The Dynamic Field of Psychedelic Medical Research: A ...

TheDynamicFieldofPsychedelicMedicalResearch:

AReviewofRecentDevelopments

August2020

Author/s:OriginallycompiledbyDrMartinWilliams,PhD-December2018UpdatedbyBenTran,MonashUniversity–August2020Introduction

Theblossomingglobalinterestinpsychedelicsciencehasitsoriginalrootsintheemergenceofpsychedelic-assistedpsychotherapyfromthelate1940stotheearly1970s,asthepotentialofthesedrugstoenhancetherapeuticoutcomeswasexplored.ResearchandclinicalpracticeinthefielddiminisheddramaticallyinresponsetotheglobalWaronDrugs,aslegalrestrictionsandsocialstigmacametodominatethelandscape.

Followingathirty-yearhiatus,interesthassteadilyreturnedasinvestigatorshavegraduallyovercomesocialandacademicconservatism,researchfundinghasbecomeavailablefromarangeofsources,andgovernmentsanctionsonpsychedelicresearchhavebeenrelaxed.

Duringtheinterveningperiod,fromthe1970stotheearly2000s,psychedelicsciencewaslargelyrelegatedtothearcanedomainofafringecommunity,whichnonethelessincludedexperienced,dedicated(andpatient)cliniciansandresearcherswhowereideallypoisedtoleadthepsychedelicrevivalasitgatheredpaceintheearlyyearsofthecurrentmillennium.

Since2010,the“mainstreaming”ofpsychedelicshasgatheredmomentumasunprecedentedmediaattention–almostentirelypositive–hasilluminatedtherenaissanceinpsychedelicmedicalresearch,informingWesternsocietyofthepotentialofpsychedelicdrugsastherapeuticadjunctsandagentsofpersonaltransformation.

HistoricalPerspective

Variousplant-derivedpsychoactivecompounds,notablypsilocybin,mescaline,N,N-dimethyltryptamine(DMT),ibogaine,andsometropanealkaloids,havebeenusedinritualandspiritualcontextsinvariouspartsoftheworldforhundreds,possiblythousands,ofyears.Someofthoseritualusescontinuetothepresentday.

Atthedawnofmodernmedicinalchemistry,mescalinewasfirstisolated,characterisedandbioassayedbyArthurHeffter,aGermanpharmacologistandchemist,in1897.However,itwasthediscoveryofthepsychoactiveeffectsofLSDin1943thatunequivocallystartedthemodernageofpsychedelics.Firstsynthesisedin1938byDrAlbertHofmannofSandozLaboratories,LSDledtorapidadvancementsinneuroscience,suchastheidentificationandelucidationoftheserotoninneurotransmittersystem.Thisledtoasignificantshiftinpsychiatry,asnumerousmedicinesweredevelopedbasedonthisnewunderstandingofthebrain.

Inthecontextofpsychotherapy,LSDitselfwasalsofoundtobeeffectiveinthetreatmentofarangeofmentaldisorders,includingaddiction,anxietyanddepression.JustoneortwosessionsofLSD-assistedpsychotherapywerefoundtoproduceprofound,rapid,long-lastingpositiveeffectswithlittleneedforfurtherinterventions,unlikepsychoanalysiswhichinvolvedyearsoftherapy.GrinspoonandBakalarstatedin1997that“between1950andthemid-1960s…morethanathousandclinicalpapersdiscussing40,000patients”hadbeenpublishedalongwith“severaldozenbooks,andsixinternationalconferencesdiscussingpsychedelictherapy”.

Thewidespreadnon-clinicaluseofLSDsoonbecameassociatedwiththecounterculturemovementofthe60s,andoppositiontotheUSmilitaryinvolvementinVietnam.InanefforttocurbtheperceiveddestabilisationofAmericansociety,USPresidentRichardNixonmadeLSDandotherpsychedelicdrugs(e.g.mescaline,psilocybinandDMT)illegal-despitetheirdemonstratedsafetyprofileandinthefaceofconcertedeffortsbypsychologistsandpsychiatriststoallowthemto

continueusingLSDinatherapeuticcontext.ThiswasthestartofNixon's"WaronDrugs",supportedbytheinternationalratificationoftheUnitedNations1971ConventiononPsychotropicSubstances,andconsequentlyledtoahaltinpsychedelictreatmentsandresearch.ApropagandacampaignexaggeratingthedangersofLSDwasinitiatedbytheNixongovernment,containingmisinformationthatpersistedforalmost45years.

Meanwhile,3,4-methylenedioxymethamphetamine(MDMA)emergedasanadjuncttopsychotherapyinthe1970s,toenhancecouplesrelationshipcounsellingandtoaddresstrauma.Later,intheearly1980s,thedrug’seuphoriceffectswerenotedmorebroadlybythegeneralcommunity,andinresponsetoincreasingrecreationaluse,theUSDrugEnforcementAdministration(DEA)soughttobanitin1984.JudgeFrancisL.YoungwasaskedbytheDEAtoconducthearingstodeterminethemostappropriateschedulingofMDMA,andfollowingthetestimonyofmanypsychiatristsandpsychologists,YoungruledthatMDMAshouldbeclassedasaScheduleIIImedicine.However,theDEAdidnottakethisadviceandmadethedrugillegalintheUSAbyplacingitinScheduleI,thesamecategoryasheroin.

Ittooksustainedeffortsonthepartofafewdeterminedindividualstorecommenceresearchinhealthyvolunteersfromaround1990,andtheninitiateclinicalresearchtotreatmentalhealthconditionsaround2000.Subsequently,awidely-toutedinternationalrenaissanceinpsychedelicsciencehasoccurred,notablyintheUSA,Switzerland,theUK,CanadaandIsrael.

Thereislittlequestionthatresearchandtheclinicalapplicationofpsychedelicsceasedinthe1970sand1980sdueentirelytothepressureexertedbytheWaronDrugs.LSD,psilocybinandDMTarenotdangerouswhenusedcarefullyinaclinicalsetting.Theyarenon-addictiveandhavelowacutetoxicity,therebeingnoreportsofdeathfromthetoxicologicaleffectsofanacuteLSD,psilocybinorDMToverdose.Increasingly,themedicalprofessionandthebroadercommunityalikearecomingtorecognisethatdueprimarilytodogmatismandthesystematicdisseminationofmisinformation,40preciousyearsofpotentialprogressinmentalhealthresearchandtreatmenthavebeenlost.RecentandCurrentPsychedelicResearch

TheWorldHealthOrganization’sInternationalClinicalTrialsRegistryPlatform(who.int/ictrp)providesdetailsofclinicaltrialsregisteredwitharangeoforganisationsaroundtheglobe.Astabulatedbelow,theICTRPcurrentlylists38activeorcompletedresearchstudiesinvolvingpsilocybin,11involvingLSD,oneayahuasca,fouribogaine,foursalvinorinA,and55mechanisticstudies,psychologicalstudiesand/orclinicaltrialsinvolvingtheempathogen,MDMA.ThereisalsoacomprehensivetrialunderwayatJohnsHopkinsUniversityinvestigatingtheeffectsofabroadrangeofhallucinogensandotherdrugsonmoodandperformance.

Table1.PsilocybinResearchProjectsandClinicalTrials*HighlightedyellowindicatesAugustupdates*

Site Sponsor Focus SampleSize StatusMechanism

UniversityofWisconsin

Site-sponsored

Pharmacokinetics 12 Completed

Yale Heffter NeuroplasticityinMajorDepressiveDisorder

18 Active,recruiting

RigshospitaletCopenhagen

Site-sponsored

5HT2Areceptormodulation 45 Active,recruiting

CzechNationalInstituteofMentalHealth

CzechMinistryofHealth

Psilocybinasamodelofpsychoticillness

Notdisclosed

Active

LiberInstituteforBrainDevelopment

MAPS Neurogenesis Mice Completed(Pre-clinical)

MentalHealthInterventionHarbor-UCLA Heffter Canceranxiety 12 CompletedJohnsHopkins Heffter Psychopharmacologyin

cancerpatients56 Completed

Imperial

CollegeLondon

UKGovt

(MRC)

Depression 12 Completed

NYU Site-sponsored

Canceranxiety 32 Completed

UCSF HeffterRiverStyxStupskiUsona

GrouptherapyforAIDSsurvivors

36 Completed

StVincent’sHospitalMelbourne

Site-sponsored;PRISMInc

AnxietyandDepressionassociatedwithLife-ThreateningIllness


Multiple Usona MajorDepressiveDisorder 80 Active,recruitingJohnsHopkins Site-

sponsored

Anorexianervosa 18 Active,recruiting

UniversityofArizona

Site-sponsored

Obsessive-CompulsiveDisorder


UniversityofZurich

SwissNationalFunds

Depression 60 Active,recruiting

Yale Site-sponsored

Post-traumaticheadache 24 Active,recruiting

Multiple Compass

PathwaysLtd

Treatment-resistant

Depression


Yale Heffter NeuroplasticityinMajorDepressiveDisorder


ImperialCollegeLondon

AlexanderMoselyTrust

MajorDepressiveDisorder 59 Active,notrecruiting

Yale Heffter Obsessive-Compulsive

Disorder


JohnsHopkins Beckley,Heffter

Nicotinedependence 95 Active,recruiting

JohnsHopkins Heffter TobaccoAddiction 15 Completed

UniversityofAlabama,Birmingham

Site-sponsored

Cocainedependence 40 Active,recruiting

NewYork

University

NYU,Heffter,

UNM

Alcoholdependence 180 Active,notrecruiting

UniversityofNewMexico

Heffter Alcoholdependence 10 Active,notrecruiting

JohnsHopkins Site-sponsored

MajorDepressiveDisorder 24 Active,notrecruiting


DepressionassociatedwithMildCognitiveImpairment/EarlyAlzheimer’sDisease


UniversityofZurich

SwissNationalFunds

Alcoholdependence 60 Active,recruiting

UniversityofHelsinki

Site-sponsored

Depression 60 Notyetrecruiting

UniversityofWisconsin

Heffter OpioidUseDisorder 10 Notyetrecruiting

LieberInstituteforBrainDevelopment

MAPS Post-TraumaticStressDisorder

Mice Completed(Pre-clinical)

PhysiologicalInterventionYale Site-

sponsoredMigraine 24 Notyetrecruiting

Yale Heffter,CH-TAC

Clusterheadache 24 Active,recruiting

GitteMoosKnudsen

Site-sponsored ChronicClusterHeadache 20 Active,recruiting

PsychologicalStudy/SpiritualityJohnsHopkins Fetzer

SFFundSpiritualpractice 75 Completed


Pilotstudyinmeditators 10 Completed

JohnsHopkins USGovt(NIDA)

Persistingeffectsofpsilocybin

12 Completed


UKGovt(MRC)

Subjectiveintensityofpsilocybin

12 Completed


Behaviour,psychologyandbrainfunctioninlong-termmeditators

100 Active,notrecruiting


Moodandperformance 20 Active,notrecruiting

UniversityofZurich

Site-sponsored

DissolutionofSelf 140 Active,notrecruiting

NYU Site-sponsored

Religiousprofessionals 12 Active,recruiting


LeadersofReligion 12 Active,recruiting

Universityof

Maastricht

Site-

sponsored

Cognitiveflexibility 60 Notrecruiting

Table2.LSDResearchProjectsandClinicalTrials


UniversityHospital,Basel

Site-sponsored

Physiological&psychologicaleffects

16 Completed


Site-sponsored

NeuronalcorrelatesofAlteredStatesofConsciousness

24 Completed


Site-sponsored

Roleofdopamine,serotoninand5-HT2Areceptorsinemotionprocessing

28 Completed


Site-sponsored

ClusterHeadache 30 Active,recruiting

Universityof

Chicago

Site-

sponsored

MoodeffectsofSerotonin

Agonists



Site-sponsored

Roleof5-HT2AreceptorinAlteredStatesofConsciousness


MentalHealthInterventionPeterGasser

MD

MAPS Illness-relatedanxiety 12 Completed


Site-sponsored

MajorDepression 60 Notyetrecruiting

University

Hospital,Basel

Site-

sponsored

Anxiety 40 Active,recruiting

PsychologicalStudy/SpiritualityUniversityofZurich

Site-sponsored

Roleof5-HT2Areceptorinperceptionofselfandpersonalmeaning

25 Completed


Site-sponsored

AlteredStatesofConsciousnesselicitedbyLSD&psilocybin


Microdosing

UniversityofMaastricht

Site-sponsored

LSDMicrodosing-ADose-findingstudy

27 Notyetrecruiting

Table3.AyahuascaResearchProjectsandClinicalTrials

Site Sponsor Focus SampleSize StatusMentalHealthIntervention

Universidade Universityof Antidepressanteffects 35 Active,notFederaldoRio SaoPaulo recruitingGrandedo Norte

Table4.IbogaineResearchProjectsandClinicalTrials


UniversityofOtago

CYP2D6pharmacokinetics 24 Completed

MentalHealthInterventionInstitutoVeracruzdePesquisaeTratamentodeDependenciaQuimica,Brazil

Cardiacsafetyofibogainetreatmentofcocaineandcrackaddiction

70 Notyetrecruiting

UniversityofSaoPaulo

Alcoholdependence 12 Notyetrecruiting

Table5.SalvinorinAResearchProjectsandClinicalTrials


Yale NationalAllianceforResearchonSchizophrenia&Depression

Effectsinhealthycontrols 41 Active,notrecruiting

CaliforniaPacificMedicalCentre

Site-sponsored

Pharmacodynamicandtolerabilitystudy



Effectonbrainfunction 20 Active,recruiting

PsychologicalStudyJohnsHopkins USGovt

(NIDA)Humanpsychopharmacology


Table6.MDMAResearchProjectsandClinicalTrials

Site Sponsor Focus SampleSize

Status

Mechanism&PhysiologyUniversity Site- EffectsofMethylphenidate, 24 CompletedHospital sponsored Modafinil,andMDMAonEmotion- Basel processinginHumans:A

Pharmaco-fMRIStudy UniversityofAuckland

Site-sponsored

MDMAandtinnitus 40 Completed

ParcdeSalutMar

NationalInstituteonDrugAbuse

MDMA-InducedChangesinDrugMetabolism:GenderandGeneticPolymorphisms

27 Completed

California Site- StudyoftheEffectsof 12 CompletedPacific sponsored MDMA/EcstasyonWater Medical Regulation,Sleep,andCognition. Center Research Institute Dept.of Hadassah FunctionalBrainImagingin 18 CompletedNuclear Medical RecreationalUsersofEcstasy Medicine, Organization Hadassah Hospital UniversityHospitalBasel

Site-sponsored

PharmacologicalInteractionBetweenClonidineandMDMA

16 Completed

UniversityHospitalBasel

Site-sponsored

PharmacologicalInteractionBetweenDoxazosinandMDMA

16 Completed


Site-sponsored

InteractionBetweenDuloxetineandMDMA

16 Completed


Site-sponsored

PharmacologicalInteractionBetweenCarvedilolandMDMA

16 Completed


Heffter PharmacologicalInteractionBetweenPindololandMDMA

16 Completed


Site-sponsored

InteractionBetweenReboxetineandMDMA:Pharmacodynamics(PD)andPharmacokinetics(PK)

16 Completed

University Site- InvestigationofSerotonin 50 CompletedHospitalof sponsored NeurotransmissioninMDMAUsers Psychiatry, UsingCombinedDexfenfluramine Zurich ChallengeandPETImaging UniversityHospitalBasel

Site-sponsored

InfluenceofBupropionontheEffectsofMDMA

16 Completed

MichaelMithoeferMD

MAPS ExploringMechanismsofActioninMDMA-assistedPsychotherapyforPTSD

10 Completed

Yale Site-

sponsored

TheEffectsofMDMAonPrefrontal

andAmygdalaActivationinPTSD



Site-sponsored

EffectofMDMA(SerotoninRelease)onFearExtinction


Universityof Netherlands MDMAenprosociaalgedrag:De 20 Active,recruitingMaastricht Organization rolvande2a-serotoninereceptor.

forScientific Research UCSF MAPS MDMAinSubjectswithModerate

HepaticImpairmentandSubjectswithNormalHepaticFunction


MentalHealthInterventionMichaelMithoeferMD

MAPS MDMA-assistedandCognitive-BehavioralConjointTherapy(CBCT)inDyadswithOneMemberwithChronicPTSD

12 Completed

PhilipWolfsonMD

MAPS MDMA-assistedPsychotherapyforAnxietyAssociatedwithaLife-threateningIllness

18 Completed

LosAngeles MAPS MDMA-assistedTherapyforSocial 12 CompletedBiomedical AnxietyinAutisticAdults Research Institute DrIngrid MAPS Randomized,Double-blind, 6 CompletedPacey ControlledofMDMA-assisted

Psychotherapyin12SubjectsWith PTSD MarcelaOt’alora

MAPS Dose-ResponseStudyofMDMA-assistedPsychotherapyinPeopleWithPTSD

27 Completed

BeerYaakov MAPS Randomized,Double-blind,Active- 10 CompletedMental placeboControlledStudyof Health MDMA-assistedPsychotherapyin Center PeoplewithChronicPTSD

MichaelMithoeferMD

MAPS AdditionalMDMA-assistedPsychotherapyforPeopleWho

3 Completed

RelapsedAfterMDMA-assisted

PsychotherapyTrial

MichaelMithoeferMD

MAPS MDMAAlongwithPsychotherapyinVeteranswithPosttraumaticStressDisorder

26 Completed

PeterOehenMD

MAPS MDMA-assistedPsychotherapyinPeoplewithPosttraumaticStressDisorder

14 Completed

MichaelMithoeferMD

MAPS MDMA-AssistedPsychotherapyinPeoplewithPosttraumaticStressDisorder

23 Completed

InstitutoPlantandoConsciência-SaoPaulo,SP,Brazil

MAPS MDMA-assistedpsychotherapyinthetreatmentoftrauma


DrSimonAmar

MAPS StudyofSafetyandEffectsofMDMA-assistedPsychotherapyforTreatmentofPTSD

4 Completed


AlexanderMosleyCharitableTrust

ExploringMDMAinpsychotherapyindetoxifiedpatientswithalcoholdependencysyndrome

Notspecified

Active,notrecruiting

MichaelMithoeferMD

MAPS

PsychologicalEffectsofMDMAWhenAdministeredtoHealthyVolunteers(MT-1)

100

Active,enrollingbyinvitation

Multiplesites

MAPS AMulti-SitePhase3StudyofMDMA-AssistedPsychotherapyforPTSD


Multiplesites

MAPS OpenLabelMulti-SiteStudyofSafetyandEffectsofMDMA-assistedPsychotherapyforTreatmentofPTSD

60 Completed

Multiplesites

MAPS AMulti-SitePhase3StudyofMDMA-AssistedPsychotherapyforPTSD(II)

100 Notyetrecruiting

MichaelMithoeferMD

MAPS PsychologicalEffectsMDMAWhenAdministeredtoHealthyVolunteers(MT-2)

150 Notyetrecruiting

MAPSEurope

MAPS OpenLabelMulti-SiteStudyofSafetyandEffectsofMDMA-assistedPsychotherapyforTreatmentofPTSDWithOptionalfMRISub-Study


UniversityofOtago

Site-sponsored

EffectofMDMA-assistedtherapyonMoodandAnxietysymptomsinadvanced-stageCancer

24 Notyetrecruiting


MAPS EenstudienaardeveiligheideneffectenvanpsychotherapieincombinatiemetMDMAalsbehandelingvoorzwarepost-traumatischestressstoornis

Notspecified

Notyetrecruiting

VALomaLindaHealthcareSystem,CA,US

Site-sponsored/MAPS�needconfirmation

MDMA-AssistedPsychotherapyinVeteransWithCombat-Related,RefractoryPTSD

10 Notyetrecruiting

BeerYaakovMentalHealthCenter

MAPS RandomizedPlacebo-controlledStudyofMDMA-assistedPsychotherapyinPeoplewithPTSD-Israel

12 Terminated

Brigham&Women’sHospital

Site-sponsored

MDMA-assistedTherapyinPeoplewithAnxietyRelatedtoAdvancedStageCancer

2 Terminated

PsychologicalStudyUniversityofChicago

NationalInstituteonDrugAbuse

EffectsofMDMAonSocialandEmotionalProcessing

65 Completed


Site-sponsored

EffectsofMDMAandMethylphenidateonSocialCognition

30 Completed


Site-sponsored

EmotionalEffectsofMethylphenidateandMDMAinHealthySubjects

16 Completed


Site-sponsored

RoleofDopamine,Serotoninand5-HT2AReceptorsinEmotionProcessing

28 Completed

MichaelMithoeferMD

MAPS ExploringMechanismsofActioninMDMA-assistedPsychotherapyforPTSD

10 Completed

CaliforniaPacificMedicalCenterResearchInstitute

Site-sponsored

RoleofSerotonininAcuteandSubacuteMDMAEffects

13 Completed

UniversityHospitalBasel,Switzerland

Site-sponsored

EffectsofMDMAandMethylphenidateonSocialCognition

30 Completed

Universityof

Chicago

Site-

sponsored

EffectsofMDMAonEmotionaland

SocialMemories

60 Active,not

recruitingUniversityofMaastricht

Site-sponsored

MDMAandmemory 16 Active,notrecruiting

UniversityofChicago

Site-sponsored

EffectofStimulantDrugsonSocialPerception


UniversityofChicago

Site-sponsored

EffectsofDrugsonResponsestoBrainandEmotionalProcesses


EmoryUniversity

MAPS EvaluationofMDMAonStartleResponse



Site-sponsored

EffectsofMDMAonmemorywhenwitnessingorcommittingasimulatedcrime


MichaelMithoeferMD

MAPS PsychologicalEffectsofMDMAWhenAdministeredtoHealthyVolunteers



NetherlandsOrganizationforScientificResearch

MDMA,CortisolandMemory 60 Active,recruiting


Site-sponsored

EffectofMDMA(SerotoninRelease)onFearExtinction

30 Notyetrecruiting


NetherlandsOrganizationforScientificResearch

MDMAandprosocialbehavior 18 Notyetrecruiting

ThesesummarytablesofrecentpsychedelicresearchhighlightthatMDMAandpsilocybinarethecompoundsbeingmostextensivelystudied,byaconsiderablemargin.Theconditionsforwhichthesedrugsarebeinginvestigatedoverlapslightly,althoughpsilocybinisbeingmorewidelystudiedforanxietyanddepression,includingwhenexperiencedinassociationwithterminaldiagnosis.Arecently-launchedtrialwillextendthestudyofpsilocybin-assistedtherapytodepressionassociatedwithearly-stageAlzheimer’sdisease,alsoknownasMildCognitiveImpairment.Psilocybinhasalsoshownefficacyinthetreatmentandpreventionofclusterheadaches,treatmentofObsessive-CompulsiveDisorder,andincessationoftheproblematicuseofsubstancesincludingtobacco,alcoholandstimulants.Anemergingfurtheravenueofpsilocybinresearchisinthetreatmentofdepressionassociatedwitheatingdisorders,notablyAnorexianervosa.

MDMAisprovingeffectiveasanadjuncttopsychotherapyprimarily,andmostspecifically,forthetreatmentofpost-traumaticstressdisorder(PTSD),andsocialanxietyinadultsontheautismspectrum.Addressingtraumaasapotentialunderlyingcontributortoalcoholdependenceisalsothe

rationalefortheBristol-Imperialopen-labelstudyofMDMA-assistedtherapyforalcoholusedisorder,whichhasrecentlytreateditsfinalparticipant.

Thefollowingdiscussionreviewsthekeyinterventionalclinicaltrialsundertakenwithinthelast10-15years,manyofwhicharecompletedbutsomeofwhichareongoing,andsomeofthemostrecentdevelopmentsintheglobalpsychedelicresearchfield.Depression

Depressionisoneofthemostcommonmentalillnessesexperiencedglobally.Anestimated5.8%ofAustralians(i.e.around123,000people)experienceamajordepressiveepisodeinanyyear,while

30%ofmenand40%ofwomenwillexperienceMajorDepressiveDisorderintheirlifetime.Whilenumerouspsychotherapeuticinterventionsareeffectivefordepression,notallpeoplerespondtothesetreatments.OftensuchindividualsareplacedonmedicationsoreventreatedwithElectroconvulsiveTherapy,buttheseinterventionsalsohavelimitedsuccess.Thisnotonlyhasanenormousimpactonthequalityoflifefortheseindividuals,butgiventhehighprevalenceofthedisorder,itcreatesasignificanteconomicburdentothehealthcaresystemandalsototheeconomymorebroadly,giventreatment-refractorydepressionimpactspeople’sabilitytowork.

A2016reviewofpsychedelic-assistedpsychotherapyfordepressionbyRuckeretalexamined21studiespublishedbetween1949and1973.Whiletheynotedthatmanyofthestudieshadmethodologicallimitations,withsamplesizesrangingfrom5to77,andonlyfourstudiesincludingacontrolgroup,theyconcludedthereissomeevidencethatpsychedelic-assistedpsychotherapycouldbeaneffectivetreatmentandthatgiventhegrowingcostsofdepressionwithinthecommunity,thistreatmentshouldbere-investigatedbywayofRCTs.

ApsychedelicneuroscienceresearchprogramhasbeenestablishedatImperialCollegeinLondon,whereanRCTamong20healthyparticipantswithnohistoryofmentalillnessdemonstratedthatadoseofLSDimprovedpeople’smood,optimismandthepersonalitytraitofopennessforatleasttwoweekswithoutcausinganylong-termpsychologicalharm.Asubsequentopen-labeltrialofpsilocybin-assistedtherapyamong12participantswithtreatment-resistantdepressionshowedpromisingresults,elicitingasignificantimprovementineightoftheparticipants(67%)whonolongermetDSMcriteriafordepressivesymptomsoneweekafterthepsilocybinsession.Hedge'sgwas3.1indicatingastrongeffect.Whilesomeparticipantshadrelapsedatthree-monthfollow-up,therewasstillasignificantreductioninthemeanBeckDepressionInventoryscoresand,interestingly,asignificantreductioninparticipants’State-TraitAnxietyscoreswasobservedfrombaselinetofollow-up.

TheImperialCollegeresearchershaveproposedthatthesepsychotherapeuticbenefitsareduetodeactivationoftheDefaultModeNetwork(DMN)bypsilocybinandotherpsychedelicdrugs.TheDMNisagroupofinterconnectedbrainregionsassociatedwithself-referentprocessingandrumination,andbrainimaginghasshownthatDMNactivationdiminisheswhilepeoplearehavingapsychedelicexperience.Inaddition,theseresearchershavealsoobservedincreasedinterconnectivityamongareasofthebrainthatarenormallysegmented.Thismightallowpeopletoperceivethemselvesandtheworldwithanewperspective.Indeed,intheopen-labeltrialofpeoplewithtreatment-refractorydepression,leadresearcherCarhart-Harrisnotedthatthoseparticipantswhoremainedinremissionat3monthfollow-upweremostlikelytohavehadthemostsignificantdeactivationoftheDMNduringtheirpsilocybinsession.

Researchusingpsychedelicdrugsmightalsoenhanceotherpsychotherapeuticinterventions.TheImperialCollegeresearchgrouphasalsoshownthatLSDenhancessuggestibility.Inaclinicalsetting,thispropertyofLSDcouldbeusedeffectivelytochangeentrenchedwaysofthinkingthathavenotrespondedtopsychotherapeuticinterventionssuchasthoseamongpeoplewithtreatment-resistantdepression,butalsoarangeofconditionsincludingsomepersonalitydisordersandanxietydisorders.Ina2015studybyBarrettetal,LSDwasshowntoenhanceemotionalresponsestomusic,whichcouldbeharnessedtoimprovetheefficacyofpsychotherapeuticinterventions.

Ayahuascahasalsobeenexaminedasatreatmentfordepression.Inadditiontothepsychologicalaspectoftheayahuascaexperience,itappearsthatthereisalsoapharmacologicalexplanationforwhyayahuascacouldbeeffectiveasatreatmentfordepression.Callawayetalfoundin1994thatmembersofasyncreticBrazilianchurchthatusesayahuascahadanincreasednumberofserotoninplateletbindingsitescomparedtothematchedcontrols.Lowdensityofserotoninreceptorshasbeenassociatedwithdepressionandsuicide.Ina2015open-labeltrialbyOsorioetal,sixBrazilianparticipantswithadiagnosisofrecurrentMajorDepressiveDisorderwereadministeredasingledoseofayahuasca.HamiltonDepressionRatingScale(HDRS)scoresdecreasedby62%within24hours,andbyday7thescoreshaddecreasedby72%.WhiletherewasasmallincreaseinHDRSscoresatday14,theywerestilllowerthanatbaselineandtheHDRSscoresonday21weresimilartothoseonday7.Asystematicreviewconductedin2016bydosSantosetalexamined21studiesoftheeffectsofayahuascaonanxietyanddepression.Theyconcludedthatthestudiesconsistentlyshowthat“...[ayahuascahas]anxiolyticandantidepressiveproperties”.Onestudytheyreviewedshowedthatitwasaneffectivetreatmentfortreatment-refractorydepression.

Palliativecare

Peoplewithterminalillnessoftenexperiencearangeofnegativepsychologicalsymptomssuchasdepressionandanxiety,whichinturnleadtoafurtherdecreaseintheirqualityoflife.Forexample,a2011meta-analysisbyMitchelletalfoundthatamongpatientswithcancer,30%-40%metDSM-IVcriteriaforarangeofmoodandanxietydisorders.Giventhatantidepressantshavelowefficacyamongpeoplewithcancer,psychologistsareincreasinglybeingaskedtoassistpatientstomanagethesesymptomswiththeaimofimprovingtheirqualityoflife.However,systematicreviewsofpsychosocialinterventionsforpeoplereceivingpalliativecarefoundfewinterventionsthatimprovedpatientsatisfaction;manyonlydemonstratedsmalleffectsizesforimprovementinqualityoflife,andtheevidenceforimprovedpsychologicalfunctioningwaslimited.Meanwhile,throughacollaborationbetweenJohnsHopkinsMedicalSchoolandUCLA,researchhasfoundthatpsilocybin-assistedpsychotherapyiseffectiveatreducinganxietyandimprovingthequalityoflifeforpeoplesufferingend-stagecancer.AninitialPhase2studywasconductedunderthedirectionofDrCharlesGrobatHarbor-UCLA,andyieldedpromisingresults.TwofurtherRCTsofpsilocybin-assistedpsychotherapyforpsychosocialdistressassociatedwithterminalillnesswerepublishedin2016,andarediscussedbelow.

ThefirstwasacrossoverstudybyRossetalinwhich16participantswererandomisedtoaniacincontrolcondition,sinceniacincancreatesomefacialflushingandotherphysiologicaleffects,and15participantstothepsilocybincondition.Thepsychotherapyprotocolinvolvedthree2-hourpreparatorysessionswithamale-femaleclinicalteamtoestablishatherapeuticalliance,reviewthemeaningandnatureofthepsychologicalandexistentialdistressassociatedwithparticipants'cancerandcollaborativelydevelopspecificmanagementplans(psychotherapeuticandpharmacological)tominimiseanypsychologicallyadverseeffectsofpsilocybin.Thepsilocybin/niacinsessionoccurredinaloungeroom-likeenvironmentwhereparticipantswereencouragedtoliecomfortablyonacouchwearingeyeshades,listeningtopre-selectedmusicthroughheadphones(standardisedtobethesameforallparticipantsandselectedbytheresearchteamtotemporallymatchthephenomenologicaleffectsofpsilocybinoveritscourseofaction)anddirectingtheirattentiontotheirinternalexperience.Thetherapistswerepresentthroughouttheentire8-hoursession.

Towardstheendofthesession,participantswereencouragedtodiscusstheentiretyoftheirsubjectiveexperiencewiththetreatmentteamtoconsolidatethememoryofitandbegintheintegrationprocess.Overthefollowingweeks,participantscompletedthree2-hourpost-integrativesessionsthataimedtofurtherconsolidatethememoryandcontinuetheprocessofpsychologicalintegration.Thepost-integrativesessionstookaninformed-eclecticapproach,utilisingcognitive-behaviouraltherapy,existentialpsychotherapyandpsychodynamic/psychoanalytic-orientedtherapies.

Rossetalfoundthatfrombaselinetoonedaypostthefirstpsilocybinsession,83%ofparticipantsinthepsilocybingroup(cf.14%intheniacingroup)metcriteriaforananti-depressantresponseaccordingtotheBeckDepressionInventory,while58%ofparticipantsinthepsilocybingroupmetcriteriaforanxiolyticresponseusingtheHADSAnxietysubscale(cf.14%intheniacin-firstgroup).Participantsinthepsilocybinarmalsohadlowerstateandtraitanxietyonedaypostthefirstpsilocybinsessioncomparedtothecontrolgroup,andreportedimprovementsintheirphysicalhealthandsocialrelationshipsasmeasuredbytheWorldHealthOrganisationQualityofLifeScale-BriefVersionfrombaselineto2weekspostthepsilocybinsessioncomparedtothecontrolgroup.AlloftheeffectswerelargewithCohen’sdrangingbetween0.8and1.69,withalmostalleffectsgreaterthan1.0.Theseeffectsweresustainedforsevenweekspostthefirstpsilocybinsession.Thecrossoveroccurredatweek7withparticipantsinthecontrolarmreceivingapsilocybinsessionwhileparticipantsinthepsilocybinarmreceivedasecondpsilocybinsession.Similaracuteeffectswereobservedamongthecrossovergroupwhentheyreceivedpsilocybin.Theeffectsamongthefirstpsilocybingroupweremaintainedata26-weekfollow-up.

Thesecondstudy,byGriffithsetal,wasadouble-blindRCTof56end-stagecancerpatientsinwhichalowdoseofpsilocybinwasusedasacontrol.ThepsychotherapyprotocolwassimilartothatdescribedbyRossetal.Thoseinthehighdoseconditionhadsignificantreductionsinseveralmeasuresofanxietyanddepression(e.g.,BeckDepressionInventory,HamiltonAnxietyRatingScale,BriefSymptomInventory,etc.),andimprovedqualityoflifeasmeasuredbytheMcGillQualityofLifeScale,comparedtothelowdosegroup(effectsizesrangedbetween0.35and1.33,withameaneffectsizeof0.82,asmeasuredusingCohen'sd).Onceallparticipantshadreceivedahighdose,a6-monthfollow-upshowedthatthereductionsinanxietyanddepressionweremaintainedwithcomparisonstobaselineshowingeffectsizesrangingbetween0.66and2.98.

Australia’sfirstclinicaltrialofpsychedelic-assistedtherapy,aPhase2RCTusingpsilocybintotreat30participantsexperiencinganxietyanddepressionassociatedwithlife-threateningillness,commencedrecruitinginJanuary2020atStVincent’sHospital,Melbourne.

Post-traumaticStressDisorder

Post-traumaticStressDisorder(PTSD)isadebilitatingpsychiatricconditionarisingafteratraumaticlifeeventthatseverelyreducesqualityoflifeandmayleadtoorexacerbateotherpsychiatricandmedicalproblems.PTSDisconsideredaworldwidepublichealthissue.Itisestimatedthat1.2%ofAustralianswillhavePTSDinany12monthperiod.In2010,PTSDwasthemostprevalentanxietydisorderintheAustralianDefenceForce,affecting8.3%ofmembers.TherehasbeenrecentmediainterestinthisissueasmoreAustraliansoldiers,particularlyyoungmen,arenowlosingtheirlivesthroughsuicidethanhavediedinrecentconflicts.

PTSDisclearlyaseriouspublichealthproblemandcontributessubstantiallytohealthcarecosts.PTSDistypicallyachronicillnessassociatedwithhighratesofpsychiatricandmedicalco-morbidity,disability,sufferingandsuicide.PeopleexperiencingPTSDfacechallengesinrelationshipsandworkproductivity.Yetquestionsremainconcerningthebestpossibletreatments.

Whenexposure-basedpsychotherapeuticinterventionsforPTSDwork,theyworkwell.Theaverageclientwhocompletesprolongedexposuretherapyhasan86%greaterreductioninsymptomsthanawait-listcontrolparticipant,andthesechangesaremaintainedinlongtermfollow-ups.However,ithasbeenestimatedatleast30%ofpeopledonotrespondtoexposure-basedpsychotherapeuticinterventions.Forexample,inaRandomisedControlTrial(RCT)ofCognitiveProcessingTherapythatrecruited171rapevictims,therewasanattritionrateof30%,andofthosewhocompletedtreatment,47%stillmetcriteriaforPTSD.Manyoftheseclientsdropoutoftreatmentastheyfindtheexposuretooconfronting,cannottalkaboutthetrauma,ordonotengageintheexposureenoughforthetreatmenttobeeffective(i.e.thewindowoftolerance).Thosewhodonotrespondtopsychotherapeuticinterventionsaretypicallytreatedwithantidepressantmedicationstoattenuatethesymptoms,thoughthistreatmenthaslowefficacyandthemedicationscancausesideeffects.

3,4-Methylenedioxymethamphetamine(MDMA)wasfirstsynthesisedbyMerckandpatentedin1913asanintermediatecompoundinthesearchforaneffectivedrugtocontrolbleeding.MDMAisnotstrictlyclassifiedasapsychedelic;betterdescribedasanentactogenorempathogen,itwasusedinpsychotherapyinthe1970sasanadjunctincouplesrelationshipcounsellingandtohelpaddresstrauma-ithastheuniquepropertiesofcreatingempathywithclinicalstaff,allowingtheclienttore-experiencethetraumaticeventwithinthewindowoftolerance,andovercomesurvivor’sguilt.ThefirstclinicalstudyreportingonthetherapeuticeffectsofMDMAwaspublishedin1986byGreerandTolbert.

Despiteoft-citedconcernsaboutthesafetyofMDMA,therehavebeennoseriousadverseeventsinanyoftheclinicalstudiescompletedsofar.OneverywellcontrolledstudyinUtahbyHalpernetalrecruited52peoplewhousedEcstasy(anearlycolloquialnameforMDMA)regularlyand59peoplewhohadneverusedthedrug.Allparticipantswerenottohaveusedanyothersubstance,includingalcohol,intheirlifetime,andweremembersoftheclub/ravescene.Theresearchersfoundnosignificantdifferencesonarangeofneuropsychologicaltests.

Despiteinitialpromisingresults,aninitialstudyofMDMAasanadjuncttopsychotherapyinthetreatmentofPTSDbyBousoetalin2000wasshutdownbytheSpanishgovernment.ThefirstRCTlookingattheefficacyofMDMA-assistedpsychotherapyfortreatment-refractoryPTSDcommencedin2001andfoundthatafter12sessionsofpsychotherapy,withjusttwoMDMAsessions,83%ofparticipantsnolongermetDSM-IVcriteriaforPTSD.Theseeffectsweremaintainedata3.5-yearfollow-up,withonly10%ofparticipantsrelapsinginthattime.

Thetreatmentprotocolinvolvedthreepreparationsessionsthatfocusedonbuildingatherapeuticalliancebetweentheclientandthemale-femaleco-therapistteam.Italsoinvolvedanassessmentoftheclient'sexistingsupportsystemsforemotionalregulationandself-care,andstressinoculationtrainingwasprovidedthatbuiltontheclient'sexistinganxietymanagementstrategies.TheMDMA(125mg)wasthenadministeredinasessionthatstartedinthemorningandoccurredinaloungeroom-likesetting,with"participantslyingonafuton,sometimeswitheyeshadesandheadphoneslisteningtomusicwithmaleandfemaletherapistssittingoneithersideforatleasteighthours".This

sessionwasfarlessdirectivethanCBT,thoughtherewasanagreementthatthetherapistswouldbringupthetraumaeventatsomepointduringeachMDMAsessionifitdidnotcomeupspontaneously.Duringdialoguethatemergedduringthesession,therewastheopportunitytoengageincognitiverestructuring,thoughremarkably,itwasnotedthattheeffectsofMDMAaloneoftenledtheclienttohaveprofoundinsightsaboutcognitivedistortionsspontaneously.Theclientstayedovernightintheclinicandanintegrationsessionoccurredthenextmorning.ItwasstatedthatthissessionisessentialastheobjectiveistoconsolidatethememoriesoftheMDMAsessionintoeverydayconsciousnessanddailylife.

Aftertheclienthadlefttheintegrationsession,theywerecontactedviaphoneaspartofacheck-inprocedure.TheythenattendedanotherMDMAsessionafewweekslater,withfurtherintegrativesessionsafterthisMDMAsession.

LaterstudiesusedthreeMDMAsessionsandreducedthedoseto75mg,withaPhase2trialcompletedinSwitzerlandandfurtherPhase2trialsmorerecentlycompletedinSouthCarolina,Colorado,CanadaandIsrael.ThesponsorofthesetrialsistheMultidisciplinaryAssociationforPsychedelicStudies(MAPS),anot-for-profitorganisationthatalsoadministersaPublicBenefitCorporation.MAPSstaffmetwiththeUSFoodandDrugAdministration(FDA)inNovember2016andreceivedapprovaltocommenceaPhase3study,theprotocolforwhichwasapprovedinApril,2017.BecauseofthelargeeffectsizeofthepooledPhase2data,withtwothirdsofparticipantsnolongermeetingcriteriaforPTSD,theFDAacceptedasmallersamplesizethantypicallywouldberequiredforaPhase3study,andthereisnowthepotentialforpeopletoaccessMDMA-assistedtherapythroughacompassionateusescheme.ThismeanspeoplecannowaccessMDMA-assistedpsychotherapywithoutnecessarilytakingpartintheresearch.ThekeygoalofMAPShasbeenforMDMAtobeapprovedasaprescriptionmedicineintheUSAby2021;however,followingtherecentpositiveoutcomes,thismightoccurevenearlier.

FurtherstudiesarebeingcompletedbyMAPS.OneisanopenlabeltrialofCognitive-BehaviouralConjointTherapy(CBCT)integratedwithMDMA-assistedpsychotherapyforthetreatmentofchronicPTSD,inwhichthesignificantotherofthepersonwithPTSDparticipatesinthetreatment.Meanwhile,aprogramtotraintherapistsinMDMA-assistedtherapyhasbeendevelopedthatisaplacebo-controlled,double-blindrandomised,crossoverstudyinwhichasingleMDMA-assistedpsychotherapysessionisadministeredtotherapists.

AutismSpectrumDisorder

Autismisagenetically-basedhumanneurologicalvariant.Autismisadevelopmentalphenomenon,meaningthatitbeginsinuteroandhasapervasiveinfluenceonmultiplelevelsofdevelopmentthroughoutthelifespan.Autisticindividualsfrequentlyexperiencedifficultyintherealmofsocialinteraction.Comparativestudiessuggestthatautisticadults,especiallythosewhoareverbalandwhoseautismmightnotbeimmediatelyrecognisabletoothersandwhoarefacedwithstrongpressuretoconformtonon-autisticsocialnorms,areatgreaterriskforlifetimeandcurrentpsychologicaldisorders,especiallysocialanxiety.

TherearecurrentlynoFDA-approvedpharmacologicaltreatmentsforautisticadultswithsocialanxiety,andconventionalanti-anxietymedicationslackclinicaleffectivenessinthispopulation.

Basedonanecdotalreports,MDMA-assistedtherapymaybeasuitableinterventionforthetreatmentofsocialanxietyinautisticadultsandwarrantsfurtherinvestigationinarandomisedcontrolledclinicaltrial.

MAPS,incollaborationwiththeLosAngelesBiomedicalResearchInstituteatHarbor-UCLAMedicalCenterandStanfordUniversity,hassponsoredarandomised,double-blind,placebo-controlledexploratorypilotstudywithdoseescalationtoassessthesafetyandfeasibilityofMDMA-assistedtherapytotreatsocialanxietyin12MDMA-naïveadultsontheautismspectrum.DrCharlesGrobandAliciaDanforthwereco-investigatorsforthisstudy.Thesubjectswereautisticadultswithsocialanxiety,age21andolder,whohadcompletedtwoyearsofcollege-leveleducationorcomparablevocationaltraining.

ThestudyalsoobtainedestimatesofeffectsizebasedontwoexperimentalMDMA-assistedtherapysessionsincomparisontoaninactiveplacebocontrolgroup.TheexperimentalphaseofthestudywascompletedinJune2017andthedataarebeinganalysed.Iftheresultswarrantfurtherinvestigation,datafromthisstudywillbeusedtodesignadditionalstudies.

Obsessive-CompulsiveDisorder

Obsessive-CompulsiveDisorder(OCD)isachronicconditioncharacterisedbydisturbing,intrusivethoughtsandcompulsiverituals.Theillnesshasalifetimeprevalenceofabout2.5%,thereforeafflictingmillionsofpeopletovariousdegrees.OCDhasarangeofcomorbidsymptoms,includinganxiety,insomnia,anddepression.Aseriouspublichealthproblemwithsignificantassociatedmorbidityandmortality,itisoneofthefewpsychiatricconditionsforwhichthelevelofsufferingandthelackofavailabletreatmentstillallowfortheuseofpsycho-surgeryinsomecountries.

Serotonin(5-HT)iswidelythoughttoplayaroleinobsessiveideationandbehaviour.Clinicalresearchhasalsofoundthatregulationof5-HTreceptorscanrelievesymptomsofOCDinsomeindividuals.However,inspiteofthedevelopmentofseveralnewtreatmentsforthisdisorder,thetotaleliminationofsymptomsisrare.

Severalindividualcasereportsoverthirtyyearsnotedbeneficialeffectsofserotonergicpsychedelicsinthetreatmentofobsessivethoughts,leadingtothehypothesisthatpsilocybinadministeredincontrolledclinicalenvironmentsmayrelievethesymptomsofobsessivecompulsivedisorderinsomeindividuals.SomereportshavesuggestedthatremissionofthesymptomsofOCDmaycontinueforseveralmonthsafterasingledoseofpsilocybin.

ThehypothesiswastestedinonePhase1double-blindRCTattheUniversityofArizona,inwhichvaryingdosesofpsilocybinwereadministeredtonineparticipants.Theresultswereencouragingbutnotconclusive,inthattransientremissionfromsymptomswasexperiencedbyallparticipants,butonlyoneparticipantexperiencedmeasureableremissionforlongerthan1-2weekspost-dose.

Recently,twodouble-blind,placebo-controlledstudiesofpsilocybinforOCDhavebeenregistered.Thefirst,aPhase1studyatYaleUniversity,aimstorecruit30participantsandcompare25mgpsilocybinto250mgniacinplacebo.Thesecond,aPhase2quadruple-blindrandomiseddose-responsestudyof15participants,willbeconductedbytheUniversityofArizonateamasafollow-up

totheoriginalPhase1.Bothareintheveryearlystagesofrecruitmentandareanticipatedtobecompletedby2021.Anorexianervosa

Anorexianervosaandothereatingdisorderssuchasbulimianervosahavealifetimeprevalenceofapproximately1%ofthepopulationinWesterncountries.Femaleshavea10-foldgreaterincidencethanmales.Anorexiaisdefinedbyanobsessiveneedtoloseweight,resultinginstrictcontrolofcaloricintakeandarangeofcomorbidmentalandphysicalhealthconditions.Asignificantproportionofpeoplewithanorexiaalsoundertakehighlevelsofregimentedexerciseorotherphysicalactivityinordertominimiseweightgain,andtheymayhaveadisturbedbodyimage,includingextremeemphasisontheirappearanceandtheperceptionthattheyareoverweight,despitebeingconsiderablyunderweight.

Basedonbrainimagingstudies,itislikelythatdiminishedneuralactivityinthebrain’srewardregions,alongwithincreasedactivityinitscontrolregions,areresponsiblefortheparticularcombinationofhighbehaviouralcontrolandlowcognitiveflexibilitythatcharacterisesanorexiaandothereatingdisorders.Inspiteofthehighmortalityandprevalenceofcomorbiddepressionandanxiety,thereiscurrentlynoeffectivetreatmentforeatingdisorders,andpharmacologicaltreatmentshavebeenlargelydirectedatmanagingtheassociatedmoodconditions.

Proposedtherapeuticmodelsofpsilocybinandotherclassicalpsychedelicsincludethedisruptionofrigidthoughtpatterns,suchasthosepostulatedtounderlieanorexiaandothereatingdisorderssuchasbulimia.Giventhedemonstratedeffectivenessofpsilocybin-assistedpsychotherapyinthetreatmentofmajordepression,alongwithanxietyassociatedwithterminalillness,theapproachmayalsobeusefulinthereliefoflowmoodconditionsassociatedwitheatingdisorders.AnxietyanddepressionformtheexplicitbasisofaPhase1OpenLabelstudyoftheeffectsofpsilocybinonanorexiarecentlyregisteredbyJohnsHopkinsUniversity,althoughseveralmeasuresrelatedtoanorexiaitselfarealsoincluded.AsecondstudyofpsilocybinforanorexiaiscurrentlyinthepipelineatImperialCollegeLondon,thoughthattrialisyettoberegistered.

EarlyAlzheimer’sDiseaseandMildCognitiveImpairment

Alzheimer’sdiseaseandotherformsofdementiaarecausinggrowingconcernworldwide,particularlyincountriesthathavesteadilyageingpopulations,duetobothitsdirectmortalityandtherisingcostsofassociatedhealthcare.Alzheimer’saffectsaround6%ofpeopleover65yearsofage.Thediseaseisprogressiveandischaracterisedbycognitivedecline,memoryloss,disorientation,andbehaviouralchanges.TheunderlyingcausesofAlzheimer’sarenotwellunderstood,andtreatmentoptionsfortheconditionitselfremainlimitedtoeffortstoslowitsprogressionandtopalliativesymptomaticrelief.

ThepreclinicalstageofAlzheimer’sDiseasehasalsobeencalledMildCognitiveImpairment(MCI).DepressionmayoccurinsomeindividualsexperiencingMCIandEarlyAlzheimer’sdisease,andaPhase1Open-labeltrialhasbeenregisteredbyJohnsHopkinsresearcherstostudytheefficacyof

psilocybin-assistedtherapyinthetreatmentofdementia-relateddepression,asquantifiedbyseveralmeasures.

Despiteitspotentialapplicationtothereliefofmooddisordersassociatedwithearly-stagedementia,itisimportanttonotethatthereisnosuggestionthatpsilocybin-assistedtherapymighthaveanydirecttherapeuticapplicationforthetreatmentofMildCognitiveImpairmentorAlzheimer’sdisease.

Migraine&ClusterHeadache

Clusterheadachesarearare,severelypainfulformofheadachethatisrelatedtobutdifferentfromthemorecommonmigraine.Thepainofaclusterheadachecommencesquickly,withoutwarning,andreachesacrescendowithin2to15minutes.Itisoftenexcruciatinginintensity,andisdeep,non-fluctuating,andexplosiveinquality.Peoplemayhaveepisodicorchronicclusterheadaches;currentresearchisfocusingontheepisodicform.Episodicclusterheadachesoccurperiodically,oftenoccurringatthesametimeeachyear.Duringacycle,apersonwithepisodicclusterheadacheswillexperienceanaverageofonetothreeheadachesperday,withfrequencyrangingfromoneheadacheeveryotherdaytoeightperday.

Conventionaltreatmentsincludetreatmentsforstoppingheadachepainasitoccurs(abortives),andtreatmentsthatreducetheoccurrenceorre-occurrenceofclusterheadaches(prophylaxis).CasereportsovermanyyearshavesuggestedthatingestingpsilocybinorLSDcanreduceclusterheadachepainand,moresignificantly,caninterruptclusterheadachecyclessothatnomoreheadacheswilloccur.

MAPSsponsoredanearlystudyofpsilocybinforclusterheadache,whichisnowbeingfollowedupwithaPhase1RCTatYaleUniversity.Thestudyisexpectedtoconcludein2021.

SubstanceUseDisorders

InalargeAustralianprospectivemultisitestudyofclientsaccessingAlcoholandOtherDrug(AOD)treatmentservices,70%completeda12-monthfollow-upassessment,ofwhich47%hadnotreducedtheirconsumptionofAODs.ProjectMATCHwasamultisitestudyconductedover8yearsintheUSAthatfoundnodifferenceintreatmentoutcomesamongpeopleseekingtreatmentforalcoholdependencewhowererandomlyallocatedtoCognitive-BehaviouralTherapy,MotivationalInterviewingor12-stepprograms.Thishasledmanytoproposethataddictionisachronicandrelapsingconditionandthatthereisnooneeffectiveintervention.However,researchconductedpriortotheprohibitionofLSDusingsmallsamplesizesfoundLSD-assistedpsychotherapytobeeffective.Forexample,among16peoplewithseverealcoholdependence,Chwelosetalreportedin1959that15hadreducedtheiruseofalcoholatasix-monthfollow-up,while10hadremainedabstinent.

Newresearchisreinforcingthecasethatpsychedelicmedicinesmightbeeffectiveinthetreatmentofsubstance-usedisorders.Forexample,anopen-labeltrialofpsilocybin-assistedpsychotherapyforthetreatmentoftobaccoaddictionamong15peoplefound10(or67%)werebiologicallyconfirmedasabstinentat12-monthfollow-up.Thisishighconsideringthata2009RCTofVarenicline,themost

efficaciouspharmacotherapyforsmokingcessation,conductedbyIgarashietalfoundthatonly25.5%ofparticipantswereabstinentat12months.Aproof-of-conceptstudyhasfoundsimilareffectsintreatingalcoholdependencewithpsilocybin-assistedpsychotherapyshowingsimilarlyimpressiveeffects.Therewasasignificantreductioninalcoholconsumptionatweek4ofthetherapywhenpsilocybinwasadministered,andthisreductionwasmaintainedfor36weeks.TheteamatJohnsHopkinsisnowrecruiting40participantstoconductaRCTtogatherfurtherevidenceforthistherapywhileateamatNewYorkUniversityisrecruiting140participantstoexaminetheefficacyofpsilocybin-assistedpsychotherapyforalcoholdependence.

Someevidenceisemergingthatusingtheshamanicbrewayahuasca,whichistypicallyadministeredinaceremonialgroupcontext,maybeaneffectivetreatmentforsubstanceusedisorders.AyahuascacontainsDMT,whichisnormallydeactivatedinthestomachandthroughoutthebodybymonoamineoxidaseenzymes.BycombiningplantscontainingDMTwithplantscontainingreversibleinhibitorsofmonoamineoxidase-A,SouthAmericanshamanshaveusedayahuascaforspiritualandhealingpurposesforhundreds,andpossiblythousands,ofyears.Inthepastdecadetherehasbeenanexponentialincreaseinthenumberofstudiespublishedinternationally,examiningayahuascafromarangeofperspectives,withobservationalstudiesfindingayahuascamightassistpeopleexperiencingsubstanceusedisorders.

Forexample,anobservationalstudybyThomasetalinCanadarecruited18peoplewhohadnotpreviouslyconsumedayahuascaandplannedtoattendanayahuascaretreattoaddresstheiraddictiontoeithertobacco,alcohol,cannabis,orcocaine.Participantswereadministeredabatteryofpsychometricinstrumentspriortoattendingtheretreatandthenre-administeredthesescalesfor5monthsposttheretreat.The4-weekSubstanceUseScaleshowedthatself-reporteduseofallsubstancesexceptcannabiswassignificantlyreducedfrombaselinetofollow-up.Interestingly,theyalsoobservedsignificantincreasesinmeasuresofqualityoflifeandhope,empowermentandmindfulness.Furtherresearchisneededtodeterminetheefficacyofayahuascaasatreatmentforaddiction.

Finally,ithaslongbeenobservedthatmanypeoplewhodevelopopiateusedisordershaveahistoryoftrauma.Forexample,Teessonetalreportedin2015that41%ofpeoplereceivingtreatmentforheroindependencemetcriteriaforPTSD.However,somehavesuggestedthattheratesoftraumaamongallpeoplewithothersubstanceusedisordersmaybesimilar.Amongasampleof423Dutchpeoplewitharangeofsubstanceusedisorders,Gielenetalreportedin2012that46.2%ofparticipantswhoseprimarydrugofchoicewasalcoholmetcriteriaforPTSD.

Aproof-of-conceptstudy,initiatedin2016intheUKbyDrBenSessa,aimstoprovideanalternativetreatmentforpeoplewithsubstanceusedisorderswhohaveahistoryoftrauma.Therationaleforhisstudyisthattrauma-relatedsymptomsleadpeopletobecomesociallyisolated,soinsteadofattachingtoothers,peoplewithtrauma-relatedsymptomsattachtosubstances.ThroughintegratingmotivationalinterviewingwithMDMA-assistedpsychotherapy,Sessaanticipatesthatparticipantswillhaveincreasedpositivesocialconnectivityasaresultofdecreasedtrauma-relatedsymptomsleadingtoabstinencefromtheirdrugofchoice.Mechanisticresearchonthetherapeuticbenefitsofpsychedeliccompounds

Asoutlinedabove,contemporaryresearchonpsychedelicsiscorroboratinghistoricalreportsoftheiranxiolyticandantidepressanteffects.Anunderstandingofthemolecularmechanismsunderpinningthetherapeuticbenefitsofpsychedeliccompoundsmaybeusefulinexpandingtheirapplicationinpsychiatry,andforresearchinstitutions,legislatorsandfundingbodiestoacknowledgetheirutility.

Arecentstudyelucidatedsomeofthosemolecularmechanisms.Inthisresearch,thepsychedeliccompoundspsilocybin,DMTandDOI(apsychedelicamphetamine)wereobservedtopromotestructuralandfunctionalneuralplasticityinvitroandinvivo,inamannersimilartothatelicitedbyketamine,adissociativeanaestheticthatisalsobeinginvestigatedforitsantidepressantproperties.Themainfindingsincludedincreasedformationofneuralinterconnections,specificallythroughtheprocessesofneuritogenesis,spinogenesisandsynaptogenesis.Itwasproposedthatthesechangesaredrivenbyincreasedreleaseofbrain-derivedneurotrophicfactor(BDNF),aproteinthatactivatesmTOR,akeysignallingcascadethatregulatesneuronalplasticityandwhichismodulatedbystandardantidepressantandanti-neurodegenerativedrugs.Giventheobservedeffectsonneuroplasticityandimmunomodulatorypathways,itisconceivablethatpsychedelicscouldproveusefulintreatingdiseasesinwhichneurodegenerationisimplicated,suchasAlzheimer’sandParkinson’sdisease.Whileextensivefurtherstudieswillbenecessarytovalidatethesefindings,therationaleiscompellingforexpandingpsychedelicresearchtothetreatmentofneurodegenerativeconditions.

Conclusion

Themanyexamplestabulatedanddiscussedinthisreviewillustratethatpsychedelicscienceisindeedundergoinganimpressiverenaissance,asbroadlydispersedresearchgroupsstudythemechanistic,psychologicalandtherapeuticeffectsofMDMA,psilocybin,LSDandseveralothercompounds.Inparticular,thetherapeuticpotentialofMDMAforPTSDandforsocialanxietyassociatedwithautism,andlikewisethepotentialofpsilocybinasanadjuncttopsychotherapyforthetreatmentofanxietyanddepression,OCDandsubstanceusedisorders,areespeciallypromising.

Thereislittledoubtthatthebodyofpsychedelicmedicalresearchwillcontinuetogrow,aslongasfundingsourcescontinuetosupporttheresearchendeavour,regulatoryauthoritiescontinuetoallowthisclinicalandtranslationalresearchtooccur,andtheresearchresultsultimatelyconfirmtheearlypromiseoftheseinterventions.

Acknowledgement

M.W.acknowledgesthecontributionofDrStephenBright,co-authorofthefollowingpaperinAustralianPsychologist(2018)thatformedthebasisofsomeofthediscussioninthisreview.

https://www.researchgate.net/publication/323773002_Should_Australian_Psychology_Consider_Enhancing_Psychotherapeutic_Interventions_with_Psychedelic_Drugs_A_Call_for_Research

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