The psychological and human brain effects of music in combination with psychedelic drugs Mendel Kaelen 2017 This thesis is submitted for the degree of Doctor of Philosophy (Ph.D) “Follow your bliss and don't be afraid, and doors will open where you didn't know they were going to be” Joseph Campbell 2 Acknowledgements This work has been a deep journey of professional and personal growth. If I may name only one important insight that emerged for me, then it will be the realisation that creative work equals the building of a community. When following my bliss, I may have walked through many doors myself, yet, there I found many companions on the way. Their support has been absolutely pivotal to its route to success. To say “thank you” to them, somehow feels unreflective and almost dismissive of their real significance. I hope this work can be seen as my gift in return to all those individuals, and to the greater community that works to alleviate human suffering with the therapeutic use of psychedelics. After a long and sometimes disheartening search to find a neuroscience research internship with psychedelics, I met Robin Carhart-Harris at a conference in the UK in 2011. He generously agreed to supervise me as a master student, and later in 2013, as a PhD candidate. Robin, thank you for teaching me the virtues of patience and commitment, and for the intellectual inspiration you brought into my life. David Nutt, thank you for teaching me the virtues of solution-focussed work, and the enlightening force of humour. I carry deep gratitude for Amanda Feilding and the Beckley Foundation. Thank you, Amanda, for your commitment to open doors to a new era of science and psychotherapy, and for enabling me to walk paths you have paved for many people to come. Thank you for your brightness and your passion, which made this possible. I thank all my colleagues from the centre for neuropsychopharmacology, yet some must be showered with special praise: Leor Roseman, thank (bark) you. Christopher Timmerman, thank you. Thank you both for grounding this work in friendship and adventure, and in in the bliss we share on our ways. Andre Santos-Ribeiro, many thanks for sharing your readiness to always help and brainstorm; Margaret Collet, thank you, for your optimism and support. Csaba Orban, Luke Williams, Taylor Lyons, Tobias Buchborn, David Erritzoe, thank you all, for bathing me in such friendly and creative energy. Mark Bolstridge, James Rucker, Camilla Day, Rosalind Watts, Michelle Baker Jones, Nicola Kalk, Liese Mick, Ashwin Venkataraman, Sam Turton, thank you all for being a beautiful team. Special thanks to the most awesome students you can dream of, Bruna Cunha, Lisa Evans, Eline Haijen and Melissa Shukuroglou: thank you for all your hard and helpful work, and for your patience, while I isolated myself long inside my writing-cave. 3 Thank you, my collaborators: Suresh Muthukumaswamy, Matthew Wall, Robert Leech, Eduardo Schenberg, Joshua Kahan, Bernadette van Wijk, Frederick Barrett, Nathalie Rodriguez, Jordan Raine, Tim Williams, Ben Sessa, Alexander Lebedev. Thank you, Karl Friston, for the times you kindly minimized my free-energy. Thank you, Neiloufar Family, for the many meaningful perspectives, your humour, and our friendship. I thank many colleagues in the field, whose encounters and conversations have significantly impacted my understanding of psychedelic therapy. In particular, I like to thank Jeffrey Guss, Torsten Passie, Katherine Maclean, Alicia Danforth, Jordi Riba, Richard Yensen, William Richards, Matthew Johnson, Roland Griffith, Michael Mithoefer, Annie Mithoefer, Marcela d’Otolora, Peter Gasser and Peter Oehen. Thank you, Omar Fayed and Rob Sullivan, for your amazing support. Thank you, George Goldsmith and Katya Malievskaya, for providing me with post-doctoral funding that allowed me to finish writing this PhD thesis and to continue research within the team. Thank you, dear friends and partners-in-crime from OPEN: Erwin Krediet, Joost Breeksema, Dorien Tatalas, Pieter Stokkink, Raoul Koning. Thank you, dear friends, Laurens Feenstra, Rutger Gjaltema, Tom Shutte, Diederik Haveman, Martin Tietema, Dieuwke Hoeijmakers, Robert Moltmaker, Camille Thomas, Elizabeth Harris, Mark Geary, Pascal Savy, Justin Senryu-Williams, Samuel Starr and Bradley Vines. I thank my family, Marjolijn Kaelen, Gerard Kaelen, Amber Kaelen, Eline Kaelen, Myrthe Kaelen, Adinda Kaelen, Baloushka, Black and Anthony Luhrman: Thank you for teaching me the virtues of curiosity and the capacity to wonder. Special words of gratitude to Romy Lorenz: Thank you, for fuelling this journey with grounding, inspiration, adventure and love. 4 Statement of publications Parts of the data and the discussions presented in chapters 3 and 5 of this thesis have been previously published in Psychopharmacology (Kaelen et al., 2015) and in Neuropsychopharmacology (Kaelen et al., 2016): Kaelen M, Barrett F S, Roseman L, Lorenz R, Family N, Bolstridge M, Curran H V, Feilding A, Nutt D J, and Carhart-Harris R L. 2015. “LSD Enhances the Emotional Response to Music.” Psychopharmacology (Berl). 232(19):3607-14. Kaelen, M, Roseman L, Kahan J, Santos-Ribeiro A, Orban C, Lorenz R, Barrett F.S Barrett, et al. 2016. “LSD Modulates Music-Induced Imagery via Changes in Parahippocampal Connectivity.” European Neuropsychopharmacology. 26(7):1099- 109. Chapter 4 and 6 are prepared for submission. Statement of copyright The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work 5 Statement of originality This research received financial and intellectual support from the Beckley Foundation and was conducted as part of a wider Beckley-Imperial research programme (Principle investigators: David Nutt and Robin Carhart-Harris). Study design, recruitment of participants and running the experiments for the study presented in Chapter 3 were performed with help from Robin Carhart-Harris, Mark Bolstridge, Matthew Wall and Neiloufar Family. Study design, recruitment of participants, fMRI scanning and running of experiments for the study presented in Chapters 4 and 5 were performed with help from Robin Carhart-Harris, Mark Bolstridge, Suresh Muthukumaraswamy, Tim Williams and Wouter Droog. Pre-processing of fMRI neuroimaging data reported in Chapters 4 and 5 was performed by Csaba Orban and Leor Roseman. Portions of the Matlab codes for the data analyses reported in Chapter 4 were developed under advice from Joshua Kahan and Andre Santos-Ribeiro. The functional connectivity analysis reported in Chapter 5 was performed under advice by Leor Roseman. Portions of the Matlab codes for the data analyses reported in Chapter 5 were developed under advice from Romy Lorenz, Robert Leech and Andre Santos-Ribeiro. Portions of the analyses presented in Chapter 6 were performed under my supervision by Bruna Cunha, Jordan Raine, Lisa Evans, Christopher Timmerman and Nathalie Rodriguez. All other work reported in this thesis is my own and conforms to the rules and guidelines set out for PhD theses by Imperial College London. 6 Abstract This research investigated how psychedelics and music work together in the brain and modulate subjective experience. Chapter 1 highlighted the prominent role of music in psychedelic therapy in the 1950s and 1960s, and how music continues to be used in modern psychotherapeutic trials with psychedelics. Although ‘psychedelic therapy’ shows promising findings for mental health care, little is known empirically about the therapeutic functions of music. The primary objective of this thesis was to address this knowledge gap, via studying the effects of psychedelics and music on human brain function in healthy volunteers, and via studying the subjective experience of music, both in healthy volunteers and in patients undergoing psychedelic therapy. Study 1 (Chapter 3) demonstrated intensified music-evoked emotions under the classic psychedelic LSD, including emotions of ‘wonder’ and ‘transcendence’. In subsequent work (study 2, Chapter 4), increased activation in the inferior frontal gyrus and the precuneus to the timbre features in the music, was associated with increased music-evoked emotions of wonder. Study 3 (Chapter 5) demonstrated that LSD and music interact to enhance information flow from the parahippocampus to the visual cortex, and that this effect correlated with increased complex mental imagery and autobiographical memories. Study 4 (Chapter 6), showed that music has a substantial influence on the therapeutic experience with psilocybin in patients with depression, and the quality of the music-experience predicted peak experiences and insightfulness during sessions, and reductions in depression after sessions. These findings support the hypothesis that the music-experience is intensified under psychedelics, and the widely-held view that this effect may be therapeutically significant. Possible brain mechanisms and therapeutic mechanisms are discussed in Chapter 7, but further research is warranted to better understand these mechanisms, and to learn how music can be best used in psychedelic therapy. 7 Table of contents Acknowledgements ……………………………………………………………………………………………………………….3 Statement