file:///E:/bn168svampegifte/psilocybin-forskningsartikel2016.pdf

www.thelancet.com/psychiatry Vol 3 July 2016 619

Articles

Lancet Psychiatry 2016;

3: 619–27

Published Online

May 17, 2016

http://dx.doi.org/10.1016/

S2215-0366(16)30065-7

See Comment page 592

*Contributed equally

Centre for

Neuropsychopharmacology,

Division of Brain Sciences,

Faculty of Medicine, Imperial

College London, London, UK

(R L Carhart-Harris PhD,

M Bolstridge MD,

J Rucker MD, C M J Day MD,

D Erritzoe MD, M Kaelen BSc,

Prof D J Nutt DM); Department

of Pharmacy and Pathology,

South London and Maudsley

NHS Foundation Trust,

London, UK (Prof D Taylor PhD);

The Institute of Psychiatry,

Psychology and Neuroscience

(J Rucker) and Institute of

Pharmaceutical Science

(Prof B Forbes PhD), King’s

College London, London, UK;

Department of Psychiatry

(M Bloomfield MD), Clinical

Psychology and Clinical

Effectiveness

(Prof S Pilling PhD), and Clinical

Psychopharmacology Unit

(Prof V H Curran PhD),

University College London,

London, UK; Barts Health

Pharmaceuticals, Barts Health

NHS Trust, The Royal London

Hospital, London, UK

(J A Rickard PhD); and The

Beckley Foundation, Beckley

Park, Oxford, UK (A Feilding)

Correspondence to:

Dr Robin L Carhart-Harris, Centre

for Neuropsychopharmacology,

Division of Brain Sciences,

Faculty of Medicine, Imperial

College London, London

W12 0NN, UK

r.carhart-harris@imperial.ac.uk

Introduction

Psilocybin er en naturligt forekommende plante alkaloidfound i svampens Psilocybe-genus. Psilocybe

svampe er blevet brugt i årtusinder til helbredende formål, men blev kun opdaget af moderne videnskab i slutningen af ​​1950'erne. 1,2 Psilocybin er et prodrug af psilocin (4-hydroxy-dimethyltryptamin), en serotoninreceptoragonist og klassisk psykedelisk lægemiddel, hvis primære psykoaktive Effektiver er medieret af serotonin 2A (5-HT2A) receptoragonisme.3 Psilocybin har derfor en ny farmakologi i sammenhæng med aktuelt tilgængelige antidepressive lægemidler, fordi selektive serotoninreceptionshæmmere ikke er direkte 5-HT2A receptoragonister. Forbedret kognitiv fleksibilitet, 4 associativ læring, 5 kortikale neurale plasticitet, 6 og antidepressive reaktioner er blevet rapporteret med 5-HT2A receptoragonisme hos dyr 7 og øgede og vedvarende forbedringer i velvære8 og optimisme9 er blevet observeret efter psykedeliske erfaringer hos mennesker. Resultater fra human imaging studier med psilocybin har suppleret disse opdagelser, der viser ændringer i hjerneaktivitet, der tyder på antidepressivt potentiale; For eksempel har en række effektive antidepressive behandlinger vist sig at normalisere hyperaktiviteten i den mediale præfrontale cortex, og vi fandt reduceret blodflow i denne region med intravenøs psilocybin.10 Desuden har data opnået fra storskala befolkningsundersøgelser for nylig udfordret se på, at psykedelik negativt affekter mental sundhed, 11-13 med en undersøgelses resultater, der viser lavere satser for psykisk lidelse og suicidalitet blandt mennesker, der havde brugt Psilocybin med psykologisk støtte til behandling-resistent depression: en åbenbar feasibility study Robin L Carhart-Harris , Mark Bolstridge, James Rucker *, Camilla MJ Day *, David Erritzoe, Mendel Kaelen, Michael Bloomfield, James A Rickard, Ben Forbes, Amanda Feilding, David Taylor, Steve Pilling, Valerie H Curran, David J Nutt Sammendrag Baggrund Psilocybin er en serotoninreceptoragonist der forekommer naturligt i nogle svampearter. Nylige undersøgelser har vurderet det terapeutiske potentiale af psilocybin til forskellige forhold, herunder livslang angst, obsessiv-kompulsiv lidelse og rygning og alkoholafhængighed med lovende foreløbige resultater. Her har vi til formål at undersøge fejlbarheden, sikkerheden og virkningen af ​​psilocybin hos patienter med unipolær behandlingsresistent depression. Metoder I dette åbenbare feasibility-forsøg modtog 12 patienter (seks mænd, seks kvinder) med moderat til alvorlig, unipolær, behandlingsresistent major depression to orale doser psilocybin (10 mg og 25 mg, 7 dage fra hinanden) i en støttende indstilling. Der var ingen kontrolgruppe. Psykologisk støtte blev leveret før, under og efter hver session. Den primære udfaldsmåling for gennemførlighed var patient-rapporteret intensitet af psilocybin's eff ects. Patienterne blev overvåget for bivirkninger under doseringssessionerne og efterfølgende klinik og fjern opfølgning. Depressive symptomer blev vurderet med standardvurderinger fra 1 uge til 3 måneder efter behandling, med 16-punkts Quick Inventory of Depressive Symptoms (QIDS), der tjener som det primære effektudfald. Denne prøve er registreret hos ISRCTN, nummer ISRCTN14426797. Resultater Psilocybins akutte psykedeliske effekter blev typisk detekterbare 30-60 minutter efter dosering, toppede 2-3 timer efter dosering og faldt til ubetydelige niveauer mindst 6 timer efter dosering. Den gennemsnitlige intensitet (på 0-1 skala) var 0 · 51 (SD 0 · 36) for lavdosis-sessionen og 0 · 75 (SD 0 · 27) for højdosisessionen. Psilocybin blev godt tolereret af alle patienterne, og der opstod ingen alvorlige eller uventede bivirkninger. Bivirkningerne vi noterede var forbigående angst under lægemiddelstart (alle patienter), forbigående forvirring eller tankeforstyrrelse (ni patienter), mild og forbigående kvalme (fire patienter) og forbigående hovedpine (fire patienter). I forhold til baseline blev depressive symptomer markant reduceret 1 uge (gennemsnitlig QIDS-differens -11,8, 95% CI -9 · 15 til -14 · 35, p = 0 · 002, Hedges'g = 3 · 1) og 3 måneder (-9 · 2, 95% CI -5 · 69 til -12 · 71, p = 0 · 003, Hedges 'g = 2) efter højdosisbehandling. Markerede og vedvarende forbedringer i angst og anhedoni blev også bemærket. Fortolkning Denne undersøgelse giver foreløbig støtte til sikkerheden og effekten af ​​psilocybin til behandlingsresistent depression og motiverer yderligere forsøg med mere stringente designs for bedre at undersøge terapeutisk potentiale ved denne tilgang. Finansiering Medicinsk Forskningsråd. Copyright © Carhart-Harris et al. Open Access artikel distribueret i henhold til CC BY. Artikler 620 www.thelancet.com/psychiatry Vol 3 juli 2016 psykedelik inden for deres levetid end blandt dem der ikke anvendte psykedelik, men en tilsvarende mængde andre lægemidler.11 I moderne forsøg har psykedelik vist sig at reducere angst, 14,15 depressive, 15,16 og obsessive compulsive symptomer, 17 såvel som vanedannende adfærd, 18,19 ofte i flere måneder efter blot en eller to eksponeringer. Omfattende historisk og moderne beviser støtter nu den opfattelse, at psykedelik har en gunstig sikkerhedsprofil, som administreres i et kontrolleret miljø med passende støtte.20 Depression er et stort folkesundhedsproblem; Det er en førende bidragyder til den globale sygdomsbyrde, der affødte hundredvis af millioner af mennesker over hele verden og koster USA alene mere end 200 milliarder dollars hvert år.21 Antidepressive lægemidler og kognitiv adfærdsterapi kan være effektive for nogle patienter, men omkring 20% ​​reagerer ikke på nogen intervention, og mange af dem, der reagerer, falder i sidste ende.22 Vi har til formål at undersøge sikkerheden og gennemførligheden af ​​psilocybin hos patienter med behandlingsresistent depression og at etablere et første indtryk af dets virkning. Vi postulerede, at behandlingen ville tolereres godt, og depressive symptomer ville blive væsentligt reduceret fra baseline på alle vurderingssteder i op til 3 måneder efter behandling. Metoder Studie design og deltagere Dette var en åbenbar feasibility undersøgelse hos patienter med behandlingsresistent depression; der var ingen kontrolgruppe. Patienter, investorer, investorer, ratere og statistikere blev ikke maskeret til behandlingsopgaver, og alle deltagere modtog undersøgelsesinterventionen (psilocybin administreret i to doseringssessioner: en initial sikkerhedsdosis [lav] dosis og en efterfølgende behandling [høj] dosis). Inklusionskriterierne var stor depression i moderat til svær grad (17 + på 21-punkts Hamilton Depression Rating scale [HAM-D]) og ingen forbedring på trods af to passende kurser af antidepressiv behandling af forskellige farmakologiske klasser på mindst 6 uger inden for den nuværende depressive episode.23 Udelukkelseskriterier var: nuværende eller tidligere diagnosticeret psykotisk lidelse; øjeblikkeligt familiemedlem med diagnosticeret psykotisk lidelse; medicinsk signifikant tilstand, der giver uundgåelighed for undersøgelsen historien om alvorlige selvmordsforsøg (kræver hospitalisering) maniets historie blod- eller nålfobi; positiv graviditetstest ved screening eller under undersøgelsen og nuværende afhængighed af narkotika eller alkohol. Oplysninger om undersøgelsens rekruttering blev sendt til praktiserende læger via North West London Clinical Research Network. Patienter fik dog også lov til selv at henvise til undersøgelsen, hvis de var britiske indbyggere. I alle tilfælde blev patienter indledt kontakt med forskergruppen (via e-mail, brev eller telefon), der blev sendt et studieinformationsblad, og der blev arrangeret en efterfølgende telefonscreening, hvor ledende psykiater på prøven (MBo) fik information om patientens demografi, medicinsk og psykiatrisk historie og andre nøgleintegrations- eller udelukkelseskriterier. Patientens praktiserende læge eller psykiater fremlagde skriftlig dokumentation af patientens diagnose og psykiske baggrund i alle tilfælde. Dette forsøg modtog en positiv udtalelse fra National Research Ethics Service London-West London, blev sponsoreret og godkendt af Imperial College London Joint Research and Compliance Office (JRCO) og blev vedtaget af National Institute for Health Research Clinical Research Network. National Institute for Health Research / Wellcome Trust Imperial Clinical Research Facility gav stedspecifik godkendelse til undersøgelsen. Forskning i kontekst Bevis før denne undersøgelse Vi søgte PubMed frem til 30. januar 2016 ved at bruge udtrykket "psilocybin", "hallucinogener", "psykedelik" og "depression". Vi fandt ikke nogen kliniske forsøg, der vurderede psilocybin som en behandling for depression, men vi fandt befolkningsanalyser, gennemgå artikler og billedstudier, der yder støtte til denne tilgang. Vi fandt også en rapport, der dokumenterer vedvarende fald i depressive symptomer efter en enkelt dosis psilocybin i en randomiseret kontrolleret undersøgelse af psilocybinassisteret psykoterapi for livslang angst, en rapport om et åbent forsøg med hurtige fald i depressive symptomer, som udholdt i op til 21 dage efter en enkelt dosis ayahuasca og to tidlige rapporter eller casestudier om effekter af lyserginsyre-diethylamid på "neurotiske" og depressive symptomer, der beskriver "forbedringer", omend uden validerede foranstaltninger af symptomværdighed. Merværdi af denne forskning Vi vidner om, at dette er den første undersøgelse af sikkerheden og effekten af ​​psilocybin som en behandling for større depression. Vores resultater indebærer, at psilocybin kan have værdi som en behandlingsmulighed i behandlingen af ​​behandlingsresistent depression. Enlige orale indgivelser på 10 mg (sikkerhedsdosis) og 25 mg (behandlingsdosis) psilocybin blev tolereret godt og førte til vedvarende reduktioner i symptomernes alvor efter de to sessioner. Virkninger af alle tilgængelige beviser Resultaterne af denne småskalige gennemførlighedsundersøgelse skal bidrage til at motivere yderligere undersøgelse af psilocybins effektivitet med psykologisk støtte til større depression. Større skala randomiserede kontrollerede forsøg er berettiget til bedre at undersøge potentialet af psilocybin som en behandlingsmulighed for denne meget udbredte, invaliderende, dyre og vanskelig at behandle lidelse. Mere bredt skal den foreliggende undersøgelse bidrage til at katalysere genopkomsten af ​​et lovende forskningsområde inden for psykiatrien. Artikler www.thelancet.com/psychiatry Vol 3 juli 2016 621 Undersøgelsen blev gennemgået og godkendt af Medicines and Healthcare Regulatory Agency (MHRA). Alle deltagere gav skriftligt informeret samtykke. Studie- og dataovervågning blev udført uafhængigt af Imperial Clinical Research Facility og JRCO. Procedurer Psilocybin blev opnået fra THC-pharm (Frankfurt, Tyskland) og formuleret i undersøgelseslægemidlet (5 mg psilocybin i størrelse 0 kapsler) af Guys og St Thomas 'Hospital's Pharmacy Manufacturing Unit (London, UK). En hjemmekontorlicens til opbevaring og dispensering af Schedule One-lægemidler blev opnået. Screening bestod af skriftligt informeret samtykke, en grundig evaluering af patientens fysiske og mentale sundhed baggrund, en psykiatrisk interview (MiniInternational Neuropsychiatric Interview), klinikernes vurdering af depression alvorlighed (21-punktet HAM-D og Montgomery-Åsberg Depression Rating Scale [ MADRS] og Global Assessment of Functioning [GAF], alle vurderet af MBo) og yderligere patientrelaterede skalaer (16-punkts Quick Inventory of Depressive Symptoms [QIDS], Beck Depression Inventory [BDI-original version], Spielberger's State- Trait Angst Inventory [formular 2, kun træk version STAI-T] og SnaithHamilton Pleasure Scale [SHAPS]). Patienterne fik også en grundig fysisk sundhedskontrol, der består af et elektrokardiogram, rutinemæssige blodprøver, blodtryk, puls og fysisk undersøgelse. Ved afslutningen af ​​screeningen fik de berettigede patienter lejlighed til at mødes med de to kliniske psykiatere, som ville støtte dem gennem resten af ​​retssagen. Støtteberettigede patienter deltog i et efterfølgende besøg, der involverede en baseline funktionel MR-scanningssession, der varede 60 minutter efterfulgt af en omfattende forberedende session med deres tildelte psykiatere; fMRI data vil blive rapporteret andetsteds. Denne forberedende session involverede patienten til at tale åbent om deres personlige historie (herunder tanker om deres depressions oprindelse), en diskussion af psilocybins psykologiske effekter og simulering af aspekter af selve doseringssessionen, såsom at lytte til en prøve af sessionsmusikken mens du bærer øjenskygger. Den forberedende session varede typisk i 4 timer, med frokost og pauser. Patienter indskrevet i studiet deltog i to efterfølgende doseringssessioner, der blev adskilt med 7 dage. Ikke mere end en patient blev doseret på en given dag. Patienter ankom til undersøgelsesanlægget (Imperial Clinical Research Facility) kl. 0900 h, gav en urinprøve til misbrugsmedicin (herunder amfetaminer, benzodiazapiner, opiater og cannabinoider), udførte en breathalyser test for alkoholbrug og afsluttede midlertidige QIDS, BDI , og STAI-T vurderinger for at sikre ingen væsentlig afvigelse fra basislinjeforanstaltninger. De blev derefter taget til et doseringsrum, der var forindrettet (fx med lav belysning). Patienterne blev inviteret til at slappe af på en afdelings seng i en liggende eller tilbagelænet stilling, og musik blev spillet gennem høj kvalitet stereohøjttalere og øretelefoner. De to psykiater sad på begge sider af sengen. Patienter blev altid overvåget af mindst to medarbejdere. Doseringen begyndte kl 1030 h i alle tilfælde. Patienterne fik en lav oral dosis psilocybin 10 mg (to 5 mg kapsler) på en første doseringsdag og en høj oral dosis psilocybin 25 mg (fem 5 mg kapsler) på en anden doseringsdag adskilt med 1 uge. Blodtryk, hjertefrekvens og observatørkvaliteter af intensiteten af ​​psilocybins akutte psykoaktive effekter (0-4, hvor 0 betegner ingen effekt og 4 betyder ekstrem effekt) blev målt ved baseline (typisk 5 min før dosering) og 30, 60, 120, 180, 240, 300 og 360 minutter efter dosering. Subjektive vurderinger af den akutte ændrede tilstand af bevidsthed ved hjælp af den reviderede Figur 1: Planlægning af studieinterventioner Rekruttering Indskrivning og behandling Opfølgning Uspecificeret tidsperiode Lav psilocybin-dosis Høj psilocybin-dosis Fjernscreening eller opfølgning Klinisk screening eller opfølgning Psilocybin doseringssession 1 uge 1 uge 2 uger 7 uger Hver bar repræsenterer 1 dag Løbende støtte fra studiepsykiatere, hvis det kræves Tidsscreening Screening besøg og baseline vurdering Patienter kontaktet til ekstern vurdering Efterbehandling fMRI og vurdering (foreløbige spørgeskemaer) Baseline fMRI og forberedende session Interim spørgeskemaer 1 ugers opfølgning på forskningsfacilitet 2 ugers opfølgning (fjern) 3 ugers opfølgning (fjern) 5 ugers opfølgning (fjern) 3 måneders opfølgning (fjernt) Artikler 622 www.thelancet.com/psychiatry Vol 3. juli 2016 11 dimensionelle ændrede tilstand af bevidstheds spørgeskema (11D ASC) 24 blev afsluttet 6-7 timer efter dosering. Psykiatere vedtog en ikke-direktiv, støttende tilgang, der tillod patienten at opleve en mest uafbrudt indre "rejse". Check-ins (dvs. spørger patienten, hvordan de føler) forekom på samme tidspunkter som de fysiologiske optagelser. Tranquilizing medications (oral lorazepam og risperidon) var tilgængelige, hvis det var nødvendigt. Fænomenologien i den akutte erfaring, herunder regnskaber om arten af ​​den terapeutiske støtte, der blev tilvejebragt før, under og efter erfaringerne, og overvejelser relateret til musikvalg og andre aspekter af den kliniske indstilling, vil blive diskuteret i separate publikationer. Returtransport fra forskningsanlægget blev organiseret forud for doseringssessioner. Patienter blev taget til og fra sessionerne ledsaget af en nær ven eller slægtning, og havde mulighed for at overnatte i indkvartering ved siden af ​​hospitalet. Der blev givet akut kontaktoplysninger, og patienterne bekræftede deres sikre afkast fra forskningsanlægget. Patienter blev kontaktet via telefon 1 dag efter deres lavdosis session for at kontrollere deres velbefindende og overvåge eventuelle bivirkninger. Patienterne vendte tilbage til forskningsanlægget 1 dag efter deres høje dosis-session for en post-behandling fMRI-scanning, der varede 60 min. Efter fMRI-scanningen gennemførte patienterne foreløbige spørgeskemaer (QIDS, STAI-T og HAM-D) og blev inviteret tilbage til forskningsanlægget, hvor de blev mødt af deres psykiatere for at diskutere deres erfaring den foregående dag. Patienter deltog i et yderligere studiebesøg på forskningscentret 1 uge efter deres høje dosis session, hvor alle baseline spørgeskemaer og vurderinger blev gentaget, og der blev givet mulighed for yderligere psykologisk debriefing (1 ugers opfølgningsbesøg). Vurderinger af HAM-D, MADRS og GAF blev igen lavet af MBo. Efterfølgende vurderinger af kliniske fremskridt blev foretaget via e-mail 2, 3 og 5 uger efter højdosis sessionen; Vi vurderede kun QIDS under efterfølgende opfølgning for ikke at overbelaste patienten. Endelig opfølgning blev udført eksternt 3 måneder efter højdosis-sessionen og omfattede QIDS, BDI, STAI-T og SHAPS. Patienterne blev gjort opmærksomme på, at de kunne kontakte studiepsykiatrene til enhver tid, hvis deres depression blev forringet. Figur 1 opsummerer screening, intervention og opfølgningsprocedurer i denne undersøgelse. Resultater Hovedformålet med denne undersøgelse er at optimere protokollen til administration af oralt psilocybin i denne patientgruppe, samtidig med at man får et første indtryk af behandlingseffekt. Det primære udfaldsmål for at vurdere gennemførligheden var patient-vurderet subjektiv intensitet af psilocybins effekter, som vi rapporterer på en 0-1 skala. Vi vurderede interventionens sikkerhed gennem klinisk overvågning under og efter doseringssessioner og i 3 måneder med ansigt til ansigt og fjern opfølgning. Vi havde også til formål at vurdere den indledende effekt af psilocybin hos patienter med behandlingsresistent depression; Det primære udfaldsmål for dette slutpunkt var en gennemsnitlig ændring i sværhedsgraden af ​​selvrapporterede depressive symptomer (med de 16 punkter QIDS) fra baseline til 1 uge efter højdosis psilocybin-sessionen. QIDS blev valgt som det primære resultatmål på grund af dets kortfattede og stadig mere udbredte anvendelse og validitet med 1 ugers intervaller.25 Vi valgte at vurdere det primære effekt-endepunkt 1 uge efter højdosisessionen for at muliggøre sammenligning med tidligere undersøgelser af ketamin infusion til behandling-resistent depression; 26 lavdosis sessionen blev opfattet a priori som en sikkerhedssession snarere end en behandling session. Vi vurderede også ændringer i BDI, STAI-T og SHAPS mellem baseline og 1 uge og 3 måneders opfølgning og ændring i HAM-D, MADRS og GAF mellem baseline og 1 uge efter opfølgning. Statistisk analyse I denne gennemførlighedsundersøgelse udførte vi ikke en formel effektberegning. Vi planlagde at rekruttere 12 patienter for at give et første indtryk af tolerancen og effekten af ​​denne nye behandlingsmetode. Et efterfølgende protokolændring (6. okt. 2015) øgede rekruttering til 20 patienter for at tilvejebringe statistisk strøm til fMRI-billeddannelse. Her rapporterer vi resultater for de 12 patienter, der oprindeligt blev indskrevet; Resultat og fMRI data for alle 20 patienter vil blive rapporteret separat. På grund af den lille befolkning blev to-tailed Wilcoxon signerede rækker tests udført for ikke-parametriske data. To-tailed t-test blev også udført, og de relevante t-værdier er angivet i tillægget. Vi giver Figur 2: Prøveprofil 95% CI'er omkring de gennemsnitlige forskelle. Vi udregnede 72 personer, der udtrykte interesse for at deltage i retssagen 34, fordi de ikke opfyldte adgangskriterierne 38 telefon screenet 20 udelukket fordi de ikke opfyldte adgangskriterierne 18 deltog i screeningsbesøg 6 udelukket på grund af utilstrækkelig alvorlig depression (HAM-D ) 12 rekrutteret til undersøgelsen og fuldt ud i overensstemmelse med protokollen Se online til bilag Artikler www.thelancet.com/psychiatry Vol 3 juli 2016 623 Effektstørrelser ved hjælp af Hedges 'g-formlen, hvilket er mere passende for små prøvestørrelser. Hedges g-værdier ligner meget Cohen's d-værdier for afhængige data. Dette forsøg er registreret i ISRCTN-registret, nummer ISRCTN14426797. Registreringen blev indledt 30. marts 2015 og færdiggjort den 7. juli 2015 (forsinkelse forårsaget af administrative problemer); Rekruttering startede den 21. april 2015 efter indledningen af ​​offentlig registrering. Finansieringskildens rolle Undersøgelsesfonden havde ingen rolle i design, dataindsamling, analyse, fortolkning eller skrivning af rapporten. Den tilsvarende forfatter havde fuld adgang til alle data i undersøgelsen og havde det endelige ansvar for beslutningen om at indsende til offentliggørelse. Resultater Registrering startede den 1. maj 2015 og sluttede den 25. august 2015. 72 personer blev oprindeligt betragtet for undersøgelsen, hvoraf de fleste selv henviste efter at have hørt om dette forsøg gennem offentligt opsøgende arbejde (fx offentlige præsentationer fra efterforskerne og medierapporter). 38 blev anset for passende til en telefonskærm, hvoraf 18 blev inviteret til et formelt screeningsbesøg, og 12 blev i sidste ende rekrutteret til retssagen (figur 2), hvoraf ti var selvreferencer. Patienternes demografiske og kliniske egenskaber er vist i tabel 1. Nio af de 12 patienter opfyldte kriterier for alvorlig eller meget alvorlig depression ved baseline (BDI score ≥30), mens de resterende tre patienter opfyldte kriterier for moderat depression (BDI score 19 til < 30). 11 patienter havde fået nogen form for psykoterapi før deltagelse i undersøgelsen. De akutte virkninger af psilocybin blev godt tolereret af alle patienterne, og der opstod ingen alvorlige eller uventede bivirkninger. Den gennemsnitlige egenvurderede intensitet af psilocybin-oplevelsen var 0 · 51 (SD 0 · 36) for lavdosessessionen og 0 · 75 (0 · 27) for højdosisessionen (forskel 0 · 24 [95% CI 0 · 06- 0, 41], Z-2, 4, p = 0, 019). Køn Alder, år Etnisk oprindelse Ansættelsesstatus Anslået sygdomstid, år Baseline score Tidligere mislykkede lægemidler * Tidligere psykoterapi Uddannelse Ugentlig alkoholindtagelse, enheder Tidligere psilocybinbrug (tid siden sidste brug) BDI HAM-D STAI-T 1 Kvinde 43 Black Caribbean Ansat 30 36 19 72 SSRI (to), SNRI (to), NDRI, NSSRI, MAOI Ingen Postgraduate 1 None 2 Mand 40 Hispanic Unemployed 25 33 28 76 SSRI (to), SNRI, NDRI, NSSRI, Na + infusion, TCA Kognitiv fortællingsterapi Postgraduate 0 Ingen 3 Mand 37 Hvid Ansat 17 22 18 63 SSRI (to), SNRI Kognitiv adfærdsterapi, gruppeterapi Postgraduate 0 Ingen 4 Kvinde 30 Hvid Studier 10 26 18 67 NDRI, NSSRI Kognitiv adfærdsterapi Postgraduate 0 En brug (6 måneder) 5 Mand 34 Hvid Arbejdsløs 12 38 25 71 SSRI (tre), TCA Kognitiv og mindfulness adfærdsterapi Undergraduate 0 Ingen 6 Kvinde 57 Hvid Arbejdsløs 29 39 23 78 SSRI (fire), SNRI, SARI Rådgivning Sekundær uddannelse 2 To brug s (45 år) 7 Mand 52 Hvid Arbejdsløs 27 33 22 57 TCA, SARI Rådgivning, mindfulness Videregående uddannelse 0 Tre anvendelser (30 år) 8 Kvinder 37 Hvid Ansat 17 39 17 71 SSRI (to), TCA Rådgivning Grunde 2 Ingen 9 Mand 37 Hvide Arbejdsløse 15 32 26 71 SSRI (tre), SNRI Rådgivning, Kognitiv Adfærdsterapi Postgraduate 6 Ingen 10 Kvinde 36 Black Caribbean Arbejdsløse 8 47 28 75 SSRI (to), NSSRI Rådgivning Grundstudie 18 Tre anvendelser (14 år) 11 Kvinde 64 Hvid Ansat 15 24 17 72 SSRI (fire), SNRI (to), NDRI, MAOI, Na⁺ channelblocker, SARI, DRI Kognitiv adfærdsterapi Postgraduate 1 Tre anvendelser (48 år) 12 Mandlige 45 White Ansat 8 35 17 68 SSRI, TCA Kognitiv adfærdsterapi Undergraduate 0 Ingen BDI = Beck Depression Inventory. HAMD-D = Hamilton Depression Rating skala. STAI-T = Stat-Trait Angst Inventory. SSRI = selektiv serotonin-genoptagelsesinhibitor. SNRI = serotonin-noradrenalin reuptake inhibitor. NDRI = noradrenalin-dopamin-genoptagelsesinhibitor. NSSRI = noradrenalin og specifik serotonin-genoptagelsesinhibitor. MAOI = monoaminoxidaseinhibitor. TCA = tricyklisk antidepressiv. SARI = serotoninantagonist og genoptagelsesinhibitor. DRI = dopamin-genoptagelsesinhibitor. * En medicin fra hver klasse, medmindre andet er angivet. Tabel 1: Patientens basislinje og demografiske egenskaber Artikler 624 www.thelancet.com/psychiatry Vol 3 juli 2016 Ingen patienter krævede beroligende medicin (oral lorazepam og risperidon) under doseringssessionerne. Psilocybins akutte psykedeliske virkninger blev typisk påviselige mellem 30 minutter og 60 minutter efter dosering, toppede mellem 2 timer og 3 timer efter dosering og nedsat til ubetydelige niveauer, hvor patienten kunne vurderes til udledning mindst 6 timer efter dosering (appendiks). Self-rated oplevelser på 11D-ASC spørgeskemaet fra de to sessioner er vist i appendiks. Resultater fra foreløbige patientundersøgelser (QIDS, BDI og STAI-T), der blev foretaget umiddelbart før lavdosisessionen til overvågning af væsentlige ændringer siden tilmelding, afvigede ikke fra basislinjen (data ikke vist). Interimspørgeskemaer udført dagen efter højdosessessionen viste en vis reduktion af depressive symptomer (data for HAM-D i appendiks; data for QIDS og STAI-T ikke vist). Alvorlighed Timing eller indtræden Varighed Patient 1 Transient angst Mild start i begge sessioner 60 min. Transient hovedpine Mild dag efter højdosis session Kun en dag Transient forvirring Mild (kerne lægemiddel effekts) Top i begge sessioner 60-120 min. Patient 2 Transient angst Mild Kun forventet angst (begge sessioner) 30 min. Patient 3 Forløbsangst Kun mild Forventende angst (begge sessioner) 30 min. Transient forvirring Mild (kerne lægemiddel effekts). Højde i begge sessioner 60-180 min. Patient. 4 Transient angst. Mild (lav dosis) moderat (høj dosis) Begyndelse af begge sessioner og maksimal højdosis 60 minutter (lav dosis), 120 min (høj dosis) Transient kvalme Moderat startfase i højdosis session Arose og nedsat inden for 60 min. Transient forvirring Mild ect) Top af begge sessioner 60-180 min. Transient paranoia Mild Peak af højdosis session Arose og nedsat inden for 30 min. Patient 5 Transient angst Moderat (lav dosis), alvorlig (høj dosis) Begyndelse af begge sessioner og højdepunkt ose 60 min (lav dosis), 150 min (høj dosis) Transient hovedpine Mild Dag efter højdosis session Kun en dag Transient forvirring Mild (kerne lægemiddel effekts) Højde af begge sessioner 60-120 min Patient 6 Transient angst Mild Forventende angst kun (begge sessioner) 30 min. Patient 7 Forløbsangst Kun mild Foreløbig angst (begge sessioner) 30 min. Transient forvirring Mild (kerne lægemiddel effekt). Højde i begge sessioner 60-180 min. Patient. 8. Transient angst. Mild eller ubetydelig Forventningsangst alene (begge sessioner) 30 min. Patient 9 Transient angst Mild (lav dosis), moderat (høj dosis) Begyndelse af lavdosis og højdosis session 60 min (lav dosis), 150 min (høj dosis) Transient hovedpine Mild dag efter høj dosis session Kun en dag Transient forvirring Mild (kerne lægemiddel effekts) Top af begge sessioner 60-180 min Patient 10 Transient angst Mild start i begge sessioner 60 min Transient kvalme Mild onset og top i lavdosis session Subsided efter 90 min Transient hovedpine Mild eller moderat dag Efter højdosis-session 2 dage Forløbsforvirring Mild (kerne-lægemiddeludbytte) Højde i begge sessioner 60-180 min. Patient 11 Transient angst Moderat (begge sessioner) Startfase og top i begge sessioner 150 min. (begge sessioner) Transient kvalme Mild høj dosis) Startfase i højdosis-session Arose og nedsat inden for 60 min. Transient forvirring Mild (kerne lægemiddel effekts) Top i begge sessioner 60-180 min. Transient paranoia Mild Peak af lavdosis session Arose og nedsat inden for 60 min. Patient 12 Transient angst Mild Foreløbig angst alene (begge sessioner) 30 min. Transient forvirring Mild (kerne lægemiddel effekts) Top af begge sessioner 60-180 min. Tabel 2: Bivirkninger af patienten Artikler www.thelancet.com/psychiatry Vol 3 juli 2016 625 The De fleste almindelige bivirkninger var forbigående angst (for det meste mild) under lægemiddelstart (n = 12), forbigående forvirring eller tankeforstyrrelse (n = 9), mild og forbigående kvalme (n = 4) og forbigående hovedpine (n = 4; tabel 2). Disse bivirkninger blev forventet psykologiske virkninger af psilocybin. Subakut hovedpine præsenteres typisk 1 dag efter psilocybin-sessionen og aftog efter 1-2 dage. Paranoia præsenteret i kun en patient, men dette var mildt og forbigående. Der blev ikke observeret længerevarende psykotiske symptomer hos nogen af ​​patienterne. En patient kontaktede studiepsykiatrerne i løbet af de 3 måneders opfølgning på grund af forringelse af deres depression og blev henvist til deres praktiserende læge. QIDS-depressionsscorer blev signifikant reduceret fra baseline til 1 uge og 3 måneder efter behandling, med maksimal effekt i 2 uger (figur 3, tabel 3). BDI og klinikeradministrerede ratings bekræftede disse resultater (figur 4, tabel 3). Alle patienter viste en vis reduktion i depressionsgraden ved 1 uge, som var vedvarende i flertallet i 3 måneder (appendiks). I henhold til standardkriterier for bestemmelse af remission (f.eks. En score på ≤9 på BDI) opnåede otte (67%) af de 12 patienter fuldstændig remission efter 1 uge og syv patienter (58%) fortsatte med at opfylde kriterier for respons (50 % reduktion i BDI score i forhold til baseline) efter 3 måneder, hvoraf fem af disse (42%) stadig er fuldstændig remission (figur 4, tabel 3). STAI-T-angstscorer blev også signifikant reduceret ved 1 uge og 3 måneder efter behandling, som var SHAPS anhedonia-scoringer i 1 uge og 3 måneder efter behandling (tabel 3). Diskussion I dette åbne pilotforsøg med en enkelt arm forsøgte vi at undersøge muligheden for at administrere psilocybin til patienter med behandlingsresistent depression som et forgrund til en større randomiseret kontrolleret undersøgelse. Vores resultater understøtter Figur 3: Gennemsnitlig depressionsværdighed (QIDS) over tid Depression alvorligheden bestemmes af selvvurderede 16-punkts QIDS. QIDS score på 16-20 anses for at reflektere svær depression, scoringer på 11-15 betragtes som moderat depression, scoringer på 6-10 betragtes som mild depression, og score på 5 og mindre betragtes som fraværende depression. Alle efterbehandlingsvurderinger blev opnået efter højdosis-sessionen (dvs. 1 uge efter behandling refererer til 1 uge efter højdosis-sessionen). Hedges 'g-værdier versus basislinjen er vist. QIDS = Quick Inventory of Depressive Symptoms. 0 5 10 15 20 25 Baseline 1 uge 2 uger 3 uger 5 uger 3 måneder QIDS score Hedges 'g 3 · 1 p = 0 · 002 Hedges' g 3 · 2 p = 0 · 002 Hedges 'g 3 · 2 p = 0 · 002 Hedges 'g 2 · 7 p = 0 · 003 Hedges' g 2 · 0 p = 0 · 003 QIDS BDI STAI-T SHAPS HAM-D MADRS GAF Baseline 1 uge 2 uger 3 uger 5 uger 3 måneder Baseline 1 uge 3 måneder Baseline 1 uge 3 måneder Baseline 1 uge 3 måneder Baseline 1 uge Baseline 1 uge Baseline 1 uge Middel (SD) 19 · 2 (2 · 0) 7 · 4 (4 · 9) 6 · 3 (4 · 6) 6 · 4 · 5 · 1 · 8 · 2 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 15 · 2 (11 · 0) 70 · 1 (5 · 8) 40 · 6 (14 · 2) 54 · 8 (14 · 5) 7 · 5 (3 · 7) 1 · 4 (2 · 7) 2 · 8 (3 · 7) 21 · 4 · 4 · 5 · 7 · 4 · 6 · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 13 · 0) Diffensens versus basislinje (95% CI) ·· -11 · 8 (-9 · 15 til -14 · 35) -12 · 9 (-10 · 64 til -15 · 16) -12 · 8 ( -9 · 9 til -15 · 6) -11 · 0 (-7 · 7 til -14 · 2) -9 · 2 (-5 · 69 til -12 · 71) ·· -25 · 0 (-20 · 1 til -29 · 9) -18 · 5 (-11 · 8 til -25 · 2) ·· -29 · 5 (-22 · 03 til -36 · 97 -15 · 3 (-7 · 77 til -22 · 83) ·· -6 · 1 (-4 · 46 til -7 · 74) -4 · 7 (-3 · 29 til -6 · 11) ·· -14 · 0 (-9 · 6 til -18 · 4) ·· -23 · 3 (-17 · 1 til -29 · 5) ·· 27 · 3 (18 · 0 til 36 · 6) Z · · -3 · 1 -3 · 1 -3 · 06 -2 · 9 -3 · 0 ·· -3 · 1 -3 · 1 ·· -3 · 1 -2 · 9 ·· -3 · 1 -3 · 1 ·· -3 · 0 ·· -3 · 1 ·· 3 Hedges 'g * ·· 3 · 1 3 · 2 3 · 2 2 · 7 2 · 0 ·· 3 · 2 2 · 0 ·· 2 · 7 1 · 4 ·· 1 · 9 1 · 3 ·· 2 · 4 ·· 2 · 7 ·· 2 · 4 p værdi · ·· 0 · 002 0 · 002 0 · 002 0 · 003 0 · 003 ·· 0 · 002 0 · 002 ·· 0 · 002 0 · 004 ·· 0 · 002 0 · 002 ·· 0 · 003 ·· 0 · 002 ·· 0 · 003 Opfølgning refererer til den periode, der starter efter den anden (høje dosis ) administration af psilocybin. Klinikeradministrerede ratings (HAM-D, MADRS og GAF) blev afsluttet kun ved baseline og 1 uge efter højdosis-sessionen. QIDS = Quick Inventory of Depressive Symptoms. BDI = Beck Depression Inventory. STAI-T = Stat-Trait Angst Inventory. SHAPS = Snaith-Hamilton Pleasure Scale. HAM-D = Hamilton Depression Rating skala. MADRS = Montgomery-Åsberg Depression Rating Scale. GAF = Global Assessment of Functioning. * Sammenlignet med basislinjen. Tabel 3: Kliniske vurderinger ved baseline og opfølgning Artikler 626 www.thelancet.com/psychiatry Vol. 3. juli 2016 Synspunktet om, at der udføres passende sikkerhedsforanstaltninger (f.eks. Omhyggelig screening og tilstrækkelig terapeutisk støtte), psilocybin kan administreres sikkert til dette patientgruppe. Fordi dette var en lilleskalig gennemførlighedsundersøgelse med et åbent design, kan der ikke gives stærke konklusioner om behandlingens terapeutiske virkning. Dataene tyder dog på, at yderligere forskning er berettiget. Responsraten til psilocybin var 67% (n = 8) 1 uge efter behandling (HAM-D og BDI), og syv af disse otte patienter opfyldte også kriterier for remission. Desuden opretholdt 58% (n = 7) patienterne deres respons i 3 måneder, og 42% (n = 5) forblev i remission. Det er også værd at bemærke, at psilocybin har en gunstig toksicitetsprofil og ikke er forbundet med tvangssygdomsfremkaldende adfærd hos dyr eller mennesker. De bivirkninger, som vi bemærkede, var mindre og forventes i lyset af tidligere undersøgelser af psilocybin.27 Spontan genopretning i ildfast depression er sjælden, og mange af patienterne i den foreliggende undersøgelse rapporterede at have depression i mange af deres voksne liv (gennemsnit Anslået sygdomstid 17,8 år [SD 8]). Nøgleproblemer til fremtidig forskning bør derfor tage fat på, hvorfor det terapeutiske effekt, der er observeret i den foreliggende undersøgelse, er så stort, og hvis det kan replikeres, når der indføres strammere eksperimentelle kontroller. Fordi behandlingen i vores undersøgelse bestod af ikke kun to psilocybinforvaltninger, men også psykologisk støtte før, under og efter disse sessioner samt et positivt terapeutisk miljø for sessionerne, skal de relative effekter af disse faktorer bestemmes, hvilket kan kun udføres ved at foretage yderligere forsøg med passende kontrolbetingelser. Et logisk næste trin ville være at gennemføre et placebocontrolled randomiseret forsøg, hvor niveauet af terapeutkontakt er konsistent mellem forholdene. Dette ville muliggøre, at eventuelle mellemgruppedifferencer i kliniske resultater tilskrives psilocybin snarere end den psykologiske støtte, der ydes. En positiv interaktion mellem disse variabler forekommer sandsynligvis, og inerte placebo-baserede persienner er kendt for at være ineffektive i undersøgelser, der involverer iøjnefaldende forsøgsinterventioner, fordi patienter let kan se, om de er i aktiv tilstand eller ej. Brug af en aktiv placebo til kontroltilstanden kan derfor være værd at overveje. Derudover kunne man også undersøge randomiserede sammenlignende effektforsøg (f.eks. Med en valgfri overgangskomponent), der inkorporerer en anden behandling for ildfast depression (fx ketamininfusion). Størrelsen og vedholdenheden af ​​de antidepressive effekter, der observeres her, er ikke i modstrid med det, som tidligere er blevet observeret med psilocybin under kroniske psykiatriske tilstande. For eksempel viste 80% af de langsigtede tunge tobaksrøgere afholdenhed fra at ryge 6 måneder efter to behandlingssessioner med psilocybin.18 Alkoholafhængige patienter viste signifikant nedsat drikadfærd over 8 måneder efter en eller to psilocybin-sessioner.19 Signifikant nedsat angst og depressionsscorer blev observeret 3 og 6 måneder efter en enkeltdosis psilocybin hos patienter med angst relateret til kræft i slutstadiet. 15 og forbedringer i trivsel, der varede i mere end 1 år, blev observeret hos raske individer givet en enkelt dosis psilocybin.8 Hurtige og vedvarende fald i depressive symptomer blev også for nylig fundet i et lilleforsøgsforsøg med psykedelisk brygning, ayahuasca.16 Det er vigtigt at overveje begrænsningerne i denne pilotundersøgelse; for eksempel, selv om alle patienter viste nogle kliniske forbedringer i mindst 3 uger efter behandlingen, og der ikke blev observeret alvorlige eller uventede bivirkninger, varige forbedringer ud over 3 uger blev ikke observeret universelt, og fem af de 12 patienter viste en grad af tilbagefald ved 3 måneder. Man bør være forsigtig med potentialet for inflatede effektsstørrelser i tidlige forsøg, især når prøvestørrelsen er lille. At alle patienter viste en vis forbedring i deres depressive symptomer i op til 3 uger efter behandlingen kunne tyde på en forventet bias. Det kan også være relevant, at de fleste patienter i denne undersøgelse var selvbetegnende og dermed aktivt søgte denne behandling. Psykedelik er kendt for at fremme suggestivitet, 28 som måske har yderligere forbedrede positive resultater. Fremtidige dobbeltblind randomiserede kontrollerede forsøg kan adressere rollen som forventet og suggestiv ved at måle og kontrollere disse variabler. For eksempel kan patienter blive spurgt om deres forventninger til behandling, forslag kunne kontrolleres mellem tilstande, og resultater fra selvrefterede patienter kunne sammenlignes med patienter fra patienter, der blev henvist via klinikere. Ud fra et mere pragmatisk perspektiv, hvis forventning eller antydning viser sig at være influential i forbindelse med psykedelisk terapi, kan de behandles som udnyttelige komponenter i behandlingsmodellen frem for at forstyrre variabler. Figur 4: Depression alvorlighedsgrad (BDI) over tid, efter patient Figur viser depression sværhedsgrad (BDI) over tid planlagt for hver af de 12 patienter. Middelværdier (SD) vises såvel som de relevante effektstørrelser (Hedges 'g) versus basislinjen. BDI = Beck Depression Inventory. 0 10 20 30 40 50 Baseline 1 uge 3 måneder BDI score 33 · 7 (7 · 1) 15 · 2 (11) g = 2 Alvorlig depression (≥30) Mild eller moderat depression (> 9 til> 30) Ingen depression ≤9) 8 · 7 (8 · 4) g = 3 · 2 P1 P2 P3 P8 P9 P10 P11 P11 P12 Høje dosisartikler www.thelancet.com/psychiatry Vol. 3. juli 2016 627 Serotonergiske antidepressiva har vist sig at nedregulere Det primære receptormål for psilocybin (5-HT2A-receptoren) og svækkede subjektive reaktioner på psykedelik er tidligere blevet rapporteret hos personer kronisk medicineret med serotonergiske antidepressiva.29 Det kan således være nødvendigt, at patienter trækker sig fra samtidig antidepressiv medicin før de modtager psilocybin, og dette bør kun nogensinde blive gjort med omhu. Til sidst forsøgte vi at vurdere sikkerheden og tolerancen af ​​psilocybin plus psykologisk støtte hos patienter med unipolar behandlingstabilt depression. Vores resultater understøtter denne tilgangs gennemførlighed, og størrelsen og varigheden af ​​efterbehandlingens reduktioner i symptomernes sværhedsevne motiverer yderligere kontrolleret forskning. Psilocybin har en ny farmakologisk virkning i sammenligning med de nuværende behandlinger for depression (dvs. 5-HT2A receptoragonisme) og kan således udgøre en nyttig tilsætning til tilgængelige terapier til behandling af depression.ax

OEIGINAL TEKST
Psilocybin is a naturally occurring plant alkaloidfound in the Psilocybe genus of mushrooms. Psilocybe mushrooms have been used for millennia for healing purposes, but were only discovered by modern science in the late 1950s.1,2 Psilocybin is a prodrug of psilocin (4-hydroxy-dimethyltryptamine), a serotonin receptor agonist and classic psychedelic drug whose principal psychoactive eff ects are mediated by serotonin 2A (5-HT2A) receptor agonism.3 Psilocybin therefore has a novel pharmacology in the context of currently available antidepressant medications, because selective serotoninreuptake inhibitors are not direct 5-HT2A receptor agonists. Enhanced cognitive fl exibility,4 associative learning,5 cortical neural plasticity,6 and antidepressant responses have been reported with 5-HT2A receptor agonism in animals,7 and increased and sustained improvements in wellbeing8 and optimism9 have been observed after psychedelic experiences in human beings. Findings from human imaging studies with psilocybin have supplemented these discoveries, showing changes in brain activity suggestive of antidepressant potential; for example, a range of eff ective antidepressant treatments have been found to normalise hyperactivity in the medial prefrontal cortex and we found reduced blood fl ow in this region with intravenous psilocybin.10 Moreover, data obtained from large-scale population studies have recently challenged the view that psychedelics negatively aff ect mental health,11–13 with one study’s findings showing lower rates of psychological distress and suicidality among people who had used Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study Robin L Carhart-Harris, Mark Bolstridge, James Rucker*, Camilla M J Day*, David Erritzoe, Mendel Kaelen, Michael Bloomfield, James A Rickard, Ben Forbes, Amanda Feilding, David Taylor, Steve Pilling, Valerie H Curran, David J Nutt Summary Background Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression. Methods In this open-label feasibility trial, 12 patients (six men, six women) with moderate-to-severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. There was no control group. Psychological support was provided before, during, and after each session. The primary outcome measure for feasibility was patient-reported intensity of psilocybin’s eff ects. Patients were monitored for adverse reactions during the dosing sessions and subsequent clinic and remote follow-up. Depressive symptoms were assessed with standard assessments from 1 week to 3 months after treatment, with the 16-item Quick Inventory of Depressive Symptoms (QIDS) serving as the primary efficacy outcome. This trial is registered with ISRCTN, number ISRCTN14426797. Findings Psilocybin’s acute psychedelic eff ects typically became detectable 30–60 min after dosing, peaked 2–3 h after dosing, and subsided to negligible levels at least 6 h after dosing. Mean self-rated intensity (on a 0–1 scale) was 0·51 (SD 0·36) for the low-dose session and 0·75 (SD 0·27) for the high-dose session. Psilocybin was well tolerated by all of the patients, and no serious or unexpected adverse events occurred. The adverse reactions we noted were transient anxiety during drug onset (all patients), transient confusion or thought disorder (nine patients), mild and transient nausea (four patients), and transient headache (four patients). Relative to baseline, depressive symptoms were markedly reduced 1 week (mean QIDS diff erence –11·8, 95% CI –9·15 to –14·35, p=0·002, Hedges’ g=3·1) and 3 months (–9·2, 95% CI –5·69 to –12·71, p=0·003, Hedges’ g=2) after high-dose treatment. Marked and sustained improvements in anxiety and anhedonia were also noted. Interpretation This study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials, with more rigorous designs, to better examine the therapeutic potential of this approach. Funding Medical Research Council. Copyright © Carhart-Harris et al. Open Access article distributed under the terms of CC BY. Articles 620 www.thelancet.com/psychiatry Vol 3 July 2016 psychedelics within their lifetime than among those who used no psychedelics but an equivalent amount of other drugs.11 In modern trials, psychedelics have been found to reduce anxious,14,15 depressive,15,16 and obsessivecompulsive symptoms,17 as well as addictive behaviours,18,19 often for several months after just one or two exposures. Extensive historical and modern evidence now supports the view that, administered in a controlled environment with appropriate support, psychedelics have a favourable safety profile.20 Depression is a major public health problem; it is a leading contributor to the global burden of disease, aff ecting hundreds of millions of people worldwide, and costing the USA alone more than US$200 billion each year.21 Antidepressant medications and cognitive behavioural therapy can be eff ective for some patients, but around 20% do not respond to any intervention, and many of those who do respond, eventually relapse.22 We aimed to investigate the safety and feasibility of psilocybin in patients with treatment-resistant depression, and to establish an initial impression of its efficacy. We postulated that the treatment would be well tolerated and depressive symptoms would be substantially reduced from baseline at all assessment points, for up to 3 months after treatment. Methods Study design and participants This was an open-label feasibility study in patients with treatment-resistant depression; there was no control group. Patients, invest igators, raters, and statisticians were not masked to treatment assignment, and all participants received the study intervention (psilocybin administered in two dosing sessions; an initial safety [low] dose and a subsequent treatment [high] dose). The inclusion criteria were major depression of a moderate to severe degree (17+ on the 21-item Hamilton Depression Rating scale [HAM-D]), and no improvement despite two adequate courses of antidepressant treatment of diff erent pharmacological classes lasting at least 6 weeks within the current depressive episode.23 Exclusion criteria were: current or previously diagnosed psychotic disorder; immediate family member with a diagnosed psychotic disorder; medically significant condition rendering unsuitability for the study; history of serious suicide attempts (requiring hospitalisation); history of mania; blood or needle phobia; positive pregnancy test at screening or during the study; and current drug or alcohol dependence. Information about the study’s recruitment was sent to general practitioners via the North West London Clinical Research Network. However, patients were also allowed to self-refer to the study if they were UK residents. In every case, patients initiated contact with the research team (via email, letter, or telephone), were sent a study information sheet, and a subsequent telephone screening was arranged, during which the lead psychiatrist on the trial (MBo) obtained information about the patient’s demographics, medical and psychiatric history, and other key inclusion or exclusion criteria. The patient’s general practitioner or psychiatrist provided written documentation of the patient’s diagnosis and mental health background in every case. This trial received a favourable opinion from the National Research Ethics Service London—West London, was sponsored and approved by Imperial College London’s Joint Research and Compliance Office (JRCO), and was adopted by the National Institute for Health Research Clinical Research Network. The National Institute for Health Research/Wellcome Trust Imperial Clinical Research Facility gave site-specific approval for the study. Research in context Evidence before this study We searched PubMed up to Jan 30, 2016, using the terms “psilocybin”, “hallucinogens”, “psychedelics”, and “depression”. We did not find any clinical trials assessing psilocybin as a treatment for depression, but we did find population analyses, review articles, and imaging studies lending support to this approach. We also found one report documenting enduring decreases in depressive symptoms after a single dose of psilocybin in a randomised controlled trial of psilocybin-assisted psychotherapy for end-of-life anxiety, one report on an open-label trial showing rapid decreases in depressive symptoms that endured for up to 21 days after a single dose of ayahuasca, and two early reports or case studies on the eff ects of lysergic acid diethylamide on “neurotic” and depressive symptoms describing “improvements”, albeit without validated measures of symptom severity. Added value of this research To our knowledge, this is the first investigation of the safety and efficacy of psilocybin as a treatment for major depression. Our findings imply that psilocybin might have value as a treatment option in the management of treatment-resistant depression. Single oral administrations of 10 mg (safety dose) and 25 mg (treatment dose) psilocybin were well tolerated and led to enduring reductions in symptom severity after the two sessions. Implications of all the available evidence The results of this small-scale feasibility study should help to motivate further research into the efficacy of psilocybin with psychological support for major depression. Larger-scale randomised controlled trials are warranted to better examine the potential of psilocybin as a treatment option for this highly prevalent, disabling, costly, and difficult-to-treat disorder. More broadly, the present study should help to catalyse the re-emergence of a promising research area in psychiatry. Articles www.thelancet.com/psychiatry Vol 3 July 2016 621 The study was reviewed and approved by the Medicines and Healthcare products Regulatory Agency (MHRA). All participants provided written informed consent. Study and data monitoring was carried out independently by the Imperial Clinical Research Facility and JRCO. Procedures Psilocybin was obtained from THC-pharm (Frankfurt, Germany) and formulated into the investigational medicinal product (5 mg psilocybin in size 0 capsules) by Guy’s and St Thomas’ Hospitals’ Pharmacy Manufacturing Unit (London, UK). A Home Office Licence for storage and dispensing of Schedule One drugs was obtained. Screening consisted of written informed consent, a thorough evaluation of the patient’s physical and mental health background, a psychiatric interview (MiniInternational Neuropsychiatric Interview), clinician assessments of depression severity (the 21-item HAM-D and the Montgomery-Åsberg Depression Rating Scale [MADRS], and Global Assessment of Functioning [GAF]; all assessed by MBo), and additional patient-rated scales (16-item Quick Inventory of Depressive Symptoms [QIDS], Beck Depression Inventory [BDI—original version], Spielberger’s State-Trait Anxiety Inventory [ form 2, trait version only; STAI-T], and the SnaithHamilton Pleasure Scale [SHAPS]). Patients also received a thorough physical health check, consisting of an electrocardiogram, routine blood tests, blood pressure, heart rate, and physical examination. At the end of screening, eligible patients were given an opportunity to meet with the two clinical psychiatrists who would support them through the remainder of the trial. Eligible patients attended a subsequent visit involving a baseline functional MRI (fMRI) scanning session lasting 60 min, followed by an extensive preparatory session with their allocated psychiatrists; fMRI data will be reported elsewhere. This preparatory session involved inviting the patient to talk openly about their personal history (including thoughts on the origins of their depression), a discussion of psilocybin’s psychological eff ects, and simulation of aspects of the dosing session itself, such as listening to a sample of the session music while wearing eyeshades. The preparatory session typically lasted for 4 h, with lunch and breaks provided. Patients enrolled in the study attended two subsequent dosing sessions that were separated by 7 days. No more than one patient was dosed on any given day. Patients arrived at the research facility (Imperial Clinical Research Facility) at 0900 h, gave a urine sample for drugs of abuse (including amphetamines, benzodiazapines, opiates, and cannabinoids), performed a breathalyser test for alcohol use, and completed interim QIDS, BDI, and STAI-T assessments to ensure no substantial deviation from baseline measures. They were then taken to a dosing room that was pre-decorated (eg, with low lighting). Patients were invited to relax on a ward bed in a supine or reclined position and music was played through high-quality stereo speakers and earphones. The two psychiatrists sat on either side of the bed. Patients were supervised at all times by at least two staff members. Dosing commenced at 1030 h in every case. Patients received a low oral dose of psilocybin 10 mg (two 5 mg capsules) on a first dosing day and a high oral dose of psilocybin 25 mg (five 5 mg capsules) on a second dosing day, separated by 1 week. Blood pressure, heart rate, and observer ratings of the intensity of psilocybin’s acute psychoactive eff ects (0–4, with 0 signifying no eff ects and 4 signifying extreme eff ects8 ) were measured at baseline (typically 5 min before dosing) and 30, 60, 120, 180, 240, 300, and 360 min after dosing. Subjective ratings of the acute altered state of consciousness using the revised Figure 1: Schedule of study interventions Recruitment Enrolment and treatment Follow-up Unspecified time period Low psilocybin dose High psilocybin dose Remote screening or follow-up Clinic screening or follow-up Psilocybin dosing session 1 week 1 week 2 weeks 7 weeks Each bar represents 1 day Ongoing support from study psychiatrists if required Time Telephone screening Screening visit and baseline assessment Patients contacted for remote assessment Post-treatment fMRI and assessment (interim questionnaires) Baseline fMRI and preparatory session Interim questionnaires 1 week follow-up at research facility 2 week follow-up (remotely) 3 week follow-up (remotely) 5 week follow-up (remotely) 3 month follow-up (remotely) Articles 622 www.thelancet.com/psychiatry Vol 3 July 2016 11 dimension altered states of consciousness questionnaire (11D ASC)24 were completed 6–7 h after dosing. Psychiatrists adopted a non-directive, supportive approach, allowing the patient to experience a mostly uninterrupted inner “journey”. Check-ins (ie, asking the patient how they are feeling) occurred at the same timepoints as the physiological recordings. Tranquilising medications (oral lorazepam and risperidone) were available if necessary. The phenomenology of the acute experience, including accounts of the nature of the therapeutic support provided before, during, and after the experience, and considerations related to the music selection and other aspects of the clinical setting, will be discussed in separate publications. Return transport from the research facility was organised ahead of dosing sessions. Patients were taken to and from the sessions accompanied by a close friend or relative, and had the option of staying overnight in accommodation adjacent to the hospital. Emergency contact details were provided, and patients confirmed their safe return from the research facility. Patients were contacted via telephone 1 day after their low-dose session to check on their wellbeing and monitor for any adverse events. Patients returned to the research facility 1 day after their high-dose session for a posttreatment fMRI scan lasting 60 min. After the fMRI scan, patients completed interim questionnaires (QIDS, STAI-T, and HAM-D), and were invited back to the research facility where they were met by their psychiatrists to discuss their experience the previous day. Patients attended one further study visit to the research facility 1 week after their high-dose session, during which all baseline questionnaires and assessments were repeated and an opportunity was provided for further psychological debriefing (the 1 week follow-up visit). Assessments of HAM-D, MADRS, and GAF were again done by MBo. Subsequent assessments of clinical progress were done via email 2, 3, and 5 weeks after the high-dose session; we assessed only QIDS during subsequent follow-up, so as not to overload the patient. Final follow-up was done remotely at 3 months after the high-dose session, and included QIDS, BDI, STAI-T, and SHAPS. Patients were made aware that they could contact the study psychiatrists at any time if their depression deteriorated. Figure 1 summarises the screening, intervention, and follow-up procedures in this study. Outcomes The main objective of this study is to optimise the protocol for the administration of oral psilocybin in this patient group, while gaining an initial impression of treatment efficacy. The primary outcome measure to assess feasibility was patient-rated subjective intensity of psilocybin’s eff ects, which we report on a 0–1 scale. We assessed the safety of the intervention through clinical monitoring during and after dosing sessions, and during 3 months of face-to-face and remote follow-up. We also aimed to assess the preliminary efficacy of psilocybin in patients with treatment-resistant depression; the primary outcome measure for this endpoint was mean change in the severity of self-reported depressive symptoms (with the 16 item QIDS) from baseline to 1 week after the high-dose psilocybin session. The QIDS was chosen as the primary outcome measure due to its brevity, increasingly widespread use, and validity at 1 week intervals.25 We chose to assess the primary efficacy endpoint at 1 week after the high-dose session to allow comparison with previous studies of ketamine infusion for treatment-resistant depression;26 the low-dose session was conceived a priori as a safety session rather than a treatment session. We also assessed change in BDI, STAI-T, and SHAPS between baseline and 1 week and 3 months of follow-up, and change in HAM-D, MADRS, and GAF between baseline and 1 week of follow-up. Statistical analysis In this feasibility study, we did not perform a formal power calculation. We planned to recruit 12 patients to provide an initial impression of the tolerability and efficacy of this novel treatment approach. A subsequent protocol amendment (Oct 6, 2015) increased the recruitment to 20 patients to provide statistical power for fMRI imaging. Here, we report findings for the 12 patients initially enrolled; outcome and fMRI data for all 20 patients will be reported separately. Due to the small population, two-tailed Wilcoxon signed ranks tests were performed for non-parametric data. Two-tailed t tests were also performed and the relevant t values are provided in the appendix. We provide Figure 2: Trial profile 95% CIs around the mean diff erences. We calculated 72 individuals expressed an interest in participating in the trial 34 excluded because they did not meet the entry criteria 38 telephone screened 20 excluded because they did not meet the entry criteria 18 attended screening visit 6 excluded because of insufficiently severe depression (HAM-D) 12 recruited to the study and fully compliant with protocol See Online for appendix Articles www.thelancet.com/psychiatry Vol 3 July 2016 623 eff ect sizes using the Hedges’ g formula, which is more appropriate for small sample sizes. Hedges’ g values are very similar to Cohen’s d values for dependent data. This trial is registered with the ISRCTN registry, number ISRCTN14426797. The registration was initiated on March 30, 2015, and finalised on July 7, 2015 (delay caused by administrative issues); recruitment started on April 21, 2015, after initiation of public registration. Role of the funding source The study funder had no role in the design, data collection, analysis, interpretation, or writing of the report. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit for publication. Results Enrolment started on May 1, 2015, and finished on Aug 25, 2015. 72 people were initially considered for the study, most of whom self-referred after hearing about this trial through public outreach work (eg, public presentations by the investigators and media reports). 38 were considered appropriate for a telephone screen, from which 18 were invited for a formal screening visit, and 12 were ultimately recruited for the trial (figure 2), of whom ten were selfreferrals. Patients’ demographic and clinical characteristics are shown in table 1. Nine of the 12 patients met criteria for severe or very severe depression at baseline (BDI score ≥30), with the remaining three patients meeting criteria for moderate depression (BDI score 19 to <30). 11 patients had received some form of psychotherapy before participation in the study. The acute effects of psilocybin were well tolerated by all of the patients and no serious or unexpected adverse events occurred. Mean self-rated intensity of psilocybin experience was 0·51 (SD 0·36) for the lowdose session and 0·75 (0·27) for the high-dose session (difference 0·24 [95% CI 0·06–0·41], Z –2·4, p=0·019). Sex Age, years Ethnic origin Employment status Estimated illness duration, years Baseline scores Past unsuccessful medications* Past psychotherapy Education Weekly alcohol intake, units Previous psilocybin use (time since last use) BDI HAM-D STAI-T 1 Female 43 Black Caribbean Employed 30 36 19 72 SSRI (two), SNRI (two), NDRI, NSSRI, MAOI None Postgraduate 1 None 2 Male 40 Hispanic Unemployed 25 33 28 76 SSRI (two), SNRI, NDRI, NSSRI, Na+ channel blocker (two), ketamine infusion, TCA Cognitive narrative therapy Postgraduate 0 None 3 Male 37 White Employed 17 22 18 63 SSRI (two), SNRI Cognitive behavioural therapy, group therapy Postgraduate 0 None 4 Female 30 White Studying 10 26 18 67 NDRI, NSSRI Cognitive behavioural therapy Postgraduate 0 One use (6 months) 5 Male 34 White Unemployed 12 38 25 71 SSRI (three), TCA Cognitive and mindfulness behavioural therapy Undergraduate 0 None 6 Female 57 White Unemployed 29 39 23 78 SSRI (four), SNRI, SARI Counselling Secondary education 2 Two uses (45 years) 7 Male 52 White Unemployed 27 33 22 57 TCA, SARI Counselling, mindfulness Secondary education 0 Three uses (30 years) 8 Female 37 White Employed 17 39 17 71 SSRI (two), TCA Counselling Undergraduate 2 None 9 Male 37 White Unemployed 15 32 26 71 SSRI (three), SNRI Counselling, cognitive behavioural therapy Postgraduate 6 None 10 Female 36 Black Caribbean Unemployed 8 47 28 75 SSRI (two), NSSRI Counselling Undergraduate 18 Three uses (14 years) 11 Female 64 White Employed 15 24 17 72 SSRI (four), SNRI (two), NDRI, MAOI, Na⁺ channelblocker, SARI, DRI Cognitive behavioural therapy Postgraduate 1 Three uses (48 years) 12 Male 45 White Employed 8 35 17 68 SSRI, TCA Cognitive behavioural therapy Undergraduate 0 None BDI=Beck Depression Inventory. HAMD-D=Hamilton Depression Rating scale. STAI-T=State-Trait Anxiety Inventory. SSRI=selective serotonin-reuptake inhibitor. SNRI=serotonin–noradrenaline reuptake inhibitor. NDRI=noradrenaline–dopamine-reuptake inhibitor. NSSRI=noradrenaline and specific serotonin-reuptake inhibitor. MAOI=monoamine oxidase inhibitor. TCA=tricyclic antidepressant. SARI=serotonin antagonist and reuptake inhibitor. DRI=dopamine-reuptake inhibitor. *One medication from each class, unless otherwise stated. Table 1: Baseline and demographic characteristics, by patient Articles 624 www.thelancet.com/psychiatry Vol 3 July 2016 No patients required tranquilising medications (oral lorazepam and risperidone) during the dosing sessions. Psilocybin’s acute psychedelic effects typically became detectable between 30 min and 60 min after dosing, peaked between 2 h and 3 h after dosing, and subsided to negligible levels at which the patient could be assessed for discharge at least 6 h after dosing (appendix). Self-rated experiences on the 11D-ASC questionnaire from the two sessions are shown in the appendix. Results from interim patient questionnaires (QIDS, BDI, and STAI-T), done immediately before the low-dose session to monitor for substantial changes since enrolment, did not differ from baseline (data not shown). Interim questionnaires done the day after the high-dose session showed some reduction in depressive symptoms (data for HAM-D in appendix; data for QIDS and STAI-T not shown). Severity Timing or onset Duration Patient 1 Transient anxiety Mild Onset of both sessions 60 min Transient headache Mild Day after high-dose session One day only Transient confusion Mild (core drug eff ect) Peak of both sessions 60–120 min Patient 2 Transient anxiety Mild Anticipatory anxiety only (both sessions) 30 min Patient 3 Transient anxiety Mild Anticipatory anxiety only (both sessions) 30 min Transient confusion Mild (core drug eff ect) Peak of both sessions 60–180 min Patient 4 Transient anxiety Mild (low dose), moderate (high dose) Onset of both sessions and peak of high dose 60 min (low dose), 120 min (high dose) Transient nausea Moderate Onset phase of high-dose session Arose and subsided within 60 min Transient confusion Mild (core drug eff ect) Peak of both sessions 60–180 min Transient paranoia Mild Peak of high-dose session Arose and subsided within 30 min Patient 5 Transient anxiety Moderate (low dose), severe (high dose) Onset of both sessions and peak of high dose 60 min (low dose), 150 min (high dose) Transient headache Mild Day after high-dose session One day only Transient confusion Mild (core drug eff ect) Peak of both sessions 60–120 min Patient 6 Transient anxiety Mild Anticipatory anxiety only (both sessions) 30 min Patient 7 Transient anxiety Mild Anticipatory anxiety only (both sessions) 30 min Transient confusion Mild (core drug eff ect) Peak of both sessions 60–180 min Patient 8 Transient anxiety Mild or negligible Anticipatory anxiety only (both sessions) 30 min Patient 9 Transient anxiety Mild (low dose), moderate (high dose) Onset of low-dose and high-dose session 60 min (low dose), 150 min (high dose) Transient headache Mild Day after high-dose session One day only Transient confusion Mild (core drug eff ect) Peak of both sessions 60–180 min Patient 10 Transient anxiety Mild Onset of both sessions 60 min Transient nausea Mild Onset and peak of low-dose session Subsided after 90 min Transient headache Mild or moderate Day after high-dose session 2 days Transient confusion Mild (core drug eff ect) Peak of both sessions 60–180 min Patient 11 Transient anxiety Moderate (both sessions) Onset phase and peak of both sessions 150 min (both sessions) Transient nausea Mild (high dose) Onset phase of high-dose session Arose and subsided within 60 min Transient confusion Mild (core drug eff ect) Peak of both sessions 60–180 min Transient paranoia Mild Peak of low-dose session Arose and subsided within 60 min Patient 12 Transient anxiety Mild Anticipatory anxiety only (both sessions) 30 min Transient confusion Mild (core drug eff ect) Peak of both sessions 60–180 min Table 2: Adverse events by patient Articles www.thelancet.com/psychiatry Vol 3 July 2016 625 The most common adverse events were transient anxiety (mostly mild) during drug onset (n=12), transient confusion or thought disorder (n=9), mild and transient nausea (n=4), and transient headache (n=4; table 2). These adverse events were expected psychological eff ects of psilocybin. Subacute headache typically presented 1 day after the psilocybin session, and subsided after 1–2 days. Paranoia presented in only one patient, but this was mild and transient. No prolonged psychotic symptoms were observed in any of the patients. One patient contacted the study psychiatrists during the 3 months of follow-up due to deterioration of their depression, and was referred to their general practitioner. QIDS depression scores were significantly reduced from baseline to 1 week and 3 months post-treatment, with the maximum eff ect at 2 weeks (figure 3, table 3). BDI and clinician-administered ratings confirmed these results (figure 4, table 3). All patients showed some reduction in depression severity at 1 week that was sustained in the majority for 3 months (appendix). According to standard criteria for determining remission (eg, a score of ≤9 on the BDI), eight (67%) of the 12 patients achieved complete remission at 1 week and seven patients (58%) continued to meet criteria for response (50% reduction in BDI score relative to baseline) at 3 months, with five of these (42%) still in complete remission (figure 4, table 3). STAI-T anxiety scores were also significantly reduced at 1 week and 3 months post-treatment, as were SHAPS anhedonia scores for 1 week and 3 months post-treatment (table 3). Discussion In this open-label, single-arm pilot study, we sought to examine the feasibility of administering psilocybin to patients with treatment-resistant depression as a prelude to a larger randomised controlled trial. Our results support Figure 3: Mean depression severity (QIDS) over time Depression severity determined by self-rated 16-item QIDS. QIDS scores of 16–20 are considered to refl ect severe depression, scores of 11–15 are considered moderate depression, scores of 6–10 are considered mild depression, and scores of 5 and less are considered absent depression. All post-treatment assessments were obtained after the high-dose session (ie, 1 week post-treatment refers to 1 week after the high-dose session). Hedges’ g values versus baseline are shown. QIDS=Quick Inventory of Depressive Symptoms. 0 5 10 15 20 25 Baseline 1 week 2 weeks 3 weeks 5 weeks 3 months QIDS score Hedges’ g 3·1 p=0·002 Hedges’ g 3·2 p=0·002 Hedges’ g 3·2 p=0·002 Hedges’ g 2·7 p=0·003 Hedges’ g 2·0 p=0·003 QIDS BDI STAI-T SHAPS HAM-D MADRS GAF Baseline 1 week 2 weeks 3 weeks 5 weeks 3 months Base- line 1 week 3 months Base- line 1 week 3 months Base- line 1 week 3 months Base- line 1 week Base- line 1 week Base- line 1 week Mean (SD) 19·2 (2·0) 7·4 (4·9) 6·3 (4·6) 6·4 (5·1) 8·2 (5·4) 10·0 (6·0) 33·7 (7·1) 8·7 (8·4) 15·2 (11·0) 70·1 (5·8) 40·6 (14·2) 54·8 (14·5) 7·5 (3·7) 1·4 (2·7) 2·8 (3·7) 21·4 (4·5) 7·4 (6·9) 31·0 (5·0) 9·7 (9·8) 50·3 (9·2) 77·7 (13·0) Diff erence versus baseline (95% CI) ·· –11·8 (–9·15 to –14·35) –12·9 (–10·64 to –15·16) –12·8 (–9·9 to –15·6) –11·0 (–7·7 to –14·2) –9·2 (–5·69 to –12·71) ·· –25·0 (–20·1 to –29·9) –18·5 (–11·8 to –25·2) ·· –29·5 (–22·03 to –36·97) –15·3 (–7·77 to –22·83) ·· –6·1 (–4·46 to –7·74) –4·7 (–3·29 to –6·11) ·· –14·0 (–9·6 to –18·4) ·· –23·3 (–17·1 to –29·5) ·· 27·3 (18·0 to 36·6) Z ·· –3·1 –3·1 –3·06 –2·9 –3·0 ·· –3·1 –3·1 ·· –3·1 –2·9 ·· –3·1 –3·1 ·· –3·0 ·· –3·1 ·· 3 Hedges’ g* ·· 3·1 3·2 3·2 2·7 2·0 ·· 3·2 2·0 ·· 2·7 1·4 ·· 1·9 1·3 ·· 2·4 ·· 2·7 ·· 2·4 p value* ·· 0·002 0·002 0·002 0·003 0·003 ·· 0·002 0·002 ·· 0·002 0·004 ·· 0·002 0·002 ·· 0·003 ·· 0·002 ·· 0·003 Follow-up refers to the period starting after the second (high-dose) administration of psilocybin. Clinician-administered ratings (HAM-D, MADRS, and GAF) were completed only at baseline and 1 week after the high-dose session. QIDS=Quick Inventory of Depressive Symptoms. BDI=Beck Depression Inventory. STAI-T=State-Trait Anxiety Inventory. SHAPS=Snaith-Hamilton Pleasure Scale. HAM-D=Hamilton Depression Rating scale. MADRS=Montgomery-Åsberg Depression Rating Scale. GAF=Global Assessment of Functioning. *Compared with baseline. Table 3: Clinical ratings at baseline and follow-up Articles 626 www.thelancet.com/psychiatry Vol 3 July 2016 the view that, done with appropriate safeguards (eg, careful screening and adequate therapeutic support), psilocybin can be safely administered to this patient group. Because this was a small-scale feasibility study with an open-label design, strong inferences cannot be made about the treatment’s therapeutic efficacy. However, the data do suggest that further research is warranted. The response rate to psilocybin was 67% (n=8) at 1 week after treatment (HAM-D and BDI), and seven of these eight patients also met criteria for remission. Moreover, 58% (n=7) of the patients maintained their response for 3 months, and 42% (n=5) remained in remission. It is also worth noting that psilocybin has a favourable toxicity profile and is not associated with compulsive drug-seeking behaviours in animals or human beings. The side-eff ects that we noted were minor, and expected in light of previous studies of psilocybin.27 Spontaneous recovery in refractory depression is rare, and many of the patients in the present study reported having depression for much of their adult lives (mean estimated illness duration 17·8 years [SD 8]). Key questions for future research therefore should address why the therapeutic eff ect observed in the present study is so large, and if it can be replicated when tighter experimental controls are introduced. Because the treatment in our study consisted of not just two psilocybin administrations but also psychological support before, during, and after these sessions, as well as a positive therapeutic environment for the sessions, the relative eff ects of these factors need to be determined, which can only be done by conducting further trials with appropriate control conditions. A logical next step would be to carry out a placebocontrolled randomised trial in which the level of therapist contact is consistent between conditions. This would enable any between-group diff erences in clinical outcomes to be attributed to psilocybin rather than the psychological support provided. However, a positive interaction between these variables seems likely, and inert placebo-based blinds are known to be ineff ective in studies involving conspicuous experimental interventions, because patients can easily discern whether they are in the active condition or not. Use of an active placebo for the control condition might therefore be worth considering. Additionally, randomised comparative efficacy trials (eg, with an optional crossover component) incorporating another treatment for refractory depression (eg, ketamine infusion) could also be explored. The magnitude and persistence of the antidepressant eff ects observed here are not incongruent with what has been observed previously with psilocybin in chronic psychiatric conditions. For example, 80% of long-term heavy tobacco smokers demonstrated abstinence from smoking 6 months after two treatment sessions with psilocybin.18 Alcohol-dependent patients demonstrated significantly reduced drinking behaviours over 8 months after one or two psilocybin sessions.19 Significantly decreased anxiety and depression scores were observed 3 and 6 months after a single dose of psilocybin in patients with anxiety related to end-stage cancer,15 and improve ments in wellbeing lasting for more than 1 year were observed in healthy individuals given a single dose of psilocybin.8 Rapid and enduring decreases in depressive symptoms were also recently found in a small-scale feasibility trial involving the psychedelic brew, ayahuasca.16 It is important to consider the limitations of this pilot study; for example, although all patients showed some clinical improvements for at least 3 weeks after treatment, and no serious or unexpected adverse reactions were observed, enduring improvements beyond 3 weeks were not observed universally, and five of the 12 patients showed a degree of relapse at 3 months. One should be cautious of the potential for infl ated eff ect sizes in early trials, particularly when the sample size is small. That all patients showed some improvement in their depressive symptoms for up to 3 weeks after treatment could be suggestive of an expectancy bias. It may also be relevant that most patients in this trial were self-referring and, thus, actively sought this treatment. Psychedelics are known to promote suggestibility,28 which might have further enhanced positive outcomes. Future double-blind randomised controlled trials could address the role of expectancy and suggestibility by measuring and controlling these variables. For example, patients could be asked about their pre-treatment expectations, suggestions could be controlled between conditions, and outcomes from self-referred patients could be compared with those from patients referred via clinicians. From a more pragmatic perspective, if expectancy or suggestibility are found to be infl uential in the context of psychedelic therapy, they could be treated as exploitable components of the treatment model rather than confounding variables. Figure 4: Depression severity (BDI) over time, by patient Figure shows depression severity (BDI) over time plotted for each of the 12 patients. Mean values (SD) are shown as well as the relevant eff ect sizes (Hedges’ g) versus baseline. BDI=Beck Depression Inventory. 0 10 20 30 40 50 Baseline 1 week 3 months BDI score 33·7 (7·1) 15·2 (11) g=2 Severe depression (≥30) Mild or moderate depression (>9 to >30) No depression (≤9) 8·7 (8·4) g=3·2 P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 High dose Articles www.thelancet.com/psychiatry Vol 3 July 2016 627 Serotonergic antidepressants have been found to downregulate the primary receptor target of psilocybin (the 5-HT2A receptor) and attenuated subjective responses to psychedelics have previously been reported in individuals chronically medicated with serotonergic antidepressants.29 Thus, patients may be required to withdraw from concurrent antidepressant medication before receiving psilocybin and this should only ever be done with care. In conclusion, we sought to assess the safety and tolerability of psilocybin plus psychological support in patients with unipolar treatment-resistant depression. Our findings support the feasibility of this approach and the magnitude and duration of the post-treatment reductions in symptom severity motivate further controlled research. Psilocybin has a novel pharmacological action in comparison with currently available treatments for depression (ie, 5-HT2A receptor agonism) and thus could constitute a useful addition to available therapies for the treatment of depression.

Contributors

RLC-H and DJN designed the study and RLC-H wrote the report. RLC-H

coordinated the study, and collected and analysed the data. MBo was the

lead psychiatrist on the trial. MBo, JR, CMJD, DE, and MBl provided

psychological support for the patients. All authors critically revised the

report or contributed important intellectual content.

Declaration of interests

DT has received research funding and lecture honoraria from Servier,

and lecture honoraria from Lundbeck. The other authors declare no

competing interests.

Acknowledgments

This study was funded by an MRC clinical development scheme grant

(MR/J00460X/1). MK was supported by the Beckley Foundation and this

work was carried out as part of the Beckley/Imperial Research

Collaboration. The research was carried out at the NIHR/Wellcome

Trust Imperial Clinical Research Facility. We would like to thank

Robert Sullivan (Meridian West London, London, UK) for provision of

high-quality audio equipment for the dosing sessions.

References

1 Hofmann A, Frey A, Ott H, Petr Zilka T, Troxler F. Elucidation of

the structure and the synthesis of psilocybin. Experientia 1958;

14: 397–99.

2 Hofmann A, Heim R, Brack A, Kobel H. Psilocybin, a psychotropic

substance from the Mexican mushroom Psilicybe mexicana Heim.

Experientia 1958; 14: 107–09.

3 Halberstadt AL, Geyer MA. Multiple receptors contribute to the

behavioral eff ects of indoleamine hallucinogens. Neuropharmacology

2011; 61: 364–81.

4 Boulougouris V, Glennon JC, Robbins TW. Dissociable eff ects of

selective 5-HT2A and 5-HT2C receptor antagonists on serial spatial

reversal learning in rats. Neuropsychopharmacology 2008;

33: 2007–19.

5 Harvey JA. Role of the serotonin 5-HT(2A) receptor in learning.

Learn Mem 2003; 10: 355–62.

6 Vaidya VA, Marek GJ, Aghajanian GK, Duman RS. 5-HT2A

receptor-mediated regulation of brain-derived neurotrophic factor

mRNA in the hippocampus and the neocortex. J Neurosci 1997;

17 (8): 2785–95.

7 Buchborn T, Schroder H, Hollt V, Grecksch G. Repeated lysergic

acid diethylamide in an animal model of depression: normalisation

of learning behaviour and hippocampal serotonin 5-HT2 signalling.

J Psychopharmacol 2014; 28: 545–52.

8 Griffi ths R, Richards W, Johnson M, McCann U, Jesse R.

Mystical-type experiences occasioned by psilocybin mediate the

attribution of personal meaning and spiritual signifi cance

14 months later. J Psychopharmacol 2008; 22: 621–32.

9 Carhart-Harris RL, Kaelen M, Bolstridge M, et al. The paradoxical

psychological eff ects of lysergic acid diethylamide (LSD).

Psychol Med 2016; 46: 1379–90.

10 Carhart-Harris RL, Erritzoe D, Williams T, et al. Neural correlates of

the psychedelic state as determined by fMRI studies with

psilocybin. Proc Natl Acad Sci USA 2012; 109: 2138–43.

11 Hendricks PS, Thorne CB, Clark CB, Coombs DW, Johnson MW.

Classic psychedelic use is associated with reduced psychological

distress and suicidality in the United States adult population.

J Psychopharmacol 2015; 29: 280–88.

12 Krebs TS, Johansen PO. Psychedelics and mental health: a population

study. PLoS One 2013; 8: e63972.

13 Bouso JC, Gonzalez D, Fondevila S, et al. Personality, psychopathology,

life attitudes and neuropsychological performance among ritual users

of Ayahuasca: a longitudinal study. PLoS One 2012; 7: e42421.

14 Gasser P, Holstein D, Michel Y, et al. Safety and effi cacy of lysergic

acid diethylamide-assisted psychotherapy for anxiety associated with

life-threatening diseases. J Nerv Ment Dis 2014; 202: 513–20.

15 Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin

treatment for anxiety in patients with advanced-stage cancer.

Arch Gen Psychiatry 2011; 68: 71–78.

16 Osorio Fde L, Sanches RF, Macedo LR, et al. Antidepressant eff ects

of a single dose of ayahuasca in patients with recurrent depression:

a preliminary report. Rev Bras Psiquiatr 2015; 37: 13–20.

17 Moreno FA, Wiegand CB, Taitano EK, Delgado PL. Safety, tolerability,

and effi cacy of psilocybin in 9 patients with obsessive-compulsive

disorder. J Clin Psychiatry 2006; 67: 1735–40.

18 Johnson MW, Garcia-Romeu A, Cosimano MP, Griffi ths RR.

Pilot study of the 5-HT2AR agonist psilocybin in the treatment of

tobacco addiction. J Psychopharmacol 2014; 28: 983–92.

19 Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa P,

Strassman RJ. Psilocybin-assisted treatment for alcohol dependence:

a proof-of-concept study. J Psychopharmacol 2015; 29: 289–99.

20 Johnson M, Richards W, Griffi ths R. Human hallucinogen research:

guidelines for safety. J Psychopharmacol 2008; 22: 603–20.

21 Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC.

The economic burden of adults with major depressive disorder in

the United States (2005 and 2010). J Clin Psychiatry 2015; 76: 155–62.

22 Gaynes BN. Identifying diffi cult-to-treat depression:

diff erential diagnosis, subtypes, and comorbidities. J Clin Psychiatry

2009; 70 (suppl 6): 10–15.

23 Sackeim HA. The definition and meaning of treatment-resistant

depression. J Clin Psychiatry 2001; 62 (suppl 16): 10–17.

24 Studerus E, Gamma A, Vollenweider FX. Psychometric evaluation

of the altered states of consciousness rating scale (OAV). PLoS One

2010; 5: e12412.

25 Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory

of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and

self-report (QIDS-SR): a psychometric evaluation in patients with

chronic major depression. Biol Psychiatry 2003; 54: 573–83.

26 Ibrahim L, DiazGranados N, Franco-Chaves J, et al. Course of

improvement in depressive symptoms to a single intravenous

infusion of ketamine vs add-on riluzole: results from a 4-week,

double-blind, placebo-controlled study. Neuropsychopharmacol 2012;

37: 1526–33.

27 Johnson MW, Sewell RA, Griffi ths RR. Psilocybin dose-dependently

causes delayed, transient headaches in healthy volunteers.

Drug Alcohol Depend 2012; 123: 132–40.

28 Carhart-Harris RL, Kaelen M, Whalley MG, Bolstridge M,

Feilding A, Nutt DJ. LSD enhances suggestibility in healthy

volunteers. Psychopharmacology 2015; 232: 785–94.

29 Bonson KR, Buckholtz JW, Murphy DL. Chronic administration of

serotonergic antidepressants attenuates the subjective eff ects of

LSD in humans. Neuropsychopharmacology 1996; 14: 425–36.

Tegn abonnement på

BioNyt Videnskabens Verden (www.bionyt.dk) er Danmarks ældste populærvidenskabelige tidsskrift for naturvidenskab. Det er det eneste blad af sin art i Danmark, som er helliget international forskning inden for livsvidenskaberne.

Bladet bringer aktuelle, spændende forskningsnyheder inden for biologi, medicin og andre naturvidenskabelige områder som f.eks. klimaændringer, nanoteknologi, partikelfysik, astronomi, seksualitet, biologiske våben, ecstasy, evolutionsbiologi, kloning, fedme, søvnforskning, muligheden for liv på mars, influenzaepidemier, livets opståen osv.

Artiklerne roses for at gøre vanskeligt stof forståeligt, uden at den videnskabelige holdbarhed tabes.