/1516-4446-2021-2317.PMID:35293520; PMCID: PMC9169481
111.LaniusRA,BrandB,VermettenE,FrewenPA,SpiegelD.Thedissociativesubtypeofposttraumaticstressdisorder:rationale,clinicalandneurobiologicalevidence,andimplications:dissociativesubtypeofPTSD.DepressAnxiety. 2012;29(8):701–8.DOI: 10.1002/da.21889.PMID:22431063
112.LaniusRA,WilliamsonPC,BluhmRL,DensmoreM,BoksmanK,Neufeld RWJ,etal.Functionalconnectivityofdissociativeresponsesinposttraumatic stressdisorder:afunctionalmagneticresonanceimaginginvestigation.Biol Psychiatry.2005;57(8):873–84.DOI: 10.1016/j.biopsych.2005.01.011.PMID: 15820708
113.Ebner-PriemerUW,MauchnikJ,KleindienstN,SchmahlC,PeperM,Rosenthal MZ,etal.Emotionallearningduringdissociativestatesinborderlinepersonalitydisorder.JPsychiatryNeurosci.2009;34(3):214.PMID:19448852;PMCID: PMC2674975
114.RibaJ,RomeroS,GrasaE,MenaE,CarrióI,BarbanojMJ.Increasedfrontaland paralimbicactivationfollowingayahuasca,thepan-Amazonianinebriant.Psychopharmacology(Berl).2006;186(1):93–8.DOI: 10.1007/s00213-006-03587.PMID:16575552
115.Palhano-FontesF,AndradeKC,TofoliLF,SantosAC,CrippaJAS,HallakJEC, etal.Thepsychedelicstateinducedbyayahuascamodulatestheactivityand connectivityofthedefaultmodenetwork.PLoSOne.2015;10(2):e0118143. DOI: 10.1371/journal.pone.0118143.PMID:25693169;PMCID: PMC4334486
116.DolderPC,SchmidY,MüllerF,BorgwardtS,LiechtiME.LSDacutelyimpairs fearrecognitionandenhancesemotionalempathyandsociality.Neuropsychopharmacology.2016;41(11):2638–46.DOI: 10.1038/npp.2016.82.PMID: 27249781;PMCID: PMC5026740
117.MuellerF,LenzC,DolderPC,HarderS,SchmidY,LangUE,etal.Acuteeffects ofLSDonamygdalaactivityduringprocessingoffearfulstimuliinhealthy subjects.TranslPsychiatry.2017;7(4):e1084.DOI: 10.1038/tp.2017.54.PMID: 28375205;PMCID: PMC5416695
118.SanchezTA,RamosLR,AraujoF,SchenbergEE,YonamineM,LoboI,etal.EmotionregulationeffectsofAyahuascainexperiencedsubjectsduringimplicit aversivestimulation:anfMRIstudy.JEthnopharmacol.2024;320:117430.DOI: 10.1016/j.jep.2023.117430.PMID:37979818
119.RossiGN,RochaJM,OsórioFL,BousoJC,OnaG,SilveiraGDO,etal.Interactive effectsofayahuascaandcannabidiolinsocialcognitioninhealthyvolunteers: apilot,proof-of-concept,feasibility,randomized-controlledtrial.JClinPsychopharmacol.2023;43(4):339–49.DOI: 10.1097/JCP.0000000000001691 PMID:37335211
120.RochaJM,RossiGN,DeLimaOsórioF,BousoJC,DeOliveiraSilveiraG,Yonamine M,etal.Effectsofayahuascaontherecognitionoffacialexpressionsofemotionsinnaivehealthyvolunteers:apilot,proof-of-concept,randomizedcontrolledtrial.JClinPsychopharmacol.2021;41(3):267–74.DOI: 10.1097/JCP. 0000000000001396.PMID:33843820
121.BousoJC,GonzálezD,FondevilaS,CutchetM,FernándezX,BarbosaPCR, etal.Personality,psychopathology,lifeattitudesandneuropsychologicalperformanceamongritualusersofayahuasca:alongitudinalstudy.PLoSOne. 2012;7(8):e42421.DOI: 10.1371/journal.pone.0042421.PMID:22905130; PMCID: PMC3414465
122.SantosRG,Landeira-FernandezJ,StrassmanRJ,MottaV,CruzAPM.Effects ofayahuascaonpsychometricmeasuresofanxiety,panic-likeandhopeless-
nessinSantoDaimemembers.JEthnopharmacol.2007;112(3):507–13.DOI: 10.1016/j.jep.2007.04.012.PMID:17532158
123.AicherHD,MuellerMJ,DornbiererDA,SuayD,ElsnerC,WickiI,etal.Potential therapeuticeffectsofanayahuasca-inspiredN,N-DMTandharmineformulation:acontrolledtrialinhealthysubjects.FrontPsychiatry.2024;14:1302559. DOI: 10.3389/fpsyt.2023.1302559.PMID:38264636;PMCID: PMC10804806
124.LiuF,WuJ,GongY,WangP,ZhuL,TongL,etal.Harmineproduces antidepressant-likeeffectsviarestorationofastrocyticfunctions.ProgNeuropsychopharmacolBiolPsychiatry.2017;79:258–67.DOI: 10.1016/j.pnpbp. 2017.06.012.PMID:28625859
125.deAlmeidaRN,deMenezesGalvãoAC,daSilvaFS,SantosSilvaEAD,PalhanoFontesF,Maia-de-OliveiraJP,etal.Modulationofserumbrain-derivedneurotrophicfactorbyasingledoseofayahuasca:observationfromarandomizedcontrolledtrial.FrontPsychol.2019;10:1234.DOI: 10.3389/fpsyg.2019. 01234.PMID:31231276;PMCID: PMC6558429
126.ChoJH,DeisserothK,BolshakovVY.Synapticencodingoffearextinction inmPFC-amygdalacircuits.Neuron.2013;80(6):1491–507.DOI: 10.1016/j. neuron.2013.09.025.PMID:24290204;PMCID: PMC3872173
127.SantiniE,MullerRU,QuirkGJ.ConsolidationofExtinctionLearningInvolvesTransferfromNMDA-IndependenttoNMDA-DependentMemory.JNeurosci.2001;21(22):9009.DOI: 10.1523/JNEUROSCI.21-22-09009.2001.PMID: 11698611;PMCID: PMC6762277
128.PetersJ,Dieppa-PereaLM,MelendezLM,QuirkGJ.Inductionoffearextinction withhippocampal-infralimbicBDNF.Science.2010;328(5983):1288–90.DOI: 10.1126/science.1186909.PMID:20522777;PMCID: PMC3570764
129.BloodgoodDW,SugamJA,HolmesA,KashTL.Fearextinctionrequiresinfralimbiccortexprojectionstothebasolateralamygdala.TranslPsychiatry. 2018;8(1):1–11.DOI: 10.1038/s41398-018-0106-x.PMID:29507292;PMCID: PMC5838104
130.VaidyaVA,MarekGJ,AghajanianGK,DumanRS.5-HT2Areceptor-mediated regulationofbrain-derivedneurotrophicfactormRNAinthehippocampusand theneocortex.JNeurosci.1997;17(8):2785–95.DOI: 10.1523/JNEUROSCI.1708-02785.1997.PMID:9092600;PMCID: PMC6573109
131.Morales-GarciaJA,Calleja-CondeJ,Lopez-MorenoJA,Alonso-GilS,SanzSanCristobalM,RibaJ,etal.N,N-dimethyltryptaminecompoundfoundinthe hallucinogenicteaayahuasca,regulatesadultneurogenesisinvitroandinvivo. TranslPsychiatry.2020;10(1):331.DOI: 10.1038/s41398-020-01011-0.PMID: 32989216;PMCID: PMC7522265
132.AghajanianGK,FooteWE,SheardMH.Lysergicaciddiethylamide:sensitive neuronalunitsinthemidbrainraphe.Science.1968;161(3842):706–8.DOI: 10.1126/science.161.3842.706.PMID:4874578
133.LowryCA,HollisJH,deVriesA,PanB,BrunetLR,HuntJRF,etal.Identification ofanimmune-responsivemesolimbocorticalserotonergicsystem:potential roleinregulationofemotionalbehavior.Neuroscience.2007;146(2):756–72.DOI: 10.1016/j.neuroscience.2007.01.067.PMID:17367941;PMCID: PMC1868963
134.GraeffFG,QuinteroS,GrayJA.Medianraphestimulation,hippocampalthetarhythmandthreat-inducedbehavioralinhibition.PhysiolBehav. 1980;25(2):253–61.DOI: 10.1016/0031-9384(80)90213-9.PMID:6447883
135.Carhart-HarrisR,NuttD.Serotoninandbrainfunction:ataleoftworeceptors. JPsychopharmacol2017;31(9):1091–120.DOI: 10.1177/0269881117725915 PMID:28858536;PMCID: PMC5606297
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OPEN RESEARCHREPORT
Anestimateofthenumberofpeople withclinicaldepressioneligiblefor psilocybin-assistedtherapyinthe UnitedStates
SyedF.Rab1 ,CharlesL.Raison2 ,andElliotMarseille3
1 EmoryUniversitySchoolofMedicine,Atlanta,GA30322,USA
2 UniversityofWisconsin-MadisonSchoolofMedicineandPublicHealth, Madison,WI53707,USA
3 UCBerkeley,CollaborativefortheEconomicsofPsychedelics, Berkeley,CA94720,USA
CorrespondingAuthor: SyedFayzanRab,EmoryUniversitySchoolof Medicine,12ExecutiveParkDriveNortheast,Atlanta,GA30329,USA.
Email: Syed.f.rab@emory.edu
Psychedelics March2025;1(2):26–30; doi: https://doi.org/10.61373/pp024r.0025
Thisstudyaimstoestimatethelower,middle,andupperboundsofpotentialdemandforpsilocybin-assistedtherapy(PSIL-AT)formajordepressivedisorder(MDD)andtreatment-resistantdepression(TRD)in theUnitedStates.WecalculatedpotentialPSIL-ATdemandforMDD andTRDbyestimatingthenumberofU.S.patientswithMDD,identifyingthoseintreatment,anddeterminingwhoqualifiesashaving TRD.Weestablishedarangeofestimatesusingtheexclusioncriteria fromthelargesttrialstodateonPSIL-ATforMDDorTRD.Estimates rangedfromlower-boundthroughstringentcriteria,mid-rangebyfocusingonlikelyreal-worldscenarios,toupper-boundbyaccounting fordoublecountingforpatientswithmultiplecomorbidities.AsignificantportionofpatientswithMDDandTRDisineligibleforPSILATduetodisqualifyingconditions.Percentageofpatientswhoare eligibleare24%(lower-bound),56%(mid-range),and62%(upperbound).Variancewaslargelyinfluencedbytheremovalofalcoholand substanceusedisordersasexclusioncriteria,aswellasremovingthe doublecountingfromcomorbidpsychiatricandcardiovascularconditions.Theanalysisoutlinesthepublichealthimplicationsofproviding PSIL-ATforMDDandTRD,emphasizingthattheeffectivedemand willbeshapedbyinsurancecoverage,state-levelregulations,andthe availabilityoftrainedproviders.Thesefindingssuggesttheneedfor carefulpolicyplanningandresourceallocationtoensureequitable accessandeffectiveimplementationofPSIL-ATacrossdiversepopulationsandregions.
Keywords: Psilocybin,depression,exclusioncriteria,psychedelic therapy.
Introduction
Psilocybin-assistedtherapy(PSIL-AT)hasbeendesignatedbytheFood andDrugAdministration(FDA)asbreakthroughtherapyforpatientswith eitheradiagnosisofmajordepressivedisorder(MDD)ortreatmentresistantdepression(TRD)(1).TRDisdefinedashavingatleasttwotreatmentswithantidepressantmedications,atadequatedosesandforan adequatedurationinthecurrentdepressiveepisode,withoutsignificant relieffromsymptomsrelatedtoMDD(2).RecentclinicaltrialshavedefinedinclusionandexclusioncriteriaspecificallyforTRD(3)orMDD(4, 5), thelatterofwhichmayalsoincludepatientswithTRD.AsFDAapproval andsubsequentlegalizationformedicaluseofpsilocybinisnowbeing considered(6),itisimportanttounderstandthepossiblepublichealth
impactfromtheintroductionofPSIL-ATintheUnitedStates.This,inturn, requiresanestimationofthepotentialdemand.Wechosetodefinea clinicallower-bound,mid-range,andupper-boundestimatesofthedemandforPSIL-ATasatreatmentforMDDorTRD.
Results
Asshownin Table1,ofthe14.8millionpeoplewithMDD,9millionare beingtreated,and2.7millionmeetcriteriaforTRD.
Table2 illustratesthepercentageofpatientsdeemedeligiblefor PSIL-AT,accompaniedbycorrespondingestimatesforthenumberofindividualsbeingtreatedforMDDorTRDwhoareeligibleforthistherapeutic approach.
Thelower-boundestimateindicatesonly24%ofpatientswithdepressionwouldmeetstrictclinicaltrialexclusioncriteriaforPSIL-AT.This amountsto2.2millionpatientscurrentlyundergoingtreatmentforMDD or0.6millionpatientswhenconsideringonlythosewithTRD.
Inapplyingexclusioncriterialikelytooperateinreal-worldclinical settings(themid-rangeestimate),weobserveanotableincreaseinthe proportionofincludedpatientsto56%.Applicationofthesemorepermissivecriteriawouldexpandthepoolofeligiblepatientsbeingtreated forMDDorTRDto5.1millionor1.5million,respectively.Theexclusionof alcoholandsubstanceusedisordersaccountsforasignificantportionof thisadjustment,contributingto32%ofthedifference.
Finally,theupper-boundestimate,whichadjustsfordoublecounting betweendifferentmedicalconditions,raisestheestimateto62%ofthe patientpopulationwithdepressionbeingeligibleforPSIL-AT.Thistranslatesto5.6millionindividualsand1.7millioneligibleforPSIL-ATwhen consideringMDDandTRD,respectively.Thisadjustedincreaseisprimarily attributedtotheco-occurrenceofcardiovascularandpsychiatriccomorbidities,witheachcontributingtoa3%–4%increaseineligiblepatients.
Inadditiontoourbaseestimates,weconductedasensitivityanalysistoevaluatetheimpactofvaryingassumptionsontheoveralldemand projectionsforPSIL-AT.Specifically,weassignedbetadistributionswith arangeofplusorminus50%ofthebaselinevaluestoeachofthecomorbidityprevalenceestimatesshownincolumn3of Table2.Using@RISK (PalisadeCorporation,version8.1.1)software,wesimulatedtheoverall uncertaintyinthefinalestimatesofthenumberofpatientseligiblefor PSIL-ATamongthosewithMDDandTRD.
Theresultsofthesensitivityanalysisaredepictedin Figures1 and 2. ForpatientswithMDD,theanalysisproduceda95%confidenceinterval (CI)of4.7millionto6.6millioneligibleindividuals,whileforpatientswith TRD,the95%CIrangedfrom1.4millionto1.9million.Theserangeshighlightthepotentialvariabilityinourestimatesbasedonchangesinthe assumptionsunderlyingcomorbidityprevalence,emphasizingboththe robustnessandtheuncertaintyinherentinourprojections.
Discussion
Thisanalysisoutlinesthedimensionsofthepublichealthimplicationsof providingPSIL-ATforthetreatmentofMDDandTRD.Ourestimatesof
Table1. Estimatesofnumberofpeoplewhowouldqualifyashaving MDD,thoseintreatment,andthosewhohaveTRD
Received:2May2024.Revised:12August2024and27August2024and29August2024.Accepted:29August2024. Publishedonline:13September2024.
Table2. PrevalenceofdisqualifyingcomorbiditiesinthelargestclinicaltrialsutilizingPSIL-ATforMDDorTRDwithnumberofpatientseligible
PrevalenceofdisqualifyingcomorbidityinpatientswithMDDor TRDaccordingto:
Disqualifyingcomorbidities
Trialswith thisexclusion criterion
1.Trialexclusioncriteria1 CI(ConfidenceInterval),OR (OddsRatio),SE(Standard Error) 2.Real-world exclusion criteria
3.Real-world exclusioncriteria adjustedfor comorbid conditions2 , 3
Psychoticormanicdisorder(3–5)19%(8)19%(8)23.2%(9)
Suicideattemptinthepastyear8.0%[95%CI=(3–14%)](10)8.0%(10)
Diabetes,uncontrolled(5)2.9%[OR=1.4(1.4–1.5)](11, 12)2.9%(11, 12)8.0%(13, 14)
Stroke(3–5)1.9%[OR=2.4(2.0–2.8)](11)1.9%(11)
Heartattackinlastyear(3–5)2.7%[OR=0.9(0.8–1.1)](11)2.7%(11)
BP140+/90+,treatment-resistant2.0%[OR=1.4(1.3–1.4)](11, 15)2.0%(11, 15)
Epilepsy3.7%[OR=2.6(2.3–3.0)](11)3.7%(11)3.7%(16)
Personalitydisorder(4)2.2%[SE=.36](16)2.2%(17)2.2%(11)
Hepaticimpairment(Child-Pugh > 7)4 (5)1.8%[SE=.10](18)1.8%(18)1%(17)
Alcoholdependence(3–5)20.0%(19)–Drugdependence12.0%(19)––
Othercardiacconditions(LongQT,cardiac hypertrophy,heartfailure,tachycardiaatrest, atrialfibrillation,prostheticvalve)
Pregnancy UnwillingnesstodiscontinueSSRIs–––
Unwillingorunabletodiscontinueformal psychotherapy
Haveusedpsychedelicsinthepast5years;have usedpsychedelics10+ timesinthepast
Have1stdegreerelativewithpsychoticdisorder orbipolardisorder
ReceivedECTorTMSinthepast90days(5)–––
Percentageofpatientswhowouldbeineligible forPSIL-AT
PercentageandnumberofpatientswithMDDandTRDeligibleforPSIL-AT
PercentageofpatientseligibleforPSIL-AT–24%56%62%
NumberofpatientsbeingtreatedforMDDwho areeligibleforPSIL-AT
NumberofpatientsbeingtreatedforTRDwho areeligibleforPSIL-AT
1 Whereavailable,confidenceintervals,oddsratios,andstandarderrorswerereported.
2 Double-countingcalculationsusedprevalenceestimatesfromthegeneralpopulationandarenotMDD-specific.
3 Forsensitivityanalysis,eachcomorbiditywasassignedabetadistributionwithalphaandbetaparametersof2andmaximum/minimumvaluesof +/ 50%
4 HepaticimpairmentestimatescamefromthegeneralpopulationandarenotMDD-specific.
demandaresubjecttocontingenciespendingFDAdecisionaroundPSILAT.Onepossibilitythatcouldelevatedemandbeyondourprojections involvesoff-labeluseofPSIL-ATforconditionsotherthandepression. Evidencefrompsychiatricprescriptionpracticessuggeststhatpsychiatric medicationsareusedtotreatarangeofconditionsoutsidetheiroriginalFDA-approvedindication.Aretrospectiveanalysis,forexample,revealedthat91%ofpatientscurrentlyprescribedantidepressantswould notmeetrandomizedclinicaltrialseligibilitybasedontheirmedicalstatus(20).ThisdiscrepancysuggeststhattheeligibilityforPSIL-ATmight besignificantlyhigherthanourestimatesifPSIL-ATisusedtotreat othermedicalconditionssuchasanxietydisorders,chronicpain,and otherpsychiatricdisorders,eitheroff-labelorfollowingeventualFDA approvalfortheseconditions.Weareawareofnoreliabledatathat wouldallowustoestimatecurrentandespeciallyfutureprevalenceof treatmentseeking,whichintroducesfurthercomplexityintoourdemand projections.
Conversely,otherpsychedelicsgrantedFDAbreakthroughstatussuch aslysergicaciddiethylamideforgeneralanxietydisorder(21)maybe
usedoff-labelinthefuturetotreatpatientswithMDDorTRDgivenhigh comorbiditybetweentheseconditions(22).Iftheseotherpsychedelics aregivenFDAapprovalinthefuture,thedemandestimatewouldneed tobemodifiedtodistributeacrosstherelativeuptakeofallpsychedelics thathavetherapeuticeffectsondepression.
Additionally,therearecountervailingpracticalconsiderationsfor PSIL-ATwhicharelikelytoconstraineffectivedemandtolevelslowerthan ourestimates.Theseincludetheavailabilityoftrainedproviders,geographicalaccesstotherapy,andpatientpreferencesrelatedtocost,treatmentduration,andculturalacceptability.Forexample,patientslivingin urbancentersarelikelytohavegreateraccesstoPSIL-ATfacilitiesand therapists,whileruralareasmaylacksufficienttrainedprofessionalsand infrastructureforeffectiveadministration.StatesthathavealreadylegalizedpsychedelictherapieslikeOregonandColoradomayasymmetrically dominatedemandintheshort-termwhileotherstatesworkthroughestablishingtheirownregulatoryframeworkforPSIL-AT.
Recentclinicaltrialshaveevaluatedpsilocybin’seffectivenessasboth monotherapyfordepression(3, 4),andasanadjuncttoestablished
Figure1. PatientsbeingtreatedforMDDwhoareeligibleforPSIL-AT.Multivariatesensitivityanalyses,20,0000iterations.
antidepressantregimens(2, 23).Ina2020article,Luo etal. reportedthat 70%ofindividualswithMDDutilizeantidepressants(24).Therefore,if FDAapprovalofPSIL-ATforMDDrestrictsittomonotherapy,itsapplicabilitywouldbesignificantlynarrowed,givenevidencesuggestingthat nearlyhalfofpatientsattemptingtotaperoffpsychotropicdrugsface difficultiesincompletelystoppingtheirmedication(25).
HeterogeneityinthewaysstateschoosetoimplementPSIL-ATwill alsoimpacteffectivedemand.ExistinglegalizationeffortsinColorado andOregonmayserveasamodelforhowPSIL-ATisrolledoutnationwidepost-FDAapproval.Colorado’sNaturalMedicineHealthAct,forexample,mandatesthatlicensedfacilitatorsrefrainfromtreatingpatients withmanyofthecomorbiditiesdiscussedinthispaper(26).However, patientsmaygetclearancefromamedicalprofessionaltoproceedwith psychedelictherapydespiteexclusionaryconditions(26).Whetherstates choosetofollowColoradoorOregon’sexampleorimplementtheirown regulationsisunknownandmakesdemandestimationdifficult.
Perhapsmostimportantly,theprospectivedemandwillbeshapedby theextenttowhichinsurers,bothpublicandprivate,includePSIL-AT intheircoverageschemes.Medicaidisthelargesthealthcarepayerin theUnitedStates.Itcovered85millionlow-incomebeneficiariesin2023 (27)and18%–20%ofitsbeneficiariesarelikelytohaveclinicaldepression(28).Thus,decisionsMedicaidmakesregardingtheconditionsunder whichPSIL-ATservicesaremadeavailableandreimbursedwillbeparticularlyimportantindeterminingeffectivedemand.Ultimately,whether PSIL-AThasasignificantimpactonthementalhealthoftheU.S.populationdependsonthedecisionsofpublicandprivatethird-partypayers, andMedicaidisthesinglemostimportantamongthem.
Therangeofeligibilityestimates(24%–62%)highlightstheneedfor flexiblehealthcareplanningandresourceallocationstrategies.Policymakersandhealthcareprovidersmustprepareforthisvariabilitybyensuringthatsufficientresources—includingtrainedtherapists,facilities,
andfinancialsupport—areavailabletomeetdemandundervariousscenarios.ThisflexibilitywillbecrucialasmoredatabecomesavailablepostFDAapproval,allowingforadjustmentsinresourcedistributionandensuringequitableaccesstoPSIL-ATacrossdiversepopulationsandregions. Thisstudyservesasabasisforpolicymakers,healthcarepayers,and pharmaceuticalcompaniestogaugethepotentialpublichealthimpactof PSIL-ATpendingFDAapproval.Asthefieldprogresses,furtherresearchis warrantedtoexplorepsilocybin’stherapeuticrange,includingitsapplicationtoabroaderarrayofmentalhealthconditionsanditsintegration intononclinicalsettings.Futurestudiesshouldfocusonregionalanddemographicvariations,theroleofstateregulations,andculturalattitudes towardpsychedelictherapies.Additionally,longitudinalstudiestracking thereal-worldimplementationofPSIL-ATwillbeessentialforassessing howinitialprojectionsalignwithactualdemand,influencingfuturepolicydecisionsandresourceallocationefforts.Suchanalyseswillrefineour understandingofthepotentialpublichealthimpactofpsychedelictherapiesandhelptoguidepolicyandclinicalpractice.
Methods Overview
TocalculatethepotentialdemandforPSIL-ATforTRDandMDDinthe UnitedStates,weestimatedthenumberofpatientswithMDD,identified howmanyofthesepatientsarecurrentlyundergoingtreatment,andfurtherdefinedwhowouldqualifyashavingTRD.Weestablishedarangeof estimates:alower-boundestimatethroughstringentapplicationofexclusioncriteriausedinclinicaltrials;amid-rangeestimatebyconsideringonlyexclusioncriterialikelytoberelevanttoreal-worldclinicalscenarios;andanupper-boundestimatebyrefiningouranalysistoaccount forpatientswithtwoormorecomorbidconditionsinadditiontoMDD. SinceeachcomorbiditywouldexcludepotentialpatientsfromsafelyaccessingPSIL-AT,weeliminatethedoublecountingthatwouldresultfrom co-occurringdisqualifyingconditions.
WeusedanestimateofMDDcasesintheUnitedStatesbasedonthe 2021NationalSurveyonDrugUseandHealth(6).Wethenfocusedon thesubgroupofindividualswhohadreceivedtreatmentfortheirMDDin thepastyearandfurtheradjustedtoestimatethenumberofindividuals whowouldqualifyashavingTRD(1).
Infocusingonindividualscurrentlyundergoingtreatmentfordepression,ourapproachensuresthatdemandestimatesaregroundedinrealworldclinicalsettings,wherePSIL-ATwilllikelybeadministeredshould theyreceiveFDAapproval.Thisallowsustoworkwithapopulationwhose treatment-seekingbehaviorsandclinicalprofilesarewelldocumented, providingareliablefoundationfordemandestimation.Bychoosingthis baseline,wealsoavoidspeculativeassumptionsaboutthefuturebehaviorofuntreatedindividuals(acknowledgingapotentialinfluxpostFDAapproval),ensuringthatourprojectionsremainconservativeand methodologicallyconsistent.Moreover,thisapproachallowsforflexibility,asfutureresearchanddatacollectioncanexpandupontheseestimatesbyincorporatingthepotentialuptakeofPSIL-ATamongcurrently untreatedindividuals.
Aportionofthispatientpopulationfailstomeetclinicaleligibilityfor PSIL-ATduetoadisqualifyingmedicalcondition.Toestimatetheportion ofsuchdisqualifiedpatients,weidentifiedtheclinicalexclusioncriteria fromthelargestclinicaltrialstodateonPSIL-ATforMDDorTRD(3–5)(see AdditionalMaterials).Whereavailable,weincludedconfidenceintervals anderrormarginsfromprevalencedatalookingatdepressionwithdifferentcomorbidities.WeconstructedthreedifferentestimatesofthepotentialdemandforPSIL-ATbasedonthreerespectivesetsofassumptions regardingeligibilityforPSIL-AT:
1.Allpatientswiththeexclusioncriteriausedinclinicaltrials,assuming nocomorbidmedicalconditions.ThisrepresentsthetheoreticallowerboundofpatientswhowouldbeeligibleforPSIL-ATandisrepresented asthecolumnlabeled“1.Trialexclusioncriteria”in Table2
2.Sameas#1butremovingexclusioncriteriathatwouldberelevantina clinicaltrialsettingbutwouldnotapplyinreal-worldclinicalsettings. Thisrepresentsamid-rangeestimateandislabeled“2.Real-world exclusioncriteria”in Table2
Figure2. PatientsbeingtreatedforTRDwhoareeligibleforPSIL-AT.Multivariatesensitivityanalyses,20,0000iterations.
3.Sameas#2butwithfurtheradjustmentfortheprevalenceofcomorbid medicalconditions(e.g.,psychosisandacutesuiciderisk).Thisrepresentsanupper-boundestimateandisrepresentedas“3.Real-world exclusioncriteriaadjustedforcomorbidconditions”in Table2
Weappliedthesesetsofassumptionstwice,topatientswithMDDand topatientswithTRD.
Acrossallestimates,wedidnotgatherprevalencedataonmedicalconditionsthatweretransient(i.e.,pregnancy),modifiablewitha provider(i.e.,taperingofaSSRI),nichewithlittletonoreliableprevalencedataavailableinpatientswithdepression(i.e.,diagnosedpsychosis infirst-degreefamilymembersorcardiacarrythmias),constructsofeffectivestudydesign(i.e.,discontinueexistingpsychotherapyorprevious psychedelicuse),orexperimental(i.e.,deepbrainstimulationorvagal nervestimulation).
Inevaluating“2.Real-worldexclusioncriteria”,weconsideredboth thepharmacologicalmechanismsofpsychedelicagentsandtheclinical insightsofoneofthepaper’sauthors(Raison).Ourpremiseisthatthe neurobiologicaleffectsofpsilocybinwillbethesameinreal-worldclinicalpracticeastheyareintrials,thuswarrantingourinclusionofconditionsknowntobeaffecteddirectlybytheseneurobiologicalmechanisms inourdemandestimation.Theneurologicalmechanismofpsilocybin(29) isthoughttodestabilizeunderlyingmaniaandpsychosis(30),triggerlatentepilepsy(31),andexacerbateacutesuiciderisk(32).PSIL-ATalsoexhibitsunderlyingserotonergiceffectsonthebody(33),whichareknown tocausecardiovascularstressexacerbatingriskofstroke,heartattack,diabeticcomplication,andothersequelaofhypertension(34).Additionally, severeliverdysfunctionmayalterthemetabolismofpsychotropicmedications,necessitatingitsinclusionasacriterionforexclusioninclinical practice(35).
ThebenefitsofPSIL-ATforthetreatmentofpersonalitydisordershave beendiscussedbutarecurrentlyunsubstantiated(35)andwetherefore retainitasanexclusioncriteriainthisanalysis.Weremovedalcoholuse disorderandsubstanceabusedisorderfromourlistofexclusioncriteriabecauseevidencesuggeststhatPSIL-ATcanbebeneficialforpatients withtheseconditions(31, 36).
Toavoiddoublecounting,wethenrefinedtheresultingestimate basedontheprevalenceofcomorbiditybetweenthedifferentexclusionaryconditions.Thisisrepresentedas“3.Real-worldexclusioncriteriaadjustedforcomorbidconditions”in Table2.Whenavailable,weusedthe prevalenceofcomorbidconditionsamongpeoplewithclinicaldepression. Wherethiswasnotpossible,weusedestimatesoftheprevalenceofcomorbidconditionsinthegeneralpopulation.Forexample,the12-month incidenceofsuicideattemptsamongpatientsreportingpsychosisandany otherpsychiatriccondition,inthiscaseclinicaldepression,was47.4%(9). Utilizingthesedata,weadjustedforthepotentialdoublecountingofpatientsineligibleduetobothpsychosisandacutesuiciderisk,resulting inarevisedcombinedprevalenceof23.2%.Similarly,wefoundhighcomorbiditybetweenuncontrolleddiabetes(13),stroke,heartattack,and treatment-resistanthypertension(14)andformulatedatotalestimateof 8.0%.
AuthorContributions
SFR:Conceptualization,Methodology,Formalanalysis,Investigation, Writing–OriginalDraft,Projectadministration. CLR:Writing–Review&Editing,Supervision. EM:Writing–Review&Editing,Supervision. Allauthorsdiscussedtheresultsandcontributedtothefinalmanuscript.
DesignationofCorrespondingAuthorandLeadContact
SFRisdesignatedasthecorrespondingauthorandleadcontactforthis paper.Hehastakenresponsibilityforcoordinatingtheeffort,overseeing thedataintegrity,handlingthesubmissionprocess,andcommunicating withthejournalpre-andpost-publication.SFRensuresthatallauthors haveapprovedthefinalversionofthemanuscriptandadheretoalleditorialandsubmissionpolicies.
ConflictsofInterest
SFRconfirmsthathewasaconsultantatSunstoneTherapies.EMserves asadjunctfacultyatUCBerkeley’sCollaborativefortheEconomicsof
PsychedelicswhichhasreceivedfinancialsupportfromtheUsonaInstitute.CLRdisclosesthatheservesasaconsultantforUsonaInstitute,Otsuka,andNovartis.Therearenootherconflictsofinterestamongtheauthors,andallauthorshavedisclosedanyrelatedworkunderconsiderationelsewhere.
Allauthorshaveagreedtotheorderofauthorship,affirmingtheir contributionstotheworkasdetailedabove.Incaseofanyauthorship disputes,theauthorswillresolvetheminternallywithoutinvolvingthe journaleditorialprocess.
Acknowledgments
Weextendourgratitudetoparticipantsandresearchersinthepsilocybin clinicalstrialsconductedtodate.
FundingSources
Nonewereutilizedforthisproject.
References
1.HealDJ,SmithSL,BelouinSJ,HenningfieldJE.Psychedelics:thresholdofatherapeutic revolution.Neuropharmacology.2023;236:109610.DOI: 10.1016/j.neuropharm.2023. 109610.PMID:37247807
2.GaynesBN,RushAJ,TrivediMH,WisniewskiSR,SpencerD,FavaM.TheSTAR∗D study:treatingdepressionintherealworld.CleveClinJMed.2008;75(1):57–66. DOI: 10.3949/ccjm.75.1.57.PMID:18236731
3.GoodwinGM,AaronsonST,AlvarezO,ArdenPC,BakerA,BennettJC,etal.Singledosepsilocybinforatreatment-resistantepisodeofmajordepression.NEnglJMed. 2022;387(18):1637–48.DOI: 10.1056/NEJMoa2206443.PMID:36322843
4.Carhart-HarrisR,GiribaldiB,WattsR,Baker-JonesM,Murphy-BeinerA,Murphy R,etal.Trialofpsilocybinversusescitalopramfordepression.NEnglJMed. 2021;384(15):1402–11.DOI: 10.1056/NEJMoa2032994.PMID:33852780
5.RaisonCL,SanacoraG,WoolleyJ,HeinzerlingK,DunlopBW,BrownRT,etal.Singledosepsilocybintreatmentformajordepressivedisorder:arandomizedclinicaltrial. JAMA.2023;330(9):843–53.DOI: 10.1001/jama.2023.14530.PMID:37651119;PMCID: PMC10472268
6.MitchellJM,BogenschutzM,LiliensteinA,HarrisonC,KleimanS,Parker-GuilbertK, etal.MDMA-assistedtherapyforseverePTSD:arandomized,double-blind,placebocontrolledphase3study.NatMed.2023;21(3):315–28.DOI: 10.1176/appi.focus. 23021011.PMID:37404971;PMCID: PMC10316215
7.Majordepression.UpdatedJanuary2022.2022[citedMarch30,2023].Availablefrom: https://www.nimh.nih.gov/health/statistics/major-depression
8.OhayonMM,SchatzbergAF.Prevalenceofdepressiveepisodeswithpsychoticfeatures inthegeneralpopulation.AmJPsychiatry.2002;159(11):1855–61.DOI: 10.1176/appi. ajp.159.11.1855.PMID:12411219
9.DeVylderJE,LukensEP,LinkBG,LiebermanJA.Suicidalideationandsuicideattemptsamongadultswithpsychoticexperiences:datafromthecollaborativepsychiatricepidemiologysurveys.JAMAPsychiatry.2015;72(3):219–25.DOI: 10.1001/ jamapsychiatry.2014.2663.PMID:25715312
10.DongM,ZengL-N,LuL,LiXH,Ungvari,GS,NgCH,etal.Prevalenceofsuicideattemptinindividualswithmajordepressivedisorder:ameta-analysisofobservational surveys.PsycholMed 2019;49(10):1691–704.DOI: 10.1017/S0033291718002301 PMID:30178722
11.SchoepfD,UppalH,PotluriR,ChandranS,HeunR.Comorbidityanditsrelevance ongeneralhospitalbasedmortalityinmajordepressivedisorder:anaturalistic 12-yearfollow-upingeneralhospitaladmissions.JPsychiatrRes.2014;52:28–35. DOI: 10.1016/j.jpsychires.2014.01.010.PMID:24513499
12.LiuL,WangF,GracelyEJ,MooreK,MellyS,ZhangF,SatoPY,EisenHJ.Burdenofuncontrolledhyperglycemiaanditsassociationwithpatientscharacteristicsandsocioeconomicstatusinphiladelphia,USA.HealthEquity.2020;4(1):525–32.DOI: 10.1089/ heq.2020.0076.PMID:34095699;PMCID: PMC8175259
13.EinarsonTR,AcsA,LudwigC,PantonUH.Prevalenceofcardiovasculardiseaseintype2 diabetes:asystematicliteraturereviewofscientificevidencefromacrosstheworldin 2007–2017.CardiovascDiabetol.2018;17(1):83.DOI: 10.1186/s12933-018-0728-6 PMID:29884191;PMCID: PMC5994068
14.CardosoCRL,SallesGF.Refractoryhypertensionandrisksofadversecardiovascular eventsandmortalityinpatientswithresistanthypertension:aprospectivecohort study.JAmHeartAssoc.2020;9(17):e017634.DOI: 10.1161/JAHA.120.017634.PMID: 32851922;PMCID: PMC7660786
15.CareyRM,SakhujaS,CalhounDA,WheltonPK,MuntnerP.Prevalenceofapparenttreatment-resistanthypertensionintheUnitedStates.Hypertension. 2019;73(2):424–31.DOI: 10.1161/HYPERTENSIONAHA.118.12191.PMID:30580690; PMCID: PMC6693520
16.HasinDS,GoodwinRD,StinsonFS,GrantBF.Epidemiologyofmajordepressivedisorder:resultsfromthenationalepidemiologicsurveyonalcoholismandrelatedconditions.ArchGenPsychiatry.2005;62(10):1097–106.DOI: 10.1001/archpsyc.62.10. 1097.PMID:16203955
17.HuangDQ,MathurinP,Cortez-PintoH,LoombaR.GlobalepidemiologyofalcoholassociatedcirrhosisandHCC:trends,projectionsandriskfactors.NatRevGastroenterolHepatol.2023;20(1):37–49.DOI: 10.1038/s41575-022-00688-6.PMID: 36258033;PMCID: PMC9579565
18.NationalCenterforHealthStatistics.SummaryHealthStatistics:NationalHealth InterviewSurvey,2018U.S.DepartmentofHealthandHumanServices,Centersfor DiseaseControlandPrevention;2018.
19.SimonGE,MoiseN,MohrDC.Managementofdepressioninadults:areview.JAMA. 2024;332(2):141–52.DOI: 10.1001/jama.2024.5756.PMID:38856993
20.ZetinM,HoepnerCT.Relevanceofexclusioncriteriainantidepressantclinicaltrials: areplicationstudy.JClinPsychopharmacol.2007;27(3):295–301.DOI: 10.1097/JCP. 0b013e318058263f.PMID:17502778
21.MindMed.MindMedReceivesFDABreakthroughTherapyDesignationandAnnounces Positive12-WeekDurabilityDataFromPhase2BStudyofMM120forGeneralized AnxietyDisorder.2024.
22.ZbozinekTD,RoseRD,Wolitzky-TaylorKB,SherbourneC,SullivanG,SteinMB,etal. Diagnosticoverlapofgeneralizedanxietydisorderandmajordepressivedisorderina primarycaresample.DepressAnxiety.2012;29(12):1065–71.DOI: 10.1002/da.22026 PMID:23184657;PMCID: PMC3629816
23.Cybinannouncespositiveend-of-phase2meetingwithFDAforCYB003inmajordepressivedisorderandphase3programdesign[pressrelease].March14,2024.
24.LuoY,KataokaY,OstinelliEG,CiprianiA,FurukawaTA.Nationalprescriptionpatterns ofantidepressantsinthetreatmentofadultswithmajordepressionintheUSbetween 1996and2015:apopulationrepresentativesurveybasedanalysis.FronPsychiatry. 2020;11:35.DOI: 10.3389/fpsyt.2020.00035.PMID:32116850;PMCID: PMC7033625
25.OstrowL,JessellL,HurdM,DarrowSM,CohenD.Discontinuingpsychiatricmedications:asurveyoflong-termusers.PsychiatrServ.2017;68(12):1232–8.DOI: 10.1176/ appi.ps.201700070.PMID:28712356
26.ColoradoRevisedStatutes,4CCR755-1(2022).
27.CenterforMedicareandMedicaidServices.December2023MedicaidandCHIPEnrollmentTrendSnapshot;2023.
28.ElmarasiM,FuehrleinB.USmedicaidprogram:ananalysisofthespendingand utilizationpatternsforantidepressantsfrom2017to2021.ExplorResClinSoc Pharm.2024;13:100392.DOI: 10.1016/j.rcsop.2023.100392.PMID:38149102;PMCID: PMC10750172
29.GattusoJJ,PerkinsD,RuffellS,LawrenceAJ,HoyerD,JacobsonLH,etal.Default modenetworkmodulationbypsychedelics:asystematicreview.IntJNeuropsychopharmacol.2023;26(3):155–88.DOI: 10.1093/ijnp/pyac074.PMID:36272145; PMCID: PMC10032309
30.ÖngürD,LundyM,GreenhouseI,ShinnAK,MenonV,CohenBM,etal.Defaultmodenetworkabnormalitiesinbipolardisorderandschizophrenia.Psychiatry Res.2010;183(1):59–68.DOI: 10.1016/j.pscychresns.2010.04.008.PMID:20553873; PMCID: PMC2902695
31.DanielsonNB,GuoJN,BlumenfeldH.Thedefaultmodenetworkandalteredconsciousnessinepilepsy.BehavNeurol.2011;24(1):55–65.DOI: 10.3233/BEN-2011-0310 PMID:21447899;PMCID: PMC3150226
32.CaoJ,AiM,ChenX,ChenJ,WangW,KuangL.Alteredresting-statefunctionalnetwork connectivityisassociatedwithsuicideattemptinyoungdepressedpatients.PsychiatryRes.2020;285:112713.DOI: 10.1016/j.psychres.2019.112713.PMID:31810745
33.MadsenMK,FisherPM,BurmesterD,DyssegaardA,StenbækDS,KristiansenS, etal.Psychedeliceffectsofpsilocybincorrelatewithserotonin2Areceptoroccupancyandplasmapsilocinlevels.Neuropsychopharmacology.2019;44(7):1328–34. DOI: 10.1038/s41386-019-0324-9.PMID:30685771;PMCID: PMC6785028
34.FrishmanWH,HuberfeldS,OkinS,WangY-H,KumarA,ShareefB.Serotoninandserotoninantagonismincardiovascularandnon-cardiovasculardisease.JClinPharmacol. 1995;35(6):541–72.DOI: 10.1002/j.1552-4604.1995.tb05013.x.PMID:7665716
35.ZeifmanRJ,WagnerAC.Exploringthecaseforresearchonincorporatingpsychedelics withininterventionsforborderlinepersonalitydisorder.JContextualBehavioral Science.2020;15:1–11.
36.BogenschutzMP,RossS,BhattS,BaronT,ForcehimesAA,LaskaE,etal.Percentageofheavydrinkingdaysfollowingpsilocybin-assistedpsychotherapyvsplacebo inthetreatmentofadultpatientswithalcoholusedisorder:arandomizedclinical trial.JAMAPsychiatry.2022;79(10):953–62.DOI: 10.1001/jamapsychiatry.2022.2096 PMID:36001306;PMCID: PMC9403854
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Psychedelics
OPEN RESEARCHREPORT
Whatmotivatesspiritualhealth practitionersinpsychedelic-assisted therapy?Aqualitativestudyand implicationsforfacilitatortraining practices
IshanPasricha1 , 2 ,CarolinePeacock1 , 3 ,RomanPalitsky1 , 3 , 4 , JaimeClark-Soles1 , 5 ,JessicaL.Maples-Keller1 , 4 , GeorgeH.Grant1 , 3 ,andDeannaM.Kaplan1 , 2 , 3
1 EmoryCenterforPsychedelicsandSpirituality,EmoryUniversity, Atlanta,GA30329
2 DepartmentofFamilyandPreventiveMedicine,EmoryUniversity SchoolofMedicine,Atlanta,GA30322
3 DepartmentofSpiritualHealth,WoodruffHealthSciencesCenter, EmoryUniversity,Atlanta,GA30329
4 DepartmentofPsychiatry,EmoryUniversitySchoolofMedicine, Atlanta,GA30322
5 PerkinsSchoolofTheology,SouthernMethodistUniversity,Dallas,TX 75205
CorrespondingAuthor: DeannaM.Kaplan,DepartmentofFamilyand PreventiveMedicineandEmoryCenterforPsychedelicsandSpirituality, EmoryUniversitySchoolofMedicine,Atlanta,GA30322,USA. Phone:(404)727-0839.E-mail: deanna.m.kaplan@emory.edu
Psychedelics March2025;1(2):31–39; doi: https://doi.org/10.61373/pp025r.0008
Spiritualhealthpractitioners(SHPs),alsoknownashealthcarechaplains,areincreasinglyinvolvedinfacilitatingpsychedelic-assisted therapiesinclinicaltrialsandcommunitysettings.Althoughthemotivationsoftherapeuticpractitionersareknowntoimpactclinical decision-makingandtreatmentoutcomes,littleresearchhasinvestigatedwhatdrivesSHPstopursuethiswork.Thisqualitativestudyexamined n = 15SHP’s(60%female; MAge = 46.57)whowereinvolved inlegaladministrationofpsychedelic-assistedtherapy.Aninductivedeductivequalitativeanalysisapproachyieldedtwomajorthemes:(1) InitialMotivationforPracticingPAT,and(2)OngoingSourcesofMeaningandFulfillment.TheSHPsinthisstudyoftencitedpersonalexperiencesaskeymotivationsforenteringthisfield,frequentlylinkedto asignificantpersonalencounterwithpsychedelicuse.ThemostcommonOngoingSourcesofMeaningandFulfillmentincludedwitnessinghealinginothersandexperiencingpositivepersonalimpactsfrom facilitatingpsychedelic-assistedcare.Thisarticleaddressesthesubstantialrolethatpersonalpsychedelicexperiencesappeartoplayin SHPs’motivationstopursuethisareaofpractice.Suchexperiences providevaluablefirst-handknowledgeoftheuniquephenomenology ofpsychedelictreatment,althoughtheycanalsopotentiallyintroduce biasesandreduceobjectivity.Trainingandcertificationguidelinesset bytheAssociationforClinicalPastoralEducation(ACPE)mayhelpaddresstheserisksforSHPsthroughheavyemphasisplacedonselfliteracyandreflectivelearningcomponents.Guidedbythesefindings, weintroduceanovelreflectivelearningexercise,aswellasseveralexistingACPElearningcomponentsthatmaysupportpsychedelicfacilitatorsandfacilitators-in-trainingfromanyprofessionalbackground.
Keywords: Chaplaincy,psychedelic-assistedtherapy,psychedelic facilitation,qualitativemethods,spiritualhealth.
Received:7February2025.Revised:31March2025.Accepted:7April2025. Publishedonline:29April2025.
Introduction
Psychedelic-assistedtherapy(PAT)involvestheadministrationofa psychedeliccompound(e.g.,classicpsychedelicssuchaspsilocybinorlysergicaciddiethylamideaswellasMDMAandothercompounds)together withtherapeuticsupport(1–3).EvidenceforthebenefitsofPATforaddressingseveraldifficult-to-treatconditions(PTSD,treatment-resistant depression,demoralizationamongcancerpatients)ismounting(4–6), andcorrespondingly,theutilizationofPATinterventionsisgrowing.In theUnitedStates,legalframeworksforsuperviseduseofpsilocybinhave beenenactedinOregonandColorado(7, 8),althoughmostpsychedelic compoundsremainfederallyillegal.Recentstate-levellegalchangesand thegrowingmentalhealthcrisishavesparkedburgeoningresearchon thetherapeuticuseofvariouspsychedeliccompounds,aswellasarapid expansionofcertificationandtrainingprogramsforPATfacilitation.
Amongevidence-basedpsychosocialtreatments,adistinctivefeature ofPATisthatitissimultaneouslyapharmacologicalintervention and aclinician-facilitatedtherapy(9).PATfacilitatorsthereforeplayakey roleintheexperiencethatclients’haveduringpreparationfortheir psychedelicdosingsession,duringthedosingsessionitself,andinintegrationoftheexperienceaftertheacuteeffectsofthepsychedelic agentshavewornoff(10, 11).SeveralattributesofPATmakeitaunique treatmenttofacilitate,comparedwithexistingevidence-basedtherapies.Theseincludetheintensephenomenologyofapsychedelicexperience(whichtypicallyinvolvesmarkedperceptual,affective,andcognitivechanges,includinghallucinations);thedurationoftheseexperiences (whichcanlast4–48h);andtheirimmediateandenduringsequelaewhich ofteninvolvechangesinthepatients’worldview(9, 12).ResearchcharacterizingthebesttherapeuticpracticesforPATfacilitationandthetrainingcomponentsthatadequatelypreparefacilitatorstoimplementthem is,therefore,importantfortheoptimizationofPAT.Todate,verylittleresearchhascharacterizedtheattributesofPATfacilitatorsorinvestigated theroleoffacilitatorattributesinprovidingeffectivecare(2).
Spiritualhealthpractitioners(SHPs;i.e.,healthcarechaplains)have increasinglyplayedrolesinPATfacilitationinclinicaltrialsandcommunitypracticecontexts.SHPsarehealthcareprofessionalswhoareemployedinapproximatelytwo-thirdsofallhospitalsintheUnitedStates (13, 14)andtrainedtoworkonintegratedcareteamstorecognizeand respondtoemotional,psychosocial,spiritual,religious,existential,and moralconcerns(15, 16).SHPstraininginvolves1600hoursofclinical traininginanaccredited,year-longclinicalresidency,andadditionalprofessionalcertificationrequirementsincludingpublishedscholarshipand committeeappearances(17).GiventheprevalenceofspiritualandexistentialthemesreportedbythosewhohaveundergonePAT(18, 19),and thepotentialmediatingrolethattheseexperiencesmayplayinPATbenefits(19, 20),thetrainingandprofessionalexpertiseofSHPsisanatural fitforPAT.SHPsareideallyequippedtoengagethespiritualdimensionof biopsychosocial-spiritualmodelsofcare(21, 22)andareuniquelyqualifiedtorespondtospirituallyimpactfulexperiencesthatmayariseforpatients,includingspiritualdistress(19).Inapriorqualitativestudy,these authorsinvestigatedtherolesthatSHPsplayinPATandthecompetencies theyidentifiedwithasmembersofPATtreatmentteams.Resultsindicatedthattrainingandformation(theongoinginternalandcommunally baseddevelopmentofthepersonasaspiritualcareproviderorclergyperson)assistinSHPsbeingabletoholdspace,accompanypersonsinnonordinarystatesofconsciousness,andrespondtospiritual,existential,religiousandtheologicalmaterialthatemergesinPAT.SHPsalsodiscussed howtheycontributetoPATteamsbynoticingandattendingtopowerdynamicsassociatedwithidentitycharacteristicsthatmayconfervulnerabilitiesforpatients(23).
Thepresentstudyismotivatedbyrecentcallstooptimizethe“psychotherapy”componentsofPAT(9, 24–26),aswellaspriorworkindicatingthatclinicians’underlyingmotivationsforpracticeimpacttherapeuticchoicesmadeduringtreatmentand,correspondingly,treatment
outcomes(27).Thisresearchisanovel,secondaryanalysisofqualitativeinterviewspreviouslycompletedwithSHPswhohaveworkedonPAT treatmentteamsinlegalsettings(forfurtherdetailontheprimarystudy, seeref. 23).Thecurrentsecondaryanalysisfocusedonidentifyingthe motivationsthatdrewSHPstothisuniquescopeofpracticeandthefactorsthatsustaintheirmotivationtocontinuetoprovidethismodalityof care.UnderstandingthebackgroundsandmotivationsthatSHPsbringto treatmentteamssupplementsagrowingresearchbaseontheattributes ofPATfacilitatorsandthefacilitator-levelfactorsthatmaycontributeto effectivecare.Methodsaredetailedattheendofthisarticle,afterthe Discussion section.
Results
Twooverarchingthemeswereidentifiedinthisanalysis:“InitialMotivationforPracticingPAT,”whichincludeddescriptionsofwhatinitially drewparticipantsintothisfieldofwork,and“OngoingSourcesofMeaningandFulfillment,”whichincludeddescriptionsofwhatprovidedSHPs withasenseofongoingmeaningorfulfillmentthatmotivatestheirwork presently.InitialMotivationforPracticingPATwasfoundtohavefive subthemes:(1)experiencewithtrauma/adversityandhealingthrough psychedelics,(2)psychedeliccareasacomponentofone’sspiritualvocationalpath,(3)desiretoalleviatesufferinginothers,(4)unplanned exposuretothefield,and(5)multilayeredmotivation.OngoingSourcesof MeaningandFulfillmenthadfoursubthemes:(1)appreciationforthepatternscommonlyassociatedwithpsychedelicexperiences,(2)witnessing thealleviationofsuffering,(3)mutualityofthefacilitationexperience, and(4)personalimpactsoffacilitatingPAT.
Theme1:InitialMotivationforPracticingPAT Subtheme:PersonalExperienceofHealingThroughPsychedelics
ThemostfrequentlyendorsedsubthemeofInitialMotivationforPracticingPATwasparticipants’ownexperienceswithhealingexperienced throughpsychedelics.Someparticipantsspokeof“healing”inbroad terms(i.e.,notassociatedwithaspecifiedailment),whileothersdescribedmorespecifichealingfromphysicalpain,illness,andortraumatic experience.Tenofthe15participantsspokeofthistheme.Asanillustrativeexample,oneparticipantdescribedexperiencingphysicalpainfroma bicycleaccident,eventuallyleadingthemtoseekPAT,whichtheyfoundto providesurprisingrelieffrompainthathadnotbeenresponsivetophysicaltherapy.Inresponsetotheprompt,“Whatledyoutothiswork?”,this individualresponded:
“Well,inoneword,pain…Ihadabikeaccidentafewyearsagoandmultiple breaks.Iwasdealingwithpainanddoingrigorousphysicaltherapy,witha greattherapistforlikeayear.Iwasonhertable,we’redoingdryneedling andmyshoulders,whichiswhereIseemtoholdalot…andfinally,mytherapistsaid,youknowthere’snothingstructurallyproblematicaboutyourbody anymore.Ithinkthatyouhavetrauma.AndI’veworkedwithalotof–Imean, I’vebeenthechaplainatadomesticviolenceshelterandinatrauma1hospital.So,I’mlike,“No.”Outofrespect,IwouldsayI’vehadhardthingshappen tome,butnottrauma.Well,mywholedefinitionofwhatthatmeanshas beencompletelyundone.AndIwenttoseesomeonewhoofferedsomatic therapyand…amplifiedwithpsychedelics,andIbeganaprocessofmyown healing.Andatfirst,IthoughtIwasjustcarryingpain.Ifeltpaininmybody. Ifeltpaininmyheart.Ifeltheavy.Ijustfeltweighted.Andthatwasmybeginning–myownhealing.Istartedtoexperiencethebenefitofwhatwas happening,andmywholeunderstandingopeneduptothefactthatmynervoussystemheldpain,heldstories,heldtraumaticexperiencesevenvicariously.Andthroughthiswork,Iwasabletoreleaseit.Istartedtofeelbetter ineveryway.”
Similarly,anotherparticipantdescribedpersonalexperienceofthe benefitsofpsychedelicsinthemanagementoftheirchronicillnessasmotivatingtheirentrytoworkinthefield:
“SoIhavechronicillness.ChronicLymedisease,Ialsohaveaformofmusculardystrophy,andinmyhealingjourney,Iwasjustintuitivelydrawn.I’d heardaboutatherapistusingspecificallyMDMAandpsilocybinandjust knewthat’swhatIneeded,andithasbeenanincrediblehealingsupport onalllevelsforme.Andso,afterseveralyearsofdoingthatworkformyself andexperiencingincrediblebenefits,IdecidedthatIwantedtogointothe field.”
Otherparticipantsspokeaboutpsychedelicexperiencesthatthey foundtobepersonallytransformative:
“ThebottomlineisthatIhadmyownexperienceswithayahuasca,anditwas deeplyhealingformeinwaysthatIjustcouldn’tevenimagine,andIkindof hadasenseandafeelingthatitwasgoingtobepartofmylifeinsomeway, butIdidn’treallyknowhow.”
Subtheme:AComponentofOne’sSpiritual-VocationalPath
Otherparticipantsdescribedimpactfulspiritualexperiencesfrom psychedelicusethatguidedtheirvocationalpath.Onepersondescribed howanexperiencewithpsychedelicsbecamecentraltotheirspiritual life:
“Twenty-fiveyearsago,IhadtheexperienceofworkingwithbothMDMA andpsilocybininmoreceremonialandhealingcapacities,andonewaswith anativeAmericanChicanomanwhostudiedinMexico,whoalsowascomingoutoftheMazatectraditioninsouthernMexico.Anditwasprofoundfor me…Itwasthethingthathelpedmefocusonmyspiritualpath,whichhas beenBuddhism,formanyyears.IwasstudyingandpracticingBuddhism, workingformanyyearsinend-of-lifecare,spiritualcare,andpalliativecare. Andthenkindofcamebackaroundfullcircletothemedicineagainformy ownhealing.”
Asillustratedbytheabovequote,thisthemesometimesco-occurred withpsychedelicexperiencesthatwerealsodescribedas“healing.”
Subtheme:DesiretoAlleviateSufferinginOthers
Severalparticipantsexpressedadesiretoalleviatethesufferinginothersasaprimarymotivationforenteringthefieldofpsychedeliccare.For example,oneparticipantdescribedthechallengingemotionalexperience ofwitnessingtheirgrandmother’scancerjourneyandsubsequentdeath. Theirfamiliaritywithpsychedelicshelpedthemunderstandthatdifferent experienceswerepossibleforpeoplewhoweresuffering.Theyshared:
“Shewasathome,noteventalkingaboutdyinguntiltwodaysbeforeshe diedandthenwenttothehospitalanddiedtheretwodayslaterandwas fullyalerttothemomentthatherspiritleftherbody,eyeswideopen,sitting upgrippingourhand,justtotallyfightingthisthing.Andthatexperiencereallyiswhatbroughtmeintochaplaincy-experiencingthefeelinglikeIknow there’sabetterwaythatthiscanhappen,andIwanttofindoutwhatthat is.…Itdoesn’tneedtobethatway,butitstillisforsomanypeople…Sofor me,thetoolofpsychedeliccareallowsustosupportpeopleintheirtransformativeprocessatthetimeintheirlivesthatthey’rebeingcalledtoinstead ofwaitingforlifetohappentothemand,likecrossingourfingersthatit’ll begood.Sothat’showIholdit-notinanywaybelievingthatit’sacureallor thatmagicallypeoplearetransformedfromjustoneexperience,butsome peopleare.Andotherpeopleneedahandtoholdforalongtime.Theyneed aparticularformofcareinanexpandedtimelinethatallowsthemtokindof workthroughonepieceatatime,dependingonhowmuchthey’recarrying.”
Subtheme:UnplannedExposuretotheField
SomeparticipantsspokeofanunplannedencounterwiththefieldofPAT thatsparkedtheirinterestinenteringthisareaofpractice.Forsome, theseexperiencescamefromtheirpersonallives;forothers,theywere unexpectedprofessionalexperiences.Oneparticipantdescribedworking asachaplainforaninstitutionthatinitiatedaclinicaltrialofPAT.Inthis context,theywereinvitedtoparticipateinalegalpsychedelicexperience toprepareforbeingafacilitator.Theysharedthefollowing:
“IwouldconsidermyselfasomewhatconservativeevangelicalChristian. Andcertainlythoserootsdon’tnecessarilyoverlapwellwiththehistoryof psychedelicsubstances,whetheritbeinthecontextofastudyorjusttheculturalrevolutionthatweexperiencedinthe50sand60sandthedrugwars inthe70sand80sandkindofwherewearetoday.AndsoIwasreallykind ofuncomfortable,tobehonest.Ididn’tknowifIhadaplaceinthisandI didn’tknowifmorallyIcouldparticipateinsuchastudy,sothisreallytook methroughasoul-searchingprocessonalotoflevels,notthatI’mcompletelydoneprocessingorcompletelydonewiththejourney…Partofthis journeythathasdrawnmeisnotjustintheprocessofhowdoIasachaplain createasafespaceandholdspaceforpeopleundermedicationandtopreparethemandtohelpthemintegratetheseprocesses,butIthinkchaplains alsobringusaparticularangleonthepracticeofmedicineandthestudies thatwehavetooffertothebiggerconversationofwhatexactlyarewedoing withpsychedelicsandwhatexactlyarewemeasuring.”
Anotherparticipantsharedaboutasituationalopportunitytoparticipateinaclinicaltrialthemselves.Theyhadanimpactfulspiritualexperiencewhichultimatelyledthemintotheworkoffacilitation:
“Myintroductiontothisfieldoccurredin(countryelided)whenIwasa23year-oldtheologicalstudent.AndIvolunteeredtohelptestsomenewdrug Ihadneverheardof…derivativesofpsilocybintheywerestudying.Andso,I laythere,openandtrustingandcurious.Andthen,thisincrediblybeautiful transcendentalstateofconsciousnessopenedupinmymind.AndIwasone verystarstruckyoungtheologicalstudent.Andinaway,Icouldsaymylife hasneverbeenthesamesince…inapositiveway…Thisincrediblybeautiful transcendentalstateofconsciousnessopenedupinmymind.InMethodism, there’sanemphasisonconversionexperiences,especiallyinearlyadolescence–givingyourlifetoJesusandbeingsavedinanexperientialsenseof belonging…Ihadalwayshadaprofoundappreciationfornature.ButIhad nevercomeclosetoexperiencingwhathappenedinthatfirstpsilocybinexperience.It’sbeyondwords-basicallyaunity,astateofconsciousness,inner beauty,andmeaningthatfeltmorerealandfundamentalthanthestateof consciousnesswe’rein.Likeahomecomingandawakening.Aremembering ofwhatis.Youknowarealrediscoveryoftheeternaldimensionofconsciousness.”
SeveralparticipantsdescribedexposuretoPATthrougheducational orcontinuingeducationprograms.Forexample,oneparticipantspokeof hearingaresearchertalkaboutthesuitabilityofchaplaincyskillsinPAT, whichwasaninfluencethatledtotheirchoiceofmakingthisafocusof theirscopeofpractice.
“WhenIwasgettingmymastersinpsychologyandreligionat(seminary nameelided)in(cityelided),IwasinthePsychologyandReligionprogram, andwehad[nameelided],who’sdoingthepsilocybinresearchinendoflife contextat(institutionelided),hecameintotalktoaspiringchaplainsatthe seminaryandagainthatjustgotmereallyexcitedinthepossibilityofkindof utilizingmybackgroundandspiritualcare…soIwouldseethosewerekind ofmyintroductionstothefield,sothatwhenopportunitiescameuplater through[companyelided]Iknewthatmyskillswererelevant,Iwasexcited aboutthefield.Ihadalotofjustkindofintellectualknowledgeaboutthe fieldthat’sreallykindofhowImadethetransitionfromchaplaincytocheck itout.”
Subtheme:MultilayeredMotivations
Notably,formostparticipants,motivationstoenterthefieldweremultifaceted.Ratesofco-occurrencebetweentheabovecategorieswere high,withnearlyallparticipantsendorsingmorethanoneoftheabove themes.Whilesomeparticipantswereprimarilydrivenbyonefactor, othersdescribedmoreblendedmotivations.Forexample,oneparticipantsuccinctlydescribedamotivationthatincludedthepromisingresultsofrecentresearch,thehealingtheyhadpersonallyexperiencedfrom psychedelics,andadesiretohelpothersexperiencesimilarhealing.This participantshared:
"Havingwitnessedalotofsufferingfromtraumainpeoplewhoweren’treallyfindingmuchreliefandsupport.Then,intermsofend-of-lifecare… someofthepsilocybinstudiesthathaveshownthatpeoplearereallyable toworkthroughexistentialdistressandotherchallengesoftheendoflife–thatalsoconnectedwithmyvocationalpath.Andthen,onapersonalnote, havinggonethroughsomechildhoodtraumamyself,Ifoundpsychedelic therapytobereallybeneficialformyself.ThosearethemainreasonsthatI startedtolookatthis.Andthenhadsomeopportunitiestobecomeinvolved intheresearch,whichI’mgratefulfor.”
ThisparticipantcametoPATasanareaofpracticeafterencounteringexistingresearchonpsychedelicsandobservingtheirownpositivepsychedelicexperiences.Otherparticipantsshareddifferentconstellationsofprecipitatingfactors.Forexample,oneparticipantidentified challengingordifficultexperienceswithpsychedelics:
"Ithenhadanexperiencethatwasvery,verydifficult,verypainful,verydisorientingduringapsychedelicjourney…thatessentiallysidelinedmeforthe nextdecade.Itscaredmeverybadly.IbelievedthatIwassortofmanifesting somekindofmentalillnessthatIwasgoingtolosemymind–thatmysense ofselfwasgoingtofragment.Thatneverhappenedbutwhatdidhappenis thatoneparticularinstancemanifestedwhatInowknowtobeanxietythat Ihadtodealwithforyearsafterthat.AndthatIstilldealwith.Becauseof thatanxiety,Iwasonthesidelines.Mycommunityandmyfriendscontinued
toexperiment,andIthereforetookonmoreorlessinadvertentlytheroleof babysitteroraguide.”
Anotherparticipantdescribedanexperiencewithpsychedelicsearly inlifethatledtoatransformativespiritualawakening,leadingtheminto chaplaincy.Muchlater,anopportunityarosetotrainasafacilitator.
“Ididalotofpsychedelicsinmyteenageyears.Ihadaverypowerfulexperiencethatwasmorespirituallybasedandhadaverysolidintentionwhen Iwas19.Andthatchangedthecourseofmylifeandhelpedmeexperiencesomethingmuchdeeper–amuchdeeperreality,ifthatmakessense, andIalsoexperiencedalotarounddeathanddying,andfromthatexperience,Iwascalledfirst,intoaspiritualpaththatledmeintomeditation thatthenkindoftookmeintothecallingofordainedministry,aswellas chaplaincywork,specificallywiththosewhoaredying.AndthenIstopped psychedelics;Ididn’tdopsychedelicsfor20years,actually,afterthatreallypowerfulexperience,andIwasapproachingnon-ordinarystatesofconsciousnessmorethroughmeditation,contemplativeprayer,thingslikelong extendedretreats.ButthenIhadanopportunitytogothroughthe(programnameelided)inthefirstcohort,asitwasapilotproject.So,Itook thatopportunity,andthat’skindofwhatthenledmetobeginfacilitating psychedelics.”
Theme2:OngoingSourcesofMeaningandFulfillment
Subtheme:AppreciationforthePatternsCommonlyAssociated withPsychedelicExperiences
Severalparticipantsdescribedderivingongoingappreciationandfulfillmentfromwitnessingcertainexperiencesorthemesthatcommonlyaccompanypsychedelicexperience.Forexample,oneparticipantdescribed aglobalsenseofconnectednessexperiencedbymanywhohavetaken psychedelics:
“Seeingthesimilarexperiencesofparticipantsinstudies…creatingnew storiesbutalsocomingintoasenseofbeingpartofsomethinglarger… thattomeisspiritualhoweveranyonedefinestheirspiritualjourneyor theirreligiouspractices…thefeelingofbeingpartofsomethinglargerthan ourselves.”
Similarly,inanotherparticipant’swords:
“Somethingthatjustseemstoconsistentlyemergewithpsychedelictherapiesandthatseemstobeabeneficialemergenceforthepeoplethatare experiencingit…toseethispatternagainandagainandagainfeelsvery spiritualandveryaffirming.Idon’thavetolabelitorknowexactlywhatit is,orputABCliststoit,butthatthereissomethingthatconnectsusall,connectsustotheplanet,connectsus…whetherwecallthatGod’sspirit,the universe,humanity,earth,whatever,…it’saveryspiritualexperienceforme towitnessagainandagainthesesamepatterns,thesesameexperiencesfor differentpeople.”
WhenSHPsspokeofthepatternsthatemergedacrossfacilitatingpsychedelicexperiences,wordssuchas“connectedness”cameup frequently.SHPsdescribedwitnessingtheseexperiencesaspersonally meaningful,inspiring,andanimportantcontributingfactortotheirmotivationtocontinueinthisfield.
Subtheme:WitnessingtheAlleviationofSuffering ParticipantsalsodescribedthesatisfactiontheyexperiencedinwitnessingthealleviationofsufferingduringPAT.Thisthemecommonlycooccurredwiththe“desiretoalleviatesuffering”subthemeofTheme1 (InitialMotivationforPracticingPAT),aswitnessingthealleviationofsufferingcreatedongoingmotivationforpersonsinitiallydrawntoPATfacilitationwiththisaim.Severalparticipantsdescribedderivingsatisfaction fromseeingothershealandgrowthroughpsychedelicuse.InoneSHP’s words:
“ThedeepestplacewhereIaccessmeaningisthroughbeingofservicetothe healingprocessofothers.Thatcomesthroughinthisworkbecauseit’svery clientcentered.It’sveryfocusedonredirectingindividualstotheirowninner wisdom,innerspiritualvoice…Itfeelslikethatisthegreaterpurpose…It givesmemeaning–thefeelingofbeinginalignmentwithlife’spathhappens whenIamholdingspaceforothersactuallytositwithintheirrelationshipto theirowninnerguide…It’sbeingofservice.It’salsoassistingfolksandmovingintowhatIwouldcalltheirspiritualalignment.Whetherthat’sreligious ornot,orwhetherit’satheist…that’swhatgivesmeaning.”
Otherparticipantsdescribedtherewardingnatureofwitnessingimprovementforclientswhohavehadlimitedsuccesswithotherformsof treatment:
“Alotofthefolksthatarecomingtoourtreatmentmodel,inparticular,have beendealingwithtreatment-resistantdepression,anxiety,orPTSD.They’ve beenhavingreallyseveresymptomsorsymptomsthattheyjusthaven’tbeen abletogetaholdofforareallylongtime.Andjustreallyseeingthisrapidly actingtransformationthatbeginstohappeninjustafewsessions.Ithink it’sjustreallyalwaysexcitingforme…Seeingpeople’shardworkcometo fruition.…beingabletousemychaplainskillsandtoacknowledgehowdifficultitistoopenupatthatmoment.SoIthinkthat’sanotherthingthat’s reallyfulfillingformeisthatalotofpeoplecomeintotreatment,maybealreadyhavingpartiallygivenuporseeingthisistheirlastresort,sotospeak. Sojustbeingabletogrowthatkindofbreakthroughtreatmentforpeople,I think,isexcitingaswell.”
Similarly,anotherparticipantdescribedhopefulnessforPATin addressingconcernstypicallycharacterizedas“subclinical,”suchas burnout.Theyshared:
“Ithinkthere’shopeinit.Othertherapieshaven’tworked.Otherthings haven’tspokentopeople.There’stoomuchthat’sunidentifiedlivinginpeople.Thatyouknowit’siftheyhadaccesstoitorknewwhattodowithit,they wouldhavedoneitalready,itwouldhavebeendealtwith,youknowpeople arenotlazyorstupid,andsotheycan’tgettoit…Iworkedthroughthewhole COVIDintheICU.Welost80nurseswhohaveresignedfromthatunitoverthe courseofthepandemic.AndI’mstilltalkingtothemandhearingthemsay, ‘I’mdeadinside.’That’saquote–‘Iamdead.’We’renotgoingtotalkyouout ofthat.Idon’tthinkwe’regonnabubblebathyououtofthat.”
Participantsalsodiscussedfindingmeaninginhelpingpeopleexperienceaconnectiontothesacred,coupledwiththecapacityofPATtotreat mentalhealthconditions:
“Iwouldn’tbedoingitifitdidn’tgivemesomuchmeaning.Psychedelicsfor meareanextremelypowerfultoolforpeopletoexperiencethesacred,the divineGod,Imeanwhateverlanguage…weknowthat’skindofineffable… alldifferentwordstodescribethat.Also,fromamentalhealthperspective, thedata,thestatisticsthatarecomingout,andtheresultsthatIseeinthe participantsthatIfacilitatecomparedtomoretraditionaltoolsinthementalhealthworldliketalktherapyandpharmaceuticaldrugs…justsuchan amazingsuccessratewiththeuseofpsychedelicsifdonecorrectly,Ireally, reallystronglybelievethat.”
Subtheme:MutualityoftheFacilitationExperience Someparticipantsspokeaboutfindingmeaninginthemutualityofthe facilitationexperience.Participantswhohadtheirown,personallyimpactfullivedexperienceswithpsychedelicsoftendescribedanappreciationfortheaspectsofsharedexperiencethataccompaniedfacilitatingpsychedelicexperiencesforothers.Forexample,asoneparticipant putit:
“…seeingpeopleheal–likereallyseeingpeopleheal–issosatisfying.To havethatandmyownexperience,knowingwhereIaminmyjourneybecause ofthiswork,andIwouldn’tbeherewithoutthisworkandthewaythatIam today,andIseethatitchangespeople’slives.”
Anotherparticipantspokeofasimilarexperienceofmutualityinthe contextofhavingachronicillness:
“AsI’veworkedwithmychronicillnessandasI’vereframedmynarrative,it makesmefeellessisolated,lessalone,partofsociety,partoftheworld.Even ifI’minpain,evenifI’mstillnotfeelingwell,Icanstillbepartofthislarger fabricoftheworldandacceptmylimitations…Psychedelicshavehelped withsymptoms,helpedhealsomeofmychronicillnessesandhelpedme stepmoredeeplyintorelationshipswithothersandwiththiswholeecosystemthatwe’repartofandfeelmoreinconnectionwiththedivine.There’s aplanformylife.There’sareasonIcameinwiththechallenges…ButI’ve gotgroundthatIcansupportotherswithnowbecauseIfoundthisground withinmyself…psychedelictherapiescansupportusalltorecognizethat weareallconnected…canhelpusfindgroundandthenthereforekindof beabletomovefromthatground.EventhoughImaystillhavesymptoms, Imaystillnotfeelgoodsomedays.Istillhavepain,butIcanstillstepinto theworldwithallofmyselfandfindaplacethat’smeaningfulformeand allowsmetohavejoy.”
Notallparticipantsdescribedmutualityintermsofhealing.Otherparticipantsspokeofaspiritualprocessthatbeganwiththeirownexperience oftakingpsychedelicsandisnowenrichedbyfacilitatingpsychedelicexperiencesforothers.Inanotherparticipant’swords:
“Personally,sittingwiththemedicinerequiresadeepcommitmenttomy ownspiritualdevelopment,andmyowninnerhealingwork.Thathasbeen, insomeways,amplifiedand,insomeways,reallydoescometotheforefronttoseeandtobeasclearaspossibleforothers.Toofferthatservice workingwithinthestructureswithinmylifehasbeenextremelyimportant. Encounteringallmybiases,healingmyownstuff,anddoingtheinnerwork. ThemoreIdothat,themoreclarityIhaveandthelessofmyownstuffIbring intotheroomwithothers…Toholdspaceforfolkshavingmysticalexperiences,there’salsobeenachangewithinmetoaccessthosestateswherethe openingisstabilizedbetweensessions.Andalotofmydevelopmentleans intovariousspirituallineagesthatarenotnecessarilyusingmedicinework butareencouragingandareusingancientpracticestoestablishthosesame openingsbutmaybeaccesstheminmoreofastableday-to-dayexpanded way.So,twofold:it’sbeenheavy-dutyspiritualpracticethathasamplifiedit inmylifeandourwork.Ithinkit’stwosidesofthesamecoin.”
Inadditiontomutualitywiththeirclients,participantsalsospoketo impactfulexperiencesofmutualitywithothermembersofclients’care teams.Forexample:
“Personalexperiencewithmedicineworkingintherapeuticandceremonial contextsandhowprofoundlythathasimpactedme,myspirituality,myhealing,mysenseofconnectionintheworld…Imean,relativetootherwork contexts,thisteamhasfeltlikeIhavearealsenseofkinshipandthatwe areinalignmentwiththemodelinamoreholisticapproach.Yeah,andjust howfrommyownexperienceandfromwhatIhearofothershow,potentially, notinevitably,butpotentiallysupportivemedicineworkcanbefornotonly healing,particularlyhealingaroundtrauma,butspiritualgrowthandselfawarenessofconnectionintheworld.”
Subtheme:PersonalImpactsofFacilitatingPAT Thissubthemedescribedexperiencingpersonalimpactfromengaging inPATthatsustainsparticipants’vocationalmotivation.Althoughthis sometimesincludedthepersonalimpactsofthepriortheme,mutuality,participantsalsospoketoseveralpersonalimpactsindependentof sharedexperiences.Oneparticipantdescribedbeinginspiredbythecommonalitiesinpsychedelicexperiencesthattheyhavewitnessedoveryears offacilitation:
“I’vecertainlybeenreinforcedinmyviewoftheworld,inmyspirituallife,in mypsychologicaltheory.I’vehadthegreathonorofbeingwithseveralhundredpeopleintheirpsychedelicsessions,andtome,that’salotofevidence. Peoplefromdifferentraces,differenteducationallevels,differentcareers, differentphysicalhealthsituationsandthehumanmindseemstofunction prettymuchthesamewithallofthem.Andthat’sinspiring…”
Anotherparticipantspokeofthepersonalimpactofworkingina group/peersupportmodelandthepowerofwatchinggroupmembers buildtrustingrelationshipswithoneanother:
“Thisgroupmodelismoreaboutpeersupport,anditismoreaboutcultivatingtoolsforpresence,forgroundedspaciousawareness,forwhatitisthatis emergingwithinusthatwecanaccept,bewith,andpossiblyallowforsome processingsimplybybeingpresenttoitwithcompassion,andthenpeople beingwitnessedbythegroupandfeelingthesenseofsupportandsafety andtrustthatideallyisdeepenedovertheweeksfromthegroup.Seeing peoplewhohave,inthiscase,significanttraumahistories,someofwhom havebeenreallyisolatedeitherforvariousreasons,sociallyorbecauseof thedegreeoftheiranxiety(notcomfortableleavingtheirhouse,especially inthecontextofthelastfewyears)eveninashortperiodoftime,feelinga senseofbondkinship,safety.Feeling‘I’mnotalone’witheachother.Being abletorelaxandfeelinganaturalheartfulness,joyfulness,compassion,and innerhealingwisdomemergewithinthatspace.Thattomeisbeautifulto witness.”
Anotherparticipantdescribedfulfillmentintheintimacyof psychedelic-assistedcare:
“Iwouldsaythingshavekindofchangedmeaboutthiswork….Ithink insomeways,likethepsychiatriccontext,insomeways,likethehospice context,it’saveryintimatesetting.Themedicine,insomeways,really
helpspeopletaketheirdefensesdownandbemoreengagedwiththework, maybetostaypresentwithmoredifficultactivatingmaterial.Ithinkthe sessionsarereallyintimate,andIthinkthere’ssometransformationjust inseeingthiskindofspiritualrevelationsthatpeoplehave.Ithinkjustbeingabletowitnessthat,beingabletoobservethat,supportthat.Ithink itreallyjustopensmyeyestothecomplexityofhumansinourspiritual lives.”
Discussion
AstheevidencebaseforPATscontinuestoexpand,optimizingthefacilitationoftheseuniquetreatmentshasbecomeincreasinglyimportant (25).Inthecontextofthespiritualandexistentialexperiencesthatoften accompanypsychedelicexperiences,SHPsareincreasinglyrecognizedas playingvitalrolesonPATcareteams(19, 23).Understandingtheroles thatSHPscanplayonPATcareteams,andhowtrainingforPATfacilitationcanbeoptimized,requiresanunderstandingofthemotivationsthat drawSHPstoPATfacilitationinthefirstplace,aswellasthefactorsthat sustaintheirongoingworkinthisfield.Themajorthemesidentifiedin thisresearchhighlightthedeeplypersonalnatureofPATfacilitationfor theSHPsinthisstudy,afindingwhichhasvaluableimplicationsforPAT facilitationtraining.
ThisstudyfoundthatpersonalpsychedelicusewasastrongmotivatorforSHPspracticingPAT—afindingconsistentwitharecentinvestigationofpsychedelicuseamongtherapistsfromaphase2clinicaltrialofpsilocybinformajordepressivedisorderthatfoundthatthe majorityoftherapistshadexperiencewithatleastonepsychedelicsubstance,mostcommonlypsilocybin(25).ManySHPsinourstudydescribed theirpsychedelicexperiencesas“healing”;othersdescribedtheirexperiencesasspiritually“transformative,”asopeningnewspiritualawareness,enhancingtheirexistingsenseofspirituality,orincreasingtheir understandingoftheirplaceintheworld.Notably,SHPspredominantly describedpersonalbenefitsassociatedwiththeirpastpsychedelicexperiences,althoughpsychedelicexperiencesarenotexclusivelyexperiencedasbeneficialandaresometimesexperiencedaschallenginginthe generalpopulation(28, 29).
WithrespecttofactorsthatprovideSHPswithongoingsources offulfillmentandmotivationforthiswork,witnessingothersexperiencehealingwasdescribedasparticularlysignificant.Manyparticipantsinthisstudyreportedderivingadeepsenseofmeaningfrom themutualityoftheexperience—thatis,guidingsomeoneelsethrough anexperiencethattheyhadfoundtobesopowerfulandpersonally impactful.Manyparticipantsalsospoketointerconnectednessasa sustainingfactor.Interconnectednesswassometimesdescribedasexperiencedwithclients,sometimesdescribedasexperiencedwithother membersofaPATcareteam,andsometimesdescribedasdrawing fromrepeatedwitnessingofthemesthatcommonlyemergeduringa psychedelicexperience.
Thesefindingsarealignedwithpriorresearchonthemotivationsthat drawpractitionerstopsychologicalhealingprofessionsmorebroadly. Studiesexaminingthemotivationsofmentalhealthproviders(includingtherapists,psychologists,andsocialworkers)havefoundthattherapistsfrequentlydescribepersonalexperiencesofadversityandhealingas significantfactorsintheirmotivationfortheirvocation.Specifically,personaladversities,livedexperiencesofsocialandculturalmarginalization, andone’sownexperienceofreceivingtherapyarecommonmotivatorsfor vocation(27, 30, 31).ThelimitedexistingliteraturecharacterizinggeneralvocationalmotivationsofSHPsfinds,similarly,thatmanycometothe professionwithahistoryofpersonaltraumaandadversityintheirfamiliesandcommunities(32, 33).SHPsarealsolikelytocitedisillusionment withreligiousinstitutionsasamotivatorforworkinginchaplaincy(33). Havinglivedexperiencewithsymptomsandexperiencesreportedbypatientshasbeennotedinthepsychotherapeuticliteraturetohavebothadvantagesanddrawbacks.Ithasbeensuggestedthatpersonalexperiences ofadversitymayconferempathyandanenhancedcapacitytounderstand humancomplexities(33),leadingtoagreatercapacityforsittingwith othersintimesofdistress(24, 34).Conversely,personalexperiencescan increasetheriskofinaccurateprojectionofone’sownexperienceontothe patient(24)andmayinterferewithobjectivityinassessmentandtreatmentplanning(35).
Thequestionofwhetherpersonalpsychedelicexperienceshouldbe aprerequisiteforprovidingpsychedelicfacilitationremainsoneofthe mostdebatedtopicsinthefieldofPATfacilitationtraining(24).This studyaddsanadditionaldatapointtoanaccumulatingfindingthat,much likementalandspiritualhealthprofessionalswhoaremotivatedbytheir ownexperiencesofadversityandhealing,psychedelicfacilitatorsarefrequentlymotivatedbypersonalexperienceswithpsychedelicuse.However,ourfindingsalsoraisethepossibilitythatfirsthandpsychedelic experiencemaynot,initself,leadtomoreeffectivecare.Becausepersonalpsychedelicexperienceswerefrequentlydescribedaskeysources ofmotivationtoprovidethiskindofcare,itmaybethatmotivation— ratherthantheexperienceitself—isamoreimmediateandinfluential factorinfacilitatingeffectivetherapy.Whilenoresearchtodatehasexaminedwhetherfacilitatorswithpriorpsychedelicexperiencearemore efficacious,wesuggestthat,evenifsuchanassociationwerefound,it couldbeattributabletoincreasedmotivationratherthananyinherent benefitofthepsychedelicexperience(orotherencounterswithnonordinarystatesofconsciousness)itself.Giventhis,werecommendthat PATfacilitationtrainingprogramsacknowledgepersonalpsychedelicuse asapotentialmotivationalfactorandexplicitlyaddressthisintraining.Regardlessofwhetherprogramschoosetoofferpsychedelicexperiencestotrainees,itisessentialfortraineestorecognizeandthoughtfullyengagewithpriorpsychedelicexperiencesthatarebroughtinto training.
WhentheProfessionalisPersonal:Implicationsfor PATFacilitationTraining
ResultsofthisresearchfoundthatformostSHPs,workinginthefield ofPATisdeeplypersonal.Manyreportedexperiencingtheirowntransformationandhealingthroughpsychedelicuseandnowseektooffer otherssupportthroughsimilarmethods.Ononehand,thislevelofpersonalexperiencecanbebeneficial:experientialknowledgemayequip SHPstoskillfullyrespondtotheuniquephenomenologyassociatedwith psychedelicagents(24, 36).Afacilitator’slivedexperiencewithandbeliefintheeffectivenessofpsychedelicsmayalsoconstitutecommonfactorsoftreatmenteffectiveness.Psychotherapyresearchoncommonfactorshasfoundthattherapistempathyaloneexertslargeeffectsizeson treatmentoutcomes(d > 0.8),andexpectationshavesmallerbutstill significanteffects(d > 0.2),independentofanyspecificcomponentsof treatment(34).
Conversely,personalexperiencescanalsointroducebiasesthat hindertheabilitytoprovideobjectivecare.Facilitatorswhoare stronglymotivatedbypersonalexperienceruntheriskof“experiential encapsulation”—atermweadaptfromculturalencapsulation,whichis usedtodescribeaclinicians’applicationoftheirownculture-boundexperienceandworldviewstothoseofaclientwithoutregardforimportant differences(37, 38).Experientialencapsulationoccurswhenfacilitators assumethattheirownpsychedelicexperiences,thetimelinesoftheseexperiences,andtheirframeworksforinterpretingtheseexperiences,are universallyapplicable.Thiscanleadfacilitatorstooverlooktheunique anddeeplypersonalwaysinwhichdifferentindividualsmayexperience psychedelicsduringPAT.Justasculturallyencapsulatedtherapistsareat riskoffailingtoconsiderculturaldifferencesbetweenthemselvesand theirclientandimposingtheirownvaluesoncare(37, 38),anexperientiallyencapsulatedfacilitatormayfailtorecognizevariationsinhowindividualsexperiencepsychedelicsandthemeaningsthatareascribedto theseexperiences.AnyfacilitatorofPAT(whetheranSHPorfromanother profession)whoseapproachisoverlyshapedbypersonalpsychedelicexperiencerunstheriskofoversightswhenworkingwithsomeonewhohas amarkedlydifferentexperience.Suchoversightscanleadtoineffectiveness,oratworst,treatmentharms(9).
ForSHPs,trainingrequirementssetbytheAssociationforClinicalPastoralEducation(ACPE)mayhelpbufferagainstthisrisk(24).ThepreparatorytrainingtobecomeanSHPthroughACPEplacesaheavyemphasison self-literacy.Self-literacytrainingoccursinthecontextoftheCommon CodeofEthicsforChaplains,PastoralCounselors,PastoralEducatorsand Students,whichsetsforthseveralstandardspertainingtoculturalhumilityandrespectforautonomyintheworldviewandbeliefsofothersinall
Figure1. Self-literacyreflectionexerciseforpsychedelicfacilitators.
professionalactivities(e.g.,Standard1.3:“Demonstraterespectforthe culturalandreligiousvaluesofthosetheyserveandrefrainfromimposingtheirourownvaluesandbeliefsonthoseserved.”)(39).ACPEtraining standardsalsoincludeseveraloutcomesandindicatorsthataskSHPs-intrainingtoreflectupontheirmotivationstoengageintheworkofspiritualcare,theorientingsystembehindtheirspiritualcarechoiceswith clients,andtheirunderstandingofpersonal,social,andculturallocation thatimpactstheirwayofbeingintheworldandwork(39).Forexample, learningoutcomesinclude“Identifyformativeandtransformativeexperiencesinone’snarrativehistoryandtheirsignificancetoone’sspiritual journey”(IA.1)and“Demonstrateanawarenessofimplicitandsystemic biasincludingculturalandvalue/belief-basedprejudiceanditsimpacton spiritualcare”(IA.7).ThisreflectivelearningaimstoaidSHPsinbringing awarenesstofactorsthatmotivatetheiractionsinspiritualcareencounters.InthecontextofPAT,thistrainingmayalsoaidSHPsinsensitively approachingaparticipant’sexperiencewithoutexpectations,regardless oftheSHPs’relationshipwithpsychedelics.Whilethepersonalhistory oftransformationthroughpsychedelicsmaybeasignificantmotivator formanySHPsengagedinthiswork,thelearningoutcomesandethical guardrailsofSHPsmayassistinmaintainingapracticethatcentersthe experienceoftheclient.
Standardssetforthbyprofessionalethicscodesformentalhealth providers(e.g.,theAmericanPsychologicalAssociationEthicsCode;the CodeofEthicsforSocialWork)articulatecomparablepracticestandards withregardstorespectforclients’autonomyandrefrainingfromimposingone’sownvalues(40, 41).However,thesestandardsfortraining andpracticedonotexplicitlyaddressreflectiononone’sownnarrative andpsychospiritualhistory.Intheabsenceofsuchstandards,training programsforclinicalmentalhealthprofessionsoftendedicateminimal timetoexperientialself-literacytrainingasanintegratedcomponentof training.FindingsfromthisresearchsuggestthatwhenitcomestoPAT, trainingcompetenciesassociatedwithself-literacyofone’snarrativeand psychospiritualhistoryandmotivationsmaybeparticularlyimportant.In thecontextofongoingdiscussionsabouttrainingguidelinesandrequirementsforPATthatcutacrossprofessions,wesuggestthatACPE’sreflectivelearningmodelforacquiringself-literacybeconsideredanelement oftrainingthatcanbenefitallPATproviders,regardlessoftheirprofession.Further,aspractitionersengageinPAT,continualreflectiononthese learningoutcomesaspartofcontinuingeducationcanbenefitproviders’ work.
GuidedbyfindingsfromthisstudyandtheACPEreflectivelearningmodel,wesuggestaself-literacyexercisethatcanbecompleted byPATfacilitatorsandfacilitators-in-trainingcomingfromanyprofessionalbackground(Figure1).Thesequestionsaimtobalancethevalue ofpersonalexperiencewiththeneedforclinicalobjectivityandtheimportanceofreflectingonhowpersonalexperiencesandmotivationscan conferbothstrengthsandgapsinawareness.Thenineself-reflection questionsprovidedin Figure1 canbeassignedasawritten,narrativeexerciseduringpsychedelicfacilitationtraining,sothattraineescanpracticereflectivelywithoutbeingrequiredtodiscloseaboutpersonalexperiencebeyondtheircomfortlevel.Practicingfacilitatorsmaybebenefit fromrevisitingthesequestionsannually,asmotivations(andpersonalexperience)maychangeovertime.
LimitationsandResearcherPositionality
Aprimarylimitationofthisworkpertainstorecruitmentandthesampleofparticipantsrepresented.Participantsintheseinterviewswere recruitedthroughanationalprofessionalnetwork(TransformingChaplaincy)thatwasoriginallyco-convenedbythisstudy’sprincipalinvestigator(PI).Thiscouldhaveledtobiassuchthattheviewsofparticipantswere similarinnaturetoeachotherandthePI.Participantsinthisstudyhad avarietyofchaplaincytrainingexperiences,notallthroughACPE.Relatedly,onlythosepracticingPATinlegalsettingswereincluded.Thismeans thatourresultsmaynotgeneralizetothenumerouspractitionersworkinginundergroundsettingsandtraditionalreligious/spiritualsettings. ProviderspracticinginthosesettingshaveuniqueexperiencesfacilitatingPAT,andmayhavedifferentmotivationsandsustainingfactorsfor theirwork.OurresultsalsomaynotgeneralizetolegalPATpractitioners fromnon-SHPtrainingbackgrounds(e.g.,psychiatry,clinicalpsychology, socialwork).Broadlyspeaking,educationalpathwaysandpracticeenvironmentsimpacttheexperiencesandmotivationsofpractitioners.Future researchshouldreachabroadernetworkofproviderstoensuremoregeneralizabilityandunderstandtowhatextentexperiencesmaydiffer.
Additionally,thevastmajorityofparticipantsinthisstudywerewhite (80%)andNorthAmerican(93%).Thisposeslimitationsonthegeneralizabilityofthisworktothepopulationsatlarge.Individualsfromother racial,ethnicandculturalbackgroundsmayapproachpsychedelicexperiencesdifferently,leadingthemtohavedifferentperspectivesthanthose representedhere.Forexample,participantsinthisstudyexpressedanorientationtowardpersonalhealing.Communaldimensionsofhealingare
centraltomanytraditionsofpsychedelicusearoundtheworld(42)and areunder-representedhere.
Thisqualitativestudyshouldalsobeinterpretedinlightofauthorpositionality.AllauthorsofthisstudyresideintheUnitedStatesandwork inprimarilyacademiccontexts,withsettingsspanningalargeacademic medicalcenter,aSchoolofPublicHealth,andaSchoolofTheology.The authorsincludeSHPs(chaplains),clinicalpsychologists,aclinicalsocial worker,andagraduatestudentinpublichealth.AllauthorshaveprofessionalexperiencewithPAT;someauthorshaveprovidedPATfacilitation, whileothershaveservedresearch-focusedrolesonPATtrials(e.g.,investigator,dataanalyst).Ourtrainingbackgroundsinformthelensthrough whichweapproachedtheseanalysesandtheirinterpretation,andindividualswithothertrainingorprofessionalbackgroundsmayhavegenerateddifferentcodingcategoriesordrawndifferentconclusionsthan thoserepresentedhere.Weacknowledgethatourperspectivesdonot representtheperspectivesofallPATfacilitatorsorrecipientsofthese treatments.
ConclusionsandFutureDirections
AsthefieldofPATcontinuestoexpandandthepotentialforFDAapproval ofpsychedelicagent(s)appearsonthehorizon,itisacriticaltimefor professionaldisciplinestosystematicallyevaluatewhatconstitutesappropriatepreparationforthoseworkinginPAT.UnderstandingthemotivatingfactorsforSHPswhoarealreadyengagedinthisworkallows thosewithinandoutsidethefieldofspiritualcaretoconsiderthecomplexdynamicsatplaywithinaPATfacilitationexperiencefromaunique perspective.
Acorefindingfromthisstudywasthatpersonalexperiencessubstantiallyinformedparticipants’initialandongoingmotivationsforworking inthisfield.Wedonotdrawconclusionsregardingwhetherexperience withpsychedelicsisnecessarytobeaneffectivePATfacilitator.However, awarenessofmotivations—whetherrelatedtoone’sownpsychedelicexperiencesornot—canassistthefacilitatorinbringinganobjectiveapproachtotheworkthatiscenteredontheexperienceofthepersonseekingcare.ResultsofthisstudysuggestthattrainingprogramsforPAT wouldbenefitfromcurriculacomponentsthatinvitetraineestoexplore personalmotivatingfactorssothatinsightintothesecanbecultivated andanyresultingbiasescanbeaddressed.Withacarefulandself-aware approach,therapistsofanydisciplinemaybeabletoprovidecarethat issensitivetopowerdynamicsandnon-imposingofpersonalexperience andperspective.
Methods
Thepresentstudyisasecondaryanalysisofaqualitativestudythataimed toidentifytherolethatSHPsplayonPATteams(23).Thissecondaryanalysiswasmotivatedbytheemergenceoftwothemesthatwereinductively identifiedduringouroriginalqualitativeanalysesfortheprimarystudy. Thesethemesfellbeyondthescopeofthatresearch,andthereforewere notexaminedorreported:(1)thefactorsthatinitiallybroughtparticipantstoPATfacilitation,and(2)thefactorsthatmotivatetheircontinued practiceofthisprofession.
Participants
ParticipantsinthisresearchhadexperiencefacilitatingPATandalsomet atleastoneofthefollowingcriteria:(1)oneormoreunitsofClinicalPastoralEducation(ACPE),(2)ordinationorstatusasareligiousleader,(3) aMasterofDivinityorotheradvancedtheologicaldegree,or(4)specific traininginspiritualitywithinpsychedelicwork,aboveandbeyondwhat isofferedinstandardPATcertificationprograms.Recruitmentoccurred betweenMarch2022throughJune2022.“ExperiencewithPAT”wasdefinedasexperiencefacilitatingPATinsettingswhereitwaslegal,includingbothceremonialand/orretreatsettings,aswellasclinicalresearch environments.
Allparticipants(n = 15)intheparentstudyarerepresentedinthe presentstudy.Participantshadanaverageageof46.57(SD = 13.38), identifiedas60%female(40%male),andwere20%Hispanic/Latinxand 80%White.Thevastmajority(93%)wereNorthAmerican,with6.67% beingSouthAmerican.ThemostcommoncontextofPATexperiencewas withinclinicaltrials(46.67%),withthenextmostcommonbeingretreat/
ceremonial(40%),andprivatepractice,clinic,andremote/virtualbeing theleastcommon(6.7%).ThemostcommonlyusedpsychedelicinPAT interventionsreportedbyparticipantswaspsilocybin(66.67%),followed byketamine(46.67%),ayahuascaandMDMA(both13.33%),andLSD, cannabis,andkambo(6.7%).
ProceduresandMeasures
SHPswereinterviewedviatheZoomtelehealthplatform,exceptforone SHP,whowasquestionedviaawrittenemailexchangeduetopoorinternetconnectivityandinabilitytoengageviaZoom.AllSHPswerequeried usingasemistructuredinterviewguideof14standardquestions,reportedintheoriginallypublishedstudy(23).Interviewquestionsincluded itemsaskingSHPstodescribevariousaspectsoftheirprofessionalactivities,theirmotivationsforengaginginPAT,theirviewoftheimportance ofpersonalexperiencewithpsychedelics,ethicalconcernsrelatedtoPAT, spiritualoutcomesofPAT,andviewsofthebuildingfieldofSHPsengaginginPAT.
Twopreviouslyunanalyzedquestionsweretheanalyticfocusforthe presentinvestigation:amotivationquestion,askedtoallparticipants (“Whatmotivatedyoutoworkinthisfield?”),andameaningandfulfillmentprobe(i.e.,“Whatbringsyoumeaningorfulfillmentinthiswork?”). Themeaningandfulfillmentprobewasincludedintheinterviewguideas anoptionalfollow-upprobe,andthereforenotaskedofallparticipants. Informationyieldedinresponsetothisprobe,whenitwasincluded,was relatedtothemotivationthemeandwasthereforeincludedinthepresent analysis.AllinterviewswerevideoandaudiorecordedandtranscribedusingtheautotranscriptionfeatureofZoom.Transcriptsweresubsequently manuallydeidentifiedandcorrectedfollowingtheautomatedtranscriptionforanyerrorsorlackofclarity(viacomparisonwithliverecording) bytworesearchers.
DataAnalysis
Thedataanalyticstrategyfortheprimaryanalysisisdescribedelsewhere (23).Duringthatprocesstwothemesemergedinductively,whichdidnot fallwithinthescopeoftheprimaryanalysis.Thesetwothemeswere(1) participants’descriptionsoftheirinitialmotivationsforfacilitatingPAT, and(2)theircurrentsourcesofongoingmotivationandfulfillmentin theirwork.Thesethemesweredeterminedtobeunrelatedtotheaims oftheprimarystudy,whichweretocharacterizetherolesandactivities ofSHPsonPATtreatmentteams,butofsufficientscientificimportanceto warranttheirowndedicatedsystematicinvestigation.
Thepresentsecondaryanalysesemployedahybridinductivedeductiveapproach(43)torapidqualitativeanalysisofthesetwo themes.Arapidqualitativeapproachwasselectedbecauseoftheshiftingregulatoryenvironmentofpsychedelics,andongoingdiscussions abouttheroleofSHPsinpsychedeliccare,towhichthisanalysismay providedirectlygermane,thoughtime-sensitive,information.Inthe secondaryanalysis,ourfirststepwastogenerateacodebookofsubthemes,whichwascreatedbytwoinvestigatorswithcontentexpertisein chaplaincyandpsychedelicfacilitation.Thecodebookwascreatedbyreviewingalltranscripts,andthenidentifying(1)pre-existingthemesthat weredeemedimportanttoexamineinadeductivestep(e.g.,theexisting unexaminedcategoriesthatemergedintheprioranalysisthatmotivated thepresentinvestigation),and(2)asetofthemesrelevanttothesetwo originalthemes,whichwererecognizedandnotedseparatelybythetwo investigators.Thesewerediscussedandconsolidatedintoonecodebook. Thatcodebookwasthenrefinedbyhavingthetwoexpertcoderscodea subsampleoftranscriptsindependently,andthenresolvedisagreements byconsensus,modifyingandaddingcategoriesasneeded.Theresulting codebookwasthentreatedasafinalizedversion.Thesecodeswere deductivelyappliedbyasinglecoderusingMAXQDAversion22.2.00 qualitativeanalysissoftware.Thismethodofrapidqualitativeanalysis hastheadvantageoftakinglesstimethandouble-codedmethods, andthelimitationthatcodingmaybesubjecttobiaseddetection,with intercoderreliabilityofthefulldatasetnotpossibletoestablish(44). Thislimitationmakesresearcherpositionalityparticularlyimportantto describeandreportaspartofdatainterpretation(see Discussion forthis reporting).
DataAvailability
Datacannotbesharedpubliclybecauseofconcernsaboutidentifiability, andtheneedtopreserveprivacyandconfidentialityofparticipants.Becausethetopicsdiscussedmayincurlegalorsocialsanctionsthedataare heldonprotectedandencrypteduniversityserversatEmoryUniversity. DatamaybemadeavailableforresearcherswhomeetthecriteriaforaccesstoconfidentialdatabycontactingtheEmoryUniversityInstitutional ReviewBoardat irb@emory.edu orthecorrespondingstudyauthor.
Acknowledgments
Theauthorswouldliketothanktheparticipantsinthisresearchforsharingtheirexperiencesandperspectiveswithus.
AuthorContributions
C.P.collectedandanalyzedreporteddata.D.M.K.,I.P.,andC.P.wrotethe firstdraftofthismanuscript,withinputfromR.P.,J.C.S.,J.M.P.,andG.H.G. RevisionstothisarticlewerecompletedbyD.M.K.andI.P.,withinputby C.P.,R.P.,J.C.S.,J.M.P.,andG.H.G.Allauthorsreviewedandapprovedthefinalversionofthismanuscript.Allauthorstakefullresponsibilityfordata andtextandapprovethecontentandsubmissionofthisarticle.Norelatedworkisunderconsiderationelsewhere.
FundingSources
Thisresearchwasnotfundedbyexternalsources.PersonneltimededicatedtopreparationofthisarticlewasgenerouslysupportedbyEmory SpiritualHealth.
AuthorDisclosures
D.M.K.hasservedasaconsultantfortheMindandLifeInstituteandthe OxfordResearchEncyclopediaofGlobalPublicHealth,andhasreceived researchsupportfromtheNIH,theGeorgiaCTSA,theTinyBlueDotFoundation,theSarloFamilyFoundation,andtheVailHealthFoundation.R.P. hasreceivedresearchsupportfromtheTinyBlueDotFoundation,the JimJosephFoundationviaShefaJewishPsychedelicSupport,theSarlo FamilyFoundationandhasconsultedfortheHarvardDivinitySchoolCenterfortheStudyofWorldReligions.J.M.K.hasreceivedconsultingpaymentsfromCOMPASSPathwaysandOstukaandreceivessupportfrom theWoundedWarriorProject(WWP)andMultidisciplinaryAssociationof PsychedelicStudies.
References
1.LuomaJB,PlattMG.Shame,self-criticism,self-stigma,andcompassioninacceptance andcommitmenttherapy.CurrOpinPsychol.2015;2:97–101.
2.SloshowerJ,GussJ,KrauseR,WallaceRM,WilliamsMT,ReedS,etal.PsilocybinassistedtherapyofmajordepressivedisorderusingAcceptanceandCommitment Therapyasatherapeuticframe.JContextBehavSci.2020;15:12–9.DOI: 10.1177/ 02698811231154852.PMID:36938991
3.Denis-LalondeD.(PDF)Emergingpsychedelic-assistedtherapies:Implications fornursingpractice.[Internet].[cited2025Feb4].Availablefrom: https://www. researchgate.net/publication/341583827_Emerging_Psychedelic-Assisted_ Therapies_Implications_for_Nursing_Practice
4.YehudaR,LehrnerA.Psychedelictherapy—anewparadigmofcareformentalhealth. JAMA.2023;330(9):813–4.DOI: 10.1001/jama.2023.12900.PMID:37651148
5.BarberGS,AaronsonST.Theemergingfieldofpsychedelicpsychotherapy.CurrPsychiatryRep.2022;24(10):583–90.DOI: 10.1007/s11920-022-01363-y.PMID:36129571; PMCID: PMC9553847
6.DavisAK,BarrettFS,MayDG,CosimanoMP,SepedaND,JohnsonMW,etal.Effectsof psilocybin-assistedtherapyonmajordepressivedisorder:arandomizedclinicaltrial. JAMAPsychiatry.2021;78(5):481–9.DOI: 10.1001/jamapsychiatry.2020.3285.PMID: 33146667;PMCID: PMC7643046
7.MonteAA,SchowNS,BlackJC,BemisEA,RockhillKM,DartRC.Theriseofpsychedelic druguseassociatedwithlegalization/decriminalization:anassessmentwiththenonmedicaluseofprescriptiondrugssurvey.AnnEmergMed.2024;83(3):283–5.DOI: 10.1016/j.annemergmed.2023.11.003.PMID:38142372
8.XenakisSN,ShannonSM.Whatisneededfortheroll-outofpsychedelictreatments? CurrOpinPsychiatry.2024;37(4):277.DOI: 10.1097/YCO.0000000000000946.PMID: 38726805
9.PalitskyR,KaplanDM,PernaJ,BosshardtZ,Maples-KellerJL,Levin-AspensonHF,etal. Aframeworkforassessmentofadverseeventsoccurringinpsychedelicassistedtherapies.JPsychopharmacol.2024;38(8):690–700.DOI: 10.1177/02698811241265756 PMID:39082259
10.LevinAW,LancelottaR,SepedaND,GukasyanN,NayakS,WagenerTL,etal.Thetherapeuticalliancebetweenstudyparticipantsandinterventionfacilitatorsisassociated withacuteeffectsandclinicaloutcomesinapsilocybin-assistedtherapytrialformajordepressivedisorder.PLoSOne.2024;19(3):e0300501.DOI: 10.1371/journal.pone. 0300501.PMID:38483940;PMCID: PMC10939230
11.ModlinNL,McPheeT,ZazonN,SarangM,HignettR,PickS,etal.Participants’experienceofpsychedelicintegrationgroupsandprocesses:aqualitativethematicanalysis. PsychedelicMed.2025;3(1):19–30.
12.GukasyanN,NayakSM.Psychedelics,placeboeffects,andsetandsetting:insights fromcommonfactorstheoryofpsychotherapy.TranscultPsychiatry.2022;59(5):652–64.DOI: 10.1177/1363461520983684.PMID:33499762
13.CadgeW.PagingGod:religioninthehallsofmedicine[Internet].UniversityofChicago Press;2013[cited2025Feb5].Availablefrom: https://books.google.com/books?hl= en&lr=&id=gFG4jQDufTIC&oi=fnd&pg=PR5&dq=Cadge,+W.+Paging+God:+Religion+ in+the+Halls+of+Medicine%3B+University+of+Chicago+Press:+Chicago,+IL,+USA, +2012&ots=oZ0nv-VWZ5&sig=-hjxumCWOwfaGedVjAy8eRrcam4 14.CadgeW,FreeseJ,ChristakisNA.TheprovisionofhospitalchaplaincyintheUnited States:anationaloverview.2008[cited2025Feb5];Availablefrom: https://books. google.com/books?hl=en&lr=&id=OMpWDwAAQBAJ&oi=fnd&pg=PA36&dq=Cadge, +W.%3B+Freese,+J.%3B+Christakis,+N.A.+The+provision+of+hospital+chaplaincy+ in+the+United+States:+A+national+overview.+South.+Med.+J.&ots=RWY0BTrTOL& sig=iSZWZujJE9siAHzZ93K3OMvOL6o 15.VanderwerkerLC,FlannellyKJ,GalekK,HardingSR,HandzoGF,OettingerSM,etal. Whatdochaplainsreallydo?III.ReferralsintheNewYorkchaplaincystudy.J HealthCareChaplain.2008;14(1):57–73.DOI: 10.1080/08854720802053861.PMID: 18686545
16.PalmerPK,SiddiquiZ,MooreMA,GrantGH,RaisonCL,MascaroJS.Hospitalchaplainburnout,depression,andwell-beingduringtheCOVID-19Pandemic.IntJEnviron ResPublicHealth.2024;21(7):944.DOI: 10.3390/ijerph21070944.PMID:39063520; PMCID: PMC11277059
17. https://www.apchaplains.org/wp-content/uploads/2022/05/2017-Common-Qualifi cations-and-Competenciesfor-Professional-Chaplains.pdf –GoogleSearch[Internet].[cited2025Mar20].Availablefrom: https://www.google.com/search?q=https% 3A%2F%2Fwww.+apchaplains.org%2Fwp-content%2Fuploads%2F2022%2F05%2F+ 2017-Common-Qualifications-and-Competenciesfor-Professional-Chaplains.pdf& oq=https%3A%2F%2Fwww.+apchaplains.org%2Fwp-content%2Fuploads%2F2022% 2F05%2F+2017-Common-Qualifications-and-Competenciesfor-ProfessionalChaplains.pdf&gs_lcrp=EgZjaHJvbWUyBggAEEUYOTIGCAEQRRg60gEHMzMyajBqN6g CALACAA&sourceid=chrome&ie=UTF-8
18.SchuttWA,ExlineJJ,PaitKC,WiltJA.Psychedelicexperiencesandlong-termspiritual growth:asystematicreview.CurrPsychol.2024;43(32):26372–94.
19.PalitskyR,KaplanDM,PeacockC,ZarrabiAJ,Maples-KellerJL,GrantGH,etal.Importanceofintegratingspiritual,existential,religious,andtheologicalcomponents inpsychedelic-assistedtherapies.JAMAPsychiatry.2023;80(7):743–9.DOI: 10.1001/ jamapsychiatry.2023.1554.PMID:37256584
20.HartogsohnI.Themeaning-enhancingpropertiesofpsychedelicsandtheir mediatorroleinpsychedelictherapy,spirituality,andcreativity.FrontNeurosci.2018;12:129.DOI: 10.3389/fnins.2018.00129.PMID:29559884;PMCID: PMC5845636
21.SaadM,DeMedeirosR,MosiniAC.Arewereadyforatruebiopsychosocial–spiritual model?Themanymeaningsof“spiritual.”Medicines(Basel).2017;4(4):79.DOI: 10. 3390/medicines4040079.PMID:29088101;PMCID: PMC5750603
22.SulmasyDP.Abiopsychosocial-spiritualmodelforthecareofpatientsattheend oflife.Gerontologist.2002;42(suppl_3):24–33.DOI: 10.1093/geront/42.suppl_3.24 PMID:12415130
23.PeacockC,MascaroJS,BrauerE,ZarrabiAJ,DunlopBW,Maples-KellerJL,etal.Spiritualhealthpractitioners’contributionstopsychedelicassistedtherapy:aqualitative analysis.PLoSOne.2024;19(1):e0296071.DOI: 10.1371/journal.pone.0296071.PMID: 38166057;PMCID: PMC10760908
24.VilligerD.Howtomakepsychedelic-assistedtherapysafer.CambQHealthcEthics. 2025;1–15.DOI: 10.1017/S0963180124000604.PMID:39618402
25.AdayJS,HortonD,Fernandes-OsterholdG,O’DonovanA,BradleyER,RosenRC, etal.Psychedelic-assistedpsychotherapy:whereisthepsychotherapyresearch?Psychopharmacology(Berl).2024;241(8):1517–26.DOI: 10.1007/s00213-024-06620-x PMID:38782821
26.PalitskyR,Maples-KellerJL,PeacockC,DunlopBW,MletzkoT,GrantGH,etal.A criticalevaluationofpsilocybin-assistedtherapyprotocolcomponentsfromclinical trialpatients,facilitators,andcaregivers.Psychotherapy(Chic).2025.DOI: 10.1037/ pst0000551.PMID:39804360Availablefrom: https://psycnet.apa.org/record/202566803-001
27.McBeathA.Themotivationsofpsychotherapists:anin-depthsurvey.CounsPsychother Res.2019;19(4):377–87.DOI: 10.1037/cou0000596.PMID:34843273
28.SimonssonO,HendricksPS,ChambersR,OsikaW,GoldbergSB.Prevalenceandassociationsofchallenging,difficultordistressingexperiencesusingclassicpsychedelics. JAffectDisord.2023;326:105–10.DOI: 10.1016/j.jad.2023.01.073.PMID:36720405; PMCID: PMC9974873
29.JohnstadPG.Daytriptohell:amixedmethodsstudyofchallengingpsychedelicexperiences.JPsychedelicStud.2021;5(2):114–27
30.FarberBA,ManevichI,MetzgerJ,SaypolE.Choosingpsychotherapyasacareer:why didwecrossthatroad?JClinPsychol.2005;61(8):1009–31.DOI: 10.1002/jclp.20174 PMID:15945066
31.BarnettM.Whatbringsyouhere?Anexplorationoftheunconsciousmotivationsof thosewhochoosetotrainandworkaspsychotherapistsandcounsellors.PsychodynPract.2025;13(3):257–74.Availablefrom: https://www-tandfonline-com.proxy. library.emory.edu/doi/full/10.1080/14753630701455796
32.GubiP,SmartH.Motivationalfactorsinmentalhealthchaplains:practitioners’Perspectives.HealthSocCareChaplain.2014;1
33.KlitzmanR,SinnappanS,GarbuzovaE,Al-HashimiJ,DiSapiaNatarelliG.Becoming chaplains:howandwhychaplainsenterthefield,factorsinvolvedandimplications.
JHealthCareChaplain.2024;30(2):75–88.DOI: 10.1080/08854726.2022.2154108 PMID:36515161
34.WampoldBE.Howimportantarethecommonfactorsinpsychotherapy?Anupdate.WorldPsychiatry.2015;14(3):270–7.DOI: 10.1002/wps.20238.PMID:26407772; PMCID: PMC4592639
35.HecksherD.Formersubstanceusersworkingascounselors.Adualrelationship. SubstUseMisuse.2007;42(8):1253–68.DOI: 10.1080/10826080701446711.PMID: 17674234
36.NielsonEM,GussJ.Theinfluenceoftherapists’first-handexperiencewith psychedelicsonpsychedelic-assistedpsychotherapyresearchandtherapisttraining. JPsychedelicStud.2018;2(2):64–73.DOI: 10.1556/2054.2018.009
37.HeppnerPP,WangKT,HeppnerMJ,WangLF.Fromculturalencapsulationtocultural competence:Thecross-nationalculturalcompetencemodel.In:FouadNA,CarterJA, SubichLM,editors,APAHandbookofCounselingPsychology,Vol.2.Practice,interventions,andapplications,433–471.AmericanPsychologicalAssociation;2012[cited 2025Feb5];Availablefrom: https://psycnet.apa.org/record/2012-03487-018
38.BergkampJ,PonsfordM.Culturalencapsulation.In:CarducciBJ,NaveCS,MioJS,RiggioRE,editors.TheWileyEncyclopediaofPersonalityandIndividualDifferences.1st ed.Wiley;2020[cited2025Feb4].p.239–41.Availablefrom: https://onlinelibrary. wiley.com/doi/10.1002/9781119547181.ch304
39.ACPE[Internet].[cited2025Feb4].CategoryA:SpiritualFormationandIntegration–ACPEManuals–2025.Availablefrom: https://www.manula.com/manuals/acpe/acpemanuals/2016/en/topic/revised-acpe-outcomes-and-indicators-spiritualformation-and-integration
40.Ethicalprinciplesofpsychologistsandcodeofconduct.[cited2025Feb4].Available from: https://www.apa.org/ethics/code
41.Socialworkers’ethicalresponsibilitiestoclients.[cited2025Feb4].Available from: https://www.socialworkers.org/About/Ethics/Code-of-Ethics/Code-of-EthicsEnglish/Social-Workers-Ethical-Responsibilities-to-Clients
42.SanabriaE,TófoliLF.Integrationorcommodification?Acriticalreviewofindividualcenteredapproachesinpsychedelichealing.JPsychedelicStud.2025[cited2025 Mar20];Availablefrom: https://akjournals.com/view/journals/2054/aop/article-10. 1556-2054.2024.00411/article-10.1556-2054.2024.00411.xml
43.LayderD.SociologicalPractice:LinkingTheoryandSocialResearch.SAGEPublications; London(PublisherLocation)1998.
44.CampbellJL,QuincyC,OssermanJ,PedersenOK.Codingin-depthsemistructuredinterviews:problemsofunitizationandintercoderreliabilityandagreement.Sociol MethodsRes.2013;42(3):294–320.DOI: 10.1177/0049124113500475
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