![](\"https://images-na.ssl-images-amazon.com/images/S/compressed.photo.goodreads.com/books/1680075735i/123578631.jpg\")
The phenomenon of individuals recovering (traumatic) memories under the effects of psychedelics and/or MDMA has been increasingly discussed recently, and for good reason. I’ve talked about this too in some conference presentations and am writing several scientific articles that relate to the topic to various degrees.
\nThe popularity of the best-selling, Oprah’s Book Club* memoir The Tell is one factor contributing to the topical nature of this conversation. The book, for those not familiar, describes how the author, billionaire venture capitalist Amy Griffin, underwent MDMA-assisted therapy and under the influence recovered vivid, detailed memories of being repeatedly raped by a schoolteacher some 30 years earlier. She reports she was never aware of this having happened to her before, nor was anyone else, and that these detailed memories appeared completely de novo to her.
\nI read the book some two months ago, and, as a trauma, memory, and psychedelics researcher, had very mixed feelings. Yesterday, a New York Times article on the book and the experiences it describes was published, which certainly further complicates my already complicated feelings about the book and its impact.
\nNow, even after this NYT investigation into the details surrounding the book and Griffin’s experiences, I don’t have any clear reason to doubt that what the author describes remembering in that book happened to her. Some details in the way the story is presented and some that this investigation uncovered do cast doubt on whether things happened exactly as the author describes her memories in the book. But no memories are ever totally accurate representations of the past, and there are several potential explanations for how the author may have come to remember what she does. In any case, what really happened mostly matters to the author herself and the accused person (who is still alive and was identified by NYT).
\nHowever, what is concerning to me about The Tell is that its enormous popularity may be further feeding into the idea that MDMA and/or psychedelics are tools to discover the hidden source of your suffering, to recover the forgotten trauma that must exist in your past to explain why you are distressed or unhappy today. The idea of psychedelics recovering repressed memories has a long history (See my recent talk at Breaking Convention for some examples), and currently appears to be quite prevalent in some psychedelic, perhaps especially ayahuasca and MDMA, circles. It further often problematically combines with the belief that “the medicine will show you what you need to see”. Thus, people go into therapeutic sessions or ceremonies with the specific purpose of trying to recover memories of what happened to them (typically as small children) and some facilitators appear to encourage this. And when they do recover something, they are very convinced that what they now remember must be true.
\nIn psychotherapy, it may never be too late to have a happy childhood. But recovered-memory therapies of past decades showed us that it’s also never too late to have a traumatic childhood. What I mean is, if you really try hard to recover terrible, traumatic memories from your childhood, and especially if you find a therapist/facilitator/guide who believes in this and uses suggestive techniques to help you do so, you may well find such memories, regardless of whether anything traumatic actually ever happened to you.
\nThe phenomenon of recovered memories is complex and its nature is somewhat contested. We do know that people can recover memories both spontaneously and in therapy. And we can say with some confidence and evidence that sometimes such memories are real in the sense that they are fairly accurate reflections of real events that had happened to the person in question, sometimes they are false memories in the sense that such an event did not happen to this person, and sometimes they are somewhere in between, e.g., partially inaccurate or combine details from different sources.
\nThis is also true for memories recovered under psychedelics. Sorry to say, but there’s no benevolent plant spirit or hidden intelligence inherent to these substances that guarantees what you seem to remember under their effects reflects reality. Whether psychedelics may enhance the potential for forming false memories (this remains unclear), there is at least no evidence to suggest they reduce such potential. So, if anything, we should be a little more skeptical about the veracity of a memory if it is recovered under psychedelics than if it is recovered sober, rather than less skeptical.
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* Incidentally(?), Michelle Remembers (1980), another book about recovering memories of abuse, later totally discredited, and in part responsible for starting the Satanic ritual abuse panic, was also promoted by Oprah Winfrey…
\n", "author": { "name": "" }, "tags": [ ], "date_published": "2025-09-25T12:29:34+03:00", "date_modified": "2025-10-01T10:59:45+03:00" }, { "id": "https://kangaslampi.net/blog/passie-review/", "url": "https://kangaslampi.net/blog/passie-review/", "title": "Torsten Passie – The History of MDMA (123-Word Book Review)", "summary": "\n
Torsten Passie – The History of MDMA
Oxford University Press, 2023
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Torsten Passie – The History of MDMA
Oxford University Press, 2023
In this absorbing book, Professor Torsten Passie presents a much-needed and authoritative look at the history of MDMA from a variety of angles, from its discovery and early history to its emergence as a recreational drug and therapeutic agent, to eventual scheduling, world-wide spread, and recently expanding research. Different chapters focus on different aspects of the history of MDMA in a roughly chronological order.
\nThe detailed but manageable and relatively succinct history offers many new perspectives and corrections to previous misunderstandings and myths, even for readers who are quite familiar with the overall topic. The text is meticulously referenced while remaining surprisingly readable and engaging. Passie’s encyclopedic knowledge of the topic and careful research based on original sources and personal interviews shine through.
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123-Word Book Review by Samuli Kangaslampi, samuli@kangaslampi.net, 07/2024
\n", "author": { "name": "" }, "tags": [ ], "date_published": "2024-07-30T10:35:32+03:00", "date_modified": "2024-07-30T10:35:33+03:00" }, { "id": "https://kangaslampi.net/blog/aixala-review/", "url": "https://kangaslampi.net/blog/aixala-review/", "title": "Marc Aixalà – Psychedelic Integration (123-Word Book Review)", "summary": "\n![\"Psychedelic](\"https://m.media-amazon.com/images/I/81KvtYWPo+L._AC_UF1000,1000_QL80_.jpg\")
Marc Aixalà – Psychedelic Integration: Psychotherapy for Non-Ordinary States of Consciousness
Synergetic Press, 2022
", "content_html": "\n
Marc Aixalà – Psychedelic Integration: Psychotherapy for Non-Ordinary States of Consciousness
Synergetic Press, 2022
Based on both Marc Aixalà’s extensive experience in providing psychedelic integration services in several contexts and wide-ranging theoretical knowledge, this is a pioneering book-length exposition of an increasingly relevant topic. It presents careful historical and theoretical analysis of the concept, a useful cartography of why people seek psychedelic integration services, and, most notably, Aixalà’s therapeutic method, including both its theoretical foundations and its practical application with different types of clients.
\nThe evident influence of Aixalà’s background in transpersonal psychology and appeals to Stanislav Grof’s theories may make some parts more appealing to some, but less palatable to others. In any case, this is a most valuable contribution to the literature – essential for anyone working in psychedelic integration, but worth reading for many others, too.
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123-Word Book Review by Samuli Kangaslampi, samuli@kangaslampi.net, 03/2024
\n", "author": { "name": "" }, "tags": [ ], "date_published": "2024-03-08T10:26:38+02:00", "date_modified": "2024-03-08T10:26:40+02:00" }, { "id": "https://kangaslampi.net/blog/saville-smith-review/", "url": "https://kangaslampi.net/blog/saville-smith-review/", "title": "Richard Saville-Smith – Acute Religious Experiences (123-Word Book Review)", "summary": "\n![\"\"](\"https://kangaslampi.net/media/posts/4/saville-smith1.jpg\")
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"content_html": "\n
Bloomsbury Academic, 2023
In this fascinating scholarly work on extraordinary/mystical/religious experiences, Richard Saville-Smith re-reads James, Otto, Osterreich, Eliade, Stace, Pahnke, and Maslow from a fresh mad studies perspective, demonstrating blind spots and problems in how they approached, described, and categorized extraordinary experiences. His criticism of mystical experiences as inherited into psychedelic research from Stace via Pahnke is particularly forceful. He then analyzes the DSM-5’s acknowledgment of non-pathological dissociation/possession (but not psychosis!) and Foucault, before offering his own definition of acute religious experiences and applying it to the life of Jesus.
\nMost writers on the mystical/numinous/religious have indeed done their best to “sanitize them from experiences of culturally accommodated madness“. For Saville-Smith, instead, “[m]ystical experiences are psychotic experiences – desirable psychotic experiences”. (p. 96) A seriously thought-provoking, provocative book!
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123-Word Book Review by Samuli Kangaslampi, samuli@kangaslampi.net, 10/2023
\n", "author": { "name": "" }, "tags": [ ], "date_published": "2023-11-02T20:16:26+02:00", "date_modified": "2023-11-02T20:16:27+02:00" }, { "id": "https://kangaslampi.net/blog/matthew-oram-review/", "url": "https://kangaslampi.net/blog/matthew-oram-review/", "title": "Matthew Oram – The Trials of Psychedelic Therapy: LSD Psychotherapy in America (123-Word Book Review)", "summary": "\n![\"\"](\"https://kangaslampi.net/media/posts/5/oram1.jpg\")
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"content_html": "\n
John Hopkins University Press, 2018
Matthew Oram’s work is a thorough presentation of the first wave of LSD therapy trials in the U.S. in the 1950s-1970s, relying on careful research and wide-ranging engagement with primary sources. Besides the overall narrative, Oram focuses on the evolving nature and precise findings of the various trials as well as the changing regulatory landscape. He establishes such factors as the main reasons for why the research eventually died out, busting several myths and inaccurate representations in the process. The hippies were generally not to blame, nor were direct government restrictions, for the most part.
\nEspecially Oram’s exploration of the difficulties past researchers had in applying the RCT model to psychedelics makes the book essential reading for those now involved in psychedelic trials.
\n123-Word Book Review by Samuli Kangaslampi, samuli@kangaslampi.net, 10/2023
\n", "author": { "name": "" }, "tags": [ ], "date_published": "2023-10-30T20:04:43+02:00", "date_modified": "2023-11-01T14:46:26+02:00" }, { "id": "https://kangaslampi.net/blog/mdma-terapian-hyvaksynta-lahenee-lapimurto-ptsdn-hoidolle-vai-yksi-vaihtoehto-muiden-joukossa/", "url": "https://kangaslampi.net/blog/mdma-terapian-hyvaksynta-lahenee-lapimurto-ptsdn-hoidolle-vai-yksi-vaihtoehto-muiden-joukossa/", "title": "MDMA-terapian hyväksyntä lähenee – läpimurto PTSD:n hoidolle vai yksi vaihtoehto muiden joukossa?", "summary": "\nTämä teksti julkaistu aiemmin Psykedeelitutkimusyhdistys ry:n blogissa 19.9.2023
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Multidisciplinary Association for Psychedelic Studies (MAPS) -järjestön kolmannen vaiheen MAPP2-tutkimuksen tulokset MDMA-avusteisen terapian hyödyntämisestä traumaperäisen stressihäiriön (PTSD) hoitoon julkaistiin juuri Nature Medicine -lehdessä. Tutkimuksessa oli mukana 104 kohtalaisesta tai vaikeasta PTSD:stä kärsivää potilasta aiempia tutkimuksia laajemmalla etnisten taustojen kirjolla. Osallistujat olivat kärsineet PTSD:stä keskimäärin 16 vuotta, ja monien tilanteissa oli myös hoitoa tyypillisesti hankaloittavia piirteitä kuten useita traumakokemuksia eri yhteyksissä sekä dissosiatiivista oireilua.", "content_html": "\n
Tämä teksti julkaistu aiemmin Psykedeelitutkimusyhdistys ry:n blogissa 19.9.2023
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Multidisciplinary Association for Psychedelic Studies (MAPS) -järjestön kolmannen vaiheen MAPP2-tutkimuksen tulokset MDMA-avusteisen terapian hyödyntämisestä traumaperäisen stressihäiriön (PTSD) hoitoon julkaistiin juuri Nature Medicine -lehdessä. Tutkimuksessa oli mukana 104 kohtalaisesta tai vaikeasta PTSD:stä kärsivää potilasta aiempia tutkimuksia laajemmalla etnisten taustojen kirjolla. Osallistujat olivat kärsineet PTSD:stä keskimäärin 16 vuotta, ja monien tilanteissa oli myös hoitoa tyypillisesti hankaloittavia piirteitä kuten useita traumakokemuksia eri yhteyksissä sekä dissosiatiivista oireilua.
\nTämä satunnaistettu, 13 eri tutkimuspaikalla toteutettu kaksoissokkotutkimus osoitti MDMA-avusteisen terapian olevan vaikuttavaa hoitoa PTSD:hen verrattuna ryhmään, joka sai saman terapeuttisen intervention yhdistettynä lumelääkkeeseen. Kolme MDMA-annosta sisältänyt hoito-ohjelma johti siihen, että 71 % osallistujista ei enää täyttänyt PTSD:n diagnostisia kriteereitä, verrattuna 48 prosenttiin lumelääkeryhmässä. MDMA-ryhmässä 46 %:n voitiin katsoa olevan remissiossa (ainakin toistaiseksi ”kokonaan parantuneen” PTSD:stä) verrattuna 21 %:iin lumelääkeryhmästä. Efektin koko PTSD-oireisiin lumeryhmään verrattuna oli d = 0.7 eli kohtalainen ja kliinikon arvioimaan toimintakykyyn d = 0.4 eli pienehkö.
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![\"\"](\"https://psyty.fi/wp-content/uploads/2023/09/mdma-vaikuttavuus-1024x313.png\")
Kuva: MDMA-avusteisen terapian vaikuttavuus PTSD-oireisiin lumelääkeryhmään verrattuna. Mitchell ym. (2023). CC BY 4.0.
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Edellisen, 90 koehenkilön MAPP1-tutkimuksen tulokset olivat varsin samansuuntaisia. Myös siinä tutkimuksessa 2/3 osallistujista ei täyttänyt PTSD:n kriteereitä kolmen MDMA-hoitosession jälkeen, efektikoon lumeryhmään verrattuna ollessa hieman suurempi, d = 0.9. Nämä tutkimukset osoittavat vain lyhyen aikavälin vaikuttavuutta. Aiempien, toisen vaiheen tutkimusten pitkäaikaisseurannassa vaikutusten on kuitenkin havaittu säilyvän ja jopa tehostuvan 12 kuukauden seurantaan saakka.
\nNäiden tutkimusten positiivisten tulosten seurauksena MAPS käynnistää nyt prosessin myyntiluvan saamiseksi MDMA:lle Yhdysvalloissa. Hyväksyntää voidaan realistisesti odottaa vuoden 2024 aikana. Euroopassa on tarpeen tehdä ainakin joitakin erillisiä kolmannen vaiheen tutkimuksia, joten hoitomuodon saapumista tänne saataneen odottaa vielä joitakin vuosia.
\nMDMA-avusteinen terapia näyttää siis vaikuttavan PTSD-oireisiin paremmin kuin lumelääke yhdistettynä vastaavaan terapiaan. Ero on selkeä ja tilastollisesti merkitsevä, joskaan ei efektikokona tarkasteltuna valtavan suuri. Kuinka hyviä ja kliinisen käytännön kannalta merkittäviä nämä tulokset ovat? Ja millaiseksi MDMA-avusteisen terapia rooli tulevaisuudessa asettuu, jos se hyväksytään traumaperäisen stressihäiriön hoidoksi?
\nKoska kyse on lääkekehitysprosessista, MAPSin tutkimuksissa MDMA-hoitoa on (epäsuorasti) verrattu lähinnä olemassa oleviin PTSD:n lääkehoitoihin ‒ käytännössä SSRI-tyyppisiin lääkkeisiin, joiden teho oireiden hoidossa onkin melko vaatimaton. PTSD:n hoitoon on kuitenkin kehitetty myös kohtalaisen hyvin toimivia psykologisia interventioita, joista etenkin traumakeskeisiä kognitiivisen käyttäytymisterapian eri muotoja suositellaan ensisijaisiksi hoidoiksi useissa maissa.
\nMAPP1-tutkimuksen julkaisun yhteydessä Halvorsen ja kollegat (2021) kritisoivatkin MDMA-avusteisen terapian luonnehtimista ”läpimurroksi” siltä pohjalta, että se näyttää olevan vaikuttavampaa kuin muut lääkkeelliset hoidot. He nostivat esiin, että meta-analyysien perusteella olemassa olevien traumakeskeisten hoitojen vaikutukset PTSD:hen ovat efektikokojen ja remissioprosenttien valossa itse asiassa samaa luokkaa tai jopa suurempia suhteessa vertailuryhmiin kuin vaikutukset, joita MAPP1-tutkimus (ja nyt MAPP2-tutkimus) raportoivat MDMA-avusteiselle hoidolle.
\nTutkimusten välillä on merkittäviä eroja etenkin osallistujissa ja heidän oireidensa vaikeudessa, vertailuryhmissä sekä käytännön toteutuksessa. Jotta hoitomuotojen vaikuttavuutta voitaisiin luotettavasti vertailla toisiinsa, tulisi toteuttaa vertailevaa tutkimusta, jossa osa osallistujista satunnaistettaisiin MDMA-avusteiseen ja osa ns. perinteiseen hoitoon. Tällaista tutkimusta ei ole vielä kukaan tehnyt. Se olisi tärkeä seuraava askel, jotta tiedettäisiin, onko MDMA-avusteinen terapia todella vaikuttavampaa tai paremmin siedettyä kuin esimerkiksi traumakeskeinen kognitiivinen käyttäytymisterapia, vai onko se lopulta vain yksi, suunnilleen yhtä toimiva, vaihtoehto lisää jo olemassa olevien hoitojen joukkoon.
\nUusimmassa tutkimuksessa huomiota herättävät myös lumeryhmässä saadut varsin hyvät hoitotulokset. Lumeryhmässäkin liki puolet keskimäärin 16 vuotta PTSD:stä kärsineistä potilaista sai niin merkittävää helpotusta oireisiinsa, ettei enää täyttänyt häiriön diagnostisia kriteereitä. Tämä siitä huolimatta, että (sokkoutuksen ollessa epätäydellistä) lumeryhmään päätyminen saattaa aiheuttaa potilaissa myös pettymystä siitä, ettei itse saanutkaan paljon odotettua MDMA-hoitoa. Kohtalaista hoitotulosta lumeryhmässä voidaan tulkita merkkinä siitä, että MDMA-hoidon osana käytetty terapeuttinen interventio on sellaisenaan ilman psykoaktiivista ainettakin varsin toimiva ja tervehdyttävä. Toisaalta vaikutukset lumeryhmässä ovat kuitenkin selvästi pienempiä kuin edellä mainituissa, eniten tutkituissa lääkkeettömissä traumakeskeisissä hoidoissa.
\nEnsisijaisesti monien parantuminen lumeryhmässäkin kuitenkin kertonee siitä, että tärkeintä traumaperäisen stressihäiriön hoidossa olisi se, että kaikki siitä kärsivät saisivat jotakin johdonmukaista, järkevää hoitoa, johon sisältyy paljon henkilökohtaista huomiota ja mahdollisuus käsitellä traumaattisia kokemuksia. PTSD on kohtalaisen hyvin hoidettavissa oleva häiriö, jonka kohdalla suurimpia ongelmia ovat (jollakin tavalla itse traumaan keskittyvään) hoitoon pääsy ja hoidon saavutettavuus.
\nTärkein käytännön askel traumaperäisestä stressihäiriöstä kärsivien auttamiseksi olisi siis nopea ja kattava hoitoon, vaikka nykyiseenkin hoitoon, pääsy. Tutkimukset kuitenkin osoittavat, että merkittävä osa potilaista ei hyödy riittävästi tyypillisistä traumakeskeisistä hoitomenetelmistä tai lopettaa tällaiset hoidot kesken. Etenkin heille MDMA-avusteisesta hoidosta tulee toivottavasti lähitulevaisuudessa vaihtoehto myös Suomessa, osoittautui hoitomuoto sitten laajemmassa mittakaavassa erityisen vaikuttavaksi läpimurroksi terapiakentällä tai ei.
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Samuli Kangaslampi
\nKirjoittaja on psykologi ja psykologian tohtori, kliinisen psykologian yliopistonlehtori Tampereen yliopistolla ja tutkijatohtori Maastrichtin yliopiston neuropsykologian ja psykofarmakologian laitoksella, sekä Psykedeelitutkimusyhdistyksen hallituksen jäsen.
As of today, there are an estimated eight billion human beings on our planet. That’s great. More human beings is a positive thing. Every new human being brings more consciousness, meaning, and potential into the universe.
\nOur planet could sustainably hold and provide for eight billion people. However, at this moment, we don’t have the appropriate structures to do this, but instead we are wasting non-renewable resources and polluting our own nest at a truly terrifying rate. Changing these circumstances is, clearly, the greatest and most immediate challenge of our times.
\nGlobal population growth appears to be slowing down. With environmental challenges this large, this is probably a good thing in the short term. As our problems related to the environment and climate are better under control, I look forward to more rapid population growth later.
\nBiological (or cybernetic) immortality, which seems likely to be achieved within the next century, will in any case accelerate population growth once more. This is no reason not to strive for this most important goal for the near future of humanity. But as the human population continues to grow well beyond its current size, we will of course need to expand onto other planets or into outer space otherwise.
\nThese three I consider the most important challenges for humanity as of today: overcoming death, developing a balanced relationship with our planet and a sustainable way of living on it, and expanding beyond our home planet. Insofar as we will not receive help in these endeavors from other possible sentient species out there, we will have to face these challenges by ourselves. For one or a thousand people, they would surely be insurmountable. That’s why I’m glad there’s eight billion of us.
\n\n
", "content_html": "\n
\nAs of today, there are an estimated eight billion human beings on our planet. That’s great. More human beings is a positive thing. Every new human being brings more consciousness, meaning, and potential into the universe.
\nOur planet could sustainably hold and provide for eight billion people. However, at this moment, we don’t have the appropriate structures to do this, but instead we are wasting non-renewable resources and polluting our own nest at a truly terrifying rate. Changing these circumstances is, clearly, the greatest and most immediate challenge of our times.
\nGlobal population growth appears to be slowing down. With environmental challenges this large, this is probably a good thing in the short term. As our problems related to the environment and climate are better under control, I look forward to more rapid population growth later.
\nBiological (or cybernetic) immortality, which seems likely to be achieved within the next century, will in any case accelerate population growth once more. This is no reason not to strive for this most important goal for the near future of humanity. But as the human population continues to grow well beyond its current size, we will of course need to expand onto other planets or into outer space otherwise.
\nThese three I consider the most important challenges for humanity as of today: overcoming death, developing a balanced relationship with our planet and a sustainable way of living on it, and expanding beyond our home planet. Insofar as we will not receive help in these endeavors from other possible sentient species out there, we will have to face these challenges by ourselves. For one or a thousand people, they would surely be insurmountable. That’s why I’m glad there’s eight billion of us.
\n\n
Maapallolla on nyt arviolta kahdeksan miljardia ihmistä. Se on hienoa. Ihmisten määrän lisääntyminen on iloinen asia. Jokainen uusi ihminen tuo maailmankaikkeuteen lisää tietoisuutta, merkitystä ja potentiaalia.
\nPlaneettamme voisi kantaa kahdeksan miljardia ihmistä kestävästi. Tällä hetkellä meillä ei kuitenkaan ole sellaisia rakenteita, joilla tämä tapahtuisi, vaan kulutamme uusiutumattomia luonnonvaroja ja saastutamme omaa pesäämme erittäin pelottavaa vauhtia. Tämän tilanteen muuttaminen on, tietenkin, aikamme suurin ja välitön haaste.
\nVäestönkasvu planeetalla näyttää olevan hidastumassa. Kun ympäristöhaasteet ovat näin suuria, tämä lienee lyhyellä aikavälillä hyvä asia. Kun ympäristöön ja ilmastoon liittyvät ongelmat on saatu paremmin hallintaan, toivon väestön määrän taas kasvavan.
\nBiologinen (tai kyberneettinen) kuolemattomuus, jonka saavuttamista seuraavan sadan vuoden aikana pidän melko todennäköisenä, tulee joka tapauksessa kiihdyttämään jälleen väestönkasvua. Se ei tietenkään ole mikään syy olla tavoittelematta tuota tärkeintä askelta ihmisyyden lähitulevaisuudessa. Mutta kun väestömäärä vielä nykyisestä selvästi kasvaa, meidän tarvitsee toki levittäytyä myös muille planeetoille tai muutoin avaruuteen.
\nNäitä pidänkin ihmiskunnan tärkeimpinä haasteina: kuoleman voittamista, kestävän planeettasuhteen ja elämäntapojen saavuttamista sekä laajentumista planeettamme ulkopuoliseen universumiin. Sikäli kun emme saa näihin haasteisiin apua muilta mahdollisilta älyllisiltä lajeilta tuolta jostakin, meidän on ratkaistava ne keskenämme. Yhdelle tai tuhannelle ihmiselle ne olisivat varmaankin mahdottomia. Siksi olen iloinen, että meitä on kahdeksan miljardia.
\n", "author": { "name": "" }, "tags": [ ], "date_published": "2022-11-15T09:17:30+02:00", "date_modified": "2022-11-15T09:23:41+02:00" }, { "id": "https://kangaslampi.net/blog/largest-study-of-psilocybin-for-depression-published-with-fairly-positive-results/", "url": "https://kangaslampi.net/blog/largest-study-of-psilocybin-for-depression-published-with-fairly-positive-results/", "title": "Largest study of psilocybin for depression published with fairly positive results", "summary": "\n\nSeveral companies and research groups continue to investigate the potential effectiveness of psilocybin, a classic serotonin 2A receptor agonist psychedelic, or psilocybin-assisted (psycho)therapy for several psychiatric indications, chief among them depression.
\nResults of the largest RCT on psilocybin-assisted treatment of treatment-resistant depression to date, with 233 patients, are now out in the New England Journal of Medicine. The main results from this private phase 2b study have previously been presented in press releases, however.
\nIn the final published results by Goodwin et al. (2022), one session of 25 mg of psilocybin, combined with psychological support during the dosing session and a few preparatory and integrative therapeutic sessions reduced depressive symptoms more than smaller doses (10 mg, 1 mg). Compared to previous research and expectations, however, the results may still be considered modest, maybe even disappointing. In the treatment group, 37% of patients had a significant response and 29% were in remission three weeks after treatment, compared with 19/18% and 8/8% of patients in the 10/1 mg groups. At 12 weeks, a sustained response was seen in 20% of patients in the treatment group.
\n", "content_html": "\n
\nSeveral companies and research groups continue to investigate the potential effectiveness of psilocybin, a classic serotonin 2A receptor agonist psychedelic, or psilocybin-assisted (psycho)therapy for several psychiatric indications, chief among them depression.
\nResults of the largest RCT on psilocybin-assisted treatment of treatment-resistant depression to date, with 233 patients, are now out in the New England Journal of Medicine. The main results from this private phase 2b study have previously been presented in press releases, however.
\nIn the final published results by Goodwin et al. (2022), one session of 25 mg of psilocybin, combined with psychological support during the dosing session and a few preparatory and integrative therapeutic sessions reduced depressive symptoms more than smaller doses (10 mg, 1 mg). Compared to previous research and expectations, however, the results may still be considered modest, maybe even disappointing. In the treatment group, 37% of patients had a significant response and 29% were in remission three weeks after treatment, compared with 19/18% and 8/8% of patients in the 10/1 mg groups. At 12 weeks, a sustained response was seen in 20% of patients in the treatment group.
\nSo, the results are positive, and the company is going ahead with phase 3 trials. But they are not amazing or that impressive if we consider, e.g., the fact that a meta-analysis found cognitive-behavioral therapy of treatment-resistant depression to lead to 42% response and 26% remission at end of treatment and 55 % response and 37 % remission at 6 months (https://doi.org/10.1016/j.psychres.2018.07.020). These treatments are of course not directly comparable, although they are of similar length in treatment hours (8 h psilocybin session + preparation and integration vs. 8-16 sessions of CBT).
\nAre these somewhat unimpressive results due to just having one psilocybin session or other (cost-saving) measures the for-profit company has introduced in this trial? What role do failure to blind, expectancy and disappointment (nocebo) effects play? Or is this really an indication that the effects of psilocybin treatment on (treatment-resistant) depression are, though real, relatively modest? Answering these questions will require (yes, I’ll say it) more research.
\nUseat yksityiset yritykset ja tutkimusryhmät jatkavat psilosybiinin, klassisen serotoniini-2A-reseptorin agonismin kautta toimivan psykedeelin, tai psilosybiiniavusteisen (psyko)terapian vaikuttavuuden tutkimista useisiin mielenterveyden häiriöihin, erityisesti masennukseen.
\nToistaiseksi suurimman, 233 potilasta kattaneen kliinisen tutkimuksen tulokset hoitoresistentin masennuksen psilosybiiniavusteisesta hoidosta on juuri julkaistu New England Journal of Medicinessä. Pääosa näistä yksityisen lääkeyrityksen 2b-tutkimusvaiheen tuloksista on jo aiemmin jaettu lehdistötiedotteella.
\nLopullisen Goodwinin ja kumppaneiden (2022) julkaisun tuloksissa kerran annettu 25 mg psilosybiiniä yhdistettynä psykologiseen tukeen hoitosession aikana sekä muutamiin valmisteleviin ja purkaviin terapiasessioihin vähensi masennusoireita merkittävästi enemmän kuin pienemmät annokset (10 mg, 1 mg). Tuloksia voidaan kuitenkin pitää aiempiin tutkimuksiin ja ehkä odotuksiinkin verrattuna hieman vaatimattomina, ehkä lievänä pettymyksenäkin. Hoitoryhmässä 37 % potilaista koki merkittävää vastetta masennusoireisiin ja 29 % oli masennusvapaita/remissiossa kolmen viikon kohdalla, verrattuna 19/18 ja 8/8 prosenttiin muissa ryhmissä. 12 viikon seurantaan pysynyt vaste nähtiin 20 prosentilla hoitoryhmän potilaista.
\nTulokset ovat siis positiivisia, ja yhtiö jatkaa niiden pohjalta viimeisen, kolmannen vaiheen tutkimuksiin. Mutta ne eivät ole mullistavia tai erityisen vaikuttavia, jos niitä verrataan esimerkiksi siihen, että meta-analyysin mukaan hoitoresistentin masennuksen CBT-pohjaisella psykoterapialla saavutetaan 42 % vaste ja 26 % remissio hoidon päättyessä ja 55 % vaste ja 37 % remissio 6 kuukauden seurannassa (https://doi.org/10.1016/j.psychres.2018.07.020). Hoitomuodot eivät toki ole täysin vertailukelpoisia, mutta ovat pituudeltaan samaa luokkaa tapaamistunneilla mitattuna (8 h psilosybiinisessio + valmistelevat ja purkavat terapiasessiot vs. 8-16 CBT-tapaamista).
\nJohtuvatko odotettua vaatimattomammat tulokset esimerkiksi siitä, että psilosybiinisessioita oli vain yksi tai muista säästöä tavoittelevista ratkaisuista? Mikä rooli sokkoutuksen epäonnistumisella sekä odotus- ja pettymysvaikutuksilla on näissä(kin) tuloksissa? Vai heijastavatko nämä tulokset sitä, että psilosybiinihoidon vaikutus on (hoitoresistentissä) masennuksessa kuitenkin vain kohtalainen? Mm. näihin kysymyksiin vastaaminen vaatii (kyllä, sanon taas näin) lisää tutkimusta.
\nThis post provides a slightly extended version of and references for my brief talk at the Interdisciplinary Conference on Psychedelic Research 2022 on September 23, 2022. This research will also be published as a peer-reviewed article later.
\n\n
Introduction
\n“[E]lements of the psychedelic experience, such as experiences of mystical-type, account for the therapeutic benefit” (Palhano-Fontes et al., 2019). “[M]ystical-type experiences are predictive of beneficial outcomes from psychedelics administered in experimental contexts” (Yaden & Griffiths, 2021). Statements such as these are commonly made in recent articles on psychedelics and their potential therapeutic effects, and are typically followed by some references to studies that have indeed found this to be the case. Meanwhile, other authors have questioned the relevance and meaning for therapeutic outcomes of the subjective effects entirely (Olson, 2021) or the concept of mystical experiences in particular (e.g., Sanders & Ziljmans, 2021).
\nSo, what is the evidence that mystical-type experiences under psychedelics associate with or predict changes in well-being and mental health a) in general and b) compared with other possibly relevant acute subjective aspects of the experience (such as psychological insights and emotional breakthroughs)? To my knowledge, no comprehensive reviews on the state of the evidence have been presented1. Therefore, I conducted a comprehensive review based on a systematic search of the available quantitative evidence for such associations.
\nThis blog post presents a rough, general summary of the results of this review to accompany my talk at ICPR 2022. A full, proper article will be published later.
\n", "content_html": "\n
This post provides a slightly extended version of and references for my brief talk at the Interdisciplinary Conference on Psychedelic Research 2022 on September 23, 2022. This research will also be published as a peer-reviewed article later.
\n\n
Introduction
\n“[E]lements of the psychedelic experience, such as experiences of mystical-type, account for the therapeutic benefit” (Palhano-Fontes et al., 2019). “[M]ystical-type experiences are predictive of beneficial outcomes from psychedelics administered in experimental contexts” (Yaden & Griffiths, 2021). Statements such as these are commonly made in recent articles on psychedelics and their potential therapeutic effects, and are typically followed by some references to studies that have indeed found this to be the case. Meanwhile, other authors have questioned the relevance and meaning for therapeutic outcomes of the subjective effects entirely (Olson, 2021) or the concept of mystical experiences in particular (e.g., Sanders & Ziljmans, 2021).
\nSo, what is the evidence that mystical-type experiences under psychedelics associate with or predict changes in well-being and mental health a) in general and b) compared with other possibly relevant acute subjective aspects of the experience (such as psychological insights and emotional breakthroughs)? To my knowledge, no comprehensive reviews on the state of the evidence have been presented1. Therefore, I conducted a comprehensive review based on a systematic search of the available quantitative evidence for such associations.
\nThis blog post presents a rough, general summary of the results of this review to accompany my talk at ICPR 2022. A full, proper article will be published later.
\n\nMethods
\nThis was a comprehensive review, based on a systematic search, of the published evidence on acute mystical-type experiences under the influence of psychedelics associating with or predicting (medium- or long-term) improvements in well-being or mental health after psychedelic use. The review included all types of studies from controlled trials with patients to surveys and field studies, and all aspects of well-being. As the review did not fulfill all the typical requirements for a systematic review, it is not named as such.
\nThe review was pre-registered on the OSF before work on it began (https://doi.org/10.17605/OSF.IO/6TGBD).
\nThe full inclusion criteria for studies to be included in the review were: 1) Peer-reviewed articles published in scientific journals, 2) in English, Spanish, Finnish, or Swedish, reporting on 3) empirical, quantitative research that measured the 4) level or intensity of mystical-type experience under the influence of 5) a psychoactive dose of a classic psychedelic and 6) changes in some aspect of well-being or mental health 7) from before to at least one week after the experience, and 8) analyzed the association between 4 and 6.
\nTo identify suitable studies, PubMed and Academic Search Ultimate (EBSCO) databases were searched with the following search string: (myst* OR ego* OR oceanic* OR transcende* OR spirit* OR MEQ* OR HMS* OR HRS* OR SOCQ* OR 5D-ASC* OR 11D-ASC*) AND (psyched* OR LSD* OR lysergic* OR psiloc* OR ayahuasc* OR DMT* OR dimethyltrypt* OR mescal* OR peyot*). The reference lists of identified and other relevant articles, as well as all articles published in the Journal of Psychedelic Studies were further examined for additional studies. The Figure below presents the flow of identified studies and the number of studies excluded at each stage, with reasons.
\n![\"\"](\"https://kangaslampi.net/media/posts/9/flow-diagram-1-1024x576.jpg\")
\n
A pre-defined data extraction form was used to extract bibliographic data and relevant data related to the study questions from all included studies. The findings were then narratively synthesized. No meta-analyses were performed.
\nResults
\nA total of 44 studies were identified. Of these,19 were based on laboratory research, 18 on surveys, and 7 on field studies. For purposes of comparison, survey and field studies were considered together, as in those studies, the dosing/doses and setting were not under the control of the study authors. 31 studies were prospective, meaning that they followed participants from before the psychedelic use to after it, while 13 were fully cross-sectional and retrospective. Notably, even in some prospective studies, changes in well-being or mental health were only assessed with retrospective questions. Regarding the particular psychedelic, 20 studies were on psilocybin, 7 on ayahuasca, one study on LSD, 5-MeO-DMT and mescaline each, while 14 included experience with other or any psychedelic. 14 studies reported on research with broadly clinical or “ill” populations, while 30 were conducted among “healthy” populations or populations with no confirmed diagnosis. Study samples ranged from 12 to 6877, with a median of 52 and standard deviation of 1147.
\nThe studies reported on 76 associations between mystical-type experience and change in some aspect of well-being or mental health. In total, 56 of these associations were found to be positive to a statistically significant degree.
\nThe studies analyzed changes in a wide variety of different aspects of well-being and mental health, which could be roughly divided into 18 categories: Depression (13 studies), anxiety (7), well-being and life satisfaction (13), positive changes in attitudes and behavior (9), smoking cessation / cigarette consumption (4), AUD / problematic alcohol use (3), connectedness with nature (3), decreased neuroticism (3), increased openness (3), increased extraversion (2), psychological flexibility (2), DUD / problematic drug use (2), smoking urge (2), PTSD (1), alcohol craving (1), alcohol abstinence self-efficacy (1), cigarette dependence (1), cigarette abstinence self-efficacy (1), meaningfulness / purpose (1), quality of life / optimism (1), spiritual well-being (1), connectedness (1), mindfulness (1).
\nThe findings of the specific analyses were further simplified into positive, meaning a statistically significant association was found or null, meaning no statistically significant association was found. The table below presents the numbers of positive and null findings for association between mystical-type experience and change in all aspects of well-being or mental health that at least two included studies analyzed.
\n![\"\"](\"https://kangaslampi.net/media/posts/9/Table-1-1024x466.jpg\")
The review included many different types of studies. The first table below presents the findings dividing the studies into those conducted in the laboratory and those based on surveys or field work. In the next table, the studies are divided based on whether they were prospective or fully cross-sectional by nature. The final table presents the findings for studies on clinical populations vs. on healthy samples. Rates of positive vs. null findings were clearly higher for survey/field vs. laboratory studies, for cross-sectional vs. prospective studies, and for studies among healthy participants vs. in clinical samples.
\n\n
![\"\"](\"https://kangaslampi.net/media/posts/9/lab-sur-table-1024x700.jpg\")
\n
\n
![\"\"](\"https://kangaslampi.net/media/posts/9/Table-2-1024x586.jpg\")
\n
![\"Clinical](\"https://kangaslampi.net/media/posts/9/Table-3-1024x643.jpg\")
\n
Out of the 44 studies, 29 also analyzed the association between other aspects of the acute experience and changes in well-being or mental health. The other acute aspects were roughly divided into challenging experience / discomfort (association with change in well-being or mental health analyzed by 14 studies), psychological insights / insightfulness (10), overall intensity (9), visual/auditory effects (6), emotional breakthrough (4), dread of ego dissolution (3), overall / other features of alteration of consciousness (4), other 5.
\nOut of the more specific aspects, most were generally not found to associate with positive changes in well-being or mental health. However, psychological insights and emotional breakthroughs were found to be associated with positive changes in nine studies and four studies, respectively.
\nFew studies directly compared the degree of association or predictive power of mystical-type experiences and insights or emotional breakthroughs with changes in well-being or mental health, in terms of, e.g., including them in the same model or explicitly analyzing differences in correlations or regression coefficients.
\nFour studies directly compared mystical-type experiences and psychological insights in this way. Psychological insights or insightfulness were found to be a better / stronger predictor of decreased depression and anxiety in two survey studies (Agin-Liebes et al., 2021; Davis et al., 2020) and increased psychological flexibility in one (Davis et al., 2021). Both were similar predictors of improved well-being and life satisfaction in one very large survey study (Perkins et al., 2021). All these studies were among healthy participants.
\nThree studies directly compared emotional breakthroughs and mystical-type experiences. Emotional breakthrough was reported to be a better or the sole predictor of decreased depression in one clinical laboratory (Murphy et al., 2022) and one survey study (Nygart et al., 2021) among depressed individuals. However, both similarly predicted improved well-being and life satisfaction in one survey study among healthy participants (Roseman et al., 2019).
\nDiscussion
\nHere, the findings of this review were only described at a rough, general level. A more detailed analysis of the strength of the evidence and the quality of the included studies will follow later.
\nEven so, we can already see that there is quite a bit of evidence for a link between acute mystical-type experience and self-reported change in some aspects of well-being and mental health from before until some time after psychedelic use. This evidence is clearest for changes in general well-being and life satisfaction, in positive changes in attitudes and behavior and in anxiety. For the first two of these categories especially, however, this evidence comes almost exclusively from studies with healthy individuals, not in clinical populations.
\nA major clinical application that psychedelics are being researched for is the treatment of depression. With this in mind, it is notable that the evidence for acute mystical-type experiences associating with improved depression is not as unequivocal. Several studies failed to find evidence for this link (Gukasyan et al., 2022; Nygart et al., 2022; Palhano-Fontes et al., 2019; Ruffell et al., 2022). Evidence for an association between acute mystical experience and positive change in personality is even less clear, with few studies and mixed findings.
\nThe majority of studies did include some analyses regarding other acute aspects of the psychedelic experience as well. Most commonly challenging experiences or discomfort were analyzed, and generally not found to be associated with changes in well-being or mental health, or to be negatively associated with it. Aspects of the acute experience that have been suggested to be linked with improved well-being and mental health include psychological insights or insightfulness and emotional breakthroughs. A few studies did directly compare the association with or predictive power of mystical-type experiences vs. these other aspects. Based on this limited evidence, it does appear that insights and breakthroughs are at least as relevant for predicting improved well-being and mental health and may in fact be more relevant than mystical-type experiences.
\nLimitations
\nThis review only considered evidence from explicit analyses presented in published studies. Accordingly, publication bias is likely to affect the findings in a major way. Many studies that did include both measures of mystical-type experience and change in aspects of well-being or mental health did not report the association between some or all of them. The same is true of other acute aspects of the experience. It seems likely that many null findings have not been reported.
\nThe studies included in this review were also of highly varying quality in terms of the level of evidence they are able to provide. The two major issues are sample size and measures of change. Sample sizes were highly varied, and clearly the smaller, often clinical / laboratory, studies may not have been adequately powered to detect potentially meaningful associations. Further, especially in the category of change in general well-being and life satisfaction, many studies relied on single retrospective questions, even when the studies were otherwise prospective. Including several points of measurement before and after is always preferable and more reliable. Several studies were fully cross-sectional, conducted months or even years after the target psychedelic experience – the quality of evidence they provide is clearly lower, as both mystical experience and change in well-being or mental health are being simultaneously measured after the fact.
\nAs regards the review overall, it is limited by only considering quantitative evidence. Qualitative research can and has already contributed to our understanding of what aspects of the acute psychedelic experience are relevant for therapeutic change (see, e.g., Breeksema et al., 2020). It is also limited by the inability to conduct quantitative meta-analysis. The highly varied outcomes and outcome measures, as well as the dissimilar study designs of the included studies, did not allow for meaningful meta-analysis.
\nFinally, this review relies on information about mystical-type experiences captured by a few particular questionnaire measures, most commonly the Mystical Experiences Questionnaire (Griffiths et al., 2006; Maclean et al., 2012). The question of whether these instruments truly and uniquely capture the level or degree of a phenomenon appropriately called a “mystical experience” is beyond my scope here.
\nSuggestions
\nMost analyses the included studies reported were exploratory. Pre-registration would increase our confidence in findings on acute mechanisms of the effects of psychedelics and is highly encouraged in future studies. It also ensures that all results, even null results, end up being published.
\nA large proportion of studies only included one aspect of the acute psychedelic experience, and few included direct comparisons between different potentially relevant aspects. Direct comparisons would be most valuable to identify what exactly it is about the psychedelic experience that is predictive for positive changes. General intensity of drug effects should always be considered, as well.
\n\n
\n
Footnotes
\n1 While preparing this work, a systematic review on the link between mystical experiences and therapeutic efficacy in clinical trials was published by Ko and colleagues (2022). That review differs from that presented here by only including clinical trials, and by also including trials with ketamine. Still, its findings are generally in line with what is presented here: Most studies do find a positive association, but are limited especially by their small and homogeneous samples.
\n\n
General references
\n\n
Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., & Schoevers, R. A. (2020). Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies. CNS Drugs, 34(9), 925–946. https://doi.org/10.1007/s40263-020-00748-y
\nGriffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187(3), 268–283. https://doi.org/10.1007/s00213-006-0457-5
\nMacLean, K. A., Leoutsakos, J.-M. S., Johnson, M. W., & Griffiths, R. R. (2012). Factor Analysis of the Mystical Experience Questionnaire: A Study of Experiences Occasioned by the Hallucinogen Psilocybin. Journal for the Scientific Study of Religion, 51(4), 721–737. https://doi.org/10.1111/j.1468-5906.2012.01685.x
\nKo, K., Knight, G., Rucker, J. J., & Cleare, A. J. (2022). Psychedelics, Mystical Experience, and Therapeutic Efficacy: A Systematic Review. Frontiers in Psychiatry, 13, 917199. https://doi.org/10.3389/fpsyt.2022.917199
\nOlson, D. E. (2021). The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science, 4(2), 563–567. https://doi.org/10.1021/acsptsci.0c00192
\nPalhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., … Araújo, D. B. (2019). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: A randomized placebo-controlled trial. Psychological Medicine, 49(4), 655–663. https://doi.org/10.1017/S0033291718001356
\nSanders, J. W., & Zijlmans, J. (2021). Moving Past Mysticism in Psychedelic Science. ACS Pharmacology & Translational Science, acsptsci.1c00097. https://doi.org/10.1021/acsptsci.1c00097
\nYaden, D. B., & Griffiths, R. R. (2021). The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science, 4(2), 568–572. https://doi.org/10.1021/acsptsci.0c00194
\n\n
All studies included in review
\nAgin-Liebes, G., Haas, T. F., Lancelotta, R., Uthaug, M. V., Ramaekers, J. G., & Davis, A. K. (2021). Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes. ACS Pharmacology & Translational Science, 4(2), 543–552. https://doi.org/10.1021/acsptsci.1c00018
\nAgin-Liebes, G. I., Malone, T., Yalch, M. M., Mennenga, S. E., Ponté, K. L., Guss, J., Bossis, A. P., Grigsby, J., Fischer, S., & Ross, S. (2020). Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Journal of Psychopharmacology, 34(2), 155–166. https://doi.org/10.1177/0269881119897615
\nBarrett, F. S., Johnson, M. W., & Griffiths, R. R. (2015). Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. Journal of Psychopharmacology, 29(11), 1182–1190. https://doi.org/10.1177/0269881115609019
\nBogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P., & Strassman, R. J. (2015). Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study. Journal of Psychopharmacology, 29(3), 289–299. https://doi.org/10.1177/0269881114565144
\nCarhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., Kaelen, M., Giribaldi, B., Bloomfield, M., Pilling, S., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Curran, H. V., & Nutt, D. J. (2018). Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up. Psychopharmacology, 235(2), 399–408. https://doi.org/10.1007/s00213-017-4771-x
\nDaldegan-Bueno, D., Maia, L. O., Massarentti, C. M., & Tófoli, L. F. (2022). Ayahuasca and tobacco smoking cessation: Results from an online survey in Brazil. Psychopharmacology, 239(6), 1767–1782. https://doi.org/10.1007/s00213-022-06063-2
\nDavis, A. K., Barrett, F. S., & Griffiths, R. R. (2020). Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety. Journal of Contextual Behavioral Science, 15, 39–45. https://doi.org/10.1016/j.jcbs.2019.11.004
\nDavis, A. K., Barrett, F. S., So, S., Gukasyan, N., Swift, T. C., & Griffiths, R. R. (2021). Development of the Psychological Insight Questionnaire among a sample of people who have consumed psilocybin or LSD. Journal of Psychopharmacology, 35(4), 437–446. https://doi.org/10.1177/0269881120967878
\nDavis, A. K., So, S., Lancelotta, R., Barsuglia, J. P., & Griffiths, R. R. (2019). 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety. The American Journal of Drug and Alcohol Abuse, 45(2), 161–169. https://doi.org/10.1080/00952990.2018.1545024
\nErritzoe, D., Roseman, L., Nour, M. M., MacLean, K., Kaelen, M., Nutt, D. J., & Carhart-Harris, R. L. (2018). Effects of psilocybin therapy on personality structure. Acta Psychiatrica Scandinavica, 138(5), 368–378. https://doi.org/10.1111/acps.12904
\nFauvel, B., Kangaslampi, S., Strika-Bruneau, L., Roméo, B., & Piolino, P. (2022). Validation of a French Version of the Mystical Experience Questionnaire with Retrospective Reports of the Most Significant Psychedelic Experience among French Users. Journal of Psychoactive Drugs, 1–10. https://doi.org/10.1080/02791072.2022.2059796
\nGarcia-Romeu, A., Davis, A. K., Erowid, E., Erowid, F., Griffiths, R. R., & Johnson, M. W. (2020). Persisting Reductions in Cannabis, Opioid, and Stimulant Misuse After Naturalistic Psychedelic Use: An Online Survey. Frontiers in Psychiatry, 10, 955. https://doi.org/10.3389/fpsyt.2019.00955
\nGarcia-Romeu, A., Davis, A. K., Erowid, F., Erowid, E., Griffiths, R. R., & Johnson, M. W. (2019). Cessation and reduction in alcohol consumption and misuse after psychedelic use. Journal of Psychopharmacology, 33(9), 1088–1101. https://doi.org/10.1177/0269881119845793
\nGarcia-Romeu, A., Griffiths, R., & Johnson, M. (2015). Psilocybin-Occasioned Mystical Experiences in the Treatment of Tobacco Addiction. Current Drug Abuse Reviews, 7(3), 157–164. https://doi.org/10.2174/1874473708666150107121331
\nGriffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12), 1181–1197. https://doi.org/10.1177/0269881116675513
\nGriffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., Jesse, R., MacLean, K. A., Barrett, F. S., Cosimano, M. P., & Klinedinst, M. A. (2018). Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. Journal of Psychopharmacology, 32(1), 49–69. https://doi.org/10.1177/0269881117731279
\nGukasyan, N., Davis, A. K., Barrett, F. S., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., & Griffiths, R. R. (2022). Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Journal of Psychopharmacology, 36(2), 151–158. https://doi.org/10.1177/02698811211073759
\nHaijen, E. C. H. M., Kaelen, M., Roseman, L., Timmermann, C., Kettner, H., Russ, S., Nutt, D., Daws, R. E., Hampshire, A. D. G., Lorenz, R., & Carhart-Harris, R. L. (2018). Predicting Responses to Psychedelics: A Prospective Study. Frontiers in Pharmacology, 9, 897. https://doi.org/10.3389/fphar.2018.00897
\nJohnson, M. W., Garcia-Romeu, A., & Griffiths, R. R. (2017). Long-term follow-up of psilocybin-facilitated smoking cessation. The American Journal of Drug and Alcohol Abuse, 43(1), 55–60. https://doi.org/10.3109/00952990.2016.1170135
\nJohnson, M. W., Garcia-Romeu, A., Johnson, P. S., & Griffiths, R. R. (2017). An online survey of tobacco smoking cessation associated with naturalistic psychedelic use. Journal of Psychopharmacology, 31(7), 841–850. https://doi.org/10.1177/0269881116684335
\nKangaslampi, S., Hausen, A., & Rauteenmaa, T. (2020). Mystical Experiences in Retrospective Reports of First Times Using a Psychedelic in Finland. Journal of Psychoactive Drugs, 52(4), 309–318. https://doi.org/10.1080/02791072.2020.1767321
\nKettner, H., Gandy, S., Haijen, E. C. H. M., & Carhart-Harris, R. L. (2019). From Egoism to Ecoism: Psychedelics Increase Nature Relatedness in a State-Mediated and Context-Dependent Manner. International Journal of Environmental Research and Public Health, 16(24), 5147. https://doi.org/10.3390/ijerph16245147
\nKiraga, M. K., Kuypers, K. P. C., Uthaug, M. V., Ramaekers, J. G., & Mason, N. L. (2022). Decreases in State and Trait Anxiety Post-psilocybin: A Naturalistic, Observational Study Among Retreat Attendees. Frontiers in Psychiatry, 13, 883869. https://doi.org/10.3389/fpsyt.2022.883869
\nMacLean, K. A., Johnson, M. W., & Griffiths, R. R. (2011). Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. Journal of Psychopharmacology, 25(11), 1453–1461. https://doi.org/10.1177/0269881111420188
\nMcCulloch, D. E.-W., Grzywacz, M. Z., Madsen, M. K., Jensen, P. S., Ozenne, B., Armand, S., Knudsen, G. M., Fisher, P. M., & Stenbæk, D. S. (2022). Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report. Frontiers in Pharmacology, 13, 841648. https://doi.org/10.3389/fphar.2022.841648
\nMurphy, R., Kettner, H., Zeifman, R., Giribaldi, B., Kartner, L., Martell, J., Read, T., Murphy-Beiner, A., Baker-Jones, M., Nutt, D., Erritzoe, D., Watts, R., & Carhart-Harris, R. (2022). Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression. Frontiers in Pharmacology, 12, 788155. https://doi.org/10.3389/fphar.2021.788155
\nNetzband, N., Ruffell, S., Linton, S., Tsang, W. F., & Wolff, T. (2020). Modulatory effects of ayahuasca on personality structure in a traditional framework. Psychopharmacology, 237(10), 3161–3171. https://doi.org/10.1007/s00213-020-05601-0
\nNicholas, C. R., Henriquez, K. M., Gassman, M. C., Cooper, K. M., Muller, D., Hetzel, S., Brown, R. T., Cozzi, N. V., Thomas, C., & Hutson, P. R. (2018). High dose psilocybin is associated with positive subjective effects in healthy volunteers. Journal of Psychopharmacology, 32(7), 770–778. https://doi.org/10.1177/0269881118780713
\nNour, M. M., Evans, L., Nutt, D., & Carhart-Harris, R. L. (2016). Ego-Dissolution and Psychedelics: Validation of the Ego-Dissolution Inventory (EDI). Frontiers in Human Neuroscience, 10. https://doi.org/10.3389/fnhum.2016.00269
\nNygart, V. A., Pommerencke, L. M., Haijen, E., Kettner, H., Kaelen, M., Mortensen, E. L., Nutt, D. J., Carhart-Harris, R. L., & Erritzoe, D. (2022). Antidepressant effects of a psychedelic experience in a large prospective naturalistic sample. Journal of Psychopharmacology, 36(8), 932–942. https://doi.org/10.1177/02698811221101061
\nPalhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., Pessoa, J. A., Mota-Rolim, S. A., Osório, F. L., Sanches, R., dos Santos, R. G., Tófoli, L. F., de Oliveira Silveira, G., Yonamine, M., Riba, J., Santos, F. R., Silva-Junior, A. A., Alchieri, J. C., Galvão-Coelho, N. L., Lobão-Soares, B., … Araújo, D. B. (2019). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: A randomized placebo-controlled trial. Psychological Medicine, 49(4), 655–663. https://doi.org/10.1017/S0033291718001356
\nPerkins, D., Schubert, V., Simonová, H., Tófoli, L. F., Bouso, J. C., Horák, M., Galvão-Coelho, N. L., & Sarris, J. (2021). Influence of Context and Setting on the Mental Health and Wellbeing Outcomes of Ayahuasca Drinkers: Results of a Large International Survey. Frontiers in Pharmacology, 12, 623979. https://doi.org/10.3389/fphar.2021.623979
\nRoseman, L., Haijen, E., Idialu-Ikato, K., Kaelen, M., Watts, R., & Carhart-Harris, R. (2019). Emotional breakthrough and psychedelics: Validation of the Emotional Breakthrough Inventory. Journal of Psychopharmacology, 33(9), 1076–1087. https://doi.org/10.1177/0269881119855974
\nRoseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2018). Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Frontiers in Pharmacology, 8, 974. https://doi.org/10.3389/fphar.2017.00974
\nRoss, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P., & Schmidt, B. L. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial. Journal of Psychopharmacology, 30(12), 1165–1180. https://doi.org/10.1177/0269881116675512
\nRuffell, S. G. D., Netzband, N., Tsang, W., Davies, M., Butler, M., Rucker, J. J. H., Tófoli, L. F., Dempster, E. L., Young, A. H., & Morgan, C. J. A. (2021). Ceremonial Ayahuasca in Amazonian Retreats—Mental Health and Epigenetic Outcomes From a Six-Month Naturalistic Study. Frontiers in Psychiatry, 12, 687615. https://doi.org/10.3389/fpsyt.2021.687615
\nRuss, S. L., Carhart-Harris, R. L., Maruyama, G., & Elliott, M. S. (2019). Replication and extension of a model predicting response to psilocybin. Psychopharmacology, 236(11), 3221–3230. https://doi.org/10.1007/s00213-019-05279-z
\nSchmid, Y., & Liechti, M. E. (2018). Long-lasting subjective effects of LSD in normal subjects. Psychopharmacology, 235(2), 535–545. https://doi.org/10.1007/s00213-017-4733-3
\nSmigielski, L., Kometer, M., Scheidegger, M., Krähenmann, R., Huber, T., & Vollenweider, F. X. (2019). Characterization and prediction of acute and sustained response to psychedelic psilocybin in a mindfulness group retreat. Scientific Reports, 9(1), 14914. https://doi.org/10.1038/s41598-019-50612-3
\nSmigielski, L., Scheidegger, M., Kometer, M., & Vollenweider, F. X. (2019). Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage, 196, 207–215. https://doi.org/10.1016/j.neuroimage.2019.04.009
\nTrichter, S., Klimo, J., & Krippner, S. (2009). Changes in Spirituality Among Ayahuasca Ceremony Novice Participants. Journal of Psychoactive Drugs, 41(2), 121–134. https://doi.org/10.1080/02791072.2009.10399905
\nWatts, R., Kettner, H., Geerts, D., Gandy, S., Kartner, L., Mertens, L., Timmermann, C., Nour, M. M., Kaelen, M., Nutt, D., Carhart-Harris, R., & Roseman, L. (2022). The Watts Connectedness Scale: A new scale for measuring a sense of connectedness to self, others, and world. Psychopharmacology. https://doi.org/10.1007/s00213-022-06187-5
\nWeiss, B., Miller, J. D., Carter, N. T., & Keith Campbell, W. (2021). Examining changes in personality following shamanic ceremonial use of ayahuasca. Scientific Reports, 11(1), 6653. https://doi.org/10.1038/s41598-021-84746-0
\nWießner, I., Falchi, M., Palhano-Fontes, F., Feilding, A., Ribeiro, S., & Tófoli, L. F. (2021). LSD, madness and healing: Mystical experiences as possible link between psychosis model and therapy model. Psychological Medicine, 1–15. https://doi.org/10.1017/S0033291721002531
\n", "author": { "name": "" }, "tags": [ ], "date_published": "2022-09-21T08:30:43+03:00", "date_modified": "2022-09-23T08:20:03+03:00" }, { "id": "https://kangaslampi.net/blog/insight-2021/", "url": "https://kangaslampi.net/blog/insight-2021/", "title": "On studying the psychological mechanisms of the (therapeutic) effects of psychedelics", "summary": "\nThis post provides extended discussion of and references for my poster-based talk given at the INSIGHT 2021 conference on September 10, 2021. My commentary published in Psychopharmacology also discusses some of these same issues and provides concrete suggestions for future research. This is a work in progress and may evolve over time.
\n\n\n\n2021-09-10 Samuli Kangaslampi, samuli@kangaslampi.net
\n\n\n\n
Increasing evidence suggests that consuming psychedelic substances in some contexts may have therapeutic effects for some people. Psilocybin-assisted psychotherapy for depression has entered Phase 2 clinical trials (Carhart-Harris et al., 2021). Meanwhile, experimental, survey-based, and register-based studies suggest links between psychedelic consumption and some areas of well-being (e.g., Agin-Liebes et al., 2021; Jiménez-Garrido et al., 2020; Hendricks et al., 2015; Simonsson et al., 2021; Uthaug et al., 2019). In order to better understand and maximize possible therapeutic effects, it would be very useful to know how, through which psychological mechanisms, psychedelics or psychedelic-assisted therapy may have beneficial outcomes.
Indeed, research on the psychological mechanisms of the effects of psychedelics is increasing. A number of recent publications have suggested various mechanisms and pathways for beneficial effects (e.g., Davis et al., 2020, 2021; Forstmann et al., 2020; Kettner et al., 2021; van Mulukom et al., 2020, Roseman et al., 2018; Thiessen et al., 2018; Zeifman et al., 2020). However, there are some problems and pitfalls in approaches several recent studies have taken to analyzing such mechanisms. Many of these problems and unstated assumptions in mechanism research have previously been pointed out and discussed in other areas of research, especially psychotherapy and social psychological research. Here, I discuss the value, challenges, and best practices of providing convincing evidence for the psychological mechanisms of the possible therapeutic effects of psychedelics.
\n\n\n\n", "content_html": "\nThis post provides extended discussion of and references for my poster-based talk given at the INSIGHT 2021 conference on September 10, 2021. My commentary published in Psychopharmacology also discusses some of these same issues and provides concrete suggestions for future research. This is a work in progress and may evolve over time.
\n\n\n\n2021-09-10 Samuli Kangaslampi, samuli@kangaslampi.net
\n\n\n\n
Increasing evidence suggests that consuming psychedelic substances in some contexts may have therapeutic effects for some people. Psilocybin-assisted psychotherapy for depression has entered Phase 2 clinical trials (Carhart-Harris et al., 2021). Meanwhile, experimental, survey-based, and register-based studies suggest links between psychedelic consumption and some areas of well-being (e.g., Agin-Liebes et al., 2021; Jiménez-Garrido et al., 2020; Hendricks et al., 2015; Simonsson et al., 2021; Uthaug et al., 2019). In order to better understand and maximize possible therapeutic effects, it would be very useful to know how, through which psychological mechanisms, psychedelics or psychedelic-assisted therapy may have beneficial outcomes.
Indeed, research on the psychological mechanisms of the effects of psychedelics is increasing. A number of recent publications have suggested various mechanisms and pathways for beneficial effects (e.g., Davis et al., 2020, 2021; Forstmann et al., 2020; Kettner et al., 2021; van Mulukom et al., 2020, Roseman et al., 2018; Thiessen et al., 2018; Zeifman et al., 2020). However, there are some problems and pitfalls in approaches several recent studies have taken to analyzing such mechanisms. Many of these problems and unstated assumptions in mechanism research have previously been pointed out and discussed in other areas of research, especially psychotherapy and social psychological research. Here, I discuss the value, challenges, and best practices of providing convincing evidence for the psychological mechanisms of the possible therapeutic effects of psychedelics.
\n\n\n\n\n\n\n\nThe question of mechanisms, of how interventions, exposures, or other causes have effects on final outcomes we are interested in, has a long history in many areas of psychological science, especially psychotherapy and social psychological research. This is understandable, because understanding mechanisms is useful for many different reasons. For instance, in the context of psychological interventions, Kazdin (2007) pointed out six benefits: 1) Research on mechanisms can help us optimize treatments, to know what to focus on in treatment, what processes we should especially target and trigger; 2) Understanding how treatments work helps us translate research into real-life clinical practice, and ensures generalizability of effects without diluting essential change processes, and may assist in dissemination and adoption; 3) Understanding (transdiagnostic) mechanisms can help us understand the diversity of outcomes of interventions, the links between what happens in treatment and how many different outcomes may change; 4) Identifying common mechanisms that different treatments work by can bring parsimony and clarity to the many different psychotherapies and interventions in use and development; 5) By uncovering mechanisms, we may also recognize moderators of treatment effectiveness and help predict who may benefit and under which circumstances; and 6) Mechanisms identified may have relevance for our understanding of people’s functioning and well-being beyond therapy. Most of these motivations certain also apply to psychedelics and psychedelic-assisted therapy.
\n\n\n\nAs analyses of mechanisms are so popular, many commentaries, reviews, and instructive articles have been written about how to best study psychological mechanisms (e.g, Bullock et al., 2010; Hayes & Rockwood, 2017: Kazdin, 2009; Pek & Hoyle, 2016; Tryon, 2018). These publications also include much guidance and critique relevant to research on psychedelics, which I draw upon below.
\n\n\n\nResearch on psychological mechanisms as relates to psychedelics is in its early stages. We should not expect perfect study designs or definite answers from the first analyses being carried out in this field. Even imperfect designs can certainly provide useful evidence. The somewhat unusual topic of interest, psychedelics, also introduces several additional challenges to the already challenging pursuit of identifying mechanisms and pathways of action. However, I think it would be important to try and set this area of research on a solid path from the start, with agreed upon good research practices and carefully considered analyses. Looking at some of the recent studies published in this area, it is apparent that there are some common problems, unstated assumptions, and pitfalls in the approaches that they have taken. Luckily, most of these problems can be solved, and even more useful, considered research can be done in the future.
\n\n\n\nContext and mechanisms – moderators and mediators
\n\n\n\nThe first issue I note is some confusion in or at least atypical usage of terminology in some recent publications (e.g., Netzband et al., 2020; Roseman et al., 2018, 2019). In several areas of psychological research, and indeed in other fields of science, too, so-called third variables have been divided into several distinct categories (Baron & Kenny, 1986; Hayes & Rockwood, 2017). Mechanisms, as processes or events transmitting or mediating the effects of a cause on an outcome, are typically modeled and studied as mediators. Meanwhile, we may often also be interested in factors (variables) that change how the cause affects the outcome, that modulate or moderate the effects of the cause on the outcome, but do not mediate it. Such factors or variables are modeled and studied as moderators. There may also be other third variables included in analyses, such as covariates or confounders.
\n\n\n\nWhile the statistical tools and formulae used to analyze them are often very similar, I believe especially the moderator-mediator distinction is useful and important and would hope that the emerging field of psychedelic research sticks to this fairly clear tradition of naming third variables (Hayes & Rockwood, 2017; Kraemer et al., 2002). Most importantly, while moderators may affect the outcome (in interaction with the cause and independently), they represent things the cause does not affect or change. Meanwhile mediators (some of which may represent mechanisms) are by definition things that the cause affects and that then affect the outcome, which transmit some of the cause’s effects on the outcome. Accordingly, things like demographic and other background variables relating to the participant; the physical, social, and psychological state in which ingestion takes place; preparation, intention, and therapeutic alliance etc. are important potentially moderating factors to take into consideration. But they are set beforehand, not affected by the ingestion of the psychedelic, and thus appropriately thought of as moderators, not mediators.
\n\n\n\nBeyond clearly separating mechanisms (studied as mediators) from contextual factors (studied as moderators), I would suggest being even more clear about whether we are studying processes or events that take place during acute psychedelic effects or changes or processes that extend beyond the acute effects. Both may be thought of as mechanisms that mediate the effects of psychedelics on different outcomes. I have suggested calling the former acute mechanisms and the latter post-acute mechanisms. This terminology may not be optimal, and perhaps better suggestions will come forward.
\n\n\n\nIf we limit our discussion to psychedelic-assisted therapy, another way of thinking about change processes and mechanisms is to separate what happens within the intervention from what happens outside it in the client or participant’s life generally. When studying the psychological mechanisms of psychological interventions for PTSD (without psychedelics), I found it helpful to ground my research in a framework offered by Brian Doss (2004), illustrated below. He divided what happens in psychological treatment into change processes taking place within the therapeutic sessions and context, and change mechanisms or mechanisms of change extending outside it. Using this framework, post-acute mechanisms of psychedelic-assisted treatment would be considered mechanisms of change that have generalized into the client’s life beyond the psychedelic session and associated therapy. In other words, they represent changes in the client’s thinking, beliefs, emotions, behavior, social relations or other areas that were caused by the psychedelic exposure and in turn have lead to or continue to result in changes in the desired final outcomes, such as reduced symptoms or improved well-being. Acute mechanisms would be more like client change processes that occur within the context of or inside the therapy or intervention.
\n\n\n\n![\"\"](\"https://kangaslampi.net/media/posts/10/doss-online.png\")
The promise and challenges of mediation analysis
\n\n\n\nMechanisms can be studied with a variety of different approaches and study designs, but a direct and fairly simple way, which several recent publications on psychedelics have also employed, is using mediation analysis. Mediation analysis is a statistical approach often used to provide evidence about the roles of particular mechanisms in changes in final outcomes. Mediation analyses allow us to examine and quantify indirect effects of causes on outcomes via mediators, in this case variables thought to represent mechanisms we are interested in. Usually, mediation analysis are carried out within a single set of data, although meta-analytic approaches are also possible.
\n\n\n\nMediation analyses are usually accompanied by graphs illustrating the mediation model proposed and estimated. Mediation models can take many shapes and forms, and can sometimes be quite complicated, but a couple of simple examples are presented below. In modern mediation analysis, we are typically interested in the statistical significance and strength of the indirect effect, which is depicted in blue.
\n\n\n\n![\"\"](\"https://kangaslampi.net/media/posts/10/image.png\")
![\"\"](\"https://kangaslampi.net/media/posts/10/image-1.png\")
One issue that is immediately apparent from looking at graphs of mediation models is that they always include directed arrows. Presenting such directed models, as well as the language used to describe the results of mediation analyses (e.g., “M mediates the effects of X on Y.”) mean that mediation analyses may be considered inherently causal (Nguyen et al., 2020). When we draw an arrow from X to Y (via M), instead of from Y to X, clearly we are suggesting that we have some basis or reasoning to claim that X is causing Y, instead of Y causing X, or them being associated without causing each other. This is is contrast to merely presenting correlational analyses and talking about covariance, correlation, or associations.
\n\n\n\nMost recent publications on mechanisms of the effects of psychedelics employ mediation analysis, but simultaneously explicitly deny studying causal processes. They present graphs with arrows and talk about processes mediating the effects of psychedelics on final outcomes, but several point out in the limitations of the study that causal interpretations cannot be made based on their analyses. I find this approach problematic and believe that researchers would do best to decide from the get go whether they are attempting to study and find evidence for causal (mediated) effects, or whether they are simply studying associations, and stick with this decision throughout. Otherwise, they risk their findings being taken for more than they are. Although researchers themselves are likely to be aware of the limitations of their data and analyses, the way their results are later used in further research, not to mention presented in the media and other outlets, rarely takes into account caveats presented in Limitations sections. Instead, if researchers (in their titles or conclusions) claim to have shown mediation of effects, this is taken seriously and taken as evidence of causal effects.
\n\n\n\nWe do often wish to study causal effects mediated by some mechanism, and for this, mediation analysis is a great tool. However, for mediation analysis to provide evidence for causal effects, there are number of assumptions that must be fulfilled (Kraemer et al., 2002; Preacher, 2015; Nguyen et al., 2020). These assumptions have typically not been made explicit in recent publications on psychedelics. The key assumption is that the model presented is in fact correct. This means that the relations between constructs have been modeled correctly, the suggested temporal order of effects is correct, errors are negligible or accounted for, and that no relevant omitted influences are missing.
\n\n\n\nAs regards possible omitted influences, in controlled research, especially randomized experiments, we can be fairly confident that there are no unmeasured confounders in the cause-mechanism and and cause-outcome relations. In other types of research, we should have other good grounds for assuming that the cause really caused (all of the) changes in the mechanism and outcome, i.e., that there are no unmeasured confounders in these relations. However, even in randomized experiments, concerns about unmeasured confounding in the mechanism-to-outcome relation remain. We need to think carefully about what confounders, variables that affect both the mechanism and outcome, or that correlate with the mechanism and affect the outcome, might exist. Any such omitted variables will bias our findings, overstating the degree of mediation through the mechanism (Bullock et al., 2010). This problem is even more pronounced in analyses that incorporate several mediators in sequence (as in Forstmann et al., 2020; van Mulukom et al., 2020), as there are many more relations that could include unmeasured confounders.
\n\n\n\nThe issue of mechanism-outcome confounding is difficult to fully address in any study design, but at the very least researchers should explicitly state that no unmeasured confounding in the mechanism-outcome relation is assumed and consider whether that assumption is realistic. Some solutions do exist, such as randomizing for the mechanism or allowing it to operate in some subjects and not in otherwise (typically very difficult for psychological mechanisms), using sensitivity analyses and particular statistical tools (MacKinnon & Pirlett, 2015; Preacher, 2015), or demonstrating the causal effect of the mechanism on the outcome or the specificity and consistency of the mediated effect in other solid studies.
\n\n\n\nOne assumption of the so-called traditional psychological mediation analysis approach that has received quite a bit of attention in the mediation analysis literature in other fields, but none in psychedelic research, is the possibility of cause X mechanism interaction on outcomes. As far as I can tell, the possibility that the cause (e.g., ingesting a psychedelic, or having a mystical experience) might change the way the suggested mechanism (e.g., increased social connectedness, increased psychological flexibility) affects the final outcome (e.g., mental well-being) has not been accounted for in any of the published research. The traditional psychological mediation analysis approach foregoes this possibility, but it can easily be analyzed, and other approaches to mediation do include it (Kraemer et al., 2008; Nguyen et al., 2020).
\n\n\n\nThere could be a number of possible sources of cause X mechanism interaction, when we study the effects of psychedelics. For example, psychedelic ingestion could affect how participants interpret and answer questions measuring the mechanism (say, social connectedness) and outcome (say, mood), affecting their relationship. Low variability in the experience of an acute mechanism such as a mystical experience in a control group, while there is high variability in the intervention group may also affect the mechanism-outcome relation. MacKinnon et al. (2020) provide a good list of possible sources of interaction to consider. In any case, I would certainly suggest that researchers take this possibility into account, and study whether such interaction effects appear to be present. In the above mediation model graphs, this is illustrated in green.
\n\n\n\nPerhaps the most crucial question many of the published studies fail to address is the temporal order of effects. The suggested mediation model being correct rests fundamentally on this issue. If we can show that the cause first caused (changes in) the mediator, and that this mediator then, that is, later, caused changes in the outcome, we may have good evidence for a mediated causal effect. However, in many if not most, recent publications, this temporal order has not been demonstrated. Some have relied on fully cross-sectional data, where it is typically not even possible to demonstrate that the cause (psychedelics) lead to changes in the outcome, let alone that a mediated, indirect effect is present (e.g., Thiessen et al., 2018). Others do have some basis for saying that changes in the outcome took place from before ingestion to after ingestion of a psychedelic, but still cannot say anything about whether changes in the mechanism preceded changes in the outcome (e.g. Davis et al., 2020, 2021). The study by Kettner et al. (2021) about psychedelic communitas and its direct and mediated effects on psychological well-being is a notable exception with five points of measurement.
\n\n\n\nWhen we cannot show the temporal order of changes in mechanism and outcome, it is in most cases equally possible that the change in outcome lead to the change in suggested mechanism. It is also possible that the change in outcome was a simultaneously occurring side effect. For instance, Forstmann et al. (2020) suggest and present in their mediation analysis that increased social connectedness would be a mechanism through which psychedelic use improves mood. However, they measured both social connectedness and mood once and simultaneously. Accordingly, there is nothing in their data that could separate a social connectedness–>mood effect from a mood–>social connectedness, provided there is any effect at all. Further, they did not establish that mood or social connectedness even changed in the first place. Similarly, in their study, van Mulukom et al. (2020) suggest that their findings based on a mediation model using cross-sectional survey data “provide support for the hypothesis that psychedelics can positively affect narcissistic personality traits, through their awe-inducing potential”. However, the data appear to be in equal concordance with the interpretation that more narcissistic people are less prone to awe experiences when taking psychedelics. Such alternative interpretations should, at a minimum, be recognized and considered.
\n\n\n\nTo study post-acute mechanisms in a way that demonstrates the temporal order of changes, a minimum of three points of measurement are necessary (before, after, later). Even more measurements are of course preferable and allow for more precise modeling of longitudinal processes (as in Kettner et al., 2021). When several measurements of both post-acute mechanisms and outcomes are available, we can perform model comparisons and be much more confident about our findings. For acute mechanisms, we can be sure that they took place during the acute effects, so two points of measurement may suffice (before and after for the outcome, [preferably immediately] after for the acute mechanism), although more are still preferable.
\n\n\n\nBeyond the model being correct, using cross-sectional data is also a problem for the estimates of indirect effects we end up with. Even if the assumed temporal order of effects is indeed correct, using cross-sectional data can bias our estimates of longitudinal effects in unpredictable ways. This was pointed out most forcefully by Maxwell et al. (2011) who state “a given pattern of cross-sectional correlations can arise from very different combinations of underlying longitudinal parameters. As a result, any attempt to infer the properties of the underlying longitudinal process on the basis of the cross-sectional parameters is almost certainly futile.” (Maxwell et al., 2011) While I would perhaps not be quite this pessimistic, I would suggest that when researchers only have cross-sectional data available with no basis for assuming the order of changes or effects, they should refrain from mediation analyses and just study and report associations. Later studies can then confirm the hypotheses such correlational research suggests.
\n\n\n\nA more technical issue in mediation analyses is how mediation is demonstrated and quantified. In the past, stepwise approaches to proving mediation exists were popular (Baron & Kenny, 1986). Somewhat more recently, the Sobel (1982) test emerged as a one-step approach. However, the traditional form of the Sobel test relies on an assumption of normality for the indirect effect (a product of two random variables), which is unrealistic, so today, it is recommended to use bootstrapping to study the significance of the indirect path (Hayes & Scharkow, 2013; MacKinnon, 2002). For quantifying how large the mediated effect is, we may use fully or partially standardized regression estimates, depending on the nature of the causal variable. Other effect size estimates have also been developed (e.g., Lachowicz et al., 2018). “Percentage mediated” estimates are sometimes presented, dividing the indirect effect by the total effect, but can be problematic as they could reach over 100% when there are different indirect effect in opposite directions.
\n\n\n\nOne idea that I believe should be abandoned is using the statistical significance of the remaining direct path (presented in red in Figures 2 and 3) to determine whether the effect was completely or fully mediated (as in Davis et al., 2020 and Kettner et al., 2020). The change from statistical significance to non-significance for a direct path when the indirect path is added may result from a tiny change in the estimate itself (as in, e.g., Thiessen et al., 2018), hardly good evidence for “full” mediation. If researchers are truly interested in whether the remaining direct effect is zero, other criteria, such as the confidence interval of the direct effect or equivalence tests that it is zero, should be considered.
\n\n\n\nIn recent years, causal mediation analysis has appeared as an alternative to the so-called traditional psychological mediation analysis approach (Nguyen et al., 2020). The causal mediation analysis approach calls for explicit, careful causal thinking before we engage in the actual analyses, specifying more exactly the effects we are pursuing, and noting the assumptions under which our findings are proof for causal effects (Imai et al., 2010; Nguyen et al., 2020). I would recommend all researchers in psychedelic research and beyond interested in studying mechanisms to familiarize themselves with this approach grounded in the counterfactual framework of causal analysis (Pearl, 2000, 2001). MacKinnon et al. (2020) have noted that many of the traditional mediation analyses can be seen as special cases in this more widely applicable causal mediation analysis framework, with the key difference being the exclusion/inclusion of the possibility of cause X mechanism interaction.
\n\n\n\nMediation analysis can be a powerful and useful tool, but it is only a tool, and one that presents some demands for the quality of the data that we need to have and one that makes assumptions we need to be aware of. Implementing and presenting mediation models is straightforward. If we take cross-sectional or otherwise inadequate data, draw graphs of a mediation model and show that an indirect path is significant, we may end up with an analysis that is convincing at first glance and allows us to tell an engaging story about, e.g., how psychedelics lead to improved well-being. But too often the only reason the arrows and claimed directed effects are there in our analyses is because we put them there. We must be careful not to fool ourselves or others into thinking that we have proved or provided evidence for something we have not. When researchers are not setting out to study causal processes, or do not have the data to do so, it would be best to not present mediation analyses. Exploratory studies about associations are fine, too.
\n\n\n\nFrom mediators to mechanisms
\n\n\n\nGoing beyond the specifics of mediation analyses, there are some other issues to consider in identifying and studying the psychological mechanisms of psychedelics. First, where should we look to find some mechanisms? It is commonplace in psychological research that all good things or developments correlate with all other good things, and all bad things correlate with all other bad things. Studying and providing evidence for fairly obvious correlations between aspects of beneficial progress in related areas may not be very worthwhile. So what makes for a good mechanism to study?
\n\n\n\nMechanisms should be non-trivial in that they have potential explanatory value and are theoretically sensible and/or empirically supported (Johansson and Høglend 2007). Accordingly, the search for mechanisms should not be ad hoc or capitalize on chance findings. Exploratory research certainly has value, and it’s worth reporting all possible correlations and even surprising connections for future study. But for research explicitly trying to provide evidence for the causal role of a mechanism in an outcome, the mechanisms studied should be decided beforehand based on theory or previous research. In the case of psychedelic-assisted treatment, such previous research could include, e.g., neurobiological findings about psychedelics, research on the mechanisms involved in non-psychedelic treatments, or earlier exploratory research. Studying meaningful potential mechanisms that psychedelic ingestion or the psychedelic-assisted treatment in question is specifically not expected to draw on for its effects may also be valuable (Kazdin 2007) to reinforce arguments for another mechanism’s specific role. Several potential mechanisms may be studied simultaneously and included in the same models.
\n\n\n\nIn any case, preregistration of the planned analyses and hypotheses is especially important for mechanism research. In the context of controlled trials, it would be important for researchers to include plans for studying psychological mechanisms in the original protocols and preregistrations prepared before commencing a study. But preregistration has great value in observational, naturalistic, survey-based, and register-based research as well.
\n\n\n\nFurther, mechanisms should be sufficiently distinct from both the cause and the outcome. Studying a mechanism that simply reflects a part of the treatment, for instance, will not tell us much about how the treatment works. Similarly, if the mechanism is just another aspect of the outcome, showing that changes in it lead to changes in the total outcome is not very informative.
\n\n\n\nWhen studying the mechanisms of the effects of some cause on some final outcome, we also need to think carefully about how to define and operationalize the cause. In the context of psychedelics, the most straightforward approach is to study exposure to / ingestion of a psychedelic vs. no exposure/ingestion. This is the usual starting point for controlled research, and can also be used in non-controlled research, especially if it is prospective. Alternatively, the level of dosage of the psychedelic might be considered as the cause. A number of studies have also taken particular effects of psychedelic ingestion as the cause they are studying, e.g., mystical experience or insight experiences (Davis et al., 2020; 2021.) or a sense of communitas acutely experienced (Kettner et al., 2021). It is also sometimes not obvious what the precise outcome that the mechanism relates to should be. Even if our interest is set on a particular phenomenon, say depression, we can model it as an outcome in many different ways (e.g., with a clinical cut-off or as continuous level of symptoms) and over many different time frames (e.g., immediate vs. long-term changes).
\n\n\n\nIt is also worth noting that the effects of psychedelics on outcomes like depression appear to be very rapid. It may be difficult to identify psychological mechanisms of such rapid or immediate effects. In many cases it might make more sense to try and identify the (post-acute) psychological mechanisms that maintain good mental health or keep away mental health symptoms that psychedelics have quickly reduced. In that case, the outcome to be studied would be change in the mental health variable from the immediate post-acute phase to a longer-term follow-up, while the mechanism would be change in the psychological process from before to after psychedelic ingestion.
\n\n\n\nA program of research
\n\n\n\nIn the end, even when carefully planned and carried out, individual studies can only reveal so much about the mechanisms by which psychedelics may have therapeutic effects. For conclusively demonstrating mechanisms, we will probably need other studies, too, especially to show causality in the mechanism to outcome relation. Besides showing that mediation occurs with a statistical analysis, for a mechanism to be useful, we also need to try and explain how, through which steps, the suggested mechanism is able to transmit effects on the outcome in question. There is always room for more micro-level analyses. We will also need to demonstrate a specific and consistent role for the mechanism over several studies in different populations. All this suggests that the final answer to identifying and providing convincing evidence for the psychological mechanisms that psychedelics tap into for their therapeutic effects will require a larger program of research. Luckily, it looks like such a program is now getting started.
\n\n\n\n
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